Professional Documents
Culture Documents
Untitled
Untitled
Anaesthetists
Second Edition
David Chambers
Salford Royal NHS Foundation Trust
Christopher Huang
University of Cambridge
Gareth Matthews
University of Cambridge
University Printing House, Cambridge CB2 8BS, United Kingdom
One Liberty Plaza, 20th Floor, New York, NY 10006, USA
477 Williamstown Road, Port Melbourne, VIC 3207, Australia
314–321, 3rd Floor, Plot 3, Splendor Forum, Jasola District Centre,
New Delhi – 110025, India
79 Anson Road, #06–04/06, Singapore 079906
www.cambridge.org
Information on this title: www.cambridge.org/9781108463997
DOI: 10.1017/9781108565011
© Cambridge University Press 2019
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
Second edition 2019
Printed in the United Kingdom by TJ International Ltd. Padstow Cornwall.
A catalogue record for this publication is available from the British Library.
Library of Congress Cataloging-in-Publication Data
Names: Chambers, David, 1979- author. | Huang, Christopher, 1951- author. |
Matthews, Gareth, 1987- author.
Title: Basic physiology for anaesthetists / David Chambers, Christopher
Huang, Gareth Matthews.
Description: Second edition. | Cambridge, United Kingdom ; New York, NY :
Cambridge University Press, 2019. | Includes bibliographical references
and index.
Identifiers: LCCN 2019009280 | ISBN 9781108463997 (pbk. : alk. paper)
Subjects: | MESH: Physiological Phenomena | Anesthesiology–methods
Classification: LCC RD82 | NLM QT 104 | DDC 617.9/6–dc23
LC record available at https://lccn.loc.gov/2019009280
ISBN 978-1-108-46399-7 Paperback
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 that 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.
DC:
To Sally, for not vetoing this second edition.
CH:
To friends and teachers: Charles Michel, Morrin Acheson, Richard
Adrian, Sir David Weatherall and John Ledingham. In memoriam absen-
tium, in salutem praesentium.
GM:
To my wife, Claire, and our beautiful baby daughter, Eleanor. I also
remain indebted to Professor Christopher Huang for fostering my original
interest in physiology, as well as supporting me throughout my career.
Contents
Foreword ix
Russell Perkins
Preface to the Second Edition xi
Preface to the First Edition xiii
List of Abbreviations xiv
vii
Contents
viii
Foreword
This second edition of Basic Physiology for Anaesthe- in the exam setting. Not only should this book be
tists has carried forward the style, depth and content essential reading for those new to the speciality or
that made the first edition such a great success. It those preparing for exams, but established specialists
covers all aspects of human physiology that are essen- and consultants should have access to a copy to give
tial for the art and science that is modern anaesthesia. structure to their teaching, as well as to rekindle
Patients need to be reassured that their anaesthetists fading knowledge. Those sitting anaesthesia exams
are well informed of the workings of the human body can be confident that many of those responsible for
in health as well as disease. testing their knowledge will themselves have con-
The authors are both expert physiology scientists sulted this book!
and clinicians – this combination is clearly seen in the
book’s structure. Each chapter explains the physiology Dr Russell Perkins FRCA
and is followed by the clinical applications relevant to Consultant Anaesthetist, Royal Manchester
the speciality. The illustrations are simple line draw- Children’s Hospital
ings that are easy to follow and, importantly for Member of Council and Final FRCA Examiner,
trainee anaesthetists, easy to recall or even reproduce Royal College of Anaesthetists
ix
Preface to the Second Edition
‘Why are you writing a second edition? Surely noth- To that end, in addition to thoroughly revising
ing in classical physiology ever changes?’ One of us and updating each chapter, we have added six new
(DC) has been asked these questions several times. It chapters, including those on the physiology of the eye
is true that many of the fundamental physiological and upper airway and on exercise testing. We have
concepts described in this second edition of Basic also sought to include more pathophysiology, such as
Physiology for Anaesthetists remain the same. What cardiac ischaemia and physiological changes in
does change, however, is how we apply that physio- obesity. We have tried to remain true to the principles
logical knowledge clinically. In the four years since we with which we wrote the first edition, keeping the
wrote the first edition of this book, high-flow nasal concepts as simple as possible whilst remaining truth-
oxygen therapy has revolutionised airway manage- ful and illustrating each chapter with points of clinical
ment, cancer surgery has become the predominant relevance and easily reproducible line diagrams. In
indication for total intravenous anaesthesia and new response to positive feedback, the question-and-
classes of oral anticoagulants have emerged, to name answer style remains to best help readers prepare for
but a few developments. All of these changes in daily postgraduate oral examinations.
anaesthetic practice are underpinned by a thorough
understanding of basic physiology.
xi
Preface to the First Edition
An academically sound knowledge of both normal for those facing postgraduate examinations. In addi-
and abnormal physiology is essential for day-to-day tion, the account should provide a useful summary of
anaesthetic practice, and consequently for postgradu- physiology for critical care trainees, senior anaesthe-
ate specialist examinations. tists engaged in education and training, physician
This project was initiated by one of us (DC) assistants in anaesthesia, operating department prac-
following his recent experience of the United King- titioners and anaesthetic nurses.
dom Fellowship of the Royal College of Anaesthetists We believe the strength of this book lies in our
examinations. He experienced difficulty locating text- mixed clinical and scientific backgrounds, through
books that would build upon a basic undergraduate which we have produced a readable and up-to-date
understanding of physiology. Many of the account of basic physiology and provided links to
anaesthesia-related physiology books he encountered anaesthetic and critical care practice. We hope to
assumed too much prior knowledge and seemed bridge the gap between the elementary physiology
unrelated to everyday anaesthetic practice. learnt at medical school and advanced anaesthesia-
He was joined by a Professor in Physiology (CH) related texts. By presenting the material in a question-
and a Translational Medicine and Therapeutics and-answer format, we have aimed to emphasize
Research Fellow (GM) at Cambridge University, both strategic points and give the reader a glimpse of how
actively engaged in teaching undergraduate and post- each topic might be assessed in an oral postgraduate
graduate physiology and in physiological research. examination. Our numerous illustrations seek to sim-
This book has been written primarily for anaesthe- plify and clearly demonstrate key points in a manner
tists in the early years of their training, and specifically that is easy to replicate in an examination setting.
xiii
Abbreviations
xiv
List of Abbreviations
xv
Section 1 The Basics
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 organised
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). Physiology might be Cardiovascular system, comprising the heart and
better described as maintaining an ‘optimal’ internal the blood vessels. The blood vessels are
environment; many diseases are associated with the subclassified into arteries, arterioles, capillaries,
disturbance of this optimal environment. venules and veins. The circulatory system is
Anaesthetists are required to adeptly manipulate partitioned into systemic and pulmonary circuits.
this complex physiology to facilitate surgical and crit- Nervous system, which comprises both neurons
ical care management. Therefore, before getting (cells that electrically signal) and glial cells
started on the areas of physiology that are perhaps (supporting cells). It can be further subclassified
of greater interest, it is worth revising some of the in several ways:
basics – this chapter and the following four chapters
have been whittled down to the absolute essentials. – Anatomically, the nervous system is divided into
the central nervous system (CNS), consisting of
How do the body’s organs develop? the brain and spinal cord, and the peripheral
nervous system (PNS), consisting of peripheral
The body is composed of some 100 trillion cells. All life nerves, ganglia and sensory receptors, which
begins from a single totipotent embryonic cell, which connect the limbs and organs to the brain.
is capable of differentiating into any cell type. This – The PNS is functionally classified into an
embryonic cell divides many times and, by the end of afferent limb, conveying sensory impulses to
the second week, gives rise to the three germ cell layers: the brain, and an efferent limb, conveying
Ectoderm, from which the nervous system and motor impulses from the brain.
epidermis develop. – The somatic nervous system refers to the
Mesoderm, which gives rise to connective tissue, components of the nervous system under
blood cells, bone and marrow, cartilage, fat and conscious control.
muscle. – The autonomic nervous system (ANS) regulates
Endoderm, which gives rise to the liver, pancreas the functions of the viscera. It is divided into
and bladder, as well as the epithelial lining of the sympathetic and parasympathetic nervous
lungs and gastrointestinal (GI) tract. systems.
Each organ is composed of many different tissues, all – The enteric nervous system is a
working together to perform a particular function. semiautonomous system of nerves that control
For example, the heart is composed of cardiac muscle, the digestive system.
conducting tissue, including Purkinje fibres, and Muscular system, comprising the three different
blood vessels, all working together to propel blood types of muscle: skeletal, cardiac and smooth muscle.
through the vasculature.
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 12:29:52, subject to the Cambridge Core terms of use, available at 1
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011
Section 1: The Basics
Skeletal system, the framework of the body, their survival. An amoeba gains its nutrients directly
comprising bone, ligaments and cartilage. from and eliminates its waste products directly
Integumentary system, which is essentially the into the external environment. The external environ-
skin and its appendages: hairs, nails, sebaceous ment also influences the cell’s temperature and pH,
glands and sweat glands. Skin is an important along with its osmotic and ionic gradients. Small
barrier preventing invasion by microorganisms fluctuations in the external environment may
and loss of water (H2O) from the body. It is also alter intracellular processes sufficiently to cause
involved in thermoregulation and sensation. cell death.
Digestive system, including the whole of the GI Humans are multicellular organisms – the vast
tract from mouth to anus and a number of majority of our cells do not have any contact with
accessory organs: salivary glands, liver, pancreas the external environment. Instead, the body bathes its
and gallbladder. cells in extracellular fluid (ECF). The composition of
Urinary system, which comprises the organs ECF bears a striking resemblance to seawater, where
involved in the production and excretion of urine: distant evolutionary ancestors of humans would have
kidneys, ureters, bladder 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, rela-
produced and nurtured. Many different organs are tively constant and optimised environment for its
involved, including the ovaries, testes, uterus and component cells:
mammary glands. Nutrients – cells need a constant supply of
Endocrine system, whose function is to produce nutrients and oxygen (O2) to generate energy for
hormones. Hormones are chemical signalling metabolic processes. In particular, plasma glucose
molecules carried in the blood that regulate the concentration is tightly controlled, and many
function of other, often distant cells. physiological mechanisms are involved in
Immune system, which is involved in tissue repair maintaining an adequate and stable partial
and the protection of the body from pressure of tissue O2.
microorganism invasion and cancer. The immune Carbon dioxide (CO2) and waste products – as
system is composed of the lymphoid organs (bone cells produce energy in the form of adenosine
marrow, spleen, lymph nodes and thymus), as well triphosphate (ATP), they generate waste products
as discrete collections of lymphoid tissue within (for example, H+ and urea) and CO2.
other organs (for example, Peyer’s patches are Accumulation of these waste products may hinder
collections of lymphoid tissue within the small cellular processes; they must be transported away.
intestine). The immune system is commonly pH – all proteins, including enzymes and ion
subclassified into: channels, work efficiently only within a narrow
range of pH. Extremes of pH result in
– The innate immune system, which produces a
denaturation, disrupting the tertiary or quaternary
rapid but non-specific response to
structure of proteins or nucleic acids.
microorganism invasion.
– The adaptive immune system, which produces Electrolytes and water – the intracellular water
volume is tightly controlled; cells do not function
a slower but highly specific response to
correctly when they are swollen or shrunken. As
microorganism invasion.
sodium (Na+) is a major cell membrane
impermeant and therefore an osmotically active
The body systems do not act in isolation; for example,
ion, the movement of Na+ strongly influences the
arterial blood pressure is the end result of interactions
movement of water. The extracellular Na+
between the cardiovascular, urinary, nervous and
concentration is accordingly tightly controlled.
endocrine systems.
The extracellular concentrations of other
electrolytes (for example, the ions of potassium
What is homeostasis? (K+), calcium (Ca2+) and magnesium (Mg2+))
Single-celled organisms (for example, an amoeba) are have other major physiological functions and are
entirely dependent on the external environment for also tightly regulated.
2
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 12:29:52, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011
Chapter 1: General Organisation of the Body
Temperature – the kinetics of enzymes and ion For example, exercising muscle rapidly consumes
channels have narrow optimal temperature O2, causing the O2 tension within the muscle to
ranges, and the properties of other biological fall. The waste products of this metabolism (K+,
structures, such as the fluidity of the cell adenosine monophosphate (AMP) and H+) cause
membrane, are also affected by temperature. vasodilatation of the blood vessels supplying the
Thermoregulation is therefore essential. muscle, increasing blood flow and therefore O2
Homeostasis is a dynamic phenomenon: usually, delivery.
physiological mechanisms continually make minor Extrinsic homeostatic mechanisms occur at a
adjustments to the ECF environment. Following a distant site, involving one of the two major
major disturbance, large physiological changes are regulatory systems: the nervous system or the
sometimes required. endocrine system. The advantage of extrinsic
homeostasis is that it allows the coordinated
How does the body exert control over its regulation of many organs and feedforward
control.
physiological systems? The vast majority of homeostatic mechanisms
Homeostatic control mechanisms may be intrinsic employed by both the nervous and endocrine systems
(local) or extrinsic (systemic) to the organ: rely on negative feedback loops (Figure 1.1). Negative
Intrinsic homeostatic mechanisms occur within feedback involves the measurement of a physiological
the organ itself through autocrine (in which a cell variable that is then compared with a ‘set point’, and if
secretes a chemical messenger that acts on that the two are different, adjustments are made to correct
same cell) or paracrine (in which the chemical the variable. Negative feedback loops require:
messenger acts on neighbouring cells) signalling.
(a) Negative feedback loop: (b) Negative feedback loop for PaCO2:
Increased alveolar
ventilation PaCO2 = 6.2 kPa
Physiological variable decreases PaCO2
Sensor
Control centre
Respiratory muscles increase
tidal volume and respiratory rate:
alveolar ventilation increases
Effector
Figure 1.1 (a) Generic negative feedback loop and (b) negative feedback loop for arterial partial pressure of CO2 (PaCO2).
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 12:29:52, subject to the Cambridge Core terms of use, available at 3
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011
Section 1: The Basics
Sensors, which detect a change in the variable. For Haemostasis. Following damage to a blood vessel,
example, an increase in the arterial partial exposure of a small amount of subendothelium
pressure of CO2 (PaCO2) is sensed by the central triggers a cascade of events, resulting in the mass
chemoreceptors in the medulla oblongata. production of thrombin.
A control centre, which receives signals from Uterine contractions in labour. The hormone
the sensors, integrates them and issues a response oxytocin causes uterine contractions during
to the effectors. In the case of CO2, the control labour. As a result of the contractions, the baby’s
centre is the respiratory centre in the medulla head descends, stretching the cervix. Cervical
oblongata. stretching triggers the release of more oxytocin,
Effectors. A physiological system (or systems) is which further augments uterine contractions
activated to bring the physiological variable back (Figure 1.2). This cycle continues until the baby is
to the set point. In the case of CO2, the effectors born and the cervix is no longer stretched.
are the muscles of respiration: by increasing Protein digestion in the stomach. Small amounts
alveolar ventilation, PaCO2 returns to the ‘set of the enzyme pepsin are initially activated by
point’. decreased gastric pH. Pepsin then activates more
pepsin by proteolytically cleaving its inactive
precursor, pepsinogen.
What is positive feedback? Depolarisation phase of the action potential.
In physiological terms, positive feedback is a means of Voltage-gated Na+ channels are opened by
amplifying a signal: a small increase in a physiological depolarisation, which permits Na+ to enter the
variable triggers a greater and greater increase in that cell, which in turn causes depolarisation, opening
variable (Figure 1.2). Because the body is primarily more channels. This results in rapid membrane
concerned with homeostasis, negative feedback loops depolarisation.
are encountered much more frequently than positive Excitation–contraction coupling in the heart.
feedback loops, but there are some important physio- During systole, the intracellular movement of
logical examples of positive feedback: Ca2+ triggers the mass release of Ca2+ from the
(a) Positive feedback loop: (b) Positive feedback loop for oxytocin during labour:
Stronger uterine
contractions push
Triggering event Baby’s head pushes on
baby’s head
cervix, causing it to stretch
against cervix
Figure 1.2 (a) Generic positive feedback loop and (b) positive feedback loop for oxytocin during labour.
4
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 12:29:52, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011
Chapter 1: General Organisation of the Body
sarcoplasmic reticulum (an intracellular Ca2+ haemorrhage: a fall in arterial blood pressure reduces
store). This rapidly increases the intracellular Ca2+ organ blood flow, resulting in tissue hypoxia. In
concentration, facilitating the binding of myosin response, vascular beds vasodilate, resulting in a fur-
to actin filaments. ther reduction in blood pressure. The resulting
Where positive feedback cycles do exist in physiology, vicious cycle is potentially fatal.
they are usually tightly regulated by a coexisting nega-
tive feedback control. For example, in the action Further reading
potential, voltage-gated Na+ channels inactivate after L. S. Costanzo. Physiology, 6th edition. Philadelphia,
Elsevier, 2018.
a short period of time, which prevents persistent
uncontrolled depolarisation. Under certain patho- W. F. Boron, E. L. Boulpaep. Medical Physiology, 3rd
edition. Philadelphia, Elsevier, 2017.
logical situations, positive feedback may appear as
an uncontrolled phenomenon. A classic example is B. M. Koeppen, B. A. Stanton. Berne and Levy Physiology,
the control of blood pressure in decompensated 7th edition. Philadelphia, Elsevier, 2017.
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 12:29:52, subject to the Cambridge Core terms of use, available at 5
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011
Section 1 The Basics
2
Describe the basic layout of a cell containing heads of the lipids are hydrophilic
and thereby form a stable lipid–water interface.
Whilst each cell has specialist functions, there are The most important function of the cell
many structural features common to all (Figure 2.1). membrane is to mediate and regulate the
Each cell has three main parts: passage of substances between the ECF and the
The cell surface membrane, a thin barrier that intracellular fluid (ICF). Small, gaseous and
separates the interior of the cell from the lipophilic substances may pass through the lipid
extracellular fluid (ECF). Structurally, the cell component of the cell membrane unregulated
membrane is a phospholipid bilayer into which (see Chapter 4). The transfer of large molecules
are inserted glycoproteins akin to icebergs or charged entities often involves the action of
floating in the sea. The lipid tails form a the glycoproteins, either as channels or carriers.
hydrophobic barrier that prevents the passage of The nucleus, which is the site of the cell’s genetic
hydrophilic substances. The charged phosphate- material, made up of deoxyribonucleic acid
Mitochondrion
Outer membrane
Nucleus
Nuclear envelope
Nuclear pore
Nucleoplasm
Nucleolus
Golgi apparatus
Secretory vesicles
Lysozyme
6
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 12:32:20, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.005
Chapter 2: Cell Components and Function
(DNA). The nucleus is the site of messenger within their own phospholipid bilayer membranes.
ribonucleic acid (mRNA) synthesis by An organelle is to a cell what an organ is to the body –
transcription of DNA and thus coordinates the that is, a functional unit within a cell. Organelles
activities of the cell (see Chapter 3). found in the majority of cells are:
The cytoplasm, the portion of the cell interior Mitochondria, sometimes referred to as the
that is not occupied by the nucleus. The ‘cellular power plants’, as they generate energy in
cytoplasm contains the cytosol (a gel-like the form of ATP through aerobic metabolism.
substance), the cytoskeleton (a protein scaffold Mitochondria are ellipsoid in shape and are larger
that gives the cell shape and support) and a and more numerous in highly metabolically active
number of organelles (small, discrete structures cells, such as red skeletal muscle. Unusually,
that each carry out a specific function). mitochondria contain both an outer and an inner
membrane, which creates two compartments,
Describe the composition of the each with a specific function:
cell nucleus – Outer mitochondrial membrane. This is a
phospholipid bilayer that encloses the
The cell nucleus contains the majority of the cell’s
mitochondria, separating it from the
genetic material in the form of DNA. The nucleus
cytoplasm. It contains porins, which are
is the control centre of the cell, regulating the func-
transmembrane proteins containing a pore
tions of the organelles through gene – and therefore
through which solute molecules less than
protein – expression. Almost all of the body’s cells
5 kDa (such as pyruvate, amino acids, short-
contain a single nucleus. The exceptions are mature
chain fatty acids) can freely diffuse. Longer-
red blood cells (RBCs; which are anuclear), skeletal
chain fatty acids require the carnitine shuttle
muscle cells (which are multinuclear) and fused
(see Chapter 77) to cross the membrane.
macrophages (which form multinucleated giant cells).
– Intermembrane space, between the outer
The cell nucleus is usually a spherical structure
membrane and the inner membrane. As part
situated in the middle of the cytoplasm. It comprises:
of aerobic metabolism (see Chapter 77), H+
The nuclear envelope, a double-layered ions are pumped into the intermembrane
membrane that separates the nucleus from the space by the protein complexes of the electron
cytoplasm. The membrane contains holes called transport chain. The resulting electrochemical
‘nuclear pores’ that allow the regulated passage of gradient is used to synthesise ATP.
selected molecules from the cytoplasm to the
– Inner mitochondrial membrane, the site of the
nucleoplasm, as occurs at the cell surface
electron transport chain. Membrane-bound
membrane.
proteins participate in redox reactions,
The nucleoplasm, a gel-like substance (the resulting in the synthesis of ATP.
nuclear equivalent of the cytoplasm) that
– Inner mitochondrial matrix, the area bounded
surrounds the DNA.
by the inner mitochondrial membrane. The
The nucleolus, a densely staining area of the matrix contains a large range of enzymes.
nucleus in which RNA is synthesised. Nucleoli are Many important metabolic processes take
more plentiful in cells that synthesise large place within the matrix, such as the citric acid
amounts of protein. cycle, fatty acid metabolism and the urea cycle.
The DNA contained within each nucleus contains the As all cells need to generate ATP to survive,
individual’s ‘genetic code’, the blueprint from which mitochondria are found in all cells of the body
all body proteins are synthesised (see Chapter 3). (with the exception of RBCs, which gain their
ATP from glycolysis alone). Mitochondria also
What are the organelles? Describe the contain a small amount of DNA, suggesting that
the mitochondrion may have been a
major ones microorganism in its own right prior to its
Organelles (literally ‘little organs’) are permanent, evolutionary incorporation into larger cells. The
specialised components of the cell, usually enclosed cytoplasm and hence mitochondria are exclusively
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 12:32:20, subject to the Cambridge Core terms of use, available at 7
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.005
Section 1: The Basics
acquired from the mother, which underlies the Golgi apparatus, responsible for the modification
maternal inheritance of mitochondrial diseases. and packaging of proteins in preparation for their
Endoplasmic reticulum (ER), the protein- and secretion. The Golgi apparatus is a series of
lipid-synthesising apparatus of the cell. The ER is tubules stacked alongside the ER. The Golgi
an extensive network (hence the name) of vesicles apparatus can be thought of as the cell’s ‘post
and tubules that occupies much of the cytosol. office’: it receives proteins, packs them into
There are two types of ER, which are connected to envelopes, sorts them by destination and
each other: dispatches them. When the Golgi apparatus
– Rough ER, the site of protein synthesis. The receives a protein from the ER, it is modified
‘rough’ or granular appearance is due to the through the addition of carbohydrate or
presence of ribosomes, the sites where amino phosphate groups, processes known as
acids are assembled together in sequence to glycosylation and phosphorylation respectively.
form new protein. Protein synthesis is These modified proteins are then sorted and
completed by folding the new protein into its packaged into labelled vesicles into which they can
three-dimensional conformation. Rough ER is be transported. Thus, the vesicles are transported
especially prominent in cells that produce a to other parts of the cell or to the cell membrane
large amount of protein; for example, for secretion (a process called ‘exocytosis’).
endocrine and antibody-producing plasma Lysosomes are found in all cells, but are
cells. particularly common in phagocytic cells
– Smooth ER, the site of steroid and lipid (macrophages and neutrophils). These organelles
synthesis. Smooth ER appears ‘smooth’ contain digestive enzymes, acid and free radical
because it lacks ribosomes. Smooth ER is species and they play a role in cell housekeeping
especially prevalent in cells with a role in (degrading old, malfunctioning or obsolete
steroid hormone synthesis, such as the cells of proteins), programmed cell death (apoptosis) and
the adrenal cortex. In muscle cells, the smooth the destruction of phagocytosed microorganisms.
ER is known as the sarcoplasmic reticulum, an
intracellular store of Ca2+ that releases Ca2+ Further reading
following muscle cell-membrane B. Alberts, D. Bray, K. Hopkin, et al. Essential Cell Biology,
depolarisation. 4th edition. Oxford, Garland Science, 2013.
8
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 12:32:20, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.005
Section 1 The Basics
Genetics
Chapter
3
In 2003, the completion of the Human Genome Pro- Nucleobases, four different ‘bases’ whose
ject resulted in the sequencing of every human gene sequence determines the genetic code:
and subsequently heralded the ‘age of the genome’. – Guanine (G);
Whilst the knowledge of genetics has revolutionised – Adenine (A);
medicine, the phenotypic significance of most genes
– Thymine (T);
remains poorly understood. This will be a major focus
– Cytosine (C).
of physiological research in the future.
The nucleobases are often subclassified based on
What is a chromosome? their chemical structure: A and G are purines,
whilst T and C are pyrimidines.
An individual’s genetic code is packed into the nucleus
of each cell, contained in a condensed structure called The double-helical arrangement of DNA has a
chromatin. When the cell is preparing to divide, chro- number of features:
matin organises itself into thread-like structures called Antiparallel DNA chains. The two strands of
chromosomes; each chromosome is essentially a single DNA run in antiparallel directions.
piece of coiled deoxyribonucleic acid (DNA). In total, Matching bases. The two strands of DNA
each cell contains 46 chromosomes (23 pairs), with the interlock rather like a jigsaw: a piece with a tab
exception of the gamete cells (sperm and egg), which cannot fit alongside another piece with a tab –
contain only 23 chromosomes. nucleotide A does will not fit alongside another
There are two main types of chromosome: nucleotide A. The matching pairs (called
Autosomes, of which there are 22 pairs. complementary base pairs) are:
Allosomes (sex chromosomes), of which there is – C matches G;
only one pair, XX or XY. – A matches T.
Both types of chromosome carry DNA, but only the Therefore, for the two DNA strands to fit together,
allosomes are responsible for determining an individ- the entire sequence of nucleotides of one DNA
ual’s sex. strand must match the entire sequence of
nucleotides of the other strand.
What is DNA? Hydrogen bonding. The two strands of DNA are
held together by hydrogen bonds (a particularly
DNA is a polymer of four nucleotides in sequence,
strong type of van der Waals interaction) between
which is usually bound to a complementary DNA
the matching bases.
strand and folded into a double helix (Figure 3.1).
The DNA strand can be thought of as having two
parts: What is RNA? How does it differ
A sugar–phosphate backbone, made of from DNA?
alternating sugar (deoxyribose) and phosphate The amino acid sequence of a protein is encoded by
groups. The sugars involved in the DNA backbone the DNA sequence in the cell nucleus. But when the
are pentose carbohydrates, which are produced by cell needs to synthesise a protein, the code is anchored
the pentose phosphate pathway (PPP; see in the nucleus, and the protein-manufacturing appar-
Chapter 77). atus (the endoplasmic reticulum (ER) and Golgi
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 12:34:04, subject to the Cambridge Core terms of use, available at 9
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.006
Section 1: The Basics
5′ end
Double-helix structure
Nucleobases Sugar–phosphate backbone
P
5′ end
3′ end
3′ end
P
G C
P
Pentose
Hydrogen bonds sugar
P
A T
P
P
C G
P
P
T A
P
3′ end
Antiparallel strands P
5′ end 3′ end 5′ end
apparatus; see Chapter 2) is located within the cyto- ribosomes of the rough endoplasmic reticulum
plasm. RNA overcomes this problem: RNA is pro- (ER), the protein-producing factory of the cell.
duced as a copy of the DNA genetic code in the Transfer RNA (tRNA). In the cytoplasm, the
nucleus and is exported to the cytoplasm, where it is 20 different types of tRNA gather the 20 different
used to synthesise protein. amino acids and transfer them to the ribosome,
In some ways, RNA is very similar to DNA. RNA ready for protein synthesis.
has a backbone of alternating sugar and phosphate Ribosomal RNA (rRNA). Within the ribosome,
groups attached to a sequence of nucleobases. How- rRNA aligns tRNA units (with the respective
ever, RNA differs from DNA in a number of ways: amino acids attached) in their correct positions
RNA sugar groups have a hydroxyl group that along the mRNA sequence. The amino acids are
DNA sugars lack (hence ‘deoxy’-ribonucleic acid). joined together and a complete protein is released.
RNA contains the nucleobase uracil (U) in place
of thymine (T). What is a codon?
RNA usually exists as a single strand; there is no A codon is a small piece of mRNA (a triplet of nucleo-
antiparallel strand with which to form a sides) that encodes an individual amino acid. For
double helix. example, GCA represents the amino acid alanine.
There are three major types of RNA: tRNA also uses codons; as tRNA must bind to mRNA,
Messenger RNA (mRNA). In the nucleus, mRNA the codons are the ‘jigsaw match’ of the mRNA codons
is synthesised as a copy of a specific section of (called anticodons). For example, CGU is the comple-
DNA – this process is called transcription. mRNA mentary anticodon tRNA sequence to GCA. CGU
then leaves the nucleus and travels to the tRNA therefore binds alanine.
10
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 12:34:04, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.006
Chapter 3: Genetics
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
Figure 3.2 Mendelian inheritance patterns: (a) autosomal dominant; (b) autosomal recessive and (c) X-linked recessive.
alleles are recessive; that is, genotype aa (referred Mendelian inheritance refers to the inheritance of the
to as homozygous). The parents of a child with an genotype. However, genetic inheritance does not
autosomal recessive disease usually do not have always result in phenotypic expression. This is known
the disease themselves: they are carriers (or as ‘penetrance’. For example, hypertrophic cardiomy-
heterozygotes) with the genotype Aa. A child of opathy has a penetrance of ~70%, meaning that
two heterozygous parents (genotype Aa) has a approximately 70 out of 100 patients who inherit the
50% chance of having genotype Aa (a carrier), a genetic mutation will actually get the disease. This is
25% chance of genotype AA (being disease free) incomplete penetrance. Complete penetrance is when
and a 25% chance of having genotype aa (i.e. penetrance is 100%; an example would be neurofibro-
homozygous, having the autosomal recessive matosis. Incomplete penetrance usually refers to auto-
disease) (Figure 3.2b). Examples of autosomal somal dominant conditions, but occasionally relates
recessive diseases are sickle cell disease, Wilson’s to autosomal recessive conditions.
disease and cystic fibrosis. Recessive diseases Most inherited characteristics do not obey the
typically present at younger ages (often from simple monogenetic Mendelian rules. For example, dis-
birth) when compared to dominant conditions, eases such as diabetes and ischaemic heart disease may
which often present in young adulthood. certainly run in families, but their heritability is much
X-linked recessive. These diseases are carried on more complex, often being polygenetic, age related and
the X chromosome. They usually only affect males involving environmental as well as genetic factors.
(XY), because females (XX) are protected by a
normal allele on the other X chromosome. Of the Further reading
offspring of female carriers (XX), 25% are female P. C. Turner, A. G. McLennan, A. D. Bates, M. R. H. White.
carriers (XX), 25% are disease-free females (XX), Instant Notes in Molecular Biology, 4th edition. Oxford,
25% are disease-free males (XY) and 25% are Taylor and Francis, 2013.
males with the disease (XY) (Figure 3.2c). A. Gardner, T. Davies. Human Genetics, 2nd edition.
Examples of X-linked recessive diseases are Banbury, Scion Publishing Ltd, 2009.
haemophilia A, Duchenne muscular dystrophy R. Landau, L. A. Bollag, J. C. Kraft. Pharmacogenetics and
and red–green colour blindness. anaesthesia: the value of genetic profiling. Anaesthesia
2012; 67(2): 165–79.
12
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 12:34:04, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.006
Section 1 The Basics
4
The cell membrane is the lipid bilayer structure that The outer surface of the phospholipid bilayer is in
separates the intracellular contents from the extracel- contact with the extracellular fluid (ECF) and the
lular environment. It controls the passage of sub- inner surface of the bilayer is in contact with the
stances into and out of the cell. This allows the cell intracellular fluid (ICF).
to regulate, amongst other parameters, intracellular The non-polar groups form a hydrophobic core,
ion and solute concentrations, water balance and pH. preventing free passage of water across the cell
The integrity of the cell membrane is of crucial membrane. This is extremely important as it
importance to cell function and survival. enables different concentrations of solutes to exist
inside and outside the cell.
What is the structure of the cell The phospholipid bilayer is a two-dimensional
membrane? liquid rather than a solid structure; the individual
phospholipids are free to move around within their
The cell membrane is composed of two layers of own half of the bilayer. The fluidity of the cell
phospholipid, sandwiched together to form a phos- membrane allows cells to change their shape; for
pholipid bilayer (Figure 4.1). Important features of example, red blood cells may flex to squeeze
this structure are: through the small capillaries of the pulmonary
The phospholipid is composed of a polar circulation.
hydrophilic phosphate head to which water is
attracted and a non-polar hydrophobic fatty acid
tail from which water is repelled.
Which other structures are found within
The phospholipid bilayer is arranged so that the the cell membrane?
polar groups face outwards and the non-polar A number of important structures are found in and
groups are interiorised within the bilayer structure. around the cell membrane:
Hydrophilic outer
membrane
Hydrophobic core
Hydrophilic inner
membrane
Cholesterol
Peripheral protein
INTRACELLULAR SIDE
Transmembrane protein
13
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 12:36:56, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.007
Section 1: The Basics
14
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 12:36:56, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.007
Chapter 4: The Cell Membrane
EXTRACELLULAR FLUID
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
▪ Leak channels, which are always open, ▪ Mechanically gated channels, which have
allowing continuous movement of the pores that respond to mechanical stimuli,
specific ion along its concentration such as stretch. For example, mechanically
gradient. gated Ca2+ channels open following
▪ Voltage-gated channels, which open by distension of arteriolar smooth muscle – this
changing shape in response to an is the basis of the myogenic response (see
electrical stimulus, typically a Chapters 34 and 56).
depolarisation of the cell membrane (see – Facilitated diffusion. A carrier protein binds a
Chapter 52).2 When the ion channel is specific substrate before undergoing a number of
open, the specific ion diffuses through the conformation changes to move the substrate
cell membrane along its concentration from one side of the cell membrane to the other.
gradient, but when the channel is closed or Once the substrate has passed through the cell
inactivated the membrane becomes membrane, it is released from the carrier protein.
impermeable. The substance passes down its concentration
▪ Ligand-gated channels, where the binding gradient, facilitated by the carrier protein
of a small molecule (ligand) causes the ion (Figure 4.3). Facilitated diffusion is much faster
channel to open or close. For example, than simple diffusion, but is limited by the
acetylcholine (ACh) binds to the nicotinic amount of carrier protein in the cell
ACh receptor (a ligand-gated cation membrane. The most important example of
channel) of the neuromuscular junction, facilitated diffusion is glucose transport into
thereby opening its integral cation channel the cell through the glucose transporter
(see Chapter 53). (GLUT). An example of passive counter-
transport is the Cl‾/bicarbonate (HCO3‾)-
channel designed for a larger ion. The reason for this is antiporter in the renal tubule, where Cl‾ and
related to the number of water molecules that surround HCO3‾ are simultaneously transported in
the ion (the hydration sphere): a smaller ion has a larger
opposite directions down their respective
hydration sphere, which cannot pass through the wrong-
sized ion channel. concentration gradients.
2
In contrast, the inward rectifying K+ channels of the Active transport. Energy from ATP hydrolysis is
cardiac action potential open when the cell membrane
used to move substances across the cell
repolarises (see Chapter 57).
15
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 12:36:56, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.007
Section 1: The Basics
EXTRACELLULAR FLUID
Substance undergoing
facilitated diffusion
Conformational Conformational
change change
Carrier protein
INTRACELLULAR FLUID
16
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 12:36:56, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.007
Chapter 4: The Cell Membrane
Macromolecule
Phospholipid bilayer
Pit forms
Cell membrane
encloses macromolecule
Vesicle forms
17
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 12:36:56, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.007
Section 1 The Basics
Enzymes
Chapter
5
Enzymes are biological catalysts whose function is to increases the rate of reaction. The three-
increase the rate of metabolic reactions. dimensional shape of the active site is of crucial
importance. If the shape of the active site is altered
What is a catalyst? (e.g. by increased temperature or pH), the function
of the enzyme may be impaired and the chemical
A catalyst is a substance that increases the rate of a reaction slowed.
chemical reaction without being itself chemically As an example, the reaction between CO2 and
altered. As the catalyst is not consumed in the reaction, water giving carbonic acid (H2CO3) is very slow:
it can be involved in repeated chemical reactions – only
relatively small numbers of catalyst molecules are CO2 þ H2 O ! H2 CO3
required.
However, addition of the enzyme carbonic anhydrase
18
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:40:29, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.008
Chapter 5: Enzymes
Carbonic
O
anhydrase
CO2
C
Zn2+ Zn2+
O H O– O
His His+
H H
CO2 binding site H
Histidine residue
O
C
Zn2+ Zn2+ O–
O
O H
His H2CO3 His+ H
H H
H 2O
Enzyme emerges from reaction unchanged
Figure 5.1 Catalysis of a reaction between water and CO2 by carbonic anhydrase.
What types of enzyme are there? enzymes require non-protein molecules (called
cofactors) to aid their enzymatic activity. Cofactors
Enzymes are classified by the type of biological reac-
can be:
tion they catalyse:
Inorganic. Many enzymes contain metal ions at
Oxidoreductases, which catalyse oxidation and their active site. For example:
reduction (redox) reactions.
Transferases, which transfer functional groups – CA contains Zn2+, as discussed above.
(e.g. a kinase transfers a phosphate group) from – The cytochrome P450 group of enzymes all
one molecule to another. contain Fe2+.
Hydrolases, which catalyse hydrolysis reactions. – Vitamin B12 contains Co2+.
Lyases, which cleave bonds by means other than – Superoxide dismutase contains Cu2+.
hydrolysis and oxidation. – Hexokinase contains Mg2+.
Isomerases, which allow a molecule to Organic. When the cofactor is organic, it is called
interconvert between its isomers. a ‘coenzyme’. Examples are:
Ligases, which use energy (derived from ATP – Coenzyme A (CoA), a coenzyme used to
hydrolysis) to join two molecules together with transfer acyl groups by a variety of enzymes
covalent bonds. (e.g. acetyl-CoA carboxylase).
– Nicotinamide adenine dinucleotide (NAD+),
What is meant by the terms ‘cofactor’ a coenzyme that accepts a hydride (H‾) ion.
NAD+ is utilised, for example, in
and ‘coenzyme’? conjunction with the enzyme alcohol
Some enzymes consist purely of protein and dehydrogenase.
catalyse biological reactions by themselves. Other
19
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:40:29, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.008
Section 1: The Basics
20
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:40:29, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.008
Section 2 Respiratory Physiology
6
What are the components and swallowing, these muscles contract to propel
food into the oesophagus.
functions of the upper respiratory tract? – Pharyngeal dilators: these muscles contract to
The upper respiratory tract refers to the air passages that maintain patency of the pharynx, so that air
lie above the larynx, outside the thorax, and include: can flow to the lungs.
Nose, nasal cavity and paranasal sinuses;
Mouth;
How does the upper airway remain
Pharynx, which consists of the nasopharynx, patent during breathing?
oropharynx and laryngopharynx. During normal breathing, contraction of the dia-
The main purpose of the upper respiratory tract is to phragm increases intrathoracic volume, which results
conduct air from the atmosphere to the lower respira- in a negative airway pressure (see Chapter 7). Within
tory tract. However, the upper airways serve a the large airways, collapse is prevented by cartilaginous
number of additional functions: support. In contrast, the pharynx is largely unsup-
ported and is therefore liable to collapse during inspir-
Nasal hairs filter any large inhaled particles.
ation. There are three groups of muscles responsible
The superior, middle and inferior nasal turbinates
for maintaining upper airway patency:
(conchae) within the nasal cavity direct the inspired
air over the warm, moist mucosa, promoting Genioglossus, the main dilator muscle of
humidification. The epithelium of the posterior the pharynx, which causes the tongue to protrude
nasal cavity is covered in a thin mucous layer, forward and away from the pharyngeal wall.
which traps finer inhaled particles. Cilia then Palatal muscles control the stiffness and position
propel this mucus to the pharynx to be swallowed. of the palate, tongue and pharynx, as well as the
The function of the four air-filled paranasal shape of the uvula.
sinuses is of debate. They decrease the weight of Muscles influencing the position of the hyoid,
the skull and protect the intracranial contents by such as geniohyoid, exhibit phasic activity.
acting as a ‘crumple zone’. They may also have a This means that their activity is increased during
role in air humidification, immunological defence inspiration, thus stiffening and dilating the upper
and speech resonance. airway, counteracting the influence of negative
Olfactory receptors are located in the posterior airway pressure. When conscious, the airway will
nasal cavity. The proximal location of the remain patent, even in the presence of
olfactory receptors means that potentially harmful intrathoracic pressures as low as –60 cmH2O.
gases can be sensed by rapid, short inspiration (i.e.
sniffing) before being inhaled into the lungs. They
What happens to the upper airway
also play a major role in taste. during sleep?
The pharynx is a complex organ whose functions During wakefulness, the activity of the pharyngeal
include the conduction of air, phonation and dilator muscles is tightly controlled to maintain upper
swallowing. The muscles of the upper airway are airway patency. Once an individual is asleep, the tone
arranged to facilitate its multiple functions: of the pharyngeal dilator muscles decreases signifi-
– Pharyngeal constrictors: inferior, middle and cantly, leading to a reduced pharyngeal diameter.
superior constrictor muscles. During The greatest loss of pharyngeal muscle tone is
21
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 12:45:44, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011
Section 2: Respiratory Physiology
associated with stage 3 non-rapid eye movement Male gender, possibly as a result of a relatively
(NREM) sleep, the stage of sleep that is the most increased amount of fat deposition around the
physically restorative. pharynx.
In the majority of the population, upper airway The effective treatment options are lifestyle modifica-
patency is maintained during sleep. Susceptible indi- tion (smoking cessation, alcohol reduction and weight
viduals may experience pharyngeal obstruction: loss), mouth devices and nasal continuous positive
Partial obstruction of the pharynx results in airway pressure (nCPAP). Overnight nCPAP set at
turbulent airflow during breathing, resulting in between +5 and +20 cmH2O probably works by
the characteristic noise of snoring, an affliction acting as a pneumatic splint to maintain upper airway
that affects approximately 30% of the population patency and has the effect of reducing daytime sleepi-
(and their bed-partners!). ness and atrial fibrillation. It also improves mood,
Complete obstruction of the pharynx, as may cognitive function and blood pressure control.
occur in obstructive sleep apnoea (OSA).
OSA is a sleep disorder characterised by recurrent epi- Patients with OSA have a higher risk of perioperative
sodes of complete upper airway obstruction during deep complications, of which the most serious is airway
sleep. The pharyngeal collapse results in cessation of obstruction due to the use of anaesthetic, sedative or
opioid drugs.
airflow despite the presence of diaphragmatic breathing
Patients may present for surgery with a diagnosis of
effort. Each apnoeic period typically lasts 20–40 seconds,
OSA or may be undiagnosed. A priority at preoperative
during which time hypoxia and hypercapnoea develop. assessment is to identify patients with undiagnosed
The resulting chemoreceptor activation (see Chapter 22) OSA, as they benefit from a period of treatment with
rouses the individual from sleep sufficiently to restore nCPAP prior to surgery. Screening is most commonly
pharyngeal muscle tone and therefore airway patency. carried out using the STOP-BANG questionnaire, in
A short period of hyperventilation occurs, until sleep which points are given for the presence of loud snoring,
deepens and airway obstruction recurs. This repeated daytime sleepiness, observed apnoeas, hypertension,
cycle of sleep interruption (loss of stage 3 NREM and raised body mass index, age >50 years, neck circumfer-
rapid eye movement sleep) and hypoxaemia is associ- ence >40 cm and male gender.
ated with the following problems: With the exception of ketamine, all anaesthetic
and sedative agents reduce central respiratory drive
Neuropsychiatric: daytime sleepiness, poor and pharyngeal muscle tone, leading to upper airway
concentration, irritability, anxiety, depression. obstruction. Sedative premedication should there-
Endocrinological: impaired glucose tolerance, fore be avoided and regional or local anaesthetic
dyslipidaemia, increased adrenocorticotropic techniques used where possible. Where general
hormone and cortisol levels. anaesthesia is required:
Cardiovascular: hypertension, atrial fibrillation, Adequate preoxygenation prior to induction is
myocardial infarction, stroke. key. This should involve oxygenating in the
sitting position (to maximise functional residual
OSA affects approximately 5–10% of the general
capacity) and using CPAP (e.g. using a Water’s
population, but the prevalence is thought to be much circuit or high-flow nasal oxygen (HFNO)).
higher in the surgical population. Risk factors for the An endotracheal tube is preferred over a laryngeal
development of OSA include: mask airway due to greater airway security and
Anatomical factors: craniofacial abnormalities reduced risk of aspiration (gastroesophageal reflux
(such as Pierre Robin and Down’s syndromes) and is common in this patient group due to raised
tonsillar and adenoidal hypertrophy (the major intra-abdominal pressure from obesity). However,
cause of OSA in children). both OSA and morbid obesity are associated with
difficult laryngoscopy, and preparations should be
Obesity, probably as a result of fat deposition
made accordingly.
around the pharynx. Abdominal obesity also
At extubation, the patient should have
decreases functional residual capacity (FRC), any residual neuromuscular blockade fully
which exacerbates the hypoxaemia experienced reversed, be positioned to maximise FRC
during apnoeas.
22
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 12:45:44, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011
Chapter 6: The Upper Airways
(i.e. semi-upright or lateral) and should be 100%. Because the inspired gas is warmed to 37°C
fully awake. and humidified to its saturation point, much higher
Post-operative CPAP, preferably with the gas flows can be tolerated – warming and humidifi-
patient’s own machine, should be commenced. cation is no longer dependent on the nasal mucosa.
Multi-modal analgesia and regional anaesthetic HFNO offers a number of benefits:
techniques should be used to minimise post-
Positive end-expiratory pressure is generated
operative opioid consumption and the
at values between +3 and +7 cmH2O depending
associated central respiratory depressant effects.
on whether the patient’s mouth is open or
closed. This has the effect of recruiting alveoli
and reducing upper airway collapse.
Clinical relevance: HFNO therapy Pharyngeal dead space washout: the high
Conventional O2 delivery devices deliver cold, dry O2 flow of O2 washes expired CO2 from the upper
at a maximum flow rate of 15 L/min and have a airway, reducing the effective anatomical dead
number of disadvantages: space. A higher fraction of minute ventilation is
therefore able to participate in gas exchange.
Masks are often poorly fitting, which may Reduced metabolic cost of breathing. No
result in damage to skin or entrainment of air. longer having to warm and humidify inspired
The maximum inspired O2 concentration of a gases may provide a significant metabolic saving
non-rebreathing mask is between 60% and 80% for a tachypnoeic patient.
as a result of air entrainment.
HFNO is increasingly being used in ward and critical
The peak inspiratory flow of a tachypnoeic
care settings as part of the management of patients
patient may exceed the O2 flow rate entering the
with acute hypoxaemic respiratory failure and has an
mask, resulting in further air entrainment.
expanding role in the perioperative setting:
Delivery of dry oxygen may result in thick, tenacious
secretions and impaired mucociliary function. Preoxygenation with HFNO allows
Low flows: conventional nasal cannulae improve denitrogenation of the lungs and provides an
patient compliance with O2 therapy, as they oxygen reservoir within the upper airway during
allow the patient to eat, drink and communicate laryngoscopy. The combination of a high fraction
more effectively. But O2 flows >4 L/min are of inspired O2 and positive end-expiratory
poorly tolerated: the capacity of the nasal cavity pressure is especially useful in the preoxygenation
to warm and humidify inspired gas is of patients with reduced FRC, such as obese and
overwhelmed. obstetric patients and in the acute abdomen.
HFNO provides a method of delivering warmed, Intraoperative oxygenation, to facilitate
humidified O2 to patients at flows of up to 60 sedation techniques or tubeless airway surgery.
L/min, with inspired O2 concentrations of up to Extubation, to re-recruit collapsed alveoli and to
prevent post-operative upper airway collapse.
23
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 12:45:44, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011
Section 2 Respiratory Physiology
7
What are the functions of the lung?
The lung has both respiratory and non-respiratory Clinical relevance: PEEP
functions:
When a patient is intubated, the vocal cords are no
Respiratory functions are those that facilitate gas longer able to adduct during exhalation, leading to a
exchange: loss of physiological PEEP. This can result in atelec-
– Movement of gases between the atmosphere tasis and ventilation–perfusion (V̇ /Q̇ ) mismatch. It is
and the alveoli; common practice to apply extrinsic PEEP (PEEPe) at
– Passage of O2 from the alveoli to the physiological levels (3–5 cmH2O) to maintain FRC
pulmonary capillaries; and prevent atelectasis following intubation.
However, PEEP increases intrathoracic pressure,
– Passage of CO2 from the pulmonary capillaries
which increases extravascular pressure on veins,
to the alveoli; causing collapse and reducing venous return. There
– Synthesis of surfactant. are a small number of situations where not applying
Non-respiratory functions are: PEEPe may be advantageous – situations where
raised venous pressure may have clinical conse-
– Acid–base balance; quences. For example:
– Immunological and lung defence;
Raised intracranial pressure (ICP) – increased
– Vascular; intrathoracic pressure may hinder venous
– Metabolic and endocrine. drainage from the cerebral venous sinuses,
leading to an increase in ICP.
Describe the functional anatomy Tonsillectomy – raised venous pressure may
increase bleeding at the tonsillar bed, obstructing
of the lower airways the surgeon’s view of the operative field.
The lower airways can be divided into the larynx and
tracheobronchial tree, which is subdivided into the
conducting and respiratory zones. Important aspects Clinical relevance: humidification
of the anatomy are: Endotracheal and tracheostomy tubes bypass the
Larynx: upper airway, so the normal warming and humidifi-
cation of inspired air cannot occur. Inhaling cold, dry
– During inhalation, the vocal cords are in an
gases results in increased mucus viscosity, which
abducted position to reduce resistance to impairs the mucociliary escalator. This causes:
inward gas flow.
– During exhalation, the cords adduct slightly, Accumulation of mucus in lower airways;
An increased risk of pulmonary infection;
increasing the resistance to gas flow, which
Microatelectasis.
results in a positive end-expiratory pressure
(PEEP) of 3–4 cmH2O. This ‘physiological’ Artificial humidification and warming of
PEEP is important for vocalisation and inspired gases are commonly achieved using a
coughing. It also maintains positive pressure in heat and moisture exchanger for surgical
the small airways and alveoli during expiration, procedures or a hot water bath humidifier in the
thus preventing alveolar collapse and intensive care unit.
maintaining functional residual capacity (FRC).
24
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 12:50:31, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.010
Chapter 7: The Lower Airways
Tracheobronchial tree:
– The tracheobronchial tree consists of a series
of airways that divide, becoming 500
400
between the trachea and the alveoli
(Figure 7.1). As the generations progress, the
total cross-sectional area increases
300
exponentially (Figure 7.2).
– The tracheobronchial tree is subdivided into
Conducting zone Respiratory zone
the conducting zone (airway generations 200
0–16) and the respiratory zone (generations
17–23). As the names suggest, the conducting
airways are responsible for conducting air 100
from the larynx to the respiratory zone, whilst
the respiratory zone is responsible for gas
exchange. 0
– In a 70‑kg man, the volume of the conducting 0 5 10 15 16 20 23
Airway generation
airways, known as the anatomical dead space,
is approximately 150 mL. The volume of the Terminal bronchioles
respiratory zone at rest is approximately
Figure 7.2 Increasing cross-sectional area with airway generation.
3000 mL.
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 12:50:31, subject to the Cambridge Core terms of use, available at 25
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.010
Section 2: Respiratory Physiology
bifurcates at the carina (T4/5 level). – The bronchioles constitute the first airway
The anterior and lateral walls of the trachea are generation that does not contain cartilage.
reinforced with ‘C’-shaped cartilaginous rings. They have a layer of smooth muscle that
The posterior gap of the cartilaginous rings is contracts (bronchoconstriction) and relaxes
bridged by the trachealis muscle. At times of (bronchodilatation) to modulate gas flow:
extreme inspiratory effort with associated high
▪ Bronchodilatation results from
negative airway pressure, these cartilaginous
sympathetic nervous system activity,
rings prevent tracheal collapse.
such as during exercise: this reduces
– The trachea divides into the right and left main
resistance to gas flow, allowing greater
bronchi. The right main bronchus is shorter,
ventilation during periods of O2 demand.
wider and more vertical than the left. Inhaled
Drugs that induce bronchodilatation
foreign bodies and endotracheal tubes (ETTs)
include β2-agonists and anticholinergics.
are therefore more likely to enter the right
▪ Bronchoconstriction is precipitated by
main bronchus than the left.
the parasympathetic nervous system,
– The right lung has three lobes (upper,
histamine, cold air, noxious chemicals
middle and lower) and the left has two lobes
and other factors. At rest, the reduction in gas
(upper and lower). The lingula (Latin for ‘little
flow velocity causes particulate material to
tongue’) is a part of the left upper lobe and is
settle in the mucus, which is then transported
considered to be a remnant of the left middle
away from the respiratory zone by the cilia.
lobe, which has been lost through evolution.
There are 10 bronchopulmonary segments on – The terminal bronchioles are the last (16th)
the right (three upper lobe, two middle lobe, airway generation of the conducting zone.
five lower lobe) and nine bronchopulmonary Respiratory zone:
segments on the left (five upper lobe, four
– Respiratory bronchioles are predominantly
lower lobe).
conducting, with interspersed alveoli that
participate in gas exchange. These further divide
into alveolar ducts, alveolar sacs and alveoli.
Clinical relevance: double-lumen ETTs
– The alveoli form the final airway generation of
The right upper lobe bronchus originates from the the tracheobronchial tree. The human lungs
right main bronchus only 2 cm distal to the carina. In contain approximately 300 million alveoli,
contrast, the left main bronchus bifurcates 5 cm from resulting in an enormous surface area for gas
the carina. exchange of 70 m2. Each alveolus is
Left-sided double-lumen ETTs (DLETTs) are often surrounded by a capillary network derived
favoured over right-sided tubes for one-lung ventila-
from the pulmonary circulation.
tion, even for some right-sided thoracic surgeries.
This is because incorrect positioning of a right-sided
DLETT risks occlusion of the right upper lobe bron-
chus by the ETT cuff. Right-sided DLETTs are available
Which cell types are found in the
and have a hole positioned for ventilation of the alveolus?
right upper lobe. However, there are anatomical vari- The wall of the alveolus is extremely thin, comprising
ations in the position of the right upper lobe bron- three main cell types:
chus; the position of the DLETT and the right upper
lobe bronchus should therefore be checked using Type I pneumocytes. These are specialised
fibre-optic bronchoscopy. epithelial cells that are extremely thin, allowing
efficient gas exchange. They account for around
90% of the alveolar surface area.
– In segmental and subsegmental bronchi, the Type II pneumocytes. These cover the remaining
epithelium is surrounded by a layer of smooth 10% of the alveolar surface. They are specialised
muscle. Irregularly shaped cartilaginous plates secretory cells that coat the alveolar surface with
prevent airway collapse. pulmonary surfactant.
26
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 12:50:31, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.010
Chapter 7: The Lower Airways
Alveolar macrophages. Derived from monocytes, Intrapleural pressure Ppl. There are two layers of
alveolar macrophages are found within the pleura that encase the lungs: visceral and
alveolar septa and the lung interstitium. They parietal. The inner visceral pleura coats each of the
phagocytose any particles that escape the lungs, whilst the outer parietal pleura is
conducting zone’s mucociliary escalator. attached to the chest wall. The space between the
visceral and parietal pleurae (the intrapleural
What is the alveolar–capillary barrier? space) contains a few millilitres of pleural fluid
whose role is to minimise friction between the
The barrier between the alveolus and the pulmonary
pleurae. The pressure in the intrapleural space
capillary is extremely thin, which facilitates efficient
is normally negative (around –5 cmH2O at rest)
gas exchange (see Chapter 10); in some places, it is as
due to the chest wall’s tendency to spring
thin as 200 nm. There are three layers:
outwards.
Type I pneumocytes of the alveolar wall; Inward elastic recoil Pel. The stretched
Extracellular matrix; elastic fibres of the lung parenchyma exert an
Pulmonary capillary endothelium. inward force, tending to collapse the lung inwards.
Despite being very thin, the alveolar–capillary barrier At rest, the lung is at FRC: Ppl and Pel are equal and
is very strong owing to type IV collagen within the opposite (Figure 7.3a). The pressure in the alveoli
extracellular matrix. The barrier is permeable to small equals atmospheric pressure and airflow ceases.
gas molecules such as O2, CO2, carbon monoxide,
During tidal inspiration (Figure 7.3b):
nitrous oxide (N2O) and volatile anaesthetics.
The functions of the alveolar–capillary barrier are: – Diaphragmatic contraction increases the
vertical dimension of the lungs. The
To allow efficient gas exchange;
diaphragm descends 1–2 cm during quiet tidal
To prevent gas bubbles entering the circulation;
breathing, but can descend as much as 10 cm
To prevent blood from entering the alveolus; during maximal inspiration.
To limit the transudation of water. – Contraction of the external intercostal muscles
increases the anterior–posterior diameter of
How does the lung inflate and deflate the thoracic cage; this is the so-called ‘bucket
during tidal breathing? handle’ mechanism.
The principal muscles involved in ventilation are the Arguably the most important aspect of lung mech-
diaphragm and the intercostal muscles: anics is the airtight nature of the thoracic cage:
Inspiration. The diaphragm is the main – When inspiratory muscle contraction
respiratory muscle during normal, quiet breathing increases the volume of the thoracic cavity, Ppl
(eupnoea); the external intercostal muscles assist falls from the resting value of –5 cmH2O to
during deep inspiration. –8 cmH2O (as is typically generated during
Expiration. During eupnoea, the elastic recoil of tidal breathing).
the lungs produces passive expiration. The – Ppl exceeds the inward elastic recoil of the lung
internal intercostal muscles are active during and the lung expands.
forced expiration. – As the alveolar volume increases:
Accessory muscle groups are used when additional ▪ The alveoli pressure PA becomes
inspiratory (sternocleidomastoid and scalene muscles) subatmospheric, resulting in air entry.
or expiratory (abdominal muscles) effort is required. ▪ The elastic fibres of the lung are stretched. Pel
The forces acting on the lung at rest are:2 increases until end-inspiration, where Pel is
again equal to Ppl. PA is now equal to
atmospheric pressure again and gas flow
2 ceases (Figure 7.3c).
Note: this account is simplified. The more complicated
account includes transpulmonary pressure – the
difference in pressure between the inside (i.e. alveolar) Transpulmonary pressure determines whether the lung
and the outside (i.e. intrapleural) of the lungs. has a tendency to inflate or deflate.
27
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 12:50:31, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.010
Section 2: Respiratory Physiology
PB = 0
No air flow
Thoracic cage
Alveolar space
Ppl = –5
Intrapleural space
Air flow
(a) At rest (end-expiration)
Air flow
Ppl = –5 Ppl = –8
No air flow
PA = PB
Pel = +8
Figure 7.3 Forces acting on the lung: (a) at rest; (b) early inspiration; (c) end-inspiration and (d) during expiration.
– The volume of air inspired per breath depends Because the thoracic cage is airtight:
on the lung compliance (volume per unit – Decreasing thoracic cage volume causes Ppl to
pressure change; see Chapter 20). For example, fall back to –5 cmH2O.
a decrease in intrapleural pressure of – The stretched lung elastic fibres passively
3 cmH2O may generate a 500‑mL tidal volume return lung volume to FRC.
(VT) in normal lungs, but much less in a patient – As lung volume decreases, the alveolar volume
with acute respiratory distress syndrome. falls, resulting in an increase in alveolar
During tidal expiration (Figure 7.3d): pressure. PA exceeds PB and air is expelled
from the lungs.
– The inspiratory muscles relax.
– Air continues to flow out of the lungs
– The ribcage and the diaphragm passively
until PA again equals PB at end-
return to their resting positions and the
expiration.
volume of the thoracic cavity decreases.
28
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 12:50:31, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.010
Chapter 7: The Lower Airways
29
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 12:50:31, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.010
Section 2 Respiratory Physiology
Oxygen Transport
Chapter
8
How is oxygen transported in the blood? (RBC) is low because all the O2 is bound to Hb. Fick’s
law of diffusion states that diffusion occurs along a
O2 is carried within the circulation from the lungs to pressure gradient, so O2 diffuses to the tissues from
the tissues in two forms: the dissolved portion in the plasma, not from Hb
Bound to haemoglobin (Hb), accounting for 98% itself. O2 then dissociates from Hb as plasma PO2
of O2 carried by the blood. Each gram of fully falls, replenishing the O2 dissolved in the plasma.
saturated Hb can bind 1.34 mL of O2 (this is called
Hüfner’s constant).
Dissolved in plasma, accounting for 2% of O2
How do the body’s oxygen stores
carried by the blood. The volume of O2 dissolved compare with its consumption
in blood is proportional to the partial pressure of of oxygen?
O2 (this is Henry’s law). Very little O2 is stored in the body, which means that
The total volume of O2 carried by the blood is the periods of apnoea can rapidly lead to hypoxia. In
sum of the two: addition to O2 in the lungs (within the functional
residual capacity), O2 is stored in the blood (dissolved
Key equation: oxygen content equation
in plasma and bound to Hb) and in the muscles
O2 content per 100 mL of blood = (1.34 [Hb] (bound to myoglobin).
SaO2/100%) + 0.023 PO2, where 1.34 mL/g is As described above, approximately 20 mL of O2 is
Hüfner’s constant at 37°C for typical adult blood, [Hb] carried in each 100 mL of arterial blood and 15 mL of
is the Hb concentration (g/dL), SaO2 is the O2 per 100 mL of venous blood. At sea level, a 70‑kg
percentage Hb O2 saturation, 0.023 is the solubility man has approximately:
coefficient for O2 in water (mLO2.dL–1.kPa–1) and PO2
5 L of blood, containing approximately 850 mL
is the blood O2 tension (kPa). of O2;
For typical arterial blood ([Hb] = 15 g/dL, SaO2 =
A further 250 mL of O2 bound to myoglobin;
97% and PO2 = 13.0 kPa):
450 mL of O2 in the lungs when breathing air.
O2 content per 100 mL arterial blood (CaO2) = (1.34
15 0.97) + 0.023 13 = 19.50 + 0.30 = 19.8 mL This gives a total of 1550 mL of O2.
An adult’s resting O2 consumption is approxi-
whereas venous blood (Hb O2 saturation of 75%, PO2 =
mately 250 mL/min, which means that apnoea need
5.3 kPa) contains
only occur for a few minutes before the onset of signifi-
O2 content per 100 mL venous blood (CvO2) = cant cellular hypoxia. Hypoxic damage occurs even
(1.34 15 0.75) + 0.023 5.3 = 15.08 + 0.12 = more quickly when there is reduced O2-carrying cap-
15.2 mL
acity (e.g. anaemia or carbon monoxide poisoning) or
an increased rate of O2 consumption (e.g. in children).
The above worked example demonstrates that Hb is a
much more efficient means of O2 carriage than O2
dissolved in plasma. However, it would be wrong to Clinical relevance: minimal-flow anaesthesia
think that dissolved O2 is unimportant. The O2 ten-
Low-flow and minimal-flow anaesthesia are anaes-
sion of blood is determined from the amount of O2
thetic re-breathing techniques used to reduce the
dissolved in plasma – the PO2 within a red blood cell
30
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 12:52:52, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.011
Chapter 8: Oxygen Transport
O2 O2
4 ⫻ O2 2,3-DPG
Fe
Fe
Fe Fe
Fe Fe
Fe
Fe
4 ⫻ O2 2,3-DPG O2 O2
Deoxyhaemoglobin Oxyhaemoglobin
31
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 12:52:52, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.011
Section 2: Respiratory Physiology
SaO2 (%)
60 Haemoglobin
of Hb with each successive O2 binding: P50
50
The first O2 molecule binds with relative
40
difficulty – strong electrostatic charges must be
overcome to achieve the required conformational
changes in the Hb molecule. This conformation is 20
referred to as the ‘tense’ conformation, where the
β-chains are far apart. 0
Once the first O2 molecule has bound, the 0 3.5 5 5.3 10 13.3 15 20
come closer together.1 This new conformation Figure 8.2 The oxyhaemoglobin and oxymyoglobin dissociation
results in a second O2 molecule having a higher curves.
binding affinity, thus requiring less energy
to bind.
Once the second O2 molecule has bound, the third
is easier to bind, and so on. In fact, the fourth O2 The position of the oxyhaemoglobin dissociation
molecule binds 300 times more easily than curve is described by the P50 value – the PO2 at which
the first. 50% of Hb is bound to O2. When the position of the
Once the fourth O2 molecule has bound, Hb is curve moves to the right, the affinity of O2 for Hb is
said to be in the ‘relaxed’ conformation. reduced – O2 is more easily offloaded (i.e. for a given
PO2, SaO2 is lower). Rightward shift is caused by
What is the oxyhaemoglobin (Figure 8.3):
Increased PCO2;
dissociation curve? Acidosis;
The oxyhaemoglobin dissociation curve describes the Increased 2,3-diphosphoglycerate (DPG)
relationship between SaO2 and blood O2 tension concentration;
(Figure 8.2). As discussed above, the cooperative Exercise;
binding of Hb is responsible for the curve’s sigmoid
Increased temperature;
shape, which has important clinical consequences:
The presence of sickle haemoglobin (HbS) in
The upper portion of the curve is flat. At this sickle cell disease.
point, even if PaO2 falls a little, SaO2 hardly
changes. However, when a patient’s PaO2 is (Mnemonic: CADETS – CO2, acidosis, DPG, exercise,
pathologically low (e.g. in patients with temperature, sickle cell disease)
respiratory disease), the patient is at a much This rightward shift of the curve is an important
steeper part of the curve; here, a small decrease in physiological mechanism:
PaO2 results in a large desaturation. The Bohr effect. Metabolically active tissues
The steep part of the curve is very important in produce CO2, heat and H+ ions. When blood
the peripheral tissues, where PO2 is low: a large arrives at these capillaries, the oxyhaemoglobin
quantity of O2 is offloaded for only a small dissociation curve is shifted to the right,
decrease in PO2. offloading O2 where it is most needed.
Anaerobic metabolism. When cellular PO2 falls
1
The actual molecular mechanism of cooperative binding
below a threshold value, anaerobic metabolism
is still a subject of debate. It has been suggested that predominates. Energy is produced through the
binding O2 to Fe2+ simultaneously displaces a histidine breakdown of glucose to pyruvate (in a process
residue, resulting in a conformation change. called glycolysis – see Chapter 77), which is then
32
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 12:52:52, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.011
Chapter 8: Oxygen Transport
60
SaO2 (%)
converted to lactate. One of the intermediates of Leftward shift of the oxyhaemoglobin dissociation
the glycolytic pathway is converted to 2,3-DPG in curve results in an increase in O2-binding affinity.
a side pathway.2 The greater the extent of This is an important physiological mechanism in
anaerobic metabolism, the greater the 2,3-DPG foetal life. HbF must be able to extract O2 from
concentration. 2,3-DPG binds specifically to the maternal oxyhaemoglobin – HbF must therefore
β-chains of deoxyhaemoglobin, stabilising have a higher O2-binding affinity than maternal
this configuration (Figure 8.1), thus reducing the Hb. This is achieved by two mechanisms:
O2-binding affinity of Hb. This mechanism HbF causes a leftward shift in the
means that additional O2 is offloaded to cells oxyhaemoglobin dissociation curve, increasing
undergoing anaerobic metabolism. O2-binding affinity.
O2 loading in the lungs. When blood reaches the While 2,3-DPG is present in foetal RBCs, it
lungs, CO2 is excreted and the pH normalises. cannot bind to HbF: 2,3-DPG is only bound by
The P50 of the oxyhaemoglobin dissociation curve β-globin chains, not the foetal γ-chain. This
then returns to its central position. The binding mechanism further increases the binding affinity
affinity of O2 therefore increases: dissolved O2 of HbF for O2.
binds to Hb, which in turn lowers the blood O2
tension, facilitating O2 diffusion across the
alveolar–capillary barrier. Clinical relevance: blood transfusion
The oxyhaemoglobin dissociation curve is shifted to
Erythrocyte 2,3-DPG concentration rapidly
the left by the following (Figure 8.3): decreases in stored blood and is effectively zero
The reverse of the above – that is, low PCO2, after 1–2 weeks’ storage. Low 2,3-DPG concentra-
alkalosis, reduced 2,3-DPG levels, hypothermia; tion shifts the oxyhaemoglobin dissociation
Carboxyhaemoglobin (COHb); curve to the left, increasing O2 binding. When
Methaemoglobin (MetHb); stored blood is transfused, it takes up to 24 h for
erythrocyte 2,3-DPG concentration to return to
Foetal Hb (HbF).
normal.
The increased O2-binding affinity means that
transfused blood is not as effective at offloading O2
as native blood. In contrast, cell-salvaged blood
2
This is thought to be controlled by an O2-sensitive maintains almost all of its 2,3-DPG; O2-binding affin-
enzyme in the glycolytic pathway, likely ity and O2 offloading are unaffected.
phosphofructokinase.
33
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 12:52:52, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.011
Section 2: Respiratory Physiology
What other forms of Hb are there? sickle cell trait and are normally asymptomatic; the
trait confers disease resistance to malaria.
Types of Hb may be classified as physiological or
Substitution of a single amino acid has a signifi-
pathological.
cant impact on how the Hb molecule behaves: under
Physiological: hypoxic conditions, Hb molecules aggregate, distort-
– HbA, which, as discussed above, is the most ing the RBC into a sickle shape. Unfortunately, the O2
common form, has two α- and two β-globin tension of normal venous blood can be sufficiently
subunits (α2β2). low to cause sickling, especially within the sluggish
– HbA2, the other normal adult variant of Hb, flow of the spleen. As the RBCs move from arterial to
accounts for around 2–3% of total Hb. It has venous O2 tensions and back to arterial, repeated
two α- and two δ-globin subunits (α2δ2). aggregation and de-aggregation results in reduced
RBC membrane elasticity. Clinical disease occurs
– HbF is the normal variant during foetal life
through two main mechanisms:
and is composed of two α- and two γ-globin
subunits (α2γ2). HbF has a higher affinity for Vascular occlusion. The reduced elasticity of the
O2 than HbA and may therefore displace O2 sickled cells means that they are less able to deform
across the placenta from maternal blood as they pass through narrow capillaries, resulting in
(see Chapter 83). HbF is produced up to increased blood viscosity, venous thrombosis and
3 months of age, when γ-globin synthesis ischaemia. Capillary and venous occlusions threaten
switches to the adult β-globin; by 6 months of whole-organ infarction, resulting in ischaemic pain
age, all HbF should have been replaced by and organ dysfunction. In childhood, vascular
normal adult variants. However, HbF can occlusion commonly causes splenic infarction –
persist in conditions where β-globin synthesis patients are subsequently susceptible to encapsulated
is impaired, such as β-thalassaemia. bacterial infection, such as meningococcal
septicaemia and salmonella osteomyelitis. Vaso-
Pathological: occlusive crises are managed by hydration, analgesia
– HbS. Found in people with sickle cell disease, and blood exchange transfusion.
HbS has an abnormal β-globin subunit: Reduced red cell survival. Normally, RBCs
a point mutation where glutamate has been survive in the circulation for 100–120 days. In
replaced by valine at the sixth position. contrast, RBCs in sickle cell disease survive for a
– MetHb. Methaemoglobinaemia is where the mere 10–20 days due to chronic haemolysis,
ferrous iron (Fe2+) within the Hb molecule resulting in an Hb concentration of 7–11 g/dL
is oxidised to ferric iron (Fe3+). Fe3+ cannot with a reticulocytosis. Sickle cell patients are
bind O2, so MetHb cannot participate in susceptible to aplastic crises; for example,
O2 transport. parvovirus B19 infection briefly stops
– COHb. This is formed when Hb binds inhaled erythropoiesis by destroying RBC precursors,
carbon monoxide molecules. preventing RBC production for 2–3 days. In
normal patients, this is clinically unimportant,
– CyanoHb. Cyanohaemoglobin is formed when but the short RBC lifespan in sickle cell disease
Hb is exposed to cyanide ions. means that the brief cessation of bone marrow
production can lead to profound anaemia.
How does the single point mutation
cause clinical disease in sickle Clinical relevance: anaesthesia for patients with
cell disease? sickle cell disease
Sickle cell disease is a genetic disease inherited in an The principles of management are:
autosomal recessive pattern. Symptomatic sickle cell Identifying undiagnosed sickle cell disease.
disease is only seen in homozygous patients; that is, Sickle cell status may not be known by the patient:
where both β-globin chains have amino acid point all patients of at-risk ethnic backgrounds should
mutations. Heterozygotic patients are said to have a
34
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 12:52:52, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.011
Chapter 8: Oxygen Transport
36
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 12:52:52, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.011
Section 2 Respiratory Physiology
9
How does carbon dioxide production and As bicarbonate. The enzyme carbonic anhydrase
(CA) catalyses the reaction between CO2 and
storage compare with that of oxygen? water to form H2CO3. The cytoplasm of red blood
CO2 is produced in the tissues as a by-product of cells (RBCs) contains ample CA, whereas CA is
aerobic metabolism. One of the important roles of absent in plasma. The reaction between CO2 and
the circulation is to transport CO2 from the tissues to water can therefore only occur within the RBC.
the lungs, where it is eliminated. Almost all the H2CO3 then dissociates into HCO3‾
A typical adult produces CO2 at a basal rate of 200 and protons (H+):
mL/min (at standard temperature and pressure), a
CO2 þ H2 O Ð H2 CO3 Ð Hþ þ HCO3 ‾
slightly lower rate than the basal O2 consumption
(250 mL/min). During vigorous exercise, CO2 pro- CO2 and water are able to directly diffuse through
duction can rise as high as 4000 mL/min. the RBC membrane, whilst H+ and HCO3‾ cannot.
As discussed in Chapter 8, the body contains only As the CA reaction between CO2 and water is an
1.5 L of O2. In contrast, an estimated 120 L of CO2 is equilibrium reaction, it would cease if the H+ or
stored throughout the body in various forms. HCO3‾ formed were allowed to build up within the
RBC. This is prevented by two processes:
How is carbon dioxide transported – Chloride shift (or Hamburger effect). HCO3‾
in the circulation? is transported across the RBC membrane
down its electrochemical gradient by a specific
CO2 is transported in the circulation in three forms:
transmembrane Cl‾/ HCO3‾ exchanger.
Dissolved in plasma. Like O2, the volume of CO2 Therefore, while the HCO3‾ ions leave the
dissolved in the plasma is proportional to the RBC, joining the blood bicarbonate buffer
partial pressure of CO2 above it (according to system, chloride ions enter the RBC
Henry’s law). Dissolved CO2 makes a much (Figure 9.1) to maintain electrical neutrality.
greater overall contribution to total CO2 carriage – Binding of H+ to histidine residues. As H+
than dissolved O2 does to O2 carriage, because the cannot cross the cell membrane of the RBC, it
solubility coefficient of CO2 is 20 times greater instead binds to histidine side chains of the Hb
than that of O2. molecule, thereby reducing the intracellular
Bound to Hb and other proteins as carbamino concentration of H+ and facilitating the Bohr
compounds. Not to be confused with COHb shift. Deoxyhaemoglobin is able to bind H+
(carbon monoxide bound to Hb), ions better than is oxyhaemoglobin (see the
carbaminohaemoglobin is a compound formed Haldane effect below).
when CO2 reacts with a terminal amine
group within the Hb molecule. The amine By keeping the levels of HCO3‾ and H+ in the RBC
groups involved are the side chains of arginine low, the reaction between CO2 and water proceeds
and lysine within the globin chains: CO2 + and there is a continual conversion of CO2 to
HbNH2 ! HbNHCOOH – this is HCO3‾. The net effect of both processes is that a
carbaminohaemoglobin. Deoxyhaemoglobin molecule of CO2 produced by the tissues results
forms carbamino compounds more readily in the addition of a Cl‾ ion to the RBC, whereas
than does oxyhaemoglobin (see Haldane the H+ is bound and HCO3‾ is removed to the
effect below). extracellular fluid. CO2 is not osmotically active
37
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 12:54:15, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.012
Section 2: Respiratory Physiology
H+
DeoxyHb
CO2
CO2 CA H+
+ H2CO3 +
H 2O HCO3 HCO3
HCO3
RBC
cytoplasm
/HCO3
Plasma
but Cl‾ is; following the chloride shift, there is In the lungs, PO2 is high. As O2 molecules
a small entry of water into the RBC. This is why bind to deoxyhaemoglobin, its ability to bind H+
venous RBCs have a 3% higher volume than and CO2 decreases, in a reversal of the Haldane
arterial RBCs. effect. In consequence:
– There is a release of H+. The H+ ions
What is the Haldane effect? How is it combine with HCO3‾ to form H2CO3.
related to the Bohr effect? Catalysis by CA results in the liberation of
CO2.
The Haldane effect is the observation that deoxyhae-
– There is a release of CO2 directly from
moglobin is a more effective net carrier of CO2 than is
carbaminohaemoglobin.
oxyhaemoglobin. As discussed above, this is for two
reasons: As the liberated CO2 diffuses into the alveoli and
away from the blood, the Hb O2-binding affinity
Deoxyhaemoglobin more readily forms
carbamino compounds. increases, facilitating the loading of O2 onto Hb, in
a reversal of the Bohr effect.
Deoxyhaemoglobin is a stronger base than
oxyhaemoglobin, and hence more readily accepts
H+ than oxyhaemoglobin, allowing increased What proportion of carbon dioxide
HCO3‾ formation.
The Bohr effect describes the finding that increased CO2
is in each transported form?
In both arterial and venous blood, CO2 is primarily
tension or reduced pH shifts the P50 of Hb to higher PO2
transported as HCO3‾.
values (i.e. shifts the oxyhaemoglobin dissociation curve
to the right), thereby resulting in Hb having an appar- Dissolved CO2 forms the smallest proportion of
ently lower O2-binding affinity (see Chapter 8). The the three CO2 transport forms.
Haldane and Bohr effects are important physiological Venous blood has a higher CO2 content than
mechanisms in both the peripheral tissues and in the arterial blood, and also has a higher concentration
lungs with regard to gas exchange and acid–base balance: of deoxyhaemoglobin. As discussed above,
+
Metabolically active tissues produce H and CO2. deoxyhaemoglobin more readily forms carbamino
Through the Bohr effect and its effect on P50, compounds than does oxyhaemoglobin, by the
additional O2 is offloaded to the most metabolically Haldane effect. The additional CO2 carried in
active tissues. According to the Haldane effect, the venous blood has a six times higher concentration
newly formed deoxyhaemoglobin is better at of carbaminohaemoglobin than does arterial
binding H+ and carrying CO2 than is blood (Table 9.1).
oxyhaemoglobin. The metabolic waste products are The proportions of the different transport forms of
therefore efficiently transported away from the CO2 can be represented graphically in the CO2 disso-
tissues to the lungs. ciation curve (Figure 9.2).
38
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 12:54:15, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.012
Chapter 9: Carbon Dioxide Transport
The CO2 dissociation curve describes the relationship In total, the circulation and lungs contain approximately
between the partial pressure of CO2 (PCO2) and the blood 2.5 L of immediately available CO2 and 1550 mL of O2
(see Chapter 8). If a healthy patient stops breathing (e.g.
CO2 content (note the difference from the oxyhaemoglo-
on induction of general anaesthesia), basal processes
bin dissociation curve, which relates PO2 and SaO2). will continue: 250 mL/min of O2 will be consumed and
The CO2 dissociation curve is often drawn as two 200 mL/min of CO2 will be produced. Therefore:
curves: arterial and venous (Figure 9.2a). The typical
PCO2 will increase by 0.4–0.8 kPa/min.
PCO2 in arterial blood is 5.3 kPa (resulting in a CO2
PO2 will fall. The rate of fall is complicated,
content of 48 mL/100 mL blood), whilst in mixed involving factors such as Hb concentration and
venous blood it is 6.1 kPa (CO2 content of 52 mL/100 total blood volume. Typically, SaO2 falls to 70%
mL blood). The two CO2 dissociation curves are, of (PO2 5.0 kPa) after 2 min.
course, diagrammatic representations of the Haldane However, if the patient breathes O2 for sufficient time to
effect: deoxygenated blood (the upper curve) carries completely de-nitrogenate their functional residual
more CO2 than oxygenated blood (the lower curve). capacity prior to the period of apnoea, the quantity of
Important features of the CO2 dissociation curve are: stored O2 increases to over 3 L – even after 5 min of
At physiological PCO2, the CO2 dissociation curve apnoea, SaO2 will remain at 100%. Basal metabolic pro-
is essentially linear. cesses will continue, and after 5 min the PaCO2 will
approach 10 kPa.
As PCO2 increases, CO2 content continues to
increase due to an increase in the fraction of CO2
dissolved in the plasma. Further reading
Table 9.1 Approximate proportions of CO2 transport forms. A. B. Lumb. Carbon dioxide. In: A. B. Lumb. Nunn’s
Applied Respiratory Physiology, 8th edition. London,
Dissolved Carbamino Bicarbonate
Churchill Livingstone, 2016; 151–68.
compounds
I. Caulder, A. Pearce. Physiology of apnoea and hypoxia.
Arterial 5% 5% 90% In: Core Topics in Airway Management, 2nd edition.
blood Cambridge, Cambridge University Press, 2011; 9–18.
Additional 10% 30% 60% G. J. Arthurs, M. Sudhakar. Carbon dioxide transport.
CO2 in Continuing Educ Anaesth Crit Care Pain 2005; 5(6): 207–10.
venous
blood
(a) (b)
Deoxyhaemoglobin
80 80
CO2 content (mL CO2 /100 mL blood)
Oxyhaemoglobin
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 9.2 (a) The CO2 dissociation curve and (b) proportions of CO2 transport forms (arterial blood shown).
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 12:54:15, subject to the Cambridge Core terms of use, available at 39
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.012
Section 2 Respiratory Physiology
Alveolar Diffusion
Chapter
10
Which factors affect the rate of diffusion How is the lung alveolus designed for
across a biological membrane? efficient gas diffusion?
The diffusion of molecules across a biological mem- Two aspects of lung anatomy are responsible for
brane 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 provide
concentration gradient (or partial pressure a massive 70 m2 surface area for gas exchange.
gradient for gases). A thin alveolar–capillary barrier, as little as
Graham’s law. The rate of diffusion of a substance 200 nm in some places.
across a membrane is inversely proportional to the It takes an average of 0.75 s for a red blood cell (RBC)
square root of its molecular weight (MW). to pass through a pulmonary capillary at rest, so the
Surface area. The rate of diffusion is directly time available for diffusion is limited. However, gas-
proportional to the surface area of the membrane. eous diffusion within the lung is so efficient that O2
Membrane thickness. The rate of diffusion is diffusion is usually complete within 0.25 s: at rest,
inversely proportional to the thickness of the there is normally a threefold safety factor for diffu-
membrane. sion. The high degree of safety for O2 diffusion means
Solubility. The rate of diffusion of a substance is that hypoxaemia is rarely due to a diffusion defect
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 do diffusion of oxygen and carbon
surface area concentration gradient solubility
dioxide compare in the lungs?
Rate of diffusion α pffiffiffiffiffiffiffiffi
thickness MW As discussed above, the rate of diffusion is affected by
two factors specific to the substance diffusing: MW
and solubility. Despite O2 and CO2 having similar
Of the five factors: MWs (32 Da and 44 Da, respectively), the rate of
Two factors relate to the diffusion barrier: diffusion of CO2 is 20 times higher than that of O2
surface area and thickness. owing to the much higher solubility coefficient of
Two factors are inherent properties of the CO2. Therefore, in clinical situations where there is
substance diffusing: solubility and MW. a diffusion defect (e.g. in pulmonary fibrosis), O2
So, for a given clinical situation, the only factor that diffusion is more likely to be limited than CO2 diffu-
can be altered is the concentration gradient; for sion, 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
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 12:56:01, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.013
Chapter 10: Alveolar Diffusion
Maximum
N 2O
Pulmonary capillary partial
O2
Equilibration of alveolar
and capillary O2 by 0.25 s
pressure (kPa)
Figure 10.1 Diffusion of O2, N2O and carbon monoxide across the alveolar–capillary barrier at rest.
How does the diffusion of oxygen never reached between alveolar and plasma PCO. The
transfer of carbon monoxide is thus said to be ‘diffu-
compare with the diffusion of sion limited’ because transfer of carbon monoxide is
other gases? limited by the rate of diffusion rather than the
Comparing the diffusion of O2 with other gases is amount of blood available (Figure 10.1). For this
complicated. As O2 diffuses into the blood, most is reason, carbon monoxide is used for testing diffusing
bound to Hb, but some is dissolved in the plasma (see capacity (see later).
Chapter 8). It is the O2 dissolved in the plasma that The transfer of N2O and the volatile anaesthetics
determines its partial pressure PO2. At rest, an RBC across the alveolar–capillary barrier is different. Unlike
takes 0.75 s to traverse a pulmonary capillary. As the O2 and carbon monoxide, N2O and the volatile anaes-
RBC transits through the pulmonary capillary, diffu- thetics do not bind to Hb. Because these gases are
sion of O2 into the plasma increases its PO2, which in relatively insoluble and can only be carried in plasma
turn reduces the pressure gradient across the in a dissolved form, an equilibrium is rapidly reached
alveolar–capillary barrier. An equilibrium is reached between the alveolus and the plasma, well before the
between the alveolar and plasma PO2 after 0.25 s, after RBC has traversed the pulmonary capillary
which net diffusion ceases (Figure 10.1). (Figure 10.1). N2O reaches equilibrium the most rap-
The inspired gases relevant to anaesthesia are idly, within 0.075 s. N2O is therefore said to be perfu-
N2O, volatile anaesthetics and carbon monoxide. sion limited because more N2O would diffuse from the
These are all small molecules with low MWs. Carbon alveolus if there were additional blood available. The
monoxide and N2O are both considerably more water volatile anaesthetics behave in a similar manner, but
soluble than O2. equilibrium is reached slightly later than for N2O.
Carbon monoxide binds to Hb with an affinity
250 times greater than that of O2. Because carbon
monoxide binds so strongly to Hb, virtually no
Is the transfer of oxygen perfusion or
carbon monoxide is dissolved in the plasma – conse- diffusion limited?
quently, the plasma partial pressure of carbon mon- Under normal conditions (as exist in Figure 10.1), the
oxide (PCO) is very low. Even when the RBC has transfer of O2 across the alveolar–capillary barrier is
transited the entire length of the pulmonary capillary, perfusion limited. Like N2O, an equilibrium is
there is still a substantial partial pressure difference reached between the alveolar and capillary PO2 before
across the alveolar–capillary barrier: an equilibrium is the RBC has traversed the pulmonary capillary.
41
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 12:56:01, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.013
Section 2: Respiratory Physiology
12
Pulmonary capillary PO2 (kPa)
10
8
Equilibrium not reached by
6 the end of capillary transit
Significant
4 hypoxaemia
2
Extreme exercise At rest
0
0 0.25 0.5 0.75
Time RBC spends in pulmonary capillary (s)
However, there are a number of circumstances can result in diffusion limitation and
where the transfer of O2 may become diffusion hypoxaemia.
limited:
Thickened alveolar–capillary barrier (e.g. What is meant by ‘lung diffusion
pulmonary fibrosis), which decreases the rate of
diffusion. Equilibrium between alveolar and
capacity’?
capillary PO2 is not achieved by the time the RBC The diffusion capacity of the lung for carbon mon-
reaches the end of the pulmonary capillary, oxide (abbreviated DLCO, or alternatively called
resulting in hypoxaemia (Figure 10.2). ‘transfer factor’ or ‘TLCO’) is a measurement of
Exercise. Cardiac output increases during the lungs’ ability to transfer gases. It is one of the
exercise, which reduces the length of time that an measurements taken during pulmonary function
RBC spends in the pulmonary capillary. Extreme testing.
exercise can reduce RBC transit time to as little as As discussed above, carbon monoxide is a
0.25 s. In patients with a normal alveolar–capillary diffusion-limited gas. The test involves a single vital
barrier, alveolar and plasma PO2 only just reach capacity breath of 0.3% carbon monoxide, which is
equilibrium during the available pulmonary held for 10 s and then exhaled. The inspired and
capillary transit time (Figure 10.2). In patients expired PCO are measured – the difference is the
with disease of the alveolar–capillary barrier, any amount of carbon monoxide that has diffused across
exercise-induced reduction in RBC transit time the alveolar–capillary barrier and bound to Hb. The
results in hypoxaemia. diffusion capacity is usually corrected for the patient’s
Hb concentration, but is also affected by altitude, age
Altitude. At high altitude, the lower barometric
pressure PB causes a reduction in alveolar PO2 and sex.
(see Chapters 18 and 87). This results in the The diffusion capacity is used to diagnose disease
transfer of O2 becoming diffusion limited at a of the alveolar–capillary barrier. Diffusion capacity is
lower threshold (Figure 10.3). The patient with reduced as a result of:
mild lung disease in Figure 10.2, where alveolar Thickened alveolar–capillary barrier. For
and plasma PO2 just reach equilibrium at rest at example, pulmonary fibrosis and other interstitial
sea level, will develop impaired O2 diffusion at lung diseases (chronic), or pulmonary oedema
altitude. Even with normal lungs, intense exercise (acutely).
42
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 12:56:01, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.013
Chapter 10: Alveolar Diffusion
Normal diffusion
8
Hypoxaemia on exercise
with normal diffusion Hypoxaemia even at rest with
6 impaired diffusion
2
Extreme exercise At rest
0
0 0.25 0.5 0.75
Time RBC spends in pulmonary capillary (s)
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 12:56:01, subject to the Cambridge Core terms of use, available at 43
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.013
Section 2: Respiratory Physiology
44
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 12:56:01, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.013
Section 2 Respiratory Physiology
11
In the lungs, what is meant by the approximately 2 mL/kg, or around a third of the
normal VT (7 mL/kg). V Anat may be altered by a
term ‘dead space’? number of factors:
D
The air inspired during a normal breath VT is divided Size of patient: V Anat
D increases as the size of the
into: lungs increases.
Alveolar volume VA, the volume of air which Lung volume: at high lung volumes, radial
reaches perfused alveoli. traction on the airway walls increases airway
Dead space VD, the volume of inspired air that diameter, thus increasing V Anat
D .
plays no part in gas exchange; that is, the air Posture: lung volume decreases in the supine
remaining in either the conducting airways or position, which reduces airway diameter and
non-perfused alveoli. therefore reduces V Anat
D .
Mathematically: Bronchoconstriction reduces airway diameter:
V Anat
D therefore decreases.
VT ¼ VA þ VD
Bronchodilatation increases airway diameter:
What are the different types V Anat
D therefore increases.
45
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:33:08, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.014
Section 2: Respiratory Physiology
8
PaCO2 (kPa)
.
6 Doubling VA results in
a halving of PaCO2
5
4
2.5
2
0
0 2 4 6 8 10 12 14
.
Alveolar ventilation, VA (L/min)
46
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:33:08, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.014
Chapter 11: Ventilation and Dead Space
47
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:33:08, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.014
Section 2: Respiratory Physiology
A
0
0 Anatomical dead space Closing capacity
Expired volume (L)
The patient starts by breathing tidal volumes of the N2-rich gas from apical alveoli is exhaled,
room air. resulting in the sudden increase in expired N2
At the end of a normal tidal expiration (i.e. concentration.
functional residual capacity), the patient takes a
vital capacity breath of 100% O2. What is the Bohr method for the
The patient then expires slowly into a mouthpiece
to maximal expiration (i.e. residual volume).
measurement of physiological
The mouthpiece is attached to a spirometer, dead space?
Phys
which measures the volume of expired air. The Bohr method is used to calculate V D . The Bohr
Also attached to the mouthpiece is a rapid N2 equation calculates the ratio of physiological dead
analyser, which measures the concentration of space to tidal volume, VD/VT. The ‘normal’ value is
expired N2. 0.20.35 during tidal breathing.
The result is a plot of expired N2 against volume of
expired gas. This graph has four phases (Figure 11.2):
Key equation: the Bohr equation
– Phase 1: gas from the anatomical dead space is
expired – it contains only O2; no N2 is present. V D Pa CO2 PET CO2
¼
– Phase 2: a mixture of dead-space gas and VT Pa CO2
alveolar gas is expired. The midpoint of this where PaCO2 is the arterial tension of CO2 and PETCO2
curve (where area A equals area B) is taken as is the end-tidal tension of CO2.2
being V Anat
D . So, to measure VD/VT, an arterial blood gas must
– Phase 3: expired N2 concentration reaches a be taken at the same time as end-tidal CO2 is
plateau. All the gas expired is now alveolar gas. measured.
Note that the plateau has a slight upwards slope.
– Phase 4: there is a sharp increase in N2 The Bohr equation can be derived using simple
concentration at the CC, the lung volume at which mathematics. It is based on the principle that all CO2
the smallest airways in the dependent parts of comes from alveolar gas, and thus from alveoli that
the lung begin to collapse during expiration. The are both ventilated and perfused, and none comes
basal alveoli are more compliant than the apical from the dead space.
alveoli: during inspiration, the basal alveolar
volume increases more than the apical alveolar We know that VT = VA + VD.
volume. Therefore, during the O2 breath, most Rearranging: VA = VT VD.
of the inspired O2 enters the basal alveoli. At the If we define
start of expiration, the process reverses: the basal
2
alveoli empty first. When the lower airways close, Note: this is a usable, simplified version of the Bohr
equation.
48
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:33:08, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.014
Chapter 11: Ventilation and Dead Space
) V T FE ¼ V A FA
Further reading
Substituting in VA = VT – VD: S. Shaefi, M. Eikermann. Analysing tidal volumes early after
a positive end-expiratory pressure increase: a new way
V T F E ¼ ðV T V D Þ F A
to determine optimal PEEP in the operating theatre?
Br J Anaesth 2018; 120(4): 623–6.
Multiplying out the brackets:
G. Tusman, F. S. Sipmann, S. H. Bohm. Rationale of dead
V T FE ¼ V T FA V D FA space measurement by volumetric capnography.
Anesth Analg 2012; 114(4): 866–74.
Rearranging:
J. M. Raurich, M. Vilar, A. Colomar, et al. Prognostic
V D F A ¼ V T ðF A F E Þ value of the pulmonary dead-space fraction during
the early and intermediate phases of acute respiratory
distress syndrome. Respir Care 2010; 55(3): 282–7.
49
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:33:08, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.014
Section 2 Respiratory Physiology
12
What is the difference between a lung – Expiratory reserve volume ERV = 1500 mL.
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 12.1) or by a gas dilution technique (see – Residual volume = 1500 mL. Residual volume
p. 52). A lung capacity is the sum of two or more is the volume of air that remains in the lungs
lung volumes; it is therefore a derived value. There are following maximum expiration.
four lung volumes and four lung capacities (values Four capacities:
given are typical for a 70‑kg man when standing):
– Functional residual capacity FRC = residual
Four volumes:
volume + ERV = 3000 mL.
– Tidal volume VT = 500 mL. VT is the volume of – Vital capacity VC = ERV + VT + IRV =
air inspired per breath during normal, quiet 4500 mL.
breathing. – Inspiratory capacity IC = VT + IRV = 3000 mL.
– Inspiratory reserve volume IRV = 2500 mL. – Total lung capacity TLC = residual volume +
IRV is the volume of additional air that can be ERV + VT + IRV = 6000 mL.
inspired over and above VT.
5 IRV
IC VC TLC
2500 mL
3000 mL 4500 mL 6000 mL
Lung volume (L)
VT 500 mL
3
ERV
2 1500 mL
0
0 5 10 15 20 25 30 35
Time (s)
50
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 21:12:40, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.015
Chapter 12: Static Lung Volumes
Clinical relevance: tidal volume in mechanically Prevention of alveolar collapse. If FRC did not
ventilated patients exist (i.e. expiration to residual volume),
alveoli would collapse. Atelectasis would result
Normal VT is typically around 500 mL for a 70‑kg adult,
in V̇ /Q̇ mismatch and hypoxaemia.
or 7 mL/kg. In mechanically ventilated patients,
ventilator-associated lung injury can occur as a result of: Re-expansion of atelectatic alveoli with every
tidal breath would significantly increase the work
Volutrauma – diffuse alveolar damage caused
of breathing.
by overdistension of the lung. Traditionally, tidal
volumes of 12 mL/kg were delivered to Optimal lung compliance. Conveniently, lung
mechanically ventilated patients. This high- compliance is at its highest at FRC. Pulmonary
volume ventilation strategy is now thought to vascular resistance is also at its lowest (see
cause volutrauma and lung damage. Most Chapter 23).
intensive care units have adopted a low-VT FRC is of crucial importance to anaesthetists:
ventilation strategy (6 mL/kg), as it has been
shown to reduce mortality in patients with acute Apnoea. FRC not only buffers swings in PAO2
respiratory distress syndrome (ARDS). during tidal breathing, but also crucially acts as an
Barotrauma – damage to the lung as a result of O2 reservoir at times of apnoea, such as at
high airway pressure. Strategies to prevent induction of general anaesthesia.
barotrauma include maintenance of peak airway Small airway closure. If FRC falls below a certain
pressure Ppeak below 35 cmH2O or plateau airway volume (the closing capacity, CC), small airways
pressure Pplat below 30 cmH2O. close, resulting in V̇ /Q̇ mismatch and
If a patient has particularly poor lung compliance hypoxaemia.
(e.g. in ARDS), ventilation using lung-protective par-
ameters (VT = 6 mL/kg and Pplat 30 cmH2O) may
not achieve sufficient V̇ A to maintain normocapnoea. Which factors affect FRC?
In this situation, it is preferable to practice ‘permis- FRC is not fixed; its volume is affected by surgical,
sive hypercapnoea’ rather than increase VT or inspira- anaesthetic and patient factors:
tory pressure, which may risk volutrauma or
barotrauma, resulting in further lung damage. This
FRC is reduced by:
is referred to as a lung-protective ventilation – Position. FRC falls by 1000 mL just by the
strategy. patient lying supine.
– Raised intra-abdominal pressure; for example,
What is the importance of the FRC? obesity, pregnancy, acute abdomen,
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. The
relaxed – the inward elastic force of the lung paren- cause is not known, but is thought to be related
chyma is exactly equal and opposite to the force with to decreased thoracic cage muscle tone and
which the chest wall springs outwards (see Chapter 7, loss of physiological positive end-expiratory
Figure 7.3). pressure (PEEP).
FRC is physiologically important for three – Younger age; that is, neonates, infants and
reasons: young children.
O2 buffer. The air within the FRC acts as an O2 – Lung disease; for example, pulmonary fibrosis,
buffer during normal breathing. O2 continuously pulmonary oedema, atelectasis, ARDS.
diffuses from the alveoli to the pulmonary
capillaries. If FRC did not exist, there would be FRC is increased by:
fewer aerated alveoli and therefore less O2 in the – PEEP, which is commonly used to maintain FRC
lungs – alveolar partial pressure of O2 (PAO2) intraoperatively, especially in paediatric
would decrease during expiration. Pulmonary anaesthesia and following intubation (where
capillary blood would be intermittently physiological PEEP has been lost – see Chapter 7).
oxygenated, only being fully oxygenated during – Emphysema. Lung elastic tissue is destroyed,
inspiration. resulting in reduced inward elastic recoil. The
51
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 21:12:40, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.015
Section 2: Respiratory Physiology
Helium
C1 C2
V1 FRC
Figure 12.2 Gas dilution method for calculation of functional residual capacity (FRC).
52
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 21:12:40, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.015
Chapter 12: Static Lung Volumes
Mouthpiece Mouthpiece
pressure pressure
P3 P4
FRC FRC + DV
Diaphragmatic
P1 P2 contraction
Before mouthpiece shutter closes Mouthpiece shutter closes, patient tries to inspire
53
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 21:12:40, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.015
Section 2: Respiratory Physiology
P3 FRC ¼ P 4 ðFRC þ ΔV Þ
1
Note: this method is different from the single-breath N2
All values except FRC are known, so FRC can be washout known as Fowler’s method, which is used to
calculated: calculate anatomical dead space and CC (see Chapter 11).
54
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 21:12:40, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.015
Chapter 12: Static Lung Volumes
What is the CC? Prior to RSI, the patient should have 100% O2
administered for at least 3 min. Pre-oxygenation and
The lungs are affected by gravity. When the subject is induction of general anaesthesia could take place with
upright, the lung parenchyma is more stretched at the the patient sitting at 45° to maximise FRC. Rapid and
apices and more compressed in the bases. One conse- profound hypoxaemia can be expected if pre-
quence of basal lung parenchymal compression is that oxygenation is insufficient. High-flow nasal oxygen
the basal airways have a reduced radius; these airways therapy allows continued oxygenation during the
are the first to be compressed during active expir- apnoeic period and laryngoscopy attempts.
ation, resulting in a V̇ /Q̇ mismatch. The lung volume
at which this occurs is called the CC. Being a capacity, How is CC measured?
CC is the sum of two volumes: residual volume and
CC is measured using Fowler’s method (single-breath
closing volume.
N2 washout method – see Chapter 11).
In young, healthy adults, airway closure is not usu-
ally a problem because CC is well below FRC. If CC Further reading
were to exceed FRC, airway closure would occur during
K. Ray, A. Bodenham, E. Paramasivam. Pulmonary
normal tidal breathing, resulting in V̇ /Q̇ mismatch and atelectasis in anaesthesia and critical care. BJA Education
hypoxaemia. CC may exceed FRC because either: 2014; 14(5): 236–45.
FRC is lower than normal, for one of the reasons B. Kilpatrick, P. Slinger. Lung protective strategies in
discussed above. For example, CC exceeds FRC in anaesthesia. Br J Anaesth 2010; 105(Suppl. 1): i108–16.
neonates because of their reduced FRC. C. R. O’Donnell, A. A. Bankier, L. Stiebellehner, et al.
CC is increased – CC increases with age, Comparison of plethysmograhic and helium dilution
encroaching on FRC at age 45 when supine and lung volumes: which is best for COPD? Chest 2010; 137
age 60 when standing. (5): 1108–15.
Airway closure during tidal expiration also means R. Sirian, J. Wills. Physiology of apnoea and the benefits of
pre-oxygenation. Continuing Educ Anaesth Crit Care
that airways must be reopened during inspiration.
Pain 2009; 9(4): 105–8.
This can increase the work of breathing significantly
and is one of the factors that predisposes both the The Acute Respiratory Distress Syndrome Network.
Ventilation with lower tidal volumes as compared to
elderly and the very young to respiratory failure. traditional tidal volumes for acute lung injury and acute
respiratory distress syndrome. N Engl J Med 2000; 342
(18): 1301–8.
Clinical relevance: emergency anaesthesia, FRC
C. J. L. Newth, P. Enright, R. L. Johnson. Multiple-breath
and CC
nitrogen washout techniques: including measurements
Consider a 65-year-old patient with an acute abdo- with patients on ventilators. Eur Respir J 1997; 10(9):
men lying supine, awaiting a rapid sequence induc- 2174–85.
tion (RSI) for an emergency laparotomy.
55
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 21:12:40, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.015
Section 2 Respiratory Physiology
Spirometry
Chapter
13
What are the clinical uses of pulmonary residual volume, functional residual capacity
(FRC) and total lung capacity (TLC).
function tests? What equipment is Dynamic spirometry. Lung measurements that
needed? depend on the rate (i.e. volume per unit time) at
Pulmonary function tests (PFTs) are used to quantify which air flows in and out of the lungs are called
an individual patient’s respiratory physiology. ‘dynamic’. Dynamic PFTs include:
A battery of tests and manoeuvres are performed to – Forced expiratory volume in 1 second (FEV1);
measure the performance of the different lung – Forced vital capacity (FVC);
components: – Peak expiratory flow rate (PEFR);
Large and small airways; – Expiratory flow–volume curve;
Alveoli; – Flow–volume loops.
Pulmonary vasculature; Special tests such as diffusion capacity (which
Respiratory muscles. gives a measure of alveolar diffusion – see
The clinical uses of PFTs are: Chapter 10), gas dilution and N2 washout (used to
Diagnosis of respiratory disease; calculate FRC – see Chapter 12).
Grading the severity of respiratory disease and
guiding its pharmacological management; How are FEV1, FVC and PEFR measured?
Estimation of surgical risk, in particular of Forced spirometry is a simple bedside test. From full
thoracic surgery. inspiration, the patient breathes out as hard and as
Spirometers are used for performing PFTs. There are rapidly as possible into the spirometer, to full expir-
many types of spirometer, classified as: ation, resulting in the expiratory volume–time graph
(Figure 13.1).
Volume-sensing; for example, the vitalograph,
Two parameters are measured: FEV1 and FVC.
based on a bellows mechanism;
These are compared with their ‘predicted’ values,
Flow-sensing; for example, the based on normal patients matched for age,
pneumotachograph, which is much more
gender, height and ethnic origin. One parameter is
portable.
calculated: FEV1/FVC ratio – an FEV1/FVC ratio less
than 0.7 is considered abnormal. Use of this ratio
Which variables are measured using identifies a relative difference between FEV1 and
spirometry? FVC: a patient with low FVC will also have a
low FEV1 simply as there is less gas to be expelled,
Spirometers are used to take many different lung rather than necessarily being due to an obstructive
measurements, broadly classified as: pathology.
Static lung volumes. The patient breathes in and PEFR can also be calculated from the forced spiro-
out of a spirometer, first with tidal volume breaths metry trace: flow is volume per unit time, so the
and then with vital capacity breaths. As discussed gradient of the spirometry curve represents flow.
in Chapter 12, all static lung volumes and The ‘peak’ flow is therefore the initial gradient of the
capacities can be measured, with the exception of forced volume–time curve (Figure 13.1). However,
56
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 21:47:08, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.016
Chapter 13: Spirometry
FVC
5
Expired volume (L)
1
Initial gradient = PEFR
0
0 1 2 3 4 5 6
Time (s)
PEFR is more commonly measured by a separate may represent an intermediary condition in the spec-
device: the peak flow meter. trum from asthma to COPD.
Forced spirometry is particularly useful for the Restrictive lung diseases (e.g. lung fibrosis,
diagnosis of obstructive and restrictive lung diseases: kyphoscoliosis, respiratory muscular weakness)
Obstructive airways diseases (asthma and chronic are characterised by (Figure 13.2b):
obstructive pulmonary disease, COPD) can be – FVC1 < 80% predicted;
diagnosed by comparing forced spirometry – FVC < 80% predicted;
measurements with predicted values
– FEV1/FVC ratio > 0.7; that is, ‘normal’ or even
(Figure 13.2a). Diagnostic criteria are:
‘high’, the latter due to increased FEV1 from
– FEV1 < 80% predicted; decreased pulmonary compliance.
– FEV1/FVC ratio < 0.7.
Severity of disease can be assessed using the FEV1: Clinical relevance: Guillain–Barré syndrome
– Mild disease, FEV1 50–79% predicted; Guillain–Barré syndrome (GBS) refers to a collection
– Moderate disease, FEV1 30–49% predicted; of acute polyneuropathies characterised by motor,
– Severe disease, FEV1 < 30% predicted. sensory and autonomic dysfunction. The most
common variant of GBS is acute inflammatory
PEFR can also be used for the diagnosis of obstructive demyelinating polyneuropathy, which is caused by
airways disease (a diurnal variation of >20% is sug- autoimmune attack of the myelin-producing
gestive of asthma), but is more commonly used to Schwann cells that surround the peripheral nerve
compare a patient’s baseline respiratory function with axon. This variant has the classic presentation of
that during an exacerbation. ascending motor paralysis.
Differentiation between asthma and COPD is Around 25% of patients with GBS will require
based on the history and the reversibility of airway respiratory support due to respiratory muscle weak-
obstruction. Forced spirometry is performed before ness or failure to clear secretions with a secondary
and 15 min after administration of a bronchodilator – pneumonia. Invasive ventilation is preferred over
non-invasive ventilation as it enables secretions to
an improvement in FEV1 of 400 mL is said to corres-
be cleared.
pond to significant airway reversibility, suggesting It is important to be able to identify patients in
asthma. Some patients, usually over the age of 40 need of respiratory support before respiratory
years, have chronic airways obstruction that is only failure occurs. Clinical features such as bulbar weak-
partially reversible, as well as features suggestive of ness and poor cough suggest a need for intubation.
both asthma and COPD. This is referred to as In addition, there are a number of well-recognised
‘asthma–COPD overlap syndrome’ (ACOS). ACOS criteria for intubation, many based on spirometry.
57
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 21:47:08, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.016
Section 2: Respiratory Physiology
(a)
FEV1/FVC ratio significantly reduced
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)
0
0 1 2 3 4 5 6 7
Time (s)
Figure 13.2 Forced expiratory volume–time graphs: (a) obstructive airways disease and (b) restrictive lung disease.
6 Obstructive
Expiratory flow (L/s)
airways disease
‘Effort independent’ 6
(c)
8 (d)
Normal
8 Normal
Expiratory flow (L/s)
Figure 13.3 Expiratory flow–volume curve: (a) normal; (b) mild obstructive airways disease; (c) severe obstructive airways disease and (d)
restrictive lung disease.
Restrictive lung disease (Figure 13.3d): At the start of forced expiration, lung volume is
– The expiratory flow–volume curve has a high:
characteristic reduction in TLC. – At high lung volume (Figure 13.4a), the lung
– In the effort-dependent part of the curve, parenchyma is generally more stretched and
PEFR may be reduced: respiratory muscle the radius of the airways is at its greatest.
weakness reduces the maximal expiratory According to the Hagan–Poiseuille equation
effort that can be generated. (see Chapter 21), airways of greater radius
– The effort-independent part of the curve allow a much greater rate of gas flow.
remains linear. – On forced expiration, the expiratory muscles
generate a high intrapleural pressure Ppl. This
in turn generates a high alveolar pressure PA
Can you explain the shape of the forced (Figure 13.4b). Expiratory flow rate is initially
expiratory flow–volume curve? ‘effort dependent’ – the greater the positive Ppl
The shape of the forced expiratory flow–volume curve generated by the expiratory muscles, the
can be explained by considering the airway radius at greater the PEFR and FEV1.
different lung volumes (Figure 13.4):1 As forced expiration continues, lung volume
decreases:
1
This account is simplified – the more complete account is – The lung parenchyma becomes less stretched
based on the ‘equal pressure point hypothesis’. and the radius of the airways decreases.
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 21:47:08, subject to the Cambridge Core terms of use, available at 59
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.016
Section 2: Respiratory Physiology
PA Early
As expiration
continues,
expiration
lung volume
0 Ppl +40 reduces +40
–10 +30 +30
– Ppl remains high. Obstructive airways disease (Figure 13.5b and c).
– The smallest airways without any cartilaginous As described above, the expiratory portion of the
support become squashed by the high loop has a reduced PEFR, a concave rather than
intrapleural pressure. This is called dynamic linear appearance of the effort-independent part
airway compression (Figure 13.4c). of the curve and may have an increased residual
– Resistance to gas flow increases, leading to a volume due to air-trapping. Inspiration is
reduced expiratory flow. relatively unaffected by small-airways obstruction.
– Expiratory flow is now said to be effort Restrictive lung disease (Figure 13.5d). As
independent. Expiratory flow is instead described above, the expiratory flow–volume
dependent on lung volume, reducing linearly curve has a reduced PEFR, a normal appearance of
as lung volume approaches residual volume the effort-independent portion of the curve and a
(Figure 13.3a). significantly reduced vital capacity. Depending on
the severity of disease, the TLC is substantially
What is the difference between a flow– lower whilst the residual volume is proportionally
less reduced. This is shown graphically as a
volume curve and a flow–volume loop? rightward-shifted loop with a substantially
A flow–volume loop has an inspiratory flow–volume reduced FRC.
curve in addition to the expiratory flow–volume Fixed upper airway obstruction; for example,
curve, thus completing a loop. The spirometry trace tracheal stenosis or foreign body (Figure 13.6a).
should be followed clockwise; that is, forced expir- ‘Fixed’ refers to airway narrowing that is
ation from TLC to residual volume, followed by unchanged throughout the respiratory cycle. Lung
inspiration at maximal effort back to TLC volumes are unchanged, but there is a reduction in
(Figure 13.5a). The tidal volume flow–volume loop both peak expiratory and inspiratory flows,
is also shown (Figure 13.5a). Note that the end- resulting in a characteristic flattening of both the
expiratory point of tidal breathing on the x-axis inspiratory and expiratory flow–volume curves.
is FRC. Additional respiratory effort cannot overcome
Clinically, flow–volume loops are especially useful this obstruction – it is said to be effort
when there is diagnostic uncertainty about the ana- independent.
tomical location of airway obstruction, as additional Variable extrathoracic airway obstruction; for
information can be gained from the inspiratory por- example, vocal cord palsy (Figure 13.6b).
tion of the flow–volume loop. For example, a patient ‘Extrathoracic’ refers to a level above the sixth
may present with wheeze and a history inconsistent tracheal ring and ‘variable’ refers to airway
with asthma or COPD. obstruction that is free to move with the changes
60
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 21:47:08, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.016
Chapter 13: Spirometry
(a) (b)
8 8
Minor concavity
Tidal breathing
Flow rate (L/s)
Figure 13.5 Flow–volume loops: (a) normal; (b) mild small-airways obstructive disease; (c) severe small-airways obstructive disease and (d)
restrictive lung disease.
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 21:47:08, subject to the Cambridge Core terms of use, available at 61
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.016
Section 2: Respiratory Physiology
(a)
Flow rate (L/s)
0 Volume (L)
TLC Residual
volume
Inspiration Expiration
–4
(b) 8
Flow rate (L/s)
0 Volume (L)
TLC Inspiration Expiration
Residual Paw > PB
Paw < PB
volume
–4
(c)
4
Flow rate (L/s)
0 Volume (L)
TLC Residual
volume
Inspiration Expiration
–4 Paw > Ppl Paw < Ppl
Figure 13.6 Flow–volume loops: (a) fixed upper airway obstruction; (b) variable extrathoracic airway obstruction and (c) variable intrathoracic
airway obstruction (PB = atmospheric pressure).
62
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 21:47:08, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.016
Section 2 Respiratory Physiology
14
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:
Hypoxaemia refers specifically to reduced PaO2. This
can result from either a failure of O2 delivery or a Hypoventilation;
failure of O2 utilisation. The following conditions Diffusion limitation;
must be fulfilled for cells to utilise O2 for aerobic Shunt;
metabolism: V̇ /Q̇ mismatch.
Adequate arterial O2 tension (PaO2) – blood
leaving the lungs must be adequately oxygenated. How does hypoventilation cause
Adequate O2-carrying capacity – blood must
have an adequate haemoglobin (Hb)
hypoxaemia?
concentration. Hypoxaemia resulting from hypoventilation is
Adequate cardiac output (CO) and arterial flow described in detail in Chapter 18. In brief:
ensures that the O2 carried by Hb reaches the V̇ A and PaCO2 are inversely related (see
tissues. Chapter 11); hypoventilation therefore leads to
Adequate mitochondrial function – the cells high PaCO2.
must be able to use O2 effectively for aerobic According to the alveolar gas equation (AGE;
metabolism. see Chapter 18), PAO2 decreases: the O2 partial
pressure gradient across the alveolar–capillary
Hypoxia is therefore classified in terms of failure of
barrier is reduced, leading to low PaO2.
one or more of the processes above:
Hypoxaemic hypoxia – caused by low PaO2.
When PaO2 falls below 8 kPa, there is a steep fall Is diffusion limitation an important
in the saturation of Hb (see Chapter 8, Figure 8.2), cause of hypoxaemia?
which reduces O2-carrying capacity.
Alveolar diffusion is discussed in detail in Chapter 10,
Anaemic hypoxia – PaO2 is normal but O2-
but in summary:
carrying capacity is reduced. This is exemplified
by severe anaemia and carbon monoxide Diffusion limitation is rarely a cause of
poisoning (see Chapter 8). hypoxaemia.
Stagnant hypoxia – PaO2 and Hb concentration PAO2 and pulmonary capillary O2 tension have
are normal, but circulatory failure means that normally reached equilibrium before the red
tissue O2 delivery is reduced. This is exemplified blood cell has travelled a third of the way along the
by cardiogenic shock and acute limb ischaemia pulmonary capillary.
following an arterial embolus. Diffusion limitation can cause hypoxaemia
when:
Cytotoxic hypoxia – PaO2, O2-carrying capacity
and O2 delivery are normal, but the mitochondria – The alveolar–capillary barrier is thickened,
fail to utilise O2 effectively. This is exemplified by as occurs in pulmonary fibrosis or severe
severe sepsis and cyanide poisoning. pulmonary oedema.
63
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:11:58, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.017
Section 2: Respiratory Physiology
– Inspired O2 tension is low, as occurs at high pressure in the LV is higher than that in the
altitude (altitude may also cause pulmonary right ventricle. Accordingly, blood flows
oedema – see Chapter 87). through a VSD in a left-to-right direction.
– Exercising, in the presence of mild However, if there were an increase in right
disturbances of either of the above. ventricular pressure (such as in Eisenmenger’s
syndrome or when there is right ventricular
What is meant by the term ‘shunt’? outflow tract obstruction such as in
tetralogy of Fallot), blood flow may change
Shunting is said to occur when blood passes from the to a right-to-left direction, resulting in
right side to the left side of the heart without taking a pathological shunt.
part in gas exchange. Deoxygenated venous blood – Through large communicating vessels,
consequently passes directly into the arterial system exemplified by a direct communication
and mixes with arterial blood, decreasing PaO2. between the pulmonary artery and either the
A shunt can either be physiological or pathological: pulmonary vein (pulmonary arteriovenous
Physiological shunt, subclassified as either malformation, AVM) or the aorta (patent
anatomical or functional: ductus arteriosus, PDA). Shunts may also
– Anatomical shunt. Deoxygenated blood enters be iatrogenically created, such as in the
the left side of the heart for anatomical Blalock–Taussig shunt used to palliate
reasons, such as: tetralogy of Fallot. In common with a VSD,
the direction of blood flow depends on the
▪ Bronchial circulation. Most of the venous pressure in each vessel:
blood from the large airways drains
directly into the pulmonary veins, ▪ A pulmonary AVM has right-to-left
returning to the left side of the heart. blood flow and therefore results in a
▪ Thebesian veins. A small amount of pathological shunt because pulmonary
coronary venous blood drains directly into arterial pressure is greater than pulmonary
the four chambers of the heart via the venous pressure. Pulmonary AVMs
Thebesian veins. The blood that drains into are classified as congenital or acquired.
the left atrium and the left ventricle (LV) The latter is exemplified by the multiple
contributes to the anatomical shunt. pulmonary AVMs that occur in hepatic
cirrhosis, resulting in hepatopulmonary
– Functional shunt. A proportion of the syndrome.
pulmonary blood passes through poorly ▪ A PDA usually has left-to-right blood flow
ventilated alveoli in the lung base. Blood because aortic pressure is normally higher
leaving these alveolar capillaries will therefore than pulmonary arterial pressure.
not be fully oxygenated (i.e. there is a local However, the direction of blood flow may
V̇ /Q̇ mismatch; see Chapter 15). change if pulmonary arterial hypertension
The normal physiological shunt fraction is 2–5%, develops, as can occur with hypoxic
approximately half of which is due to anatomical pulmonary vasoconstriction in a neonate,
shunt and half due to functional shunt. resulting in pathological shunt.
Physiological shunt can be thought of as being – Intra-pulmonary shunts. These constitute by
analogous to physiological dead space: far the commonest cause of pathological
physiological dead space is the sum of anatomical shunts. Shunting occurs when alveoli are
dead space (analogous to anatomical shunt) and perfused but are unable to participate in gas
alveolar dead space (analogous to functional exchange. This may occur when alveoli are
shunt). completely filled with fluid (e.g. as occurs
Pathological shunt, classified on the basis of its in pulmonary oedema or pneumonia) or
location: as a result of a proximal airway occlusion
– Intra-cardiac; for example, as the result of a (e.g. with bronchial obstruction or one-lung
ventricular septal defect (VSD). Normally, the ventilation).
64
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:11:58, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.017
Chapter 14: Hypoxia and Shunts
65
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:11:58, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.017
Section 2: Respiratory Physiology
Alveolus
Pulmonary vein
Pulmonary artery
QT QT
QS
66
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:11:58, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.017
Chapter 14: Hypoxia and Shunts
60
50
Arterial PO2 (kPa)
40
20%
Breathing
30 room air
20 30%
40%
10
50%
0
0 20 40 60 80 100
Inspired fraction of O2 (%)
67
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:11:58, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.017
Section 2 Respiratory Physiology
Ventilation–Perfusion Relationships
Chapter
15
How does gravity affect blood flow to What is the effect of gravity on alveolar
the lungs? ventilation?
Lung perfusion1 increases linearly from the top to the The effect of gravity on alveolar ventilation V̇ A is
bottom of the lungs (Figure 15.1, lung perfusion line). discussed in detail in Chapter 20. In summary:
The difference in perfusion at the top and bottom of The weight of the lung parenchyma results in
the lung can be explained by the effect of gravity on intrapleural pressure being more negative at the
the alveolar volume, which in turn determines the apex than the base. At functional residual capacity
pulmonary capillary pressure. The difference in pul- (FRC), the apical alveoli are nearly fully inflated,
monary capillary pressure between the lung apex whereas the basal alveoli are hardly inflated at all.
and base is equivalent to the hydrostatic pressure At FRC, the basal alveoli have a greater
exerted by a column of blood. The distance from compliance (i.e. a greater increase in volume per
apex to base is 30 cm, so the pressure difference is unit pressure applied) than the apical alveoli, as
30 cmH2O (equivalent to 22 mmHg). The pulmonary they are less distended by the weight of the lung
circulation is a low-pressure system: mean pulmonary parenchyma.
artery pressure (MPAP) is typically just 15 mmHg. During inspiration, intrapleural pressure becomes
A pressure difference of 22 mmHg between the top more negative, which causes the volume of the
and the bottom of the lungs is therefore potentially basal alveoli to increase more than the apical
significant (this is discussed further in Chapter 16). alveoli. V̇ A therefore increases from apex to base
The regional differences in lung perfusion are (Figure 15.1, alveolar ventilation line).
altered by:
Exercise. When cardiac output (CO) increases,
MPAP also increases. The difference in capillary
What is meant by the term ‘ventilation–
hydrostatic pressure between the lung apex and perfusion ratio’?
base therefore becomes less significant; blood is For ideal gas exchange, the ventilation and perfusion
distributed more evenly throughout the lung. to each alveolus should be matched, giving exactly the
Body position. When a patient is supine, the right amount of V̇ A to fully oxygenate all the passing
vertical difference between the apex and base is blood; that is, a ventilation–perfusion ratio V̇ /Q̇ = 1.
abolished. Instead, the anterior lung becomes Too little ventilation would lead to partial oxygen-
vertically higher than the posterior lung. For the ation of blood, whereas too much ventilation is
same reasons as above, perfusion of the posterior unnecessarily wasteful of respiratory effort. However,
lung becomes greater than that of the anterior normal lung perfusion is 5 L/min (i.e. normal CO)
lung. Similarly, in the lateral position, the and V̇ A is 4 L/min.2 The average V̇ /Q̇ ratio is therefore
dependent lung (the lowermost) has a greater 0.8.
perfusion than the non-dependent lung (the Whilst the global V̇ /Q̇ ratio in healthy lungs is 0.8,
uppermost). there is considerable regional variation. Owing to the
1
Pulmonary blood flow is referred to as the ‘perfusion’, 2
Note: V_ E is around 5 L/min, but approximately a fifth is
termed Q̇ . dead-space ventilation (see Chapter 11).
68
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:09:43, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.018
Chapter 15: Ventilation–Perfusion Relationships
0.15
3
Ventilation–perfusion ratio
L/min % of lung volume
0.1
2
0.05 1
0 0
6 5 4 3 2 1
Anterior rib number
Bottom of lungs Top of lungs
direct and indirect effects of gravity respectively, both – Upper airway obstruction;
ventilation and perfusion are increased in the lung – Foreign body aspiration;
bases compared with the apices. However, there is a – Pneumonia;
greater effect on perfusion than on ventilation, as – Pneumothorax;
represented by the steeper gradient of the lung perfu- – Atelectasis;
sion line in Figure 15.1. The V̇ /Q̇ ratio therefore – Acute respiratory distress syndrome;
increases from the bottom to the top of the lungs: – Emphysema;
In the bases, the V̇ /Q̇ ratio is approximately 0.6. As – One-lung ventilation;
perfusion is greater than ventilation, blood may – Normal ageing;
leave the pulmonary capillaries without being fully
– Increased closing capacity associated with
oxygenated, resulting in a right-to-left shunt.
obesity.
A greater amount of O2 is extracted from the alveoli,
resulting in a low alveolar O2 tension (PAO2). Problems with lung perfusion resulting in high
In the apices, V̇ /Q̇ > 3. As ventilation is V̇ /Q̇ ratio.
proportionally greater than perfusion, blood Causes include:
leaving the apical pulmonary capillaries is fully – Pulmonary embolus (PE);
oxygenated. However, as only a small volume of – Reduced right ventricular stroke volume due
blood passes by the apical alveoli, little gas to hypovolaemia, right ventricular infarction
exchange takes place: PAO2 is high and PACO2 is or pericardial tamponade.
low.
How might you manage hypoxaemia
What are the causes of abnormal associated with V̇ /Q̇ mismatch?
V̇ /Q̇ ratio? The commonest cause of hypoxaemia (defined as a
There are many pathological causes of V̇ /Q̇ mismatch. PaO2 < 8 kPa) is V̇ /Q̇ mismatch with a low V̇ /Q̇ ratio.
These are broadly grouped into: The mainstay of treatment is:
Problems with lung ventilation resulting in O2 administration. Hypoxaemia associated with
low V̇ /Q̇ ratio. low V̇ /Q̇ ratio is responsive to O2 therapy. As
This is the most common cause of hypoxaemia. discussed earlier, poorly ventilated alveoli with
Causes include: normal perfusion have low PAO2. By
69
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:09:43, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.018
Section 2: Respiratory Physiology
70
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:09:43, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.018
Section 2 Respiratory Physiology
16
What are the West zones of the lung? As the alveoli occupy a small volume, they exert
minimal extramural pressure on the pulmonary
In the upright position, ventilation and perfusion vasculature. Capillary blood flows continuously
both increase from the top to the bottom of the lung. throughout the cardiac cycle – flow is dependent
This was previously attributed to the effect of gravity on the arterial–venous pressure difference, which
(the so-called gravitational model), but it is now is generated by the right ventricle. West zone 3 is
thought that structural similarities between the pul- how normal, healthy lungs behave below the level
monary arteries and bronchioles contribute (see of the hilum.
Chapter 15).
In West zone 2, Pa > PA > Pv. As the lung is
J. B. West built on a gravitational model of venti-
ascended, there is an increasing effect of the
lation and perfusion. This assumes that capillary
weight of the lung. Alveoli are pulled open and
blood flow to the alveolus is dependent on the
become less compliant. PA therefore increases and
pressure of the gas within the alveolus. This is par-
the lung exerts increased extramural pressure on
ticularly important in anaesthesia, as positive-
the pulmonary vasculature: alveolar pressure thus
pressure ventilation significantly alters alveolar
exceeds venous pressure, causing compression of
pressure. West divided the upright lung into three
the venous end of the pulmonary capillary.
vertical zones, numbered 1 (at the apex) to 3 (at the
Capillary blood flow is therefore dependent on the
base). The arterial, venous and alveolar pressures
arterial–alveolar pressure difference. Systolic
differ in each zone, which has implications for the
pulmonary arterial pressure is greater than
V̇ /Q̇ ratio.
alveolar pressure, but diastolic pulmonary arterial
pressure is not – blood therefore only flows
How do the changes in arterial, venous through the pulmonary capillary during systole.
and alveolar pressures affect alveolar The intermittent nature of blood flow causes a
perfusion? mismatch between alveolar ventilation and
perfusion. Thus, the V̇ /Q̇ ratio is higher in West
The variation in alveolar perfusion in the three West zone 3, with an increased alveolar dead space and,
zones (Figure 16.1) is most easily explained by consequently, wasted ventilation. West zone 2 is
starting from West zone 3, at the base of the lung: how normal lungs behave between the apex and
In West zone 3, Pa > Pv > PA (a: arterial; v: the hilum.
venous; A: alveolar). Both arterial and venous In West zone 1, PA > Pa > Pv. Alveolar pressure
pressures are greater than alveolar pressure. exceeds systolic pulmonary arterial pressure as the
This is because of the effects of gravity on alveoli are maximally distended by the weight of
alveolar volume. The lungs are suspended the whole lung. The pulmonary capillary is
superiorly in the chest from the large airways and completely compressed by the alveolus, with
therefore there is little weight acting upon the base alveolar perfusion ceasing. The apical alveoli are
of the lung. For this reason, the basal alveoli are still ventilated – V̇ /Q̇ ratio is therefore high, with a
not particularly distended and thus sit upon a high alveolar dead space. West zone 1 does not
more compliant part of the pressure–volume loop. exist in normal lungs.
71
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:07:37, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.019
Section 2: Respiratory Physiology
Vertical height
West zone 1 does not
normally occur
Pa Pv
West zone 1:
PA
PA > Pa > Pv
PA
West zone 2:
Pa > PA > Pv
QT Pa Pv QT
West zone 3:
PA Pa > Pv > PA
Blood flow
When does West zone 1 become case of acute severe asthma, the increased ventilatory
effort required may precipitate respiratory failure.
clinically significant?
In a healthy, non-anaesthetised person, alveolar pres-
Clinical relevance: pulmonary artery
sure is approximately equal to atmospheric pressure, catheters (PACs)
with small pressure variations due to inspiration and
One of the key measurements obtained from the
expiration (0 ± 2 cmH2O). The situation of West zone
PAC is the pulmonary capillary wedge pressure
1, where alveolar pressure exceeds systolic pulmonary
(PCWP). When inflated, the balloon-tipped end of
arterial pressure, therefore does not normally occur. the PAC is ‘floated’ through the right ventricle and
However, West zone 1 can occur when: into the pulmonary arterial tree until it wedges in a
Pulmonary arterial pressure is abnormally low, branch of the pulmonary artery.
such as in haemorrhagic shock. Normal alveolar For accurate measurement of PCWP, the PAC
pressure may therefore exceed pulmonary arterial must wedge in a pulmonary artery within West zone
pressure. 3. It is essential that the PAC is in communication
with an uninterrupted static column of blood
Alveolar pressure is abnormally high, such as
between the pulmonary artery and the left atrium.
during positive-pressure ventilation or high
As discussed above, this can only occur in West zone
intrinsic positive end-expiratory pressure 3 where capillary blood flow is continuous.
associated with acute severe asthma. Because the majority of pulmonary blood flow is
When West zone 1 does occur, the increase in alveolar to West zone 3, the tip of the flow-directed PAC is
dead space means that ventilation is wasted. In the likely to position itself correctly. A clinical method of
72
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:07:37, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.019
Chapter 16: Ventilation–Perfusion Zones in the Lung
73
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:07:37, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.019
Section 2 Respiratory Physiology
17
What is meant by the term ‘global as reflected in the difference in arterial and venous O2
contents. CO and CvO2 can be measured with the aid
oxygen consumption’? of a pulmonary artery catheter (as CvO2 should really
Global O2 consumption V̇ O2 (mL/min) is the volume be measured using mixed venous blood) and CaO2
of O2 that is consumed by the body per minute. can be measured by peripheral arterial blood gas
During aerobic metabolism, V̇ O2 is closely matched analysis.
to the body’s metabolic rate. Resting V̇ O2 for a 70‑kg
man is typically 250 mL/min (at sea level and standard
temperature). During exercise, V̇ O2 increases as the What is meant by the term ‘global
body consumes additional O2 to power muscle contrac- oxygen delivery’?
tion. As exercise intensity increases, V̇ O2 increases.
Global O2 delivery ḊO2 (mL/min) is the volume of
There comes a point where V̇ O2 is limited by the rate
O2 delivered to the tissues from the lungs per minute.
of O2 delivery to the tissues, which is likely due to
ḊO2 can be calculated using the O2 flux equation:
diffusion limitation being reached in the muscle
microcirculation. When this happens, the muscles Key equation: oxygen flux equation
switch from aerobic metabolism, where O2 is con-
sumed, to anaerobic metabolism, where energy is _ 2 ¼ CO C a O2 10
DO
obtained from glycolysis. The O2 consumption at this
transition point is termed V̇ O2max and is closely related where 10 is a unit conversion factor.
to maximal exercise performance (see Chapter 43).
Training increases the V̇ O2max and therefore What is a typical resting global oxygen
performance.
Global V̇ O2 can be calculated using the reverse delivery?
Fick principle: Using the O2 flux equation with typical values for a
resting patient breathing room air (CO = 5 L/min,
Key equation: reverse Fick principle [Hb] = 15 g/dL, SaO2 = 98%, PaO2 = 13 kPa), first the
CaO2 is calculated:
V_ O2 ¼ CO ðC a O2 C v O2 Þ 10
Ca O2 ¼ ð1:34 ½Hb Sa O2 =100%Þ þ 0:023 Pa O2
where CO (L/min) is the cardiac output, CaO2 is the
O2 content of arterial blood (mLO2/100 mL of blood), Therefore:
CvO2 is the O2 content of venous blood (mLO2/100
mL of blood), 10 is a unit conversion factor and Ca O2 ¼ ð1:34 15 98=100Þ þ 0:023 13
¼ 20:0 mLO2 =100 mL blood
C a O2 ¼ ð1:34 ½Hb Sa O2 =100%Þ þ 0:023 Pa O2
Then ḊO2 is calculated:
(see Chapter 8), where [Hb] (g/dL) is the Hb
concentration. _ 2 ¼ CO Ca O2 10
DO
Therefore:
The equation above essentially states that the V̇ O2
is the same as the O2 ‘taken out of the arterial blood’, _ 2 ¼ 5 20:0 10 ¼ 1000 mLO2 =min
DO
74
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:06:13, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.020
Chapter 17: Oxygen Delivery and Demand
How are ḊO2 and V̇ O2 related? Additional factors may significantly increase V̇ O2:
Inflammation, sepsis and pyrexia;
At rest in a normal patient, ḊO2 (typical value 1000 Administration of adrenergic drugs;
mL/min) is much higher than V̇ O2 (typical value 250 Weaning from the ventilator;
mL/min). Thus, the tissues are said to have an O2 Interventions such as physiotherapy;
extraction ratio (OER) of 25%. Conditions such as burns, trauma and seizures.
There is an altered relationship between V̇ O2 and
Key equation: OER ḊO2 in patients with severe sepsis or acute respira-
tory distress syndrome. V̇ O2 becomes supply
V_ O2 dependent at a much higher ḊO2 (Figure 17.1b) –
OER ¼
_ 2
DO the normal biphasic relationship between V̇ O2 and
Normal OER is 0.2–0.3; that is, only 20–30% of ḊO2 is no longer observed. It is not clear whether this
effect is the result of critical ḊO2 being much higher
delivered O2 is consumed by the tissues, the rest
than normal in critical illness or whether the tissues
being returned to the lungs in the venous blood.
are less able to extract O2 from the blood.
An OER of 0.2–0.3 corresponds to a mixed venous Early goal-directed therapy has traditionally
Hb O2 saturation of 70–80%. involved the invasive monitoring and aggressive
haemodynamic management of patients at risk of
As ḊO2 falls (e.g. as a result of hypotension) or organ failure. However, patient outcomes of the
V̇ O2 rises (e.g. as a result of exercise or sepsis), the more recent randomised trials have had contradict-
tissues must extract more O2 from the passing ory outcomes (see Further reading).
blood if they are to continue to undergo aerobic
metabolism. There is also a considerable difference
in the normal OER between different organs. For Clinical relevance: anaesthesia, oxygen
example: consumption and oxygen delivery
The carotid bodies have high ḊO2 but low V̇ O2, In the perioperative period, V̇ O2 is frequently higher
resulting in a low OER, reflecting their role in than the ‘resting’ value of 250 mLO2/min. A number
sensing changes in blood composition. of factors are implicated:
The heart has a high OER (approximately 0.6), Surgery;
which makes it very susceptible to ischaemia Pain and anxiety;
following a reduction in coronary artery perfusion Inflammation, sepsis and pyrexia;
pressure. Post-operative shivering;
75
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:06:13, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.020
Section 2: Respiratory Physiology
(a) Normal O2 supply and demand (b) Critical illness O2 supply and demand
400
400
Oxygen consumption, VO2 (mL/min)
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 17.1 O2 supply and demand: (a) normal situation and (b) critical illness.
76
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:06:13, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.020
Section 2 Respiratory Physiology
18
Can you measure the partial pressure Barometric pressure. PB decreases exponentially
with ascent to altitude (see Chapter 87).
of oxygen in the alveolus? According to the AGE, as the elevation above sea
The partial pressure gradient of O2 between the alveo- level increases, the fall in PB results in a lower
lus and the pulmonary capillaries is one of the key PAO2 and thus a reduced rate of O2 diffusion
factors that determine the rate of O2 diffusion across across the alveolar–capillary barrier.
the alveolar–capillary barrier (see Chapter 10). Unfor- Alveolar ventilation. As PaCO2 is inversely
tunately, it is not possible to directly measure the proportional to V̇ A (see Chapter 11):
PAO2. Instead, PAO2 can be estimated using the alveo- – An increase in V̇ A (hyperventilation) results in
lar gas equation (AGE). a decrease in PaCO2. According to the AGE,
PAO2 will increase, thus increasing the rate of
What is the AGE? O2 diffusion across the alveolar–capillary
The AGE1 allows PAO2 to be estimated from variables barrier.
that are easily measured. – A decrease in V̇ A (hypoventilation) results in
an increase in PaCO2. According to the AGE,
Key equation: simplified AGE PAO2 will decrease, thus reducing the rate of O2
diffusion across the alveolar–capillary barrier.
Pa CO2
PA O2 ¼ F i O2 ðPB PSVP water Þ
R What is the respiratory quotient?
where FiO2 for dry air is 20.93%; PB at sea level is
101.325 kPa. Inspired air becomes fully saturated
Why does it differ for different
with water vapour by the time it reaches the carina. dietary substrates?
PSVP water is the saturated vapour pressure of water, The respiratory quotient R is the ratio of CO2 pro-
which at body temperature is 6.3 kPa. PaCO2 is duction and O2 consumption:
measured in kilopascals. R is the respiratory quotient,
rate of CO2 produced
usually taken as 0.8. R¼
rate of O2 consumed
The AGE tells us that PAO2 is essentially depend- R differs between the three dietary metabolic sub-
ent on three variables: strates: fat, protein and carbohydrate. R can be calcu-
The inspired fraction of O2. According to the lated for each substrate using the chemical formula of
AGE, increasing FiO2 will result in a greater PAO2, the overall aerobic metabolism reaction. For example,
thus increasing the pressure gradient across the consider glucose:
alveolar–capillary barrier; the rate of O2 diffusion C6 H12 O6 þ 6O2 ! 6CO2 þ 6H2 O
will increase (Fick’s law – see Chapter 10).
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
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:04:06, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.021
Section 2: Respiratory Physiology
78
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:04:06, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.021
Chapter 18: Alveolar Gas Equation
13.3
10
0
0 5 10 15
Minute ventilation (L/min)
Hyperventilation therefore increases PAO2 sufficiently in PaCO2. Therefore, as V̇ A increases, PAO2 reaches a
to allow human existence at altitude, albeit with a plateau. As demonstrated in Figure 18.1, O2 adminis-
chronic respiratory alkalosis. tration will increase PAO2 (and therefore PaO2) sub-
However, there is a limit to the extent to which stantially more than hyperventilation.
hyperventilation can increase PAO2 (Figure 18.1), The
hyperbolic relationship between V̇ A and PaCO2 (see Further reading
Chapter 11 and Figure 11.1) means that, beyond a S. Cruickshank, N. Hirschauer. The alveolar gas equation.
modest increase in V̇ A (around 10 L/min), a large Continuing Educ Anaesth Crit Care Pain 2004; 4(1):
increase in V̇ A is required to achieve a small decrease 24–7.
79
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:04:06, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.021
Section 2 Respiratory Physiology
Oxygen Cascade
Chapter
19
The O2 cascade concept draws together areas of Atmosphere. PB at sea level is 101.325 kPa and
respiratory physiology covered in the previous few FiO2 of dry air is 20.93%. Atmospheric PO2 is
chapters. In an examination setting, it allows the calculated as follows:
examiner to assess your knowledge of more than
PO2 ¼ PB F i O2
one topic within a single question.
⇒PO2 ¼ 101:325 20:93% ¼ 21:2 kPa
What is the oxygen cascade? Trachea. By the time inspired air reaches the
Aerobic metabolism is the body’s most efficient carina, it has become fully saturated with water
method of energy production. O2 tension (PO2) is vapour. Water has a saturated vapour pressure
high in the atmosphere (21.2 kPa) and low in the PSVP water of 6.3 kPa at 37°C. The PO2 of
mitochondria (<5 kPa). The O2 cascade refers to the humidified air at the carina is calculated as
stepwise reduction in PO2 as O2 passes from the follows:
environment to the tissues (Figure 19.1). PO2 ¼ ðP B PSVP water Þ F i O2
⇒PO2 ¼ ð101:325 6:3Þ 20:93% ¼ 19:9 kPa
Explain each of the steps in the oxygen Alveolus. PAO2 is mainly dependent on FiO2, PB
and V̇ A, as described by the AGE (see Chapter 18):
cascade P a CO2
The steps along the O2 cascade are: PA O2 ¼ F i O2 ðP B −PSVP water Þ−
R
21.2 Humidification
20
19.9 Alveolar gas equation
15 Diffusion
PO2 (kPa)
13.0
Pulmonary capillary
10
6.3
Mitochondria
Atmosphere
5
Alveolus
Trachea
Artery
Vein
1.0
0
Location
80
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:01:18, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.022
Chapter 19: Oxygen Cascade
PAO2 can be calculated using the typical values: Mitochondria. The mitochondrial PO2 is very
PaCO2 = 5.3 kPa and R = 0.8: much lower than that of arterial blood and is
related to the metabolic activity of the tissues. For
5:3
P A O2 ¼ 20:93%ð101:325−6:3Þ− example, in exercising skeletal muscle, O2
0:8 utilisation is high and so the mitochondrial PO2 is
⇒PA O2 ¼ 13:3 kPa
very low. Therefore, there is a large O2 partial
Arterial blood. There is a ‘step’ reduction in PO2 pressure gradient between the capillary blood and
between the alveolus and the systemic arteries. the mitochondria, increasing the rate of O2
This A–a gradient is the result of three factors: diffusion. In addition, metabolites (e.g. H+ and
– Diffusion across the alveolar–capillary barrier. CO2) cause arteriolar vasodilatation, increasing
Normally, there is sufficient time for O2 to local blood flow and hence O2 delivery.
diffuse across the alveolar–capillary barrier;
that is, for PAO2 and pulmonary capillary PO2
to equilibrate at 13.3 kPa. Transfer of O2 is Clinical relevance: the Pasteur point and anaerobic
then said to be perfusion limited (see metabolism
Chapter 10). However, in lungs with a If the mitochondrial PO2 falls below a critical point
thickened alveolar–capillary barrier or a (between 0.15 and 0.3 kPa), there is insufficient O2
decreased alveolar surface area, O2 may tension for aerobic metabolism. Anaerobic metabol-
become diffusion limited; pulmonary capillary ism then takes over as the dominant mechanism of
PO2 then becomes a step lower than PAO2. ATP production. This critical threshold is called the
– Shunts. There is normally a small anatomical Pasteur point.
right-to-left shunt arising from the bronchial For mitochondrial PO2 to be adequate, capillary
circulation and the Thebesian veins (see blood PO2 must be high enough for O2 to diffuse
readily from the blood to the tissues. Well-
Chapter 14).
oxygenated capillary blood is dependent on all the
– V̇ /Q̇ mismatch. Any area of lung with preceding steps of the O2 cascade. Anaerobic metab-
relatively more perfusion than ventilation olism can occur if any of the ‘steps’ of the cascade are
results in a functional right-to-left shunt, disturbed. For example:
causing a further reduction in PaO2 (see High altitude reduces atmospheric PO2, the
Chapter 15). The normal physiological shunt starting point of the cascade. All subsequent
fraction (the sum of anatomical and functional steps will then have a lower PO2 than at sea level.
shunts) is 2–5%, which corresponds to a fall in Hypoventilation increases PaCO2, which in turn
PaO2 to 13.0 kPa. reduces PAO2 (see Chapter 18).
Pneumonia causes a V̇ /Q̇ mismatch, resulting in a
Tissue capillaries. As O2 is taken up by the tissues,
lower PaO2.
the PO2 falls progressively from the arterial end to
the venous end of the capillary. However, not all
the arteriolar blood flows through the capillaries: Further reading
pre-capillary sphincters control how much blood C. C. W. Hsia, A. Schmidt, M. Lambertz, et al. Evolution of
flows into each capillary network. The remaining air breathing: oxygen homeostasis and the transitions
blood bypasses the capillaries and flows directly from water to land and sky. Compr Physiol 2013; 3(2):
into the venules via arteriovenous anastomoses, 849–915.
which in humans are likely to be dilated skeletal
muscle capillary beds.
81
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:01:18, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.022
Section 2 Respiratory Physiology
Lung Compliance
Chapter
20
What is lung compliance? What is respiratory compliance?
Compliance is defined as the change in lung volume How does it differ from lung
produced by a unit change in transpulmonary pres-
sure. Lung compliance is represented by the gradient compliance?
of the pressure–volume curve: Respiratory compliance refers to the compliance
of the whole lung–chest unit. It is made up of two
ΔVolume
Compliance ¼ components:
ΔTranspulmonary pressure
Lung compliance;
Essentially, compliance is the property that deter- Thoracic cage compliance.
mines the volume by which the lungs expand when
pressure is applied to them: either negative pressure
(as in spontaneous ventilation) or positive pressure Key equation: respiratory compliance
(as in intermittent positive-pressure ventilation). For Respiratory, lung and thoracic cage compliances are
a spontaneously breathing patient: mathematically related:
When compliance is high, the respiratory muscles 1 1 1
only need to generate a small transpulmonary ¼ þ
RC LC TCC
pressure to achieve inspiration to VT. However, as
less work is done in expansion, so too is less work where RC is respiratory compliance, LC is lung com-
pliance and TCC is thoracic cage compliance. Typ-
stored as elastic potential energy. Therefore,
ical values for both lung and thoracic cage
exhalation becomes more difficult as there is less compliance are 200 mL/cmH2O. Therefore, a typical
elastic recoil of the lungs. value for respiratory compliance is 100 mL/cmH2O.
When compliance is low, a high transpulmonary Thus as compliances in series add as inverses, the
pressure is required to expand the lung to the overall compliance is always less than the sum of
same VT: the respiratory muscles must then work its parts.
harder during inspiration and respiratory failure
may ensue.
Normal tidal breathing starts from the functional Which factors affect lung and thoracic
residual capacity (FRC), the rest point where inward
elastic recoil is equal and opposite to the force tend-
cage compliance?
ing to spring the thoracic cage outwards. Conveni- Thoracic cage compliance is affected by:
ently, the lungs are at their most compliant at FRC, Chest wall shape, including the spine and
which means that the work of breathing at rest is rib cage;
minimal: Muscle tone.
For a typical patient at FRC, compliance is Lung compliance is broadly affected by two factors:
200 mL/cmH2O. Elastic recoil of the lung connective tissue;
Therefore, at FRC, a VT of 500 mL is achieved with Surface tension at the air–fluid interface in the
a transpulmonary pressure of just 2.5 cmH2O. alveoli.
82
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 19:29:25, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.023
Chapter 20: Lung Compliance
Outline some clinical situations in which – Obesity: thoracic cage compliance is reduced
due to the increased weight of the chest wall
respiratory compliance is increased or opposing thoracic expansion.
decreased. – Chest wall deformity/rigidity: hinders
Respiratory compliance may be affected by both the expansion of the thoracic cage, such
physiological and pathological factors. as in kyphoscoliosis and ankylosing
spondylitis.
Causes of increased respiratory compliance
include:
– Emphysema, in which there is destruction of
How does surfactant increase lung
lung elastic tissue. compliance?
– Advancing age, in which there is degeneration Surface tension is caused by forces of attraction
of lung elastic tissue, similar to mild between water molecules. These forces act to minim-
emphysema. ise the air–liquid interface by causing the water to
– Neuromuscular conditions: decreased muscular form a spherical droplet. As the inner surface of the
tone results in an easier expansion of the alveolus has a thin layer of fluid, an inward force –
thoracic cage, as occurs in motor neurone the surface tension – is created as the water tends to
disease. form a droplet. Opposing this inward force of surface
tension is the alveolar transpulmonary pressure.
Causes of decreased respiratory compliance As alveoli are approximately spherical, they obey
include: Laplace’s law.
– Posture: the lung is generally less compliant
when supine.
– Pregnancy: lung compliance is relatively Key equation: Laplace’s law
unaffected, but thoracic cage compliance is For a sphere with only one surface,
reduced in late pregnancy. 2T
– Fluid within the alveoli or lung interstitium, P¼
r
exemplified by pneumonia and pulmonary
where, in this case, P is the transpulmonary pressure
oedema. Owing to the effects of surface required to keep the alveolus open, T is the surface
tension, fluid-filled alveoli require a much tension and r is the radius of the alveolus.
higher transmural pressure to expand than
aerated alveoli do. Consequently, compliance
is significantly reduced. Surface tension poses a number of problems:
– Atelectasis: collapsed alveoli (i.e. alveoli with An alveolus has reduced compliance when its
small radii) require a much higher transmural radius is low. In expiration, the alveolus becomes
pressure than larger alveoli do to overcome smaller; that is, its radius decreases. According to
surface tension forces (see Laplace’s law Laplace’s law, if surface tension is constant, a
below). larger transmural pressure will be required to
– Pulmonary hypertension, in which the reinflate the alveolus.
pulmonary capillaries are engorged with Smaller alveoli empty into bigger alveoli. When
blood. This hinders alveolar enlargement, thus two connected alveoli are of different sizes, the
decreasing lung compliance. alveolus with the smaller radius will require a
– Pulmonary fibrosis: the lung interstitium higher transpulmonary pressure to remain
becomes stiff and less easily distensible. inflated than the larger alveolus. As airway
– Extremes of lung volume: at high lung volume, pressure is uniform throughout the lung, the
compliance is reduced because the elastic smaller alveolus would collapse, emptying its air
fibres are stretched to their limit. At low lung into the bigger alveolus.
volume, lung compliance is reduced as a result Transudation of interstitial fluid. The inward
of atelectasis. force of surface tension tends to suck fluid from
83
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 19:29:25, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.023
Section 2: Respiratory Physiology
84
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 19:29:25, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.023
Chapter 20: Lung Compliance
TLC
Expiration
Gradient = compliance
VT
Lung volume (L)
Expiration
Inspiration
Inspiration
FRC
Residual
volume –4 –5 –6 –7 –8
Intrapleural pressure (cmH2O)
+5 0 –5 –10 –15 –20
Intrapleural pressure (cmH2O)
Figure 20.1 Static compliance curve (TLC = total lung capacity; VT = tidal volume; FRC = functional residual capacity).
compliant at FRC during normal tidal breathing, When lung volume is plotted against intrapleural
resulting in low work during tidal inspiration. pressure for both inspiration and expiration, the two
At high intrapleural pressure, the pressure–volume curves follow different courses: a pressure–volume
curve flattens out again. Alveoli are already well loop is formed. This loop effect is hysteresis – it is
inflated and near to their elastic limit – a large the result of viscous resistance to changes in lung
decrease in intrapleural pressure is required for volume. The area of the loop represents the amount
a small increase in lung volume; that is, of energy expended as heat in overcoming the resistive
compliance is low. forces. The phenomenon of hysteresis occurs when
Dynamic compliance is calculated when continuous both static and dynamic compliance are measured.
pressure and volume measurements are taken Dynamic hysteresis is illustrated in Figure 20.2a.
throughout the respiratory cycle; that is, there is no The airway resistance increases when the velocity of
pause between measurements. There are two points in gas flow is increased. The flow of air through the
the respiratory cycle where gas flow ceases: end- conducting airways is most rapid, and therefore most
inspiration and end-expiration. If these two points turbulent, at the beginning of inspiration and expir-
are plotted on a pressure–volume graph with a ation. Consequently, airway resistance is at its greatest
straight line joining them, the gradient (i.e. the and compliance at its lowest (and accordingly the
dynamic compliance) is less than that of the static pressure–volume curve is at its flattest) at the beginning
pressure–volume curve. The dynamic compliance is of inspiration and expiration. Similarly, if the respira-
always lower than the static compliance. This reduc- tory rate increases but the VT remains the same, inspir-
tion is due to airway resistance. In fact, the difference ation must occur within a shorter time period. As
between static and dynamic compliance can be used the velocity of gas flow increases, airway resistance
as an indirect measure of the flow-resistive properties increases and dynamic compliance falls. Conditions
of the airways. that increase airway resistance (e.g. acute asthma) fur-
ther decrease the dynamic compliance (Figure 20.2b).
What is hysteresis? Static hysteresis is illustrated in Figure 20.1.
Unlike dynamic compliance, static compliance con-
Hysteresis is the phenomenon whereby a measure- tains no airway resistance element because gas flow
ment differs depending on whether the value meas- ceases during the pauses between measurements. Des-
ured is rising or falling. pite this, the inspiratory and expiratory curves still
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 19:29:25, subject to the Cambridge Core terms of use, available at85
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.023
Section 2: Respiratory Physiology
(a) 10 breaths per minute (b) Acute asthma, 30 breaths per minute
volume loop
High compliance
(steep gradient)
Figure 20.2 Dynamic hysteresis: (a) respiratory rate of 10 breaths per minute and (b) acute asthma with a respiratory rate of 30 breaths
per minute.
Change in lung
volume at the
apex
Apex
Change in lung
volume at the
base
Base
display hysteresis; that is, they follow different paths. parenchyma, resulting in intrapleural pressure being
Static hysteresis is attributed to the viscous resistance more negative at the apex (typically –10 cmH2O) and
of the pulmonary surfactant and of the lung paren- less negative at the base (typically –3 cmH2O). Con-
chyma itself. sider the effect of this regional variation in intra-
pleural pressures on static lung compliance
How does the static compliance curve (Figure 20.3):
help to explain regional differences At the end of tidal expiration (i.e. FRC),
intrapleural pressure is –10 cmH2O at the apex
in lung ventilation? and –3 cmH2O at the base. Therefore, at FRC, the
The lung parenchyma is not uniformly distributed apical alveoli are at near-maximum inflation,
from top to bottom. Gravity acts on the lung whereas the basal alveoli are barely inflated at all.
86
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 19:29:25, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.023
Chapter 20: Lung Compliance
87
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 19:29:25, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.023
Section 2 Respiratory Physiology
Work of Breathing
Chapter
21
What is meant by the term ‘work of – Obesity, which opposes outward chest wall
elastic recoil;
breathing’? – Pulmonary fibrosis, which reduces the
The work of breathing is the energy consumed by compliance of the lung parenchyma;
the respiratory muscles throughout the respiratory – Infant respiratory distress syndrome, in
cycle. which there is insufficient pulmonary
Mathematically, for a single breath: surfactant, leading to increased alveolar
Work ðJÞ ¼ PressureðPaÞ VolumeðLÞ surface tension.
Resistive work is the work done against friction –
However, the work of breathing usually refers to the
the energy used is ‘wasted’, as it is dissipated as
rate of work rather than the work for a single respira-
heat (and sound). The resistive work of breathing
tory cycle. It should really be called the power of
is the work done to overcome:
breathing and measured in watts (J/s).
Quiet tidal breathing is usually very efficient, – Tissue resistance. As the tissues move against
requiring relatively little work. The energy required each other during lung inflation and deflation,
for tidal breathing is usually less than 2% of basal frictional forces cause an increase in tissue
metabolic rate (BMR). Lung pathology can increase resistance. Tissue resistance usually accounts
the work of breathing substantially, in some cases up for around 10% of the total resistive work.
to 30% of BMR, with the potential for respiratory Tissue resistive work is increased by any
muscle fatigue and respiratory failure. condition that increases the amount of
interstitial lung tissue, such as pulmonary
What are the two main components fibrosis.
– Airway resistance. Gas molecules are subject
that comprise the work of breathing? to frictional forces when they interact
The work of breathing is composed of elastic work with each other and with the walls of the
and resistive work. In normal lungs, elastic work is airways.
responsible for most (approximately 65%) of the
overall work of breathing: What factors affect airway resistance?
Elastic work is the work done on inspiration to The resistance to gas flow is affected by two main
overcome the elastic forces of the: factors: turbulence and the airway radius.
– Chest wall (outward); Turbulent gas flow results in a much higher
– Lung parenchyma (inward); airway resistance than laminar gas flow does.
– Alveolar surface tension (inward). During normal tidal breathing, gas flow is usually
The work done against elastic forces is not all only turbulent in the trachea, but may become
wasted. Some is stored as potential energy rather turbulent in the larger bronchi during peak
than being dissipated as heat. The stored potential inspiratory flow. If the velocity of gas flow
energy is then used in expiration (see below). increases (e.g. with increasing respiratory rate,
Elastic work is increased by diseases that affect the RR), gas flow becomes turbulent in the larger
three factors above; for example: bronchi for a greater portion of the respiratory
88
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 19:31:10, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.024
Chapter 21: Work of Breathing
cycle, increasing airway resistance. The point at Factors that result in turbulent flow.
which gas flow changes from laminar to turbulent – High RR: gas velocity increases, resulting in
is estimated using the Reynolds number. turbulent flow in the large bronchi.
Key equation: Reynolds number – Increased airway diameter: turbulent flow is
more common in the larger upper airways
vρd such as the trachea. This is why bronchial
Reynolds number ¼
η breathing can be heard physiologically over
these airways. Bronchodilatation by the
where ν is velocity of gas flow, ρ is the density of gas,
sympathetic nervous system facilitates greater
d is the airway diameter and η is the viscosity of gas.
alveolar ventilation rates, but increases the
A Reynolds number of 2000 predicts an 80%
amount of turbulent flow.
chance of turbulent flow. A Reynolds number of
200 predicts an 80% chance of laminar flow. – Upper airway obstruction, as exemplified by
laryngeal oedema or the presence of a foreign
Airway radius. According to the Hagan– body. The increased velocity of gas flow
Poiseuille equation, resistance to gas flow is around the obstruction results in turbulent
proportional to r4 (r is the radius). Therefore, flow. Heliox, a mixture of helium (He) and O2,
small reductions in airway radius can have a large is sometimes used in the management of
impact on the resistance to flow. upper airway obstruction: the lower density of
heliox reduces Reynolds number, thereby
Key equation: Hagen–Poiseuille equation for a tube reducing turbulent flow.
– Deep-sea diving. The barometric pressure of
_
8Qηl air, and therefore its density, increases with
ΔP ¼ 4
πr increasing underwater depth. Because of the
where ΔP is the pressure drop along the tube, Q̇ is increased air density, Reynolds number
flow, η is the viscosity of the fluid, l is tube length and predicts turbulent flow at lower gas velocity.
r is the radius. As a result, gas flow becomes turbulent in the
Darcy’s law1 states: bronchi even during normal tidal breathing,
ΔP ¼ QR_ increasing the airway resistance. Again, a
Therefore, if ΔP is pressure difference and Q̇ is flow, mixture of He and O2 is used by divers; the
then the resistance to flow R = 8ηl/πr4. lower density promotes laminar gas flow,
thereby reducing the work of breathing.
On the basis of the Hagan–Poiseuille equation in Factors that reduce airway radius.
isolation, one would expect airway resistance to be
– Bronchoconstriction, as occurs physiologically
highest in the terminal bronchioles, as these airways
during parasympathetic nervous system
have the smallest radius. However, many terminal
activation or pathologically in asthma and
bronchioles are arranged in parallel, with a total
chronic obstructive pulmonary disease
cross-sectional area much larger than that of the more
(COPD). The radius of the small airways is
proximal airways. Overall, the main site of airway
reduced, which increases airway resistance.
resistance is between the lobar bronchi and the sub-
segmental bronchi. – Low lung volume. Airway radius increases
Based on the discussion above, airway resistance is during inspiration as a result of radial traction
increased by: of the lung parenchyma. Likewise, airway
radius decreases during expiration, which
results in increased airway resistance. This
partially explains why patients with asthma
and COPD have more difficulty with
expiration than inspiration.
1
Darcy’s law of flow is analogous to Ohm’s law of – Dynamic airway compression. During forced
electricity: potential difference = current resistance. expiration, the respiratory muscles generate a
89
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 19:31:10, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.024
Section 2: Respiratory Physiology
VT VT
Inspiration if lungs
were ‘perfect’
X X
Inspiration Expiration
(normal lungs) (normal lungs)
Y Z
Expiration if lungs
were ‘perfect’
FRC FRC
–4 –5 –6 –7 –8 –4 –5 –6 –7 –8
Intrapleural pressure (cmH2O) Intrapleural pressure (cmH2O)
Figure 21.1 Pressure–volume curves: (a) normal tidal inspiration and (b) normal tidal expiration.
positive intrapleural pressure, which causes – The remaining area Y is the resistive work
compression of airways that lack cartilaginous done, which is dissipated as heat.
support, particularly the bronchioles, further During tidal expiration (Figure 21.1b).
reducing their airway radius and thus
increasing airway resistance. In COPD, there – The black dotted diagonal line again represents
is destruction of supportive elastic tissue with expiration in the absence of resistive forces.
the lung parenchyma, which reduces radial – The triangular area X is the potential energy
traction on the airways, making these patients stored from inspiration that can now be used
particularly susceptible to dynamic airway during expiration.
compression. – The area Z is the resistive work done during
expiration.
– So long as area Z is within area X, the stored
How can work of breathing be described potential energy is sufficient to overcome the
graphically? resistive forces of expiration, resulting in
As mentioned above, work = pressure volume. passive expiration.
Therefore, the work of breathing can be repre- – At the end of expiration, any potential energy
sented as an area on the pressure–volume graph not used for expiration is wasted, as it is
(Figure 21.1). dissipated as heat.
Pressure–volume loops exhibit hysteresis: the
inspiratory and expiratory curves follow different How does this graph change for
paths (see Chapter 20). The area (i.e. pressure
volume) between the two curves represents the energy patients with restrictive or obstructive
expended in overcoming the resistive forces; that is, lung disease?
the overall work done that is dissipated as heat: In restrictive lung disease, lung compliance is
During tidal inspiration (Figure 21.1a). reduced. A higher (more negative) intrapleural pres-
– The black dotted diagonal line represents sure is required to achieve a VT of 500 mL. The work
inspiration for idealised lungs in which of inspiration is greater, as there is an increase in
resistive forces are absent. In reality, this is not elastic work. Airway resistance is unchanged, so the
the case: the deviation of the black solid line resistive work is similar to normal lungs. Expiration
from the black dotted line shows how much remains passive, as the resistive work still lies within
resistance there is to lung inflation. the area of potential energy (Figure 21.2a).
– The triangular area X is the elastic work done, In obstructive lung disease, the problem is an
which is stored as potential energy. increase in airway resistance. Both inspiratory and
90
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 19:31:10, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.024
Chapter 21: Work of Breathing
FRC FRC
–4 –5 –6 –7 –8 –9 –10 –4 –5 –6 –7 –8
Intrapleural pressure (cmH2O) Intrapleural pressure (cmH2O)
Figure 21.2 Pressure–volume loops: (a) restrictive lung disease and (b) obstructive lung disease.
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 19:31:10, subject to the Cambridge Core terms of use, available at 91
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.024
Section 2: Respiratory Physiology
92
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 19:31:10, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.024
Section 2 Respiratory Physiology
Control of Ventilation
Chapter
22
Which anatomical sites are involved What are the inputs to the
in the control of ventilation? respiratory centre?
Ventilation is controlled by means of neuronal feed- The major inputs to the respiratory centre are
back loops. All feedback loops involve sensors, effect- the peripheral chemoreceptors, central chemo-
ors and a control centre. For ventilation, these are: receptors, mechanoreceptors and bronchial irritant
Sensors – the central and peripheral receptors.
chemoreceptors, pulmonary stretch receptors, Peripheral chemoreceptors. These are located
J-receptors, irritant receptors and joint in the:
proprioceptors.
– Carotid bodies at the bifurcation of the carotid
Control centre – the respiratory nuclei in the artery. Their afferent nervous impulses
brainstem. are carried by the glossopharyngeal nerve.
Effectors – the muscles of respiration. The carotid bodies are the most important
peripheral chemoreceptors for respiratory
How does the respiratory centre responses.
control ventilation? – Aortic bodies on the aortic arch. Their afferent
nervous impulses are carried by the vagus
The respiratory centre has four main anatomical
nerve. They play a more important role in
areas, each with a different function:
cardiovascular responses.
The dorsal respiratory group (DRG) of neurons
primarily controls the diaphragm and thus is The peripheral chemoreceptors have a very high
responsible for normal tidal inspiration. blood flow in relation to their weight. They are
stimulated by:
The ventral respiratory group (VRG) of neurons
controls the intercostal muscles; its function is to – Low PaO2. The aortic and carotid bodies are
initiate forced expiration and to increase the force the only chemoreceptors in the body that
of inspiration. Additionally, the VRG contains the respond to hypoxaemia. Note: the peripheral
pre-Bötzinger complex, a cluster of neurons chemoreceptors are stimulated by low arterial
thought to be the respiratory pacemaker.1 O2 tension, not low O2 content – anaemia
The apneustic centre modifies the activity of and carbon monoxide poisoning do not
DRG neurons to prevent overexpansion of stimulate the chemoreceptors.
the lungs. – High PaCO2. The peripheral chemoreceptors
The pneumotaxic centre modifies DRG impulses are only responsible for 20% of the body’s
to reduce the depth of inspiration, acting to fine- response to hypercapnoea, with the central
tune the respiratory pattern. The pneumotaxic chemoreceptors responsible for the remainder.
centre can also increase the respiratory rate (RR). However, the peripheral chemoreceptors
respond the most rapidly, within the order
of 1–3 s.
1
These neurons express hyperpolarisation-activated cyclic – Acidaemia (pH < 7.35). Only the carotid
nucleotide-gated channels, the same channels as the bodies are stimulated by acidaemia.
pacemaker cells of the sinoatrial node.
93
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:19:31, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.025
Section 2: Respiratory Physiology
94
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:19:31, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.025
Chapter 22: Control of Ventilation
impulses are conveyed to the apneustic centre – Limbic system. Extreme emotional states
by the vagus nerve, causing a reduction in stimulate the respiratory centre, resulting in
the depth of inspiration. This is called the hyperventilation.
Hering–Breuer reflex. During normal – Cerebral cortex. All of the other inputs to
physiological breathing, it is unlikely that the respiratory centre can be transiently
sufficient stretch will occur to trigger the overridden by voluntary thought. However,
Hering–Breuer reflex. However, stretch one cannot breath-hold indefinitely; after a
responses may be important in neonates and short period of apnoea, chemoreceptor
ventilated patients. stimulation by hypoxaemia or hypercapnoea
– Muscle spindles. The ventilatory response to overrides voluntary control, known as the
exercise is thought to be initiated by muscle ‘break point’.
spindle activity.
Other factors. The respiratory centre also receives Summarise the ventilatory response
other inputs from the peripheral and central
nervous systems:
to hypoxaemia
When PaO2 falls below 8 kPa, the peripheral chemo-
– Juxtacapillary receptors (J-receptors). These receptors rapidly stimulate the respiratory centre,
are non-myelinated C-fibres in the alveolar which significantly increases V̇ E (Figure 22.1a). This
walls. Activation causes an increase in ventilatory response is further augmented in the pres-
ventilation, a feeling of dyspnoea, bradycardia ence of hypercapnoea. However, severe prolonged
and hypotension. It is thought that J-receptors hypoxaemia has a depressive effect on the respiratory
are stimulated by pulmonary oedema and centre, causing apnoea.
pulmonary emboli.
– Irritant receptors. Located in the airway Summarise the ventilatory response
epithelium, these cause bronchoconstriction
and stimulate ventilation in the presence to hypercapnoea
of noxious gases. The respiratory centre is stimulated by:
– Pain receptors. Activation of pain receptors High PaCO2, which activates both peripheral
stimulates ventilation. chemoreceptors;
– Thalamus. An increase in core body Low arterial pH, which activates the carotid
temperature stimulates ventilation. bodies;
response to hypoxaemia
15 Linear response
20 between 5 and 10 kPa
Hypercapnoea
(PaCO2 = 8 kPa)
10
Rightward shift with
10 anaesthetic agents
Normocapnoea and opioids
5 Dramatic increase (PaCO2 = 5.3 kPa)
in ventilation at
PaO2 = 8 kPa
0 0
0 5 8 10 15 20 0 5 10 15
PaO2 (kPa) PaCO2 (kPa)
Figure 22.1 Ventilatory response to: (a) hypoxaemia and (b) hypercapnoea.
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:19:31, subject to the Cambridge Core terms of use, available at 95
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.025
Section 2: Respiratory Physiology
96
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:19:31, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.025
Section 2 Respiratory Physiology
Pulmonary Circulation
Chapter
23
What are the unique features of the re-anastomosed. Because most grafts survived des-
pulmonary circulation? pite the loss of the bronchial artery, the bronchial
circulation had been considered to be unnecessary.
The pulmonary circulation differs significantly in However, a subset of lung transplant patients
characteristics from the systemic circulation. The pul- develop an ischaemic bronchiolitis obliterans,
monary circulation is a low-pressure, low-resistance, thought to be due to loss of the bronchial circulation.
high-flow circulation: a blood flow of 5 L/min There is currently a trend towards direct bronchial
(i.e. 100% of cardiac output, CO) is achieved with a artery revascularisation to overcome this problem.
driving pressure (i.e. mean pulmonary artery pres-
sure, MPAP) of only 15 mmHg. Important features
of the anatomy of the pulmonary circulation are as
Why can the pressure within the
follows: pulmonary circulation be low?
As may be expected, there are two pulmonary Unlike the systemic circulation, the pulmonary circu-
arteries: one for each lung. In contrast, there are at lation does not need to direct blood flow from one
least four pulmonary veins: two arising from region to another, with the exception of the property
each lung. of hypoxic pulmonary vasoconstriction (see later).
Initially, the arteries, veins and bronchi run in Therefore, pulmonary arterial pressure only needs to
close proximity to each other, dividing at the same be high enough to propel blood to the lung apices.
points. In the periphery of the lung, the vessels The pulmonary capillaries are unique in being
separate: the veins pass between lung lobules, almost entirely surrounded by alveolar gas. They are also
whilst the arteries and bronchi travel together to very fragile, with little connective tissue, and are there-
the centre of the lobules. fore prone to distension or collapse. Transudation of
The pulmonary capillaries are fragile and very fluid from the pulmonary capillary to the alveolus (i.e.
narrow (diameter 7–10 µm), just wide enough for pulmonary oedema) is dependent in part1 on the trans-
red blood cells to squeeze through. mural pressure, given by the difference in pressures
The conducting airways of the lung also have their between the capillary and the alveolus. As alveolar pres-
own blood supply, called the bronchial circulation. sure is very low, having a low-pressure pulmonary capil-
Some of the deoxygenated blood is carried away lary is essential if pulmonary oedema is to be avoided.
by the pulmonary veins, where it mixes with
oxygenated blood and enters the systemic How do the pulmonary and systemic
circulation. This is one of the causes of an
anatomical shunt (see Chapter 14).
vascular resistances compare?
Clinical relevance: lung transplantation and the Key equation: Darcy’s law
bronchial circulation This is akin to Ohm’s law in an electrical circuit:
Historically during lung transplant surgery, despite
the fact that the bronchial arteries normally receive
1
3–5% of CO, the donor bronchial artery was not Pulmonary surfactant also contributes to the prevention
of fluid transudation.
97
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:23:13, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.026
Section 2: Respiratory Physiology
SVR ≈ 80
MAP−mean right atrial pressure
CO
Which factors affect PVR?
PVR is affected by three main factors:
where MPAP (mmHg) is the mean pulmonary artery
pressure, PCWP (mmHg) is the pulmonary capillary
Pulmonary artery pressure. Increased MPAP
wedge pressure, MAP (mmHg) is the mean arterial results in a significant reduction in PVR
pressure (MAP), SVR (dyn.s.cm−5) is the systemic vas- (Figure 23.1a). This is the result of two
cular resistance, PVR (dyn.s.cm−5) is the pulmonary mechanisms:
vascular resistance, CO (L/min) is the cardiac output – Recruitment, where collapsed pulmonary
and 80 is a constant related to unit conversion. capillaries are reopened. This is the most
important mechanism at low MPAP.
Calculating SVR using typical values (MAP = 100 – Distension, where open pulmonary capillaries
mmHg, mean right atrial pressure is 2 mmHg and are further distended. This is the most
CO = 5 L/min): important mechanism at high MPAP.
MAP−mean right atrial pressure During exercise, despite a large increase in CO,
SVR ¼ 80
CO MPAP only rises moderately due to the
100−2
⇒SVR ¼ 80 ¼ 1568 dyn s cm−5 recruitment and distension of pulmonary
5 capillaries and the corresponding fall in PVR.
(a) Relationship between PVR and MPAP (b) Relationship between PVR and lung volume
Pulmonary vascular resistance (dyn.s.cm–5)
160
150
100
Alveolar vessels
50
Extra-alveolar vessels
0
10 15 20 25 30 Residual FRC TLC
Mean pulmonary arterial pressure (mmHg) volume Lung volume (L)
Figure 23.1 Relationship between (a) PVR and MPAP and (b) PVR and lung volume (FRC = functional residual capacity; TLC = total lung capacity).
98
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:23:13, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.026
Chapter 23: Pulmonary Circulation
However, there is a limit to recruitment and pulmonary arterioles are the main site of
distension of the pulmonary capillaries. In vasoconstriction, venoconstriction of small
racehorses, this limit is reached at moderate pulmonary venules also contributes to HPV (albeit
exercise – severe exercise can lead to very high to a lesser degree). The response of HPV to low PAO2
MPAP and pulmonary haemorrhage can result. is rapid, occurring within seconds; pulmonary lobar
Fortunately, this is not common in humans. blood flow can halve within minutes. When alveolar
Lung volumes. Functionally, there are two types hypoxia is prolonged, there is a second phase of slow,
of pulmonary blood vessels: sustained pulmonary vasoconstriction.
– Alveolar capillaries, which have little The exact mechanism for HPV is not fully
connective tissue and are compressed when established:
subjected to raised alveolar pressure. – The main determinant of HPV is low alveolar
– Extra-alveolar vessels, which are not exposed PO2, but low mixed venous PO2 contributes
to alveolar pressure and can be pulled open by around a fifth of the response.
radial traction of the surrounding lung – HPV continues to operate in denervated lungs
parenchyma. (i.e. following lung transplantation), so is not
The changes in the shape of alveolar and extra- extrinsically (neurally) mediated.
alveolar vessels account for the changes in PVR at – The factors thought most likely to mediate
different lung volumes (Figure 23.1b): HPV are:
– At functional residual capacity (FRC), PVR is ▪ Nitric oxide (NO), a potent pulmonary
at its lowest. This is a useful piece of design: arteriolar vasodilator that is synthesised in
tidal breathing takes place around FRC and the pulmonary endothelium when PAO2 is
PVR is therefore low for the majority of the >9.3 kPa. Alveolar hypoxia decreases the
time, reducing right ventricular workload. amount of NO produced, resulting in
– At high lung volume, PVR increases primarily arteriolar vasoconstriction.
as a result of resistance to blood flow within the ▪ O2-sensitive K+ channels, which are
alveolar capillaries; these capillaries are stimulated by alveolar hypoxia, leading to a
stretched and distorted, which significantly depolarisation of the arteriolar membrane
increases their resistance to flow. The extra- potential. Ca2+ channels are opened,
alveolar vessels contribute little resistance to resulting in arteriolar vasoconstriction.
blood flow as lung volume increases; the radius
of the vessels increases by radial traction,
thereby reducing resistance to blood flow.
Give some examples of HPV in clinical
– At low lung volumes, PVR is high primarily as practice
a result of resistance to flow within the extra- HPV plays a key role in a number of physiological
alveolar vessels; these vessels are very narrow and pathological situations:
and offer high resistance to flow. The foetal circulation. In utero, the foetal lungs
Hypoxic pulmonary vasoconstriction (HPV). have yet to expand: PAO2 is zero, and HPV causes
The response of the pulmonary circulation to widespread pulmonary vasoconstriction. The
hypoxia is unique. In the systemic circulation, tissue resulting high PVR means that only 10% of the
hypoxia causes vasodilatation of neighbouring blood foetal CO passes through the foetal lungs, with
vessels, so that local perfusion is matched to local blood instead being redirected through the ductus
metabolism. In contrast, the pulmonary vessels arteriosus. At the first breath, O2 enters the
vasoconstrict in response to low alveolar O2 tension alveoli; PVR decreases dramatically, resulting in
(PAO2 < 8 kPa). This is a useful physiological an increase in pulmonary blood flow.
mechanism: vasoconstriction of the pulmonary Infant respiratory distress syndrome. Lack of
arterioles adjacent to hypoxic alveoli increases local surfactant results in increased surface tension,
vascular resistance, thus redirecting blood flow to which leads to widespread atelectasis. The first
better-ventilated areas of the lung. While the breath is therefore extremely difficult, and PVR
99
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:23:13, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.026
Section 2: Respiratory Physiology
100
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:23:13, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.026
Chapter 23: Pulmonary Circulation
25
20
Pressure (mmHg)
PCWP
15
10
0
RA RV PA Branch of
Location of catheter tip PA
Figure 23.2 Characteristic pressure waveforms as a pulmonary artery catheter is advanced (RA = right atrium; RV = right ventricle; PA =
pulmonary artery; PCWP = pulmonary capillary wedge pressure).
Describe the changes in pressure and used to identify the tip’s location (Figure 23.2).
Once the PAC has been inserted as far as the right
waveform seen when ‘floating’ a ventricle (Figure 23.2b) (about 20 cm), the balloon is
balloon-tipped PAC inflated. The tip of the PAC is guided by the flow of
The flow-directed, balloon-tipped PAC (also known blood through the pulmonary valve and into a pul-
as the Swan–Ganz catheter) has many uses: monary artery (Figure 23.2c), until it wedges in a
branch of the pulmonary artery (Figure 23.2d), giving
Diagnostic; for example, pulmonary hypertension the PCWP.
and acute respiratory distress syndrome.
Measurement of haemodynamic parameters; for Further reading
example, CO and mixed venous O2 saturation. A. B. Lumb. The pulmonary circulation. In: A. B. Lumb.
Therapeutic; for example, aspiration of air Nunn’s Applied Respiratory Physiology, 8th edition.
emboli. London, Churchill Livingstone, 2016; 89–108.
Despite its wide applicability in critical illness, the use K. Nowak, M. Kamler, M. Bock, et al. Bronchial artery
of the Swan–Ganz catheter has declined in recent revascularisation affects graft recovery after lung
years: in the general adult intensive care population, transplantation. Am J Respir Crit Care Med 2002; 165(2):
216–20.
using a PAC has not been shown to reduce mortality.
In addition, the PAC is associated with several serious J. Eastwood, R. Mahajan. One-lung anaesthesia. Continuing
Educ Anaesth Crit Care Pain 2002; 2(3): 83–7.
complications, such as line infection, pulmonary
infarction and pulmonary artery rupture. R. Naeije, S. Brimioulle. Physiology in medicine:
The PAC has a length of 150 cm and is usually importance of hypoxic pulmonary vasoconstriction in
maintaining arterial oxygenation during acute
inserted through a sheath in the right internal jugular respiratory failure. Crit Care 2001; 5(2): 67–71.
vein. The pressure at the tip of the PAC is transduced
101
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:23:13, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.026
Section 2 Respiratory Physiology
Oxygen Toxicity
Chapter
24
superoxide anion (O2• ), hydrogen peroxide (H2O2)
What is oxygen toxicity? and hydroxyl free radicals (OH•): these are collect-
Breathing O2 at high partial pressure can have harm- ively known as reactive oxygen species (ROS). ROS
ful effects on the body. Many organ systems can be are also generated when cells are exposed to ionising
affected by O2 toxicity, but the most common are: radiation. O2 toxicity is thought to be due to the
The central nervous system (CNS), causing harmful effects of ROS on nucleic acids, fatty acids,
seizures and unconsciousness when breathing amino acids and sulphydryl-containing enzymes.
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 acute Exogenous antioxidants are obtained from the diet
respiratory distress syndrome (ARDS). Lung and include ascorbic acid (vitamin C). The body has
toxicity is known as the Lorraine Smith effect. many endogenous antioxidant systems to protect
The retina, leading to retrolental fibroplasia in against oxidative stress. The most important are the
neonates, also known as the retinopathy of 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?
Toxicity is due to the unique structure of the O2 Does the body make any use of ROS?
molecule. The O2 molecule is made up of two oxygen Despite their potential toxicity, ROS are also essential
atoms, each with an unpaired electron in its outer to the normal function of the body:
shell. It is these unpaired electrons that give O2 its Neutrophils and macrophages kill phagocytosed
property of paramagnetism. Molecules containing bacteria by synthesising and secreting ROS into
unpaired electrons – or free radicals – are usually the phagosome. The consumption of O2 during
highly reactive. Fortunately, the unpaired electrons this process is called the respiratory burst.
of the O2 molecule are fairly unreactive, requiring Thyroid follicular cells synthesise H2O2, which is
metal ions (such as those found in metalloproteins) used to oxidise iodine anions (I ) to iodine (I2)
to help the O2 molecule accept electrons. This is of (see Chapter 81).
particular importance in the electron transport chain,
where electrons are transferred to O2 molecules,
mediated by the copper-containing cytochrome c oxi- How much oxygen is harmful?
dase (Complex IV), to form water molecules. Inspired O2 below 50 kPa (an inspired fraction of O2
The reduction of O2 to 2H2O requires four elec- FiO2 of 50% at atmospheric pressure) is considered to
trons: O2 molecules accept one electron at a time, be safe. The risk of O2 toxicity increases as the
passing through a number of oxidation states along inspired partial pressure of O2 increases and the dur-
the way. Known intermediate molecules are the ation of exposure increases.
102
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:25:56, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.027
Chapter 24: Oxygen Toxicity
Divers are particularly susceptible to CNS toxicity pneumonia or general anaesthesia) appear to be at
due to the breathing of gases at hyperbaric pressures increased risk of a rapidly developing life-threatening
and due to the consequences of losing consciousness pulmonary fibrosis. Because of this, patients who
underwater. To minimise the risk of O2 toxicity, have been treated with bleomycin carry an alert card –
divers calculate their maximum O2 exposure times O2 administration should be avoided if possible, and
based on the depth of the dive and the total time if O2 is absolutely necessary, it should be titrated to an
underwater. SaO2 of 88–92%.
The connection between bleomycin and O2-induced
Clinical relevance: intensive care and oxygenation lung injury is controversial, and the mechanism of
bleomycin-induced lung toxicity is not completely
Studies have shown evidence of a reduction in pul-
monary function in healthy volunteers following 24 h
resolved. However, it is known that bleomycin acts
of exposure to 100% O2. After 48 h of 100% O2 by chelating iron. The bleomycin–iron complex reacts
exposure, subjects may develop early features of with O2, resulting in ROS (superoxide and hydrox-
ARDS. However, there is significant variability in the ide), which cleave DNA. It is certainly possible that
length of exposure and FiO2 required to develop administration of O2 results in an excess of ROS,
toxicity between patients. which overwhelm the body’s protective mechanisms.
Most intensive care guidelines recommend keep-
ing the FiO2 below 50% where possible. If higher FiO2 Further reading
is required, the time that the patient is exposed A. B. Lumb. Oxygen toxicity and hyperoxia. In: A. B. Lumb.
should be minimised. However, in the hypoxaemic Nunn’s Applied Respiratory Physiology, 8th edition.
patient, high inspired concentrations of O2 should London, Churchill Livingstone, 2016; 341–56.
never be withheld for fear of O2 toxicity.
U. Nimmagadda, M. R. Salem, G. J. Crystal.
Preoxygenation: physiologic basis, benefits, and potential
What is the connection between risks. Anesth Analg 2017; 124(2): 507–17.
N. Allan, C. Siller, A. Breen. Anaesthetic implications of
bleomycin and oxygen toxicity? chemotherapy. Continuing Educ Anaesth Crit Care Pain
Bleomycin is a chemotherapy drug used in the treat- 2012; 12(2): 52–6.
ment of Hodgkin’s lymphoma and testicular carcin- R. Taneja, R. S. Vaughan. Oxygen. Continuing Educ Anaesth
oma. The most serious side effect of bleomycin is Crit Care Pain 2001; 1(4): 104–7.
pulmonary fibrosis, which usually occurs within the I. Fridovich. Oxygen toxicity: a radical explanation. J Exp
first 6 months of treatment. Of concern to anaesthe- Biol 1998; 201(8): 1203–9.
tists is that patients who have received bleomycin who D. D. Mathes. Bleomycin and hyperoxia exposure in the
subsequently require supplemental O2 (e.g. owing to operating room. Anesth Analg 1995; 81(3): 624–9.
103
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:25:56, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.027
Section 2 Respiratory Physiology
Ventilatory Failure
Chapter
25
What is meant by the term ‘respiratory (see Chapter 11). Failure of alveolar ventilation
leads to increased PaCO2; that is, type 2 respiratory
failure’? failure.
Respiratory failure occurs when the respiratory
system fails in one or both of its main functions; Which pathophysiological processes
namely, the oxygenation of blood and the elimination
of CO2. Respiratory failure is categorised as ‘type 1’ or cause type 2 respiratory failure?
‘type 2’ on the basis of blood gas analysis: Normally, ventilation is controlled by a negative-
Type 1 respiratory failure is defined as a PaO2 feedback mechanism:
< 8.0 kPa with a normal or low PaCO2. A rise in PaCO2 stimulates the respiratory centre
Type 2 respiratory failure is defined as a PaO2 in the medulla oblongata via the peripheral and
< 8.0 kPa with a raised PaCO2 > 6.0 kPa. central chemoreceptors (see Chapter 22).
The respiratory centre sends excitatory impulses
to the respiratory muscles to increase the rate and
What is the difference between depth of inspiration. V̇ E and V̇ A both increase.
oxygenation and ventilation? Owing to the inverse relationship between PaCO2
and V̇ A, PaCO2 decreases.
The respiratory system can be considered as two
parts: a gas-exchange system and a ‘bellows’. In health, this system is very sensitive: PaCO2 is kept
within tight limits. If PaCO2 rises above 6 kPa, V̇ A
The gas-exchange system is made up of:
must be inadequate and one of the components of
– Alveolar–capillary units; ventilation must be malfunctioning:
– Pulmonary circulation. Failure of the respiratory centre to respond
The gas-exchange system is responsible for appropriately. This may be due to:
oxygenation; deficiency leads to hypoxaemia and – Respiratory centre depression by opioids or
type 1 respiratory failure. general anaesthesia;
The bellows system is made up of: – Reflex desensitisation of the respiratory centre
– Chest wall and pleura; to high PaCO2 in order to prevent respiratory
– Respiratory muscles; muscle fatigue.
– Airways; A problem with chest wall movement. This could
– Nerves; be:
– Respiratory centre. – Mechanical; for example, flail chest;
The bellows system is responsible for ventilation: – Neuropathic; for example, Guillain–Barré
moving air from the atmosphere to the alveoli on syndrome;
inspiration and from the alveoli to the atmosphere – Muscular; for example, myopathies.
on expiration.
Respiratory muscle fatigue. Fatigue occurs when
Importantly, V̇ A facilitates the diffusion of CO2 the respiratory muscles cannot synthesise sufficient
from the pulmonary capillaries to the alveoli: V̇ A ATP to meet the demands of muscle contraction
(and not V̇ E) is inversely proportional to PaCO2 despite an intact respiratory drive and chest wall.
104
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 20:58:34, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.028
Chapter 25: Ventilatory Failure
Describe how a patient with myasthenia Most patients with chronic hypercapnoea can
bring their PaCO2 back down to normal levels
gravis may develop respiratory failure through voluntary hyperventilation.
Myasthenia gravis is an autoimmune disease resulting These patients start to develop respiratory muscle
in antagonism and destruction of postsynaptic nico- fatigue after a few minutes of voluntary
tinic acetylcholine receptors at the neuromuscular hyperventilation.
junction (see Chapter 53). Clinically, this results in
It is likely, therefore, that these patients’ respiratory
weakness of voluntary muscle with characteristic
centres have ‘chosen’ to hypoventilate rather than
fatigability. The muscle groups most commonly
ventilating to achieve a normal PaCO2 and risking
affected are ocular, facial, bulbar and limb. Respira-
respiratory muscle fatigue. This is known as reflex
tory muscles are usually only mildly affected.
desensitisation of the respiratory centre and high-
During a myasthenic crisis, the respiratory muscles
lights the concept of optimisation over homeostasis
may become profoundly weak. The inspiratory muscles
in physiology.
become too weak to maintain normal VT and breathing
becomes shallow and rapid. Shallow breathing is particu-
larly ineffective as dead space makes up a higher propor- Clinical relevance: exacerbation of COPD
tion of V̇ E: V̇ A decreases, resulting in hypercapnoea (i.e.
type 2 respiratory failure). In addition, the small inspira- An exacerbation of COPD is defined as an acute
change in a COPD patient’s dyspnoea, cough and/
tory volumes cause microatelectasis, which decreases
or sputum that is beyond normal day-to-day vari-
lung compliance and further increases the work of
ations. Exacerbations are commonly infective in
breathing. This situation can be worsened if there is an origin, but also have a number of other causes,
associated pneumonia or aspiration due to poor cough including atmospheric pollution.
and secretion clearance, leading to a V̇ /Q̇ mismatch. During COPD exacerbations, there is a significant
increase in the resistive and elastic work of
Describe how patients with stable breathing. During expiration, dynamic airway
105
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 20:58:34, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.028
Section 2: Respiratory Physiology
106
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 20:58:34, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.028
Section 2 Respiratory Physiology
26
What effects do anaesthetic drugs have cardiovascular stability, ketamine preserves
airway reflexes and spontaneous
on the respiratory system? ventilation.
Many of the drugs used by anaesthetists have effects Other drugs commonly used in anaesthesia with
on the medullary respiratory centre, the peripheral effects on the respiratory system are:
chemoreceptors and the airways. Their effects are
Opioids, causing:
most easily classified by drug class:
– Depression of the respiratory centre, resulting
Volatile anaesthetic agents. The inhalational
agents have dose-dependent effects on the in a reduced RR and blunting of the
respiratory system: ventilatory response to hypercapnoea.
– Antitussive action, depressing the cough reflex.
– An increase in respiratory rate (RR), but with
– Histamine release (with morphine), which may
reduced VT.
precipitate bronchospasm in susceptible
– Blunted ventilatory response to hypercapnoea, patients.
the extent of which varies between volatile
– Rarely, chest wall rigidity (wooden chest
agents: enflurane > desflurane > isoflurane > syndrome) following the rapid intravenous
sevoflurane > halothane. The exceptions are injection of strong opioids, which can interfere
N2O (which has no effect) and ether (which with ventilation.
may increase V̇ E).
Benzodiazepines cause depression of the
Intravenous anaesthetic agents. respiratory centre, resulting in a decrease in RR
– Initial respiratory stimulation following and blunting of the ventilatory response to
induction of general anaesthesia. hypercapnoea.
– Subsequent respiratory depression. Respiratory Depolarising and non-depolarising muscle
stimulation is followed by abrupt relaxants. The most obvious effect of the
respiratory centre depression. VT falls and muscle relaxants on the respiratory system is
apnoea may occur, especially with the use of respiratory muscle paralysis necessitating
propofol. mechanical ventilation. Adequate reversal
– Specific to certain drugs: of neuromuscular blockade is required
to prevent post-operative respiratory failure.
▪ Propofol depresses laryngeal reflexes. This
Other respiratory effects specific to particular
is used to the anaesthetist’s advantage:
agents are:
depression of laryngeal reflexes allows the
insertion of a laryngeal mask airway – Atracurium may cause histamine release,
(LMA). resulting in bronchospasm.
▪ Propofol is thought to abolish the – Suxamethonium and mivacurium may
peripheral chemoreceptor response to cause prolonged respiratory muscle
hypoxaemia. weakness in patients with reduced levels of
▪ Ketamine differs from the other plasma cholinesterase (suxamethonium
intravenous agents – in addition to its apnoea).
107
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:28:16, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.029
Section 2: Respiratory Physiology
108
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:28:16, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.029
Chapter 26: Anaesthesia and the Lung
– Compression atelectasis. Under general exacerbates atelectasis and predisposes the patient
anaesthesia, a combination of reduced to secretion retention and pneumonia.
diaphragmatic tone and compression from the Post-operative shivering sometimes occurs at
abdominal contents causes basal atelectasis. emergence from anaesthesia. Shivering
This is exacerbated by the loss of physiological increases metabolic demand at a time when
PEEP and increased abdominal pressure (e.g. the respiratory centre’s response to hypercapnoea
due to pneumoperitoneum). and hypoxaemia is blunted by the residual
V /Q̇ mismatch as a result of:
̇ effects of anaesthetic agents and opioids.
Respiratory failure (either type 1 or type 2) may
– Low lung volume, causing closure of small
then occur.
airways (due to CC encroaching on FRC).
Where neuromuscular blockade has been used,
– Increased tendency for atelectasis.
inadequate reversal may cause respiratory muscle
– Positive pressure ventilation, which alters weakness in the immediate post-operative period.
intrathoracic pressure, reducing right Muscular weakness may be exacerbated by
ventricular preload and changing pulmonary electrolyte disturbances (hypokalaemia or
capillary dynamics; West zone 1 occurs in the hypocalcaemia) resulting from fluid shift between
lung apex (see Chapter 16). body compartments and increased
– Impairment of hypoxic pulmonary mineralocorticoid activity as part of the stress
vasoconstriction by volatile anaesthetic agents. response.
The hypoxaemia resulting from V̇ /Q̇ mismatch One of the aims of anaesthetic management is to
can usually be managed simply by increasing FiO2 minimise the disturbance in post-operative lung func-
and adding extrinsic PEEP to reduce atelectasis tion. The approach is multifactorial, taking into
and increase lung volume. account many of the factors discussed above:
Preoperative assessment. Risk stratification of
How does general anaesthesia affect patients based on type of surgery and presence of
post-operative respiratory function? any underlying lung disease.
Post-operative pulmonary complications are Regional versus general anaesthesia. Depending
common in the week following surgery, and include: on the type of surgery, the use of regional
anaesthesia avoids many of the adverse effects of
Atelectasis;
general anaesthesia on the lungs.
Bronchospasm;
Laparoscopic surgery reduces the prevalence of
Pneumonia; post-operative pulmonary complications.
Pulmonary oedema; Intraoperative ventilation strategy. There is a
Ventilatory failure. significant reduction in postoperative pulmonary
Whilst underlying lung and cardiac disease may pre- complications when patients are ventilated with
dispose patients to post-operative pulmonary compli- low VT (<8 mL/kg). The most effective level of
cations, surgical and anaesthetic techniques also intraoperative PEEP and the role of recruitment
contribute: manoeuvres are yet to be determined.
Upper abdominal and thoracic surgery carry the Avoiding 100% O2 to avoid absorption atelectasis.
highest risk of post-operative pulmonary Even adding 20% nitrogen to the fresh gas flow is
complications. Reduced FRC, basal atelectasis and useful in splinting open alveoli.
V̇ /Q̇ mismatch are inevitable and often persist for Normothermia. Intraoperative temperature
many days. V̇ /Q̇ mismatch causes hypoxaemia, management minimises the risk of post-operative
whilst atelectasis and reduced lung volume both shivering.
contribute to an increased work of breathing. Neuromuscular monitoring and reversal of
Inadequate analgesia following laparotomy, neuromuscular blockade. Long-acting
sternotomy and thoracotomy results in an neuromuscular blocking agents (e.g.
inadequate cough and limited inspiration. This pancuronium) are more likely to lead to
109
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:28:16, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.029
Section 2: Respiratory Physiology
post-operative respiratory failure than short- and E. Scarth, S. Smith. Drugs in Anaesthesia and Intensive Care,
intermediate-acting agents. 5th edition. Oxford, Oxford University Press, 2016.
Adequate pain relief. This is especially important T. E. Peck. Pharmacology for Anaesthesia and Intensive
in upper abdominal and thoracic surgery where a Care, 4th edition. Cambridge, Cambridge University
regional anaesthetic technique is commonly used; Press, 2014.
for example, a continuous infusion of local G. H. Mills. Respiratory complications of anaesthesia.
anaesthetic via a thoracic epidural or paravertebral Anaesthesia 2018; 73(Suppl. 1): 25–33.
catheter. A. Miskovic, A. B. Lumb. Postoperative pulmonary
complications. Br J Anaesth 2017; 118(3): 317–34.
Further reading V. A. Lawrence, J. E. Cornell, G. W. Smetana. Strategies to
A. B. Lumb. Ventilatory failure. In: A. B. Lumb. Nunn’s reduce postoperative pulmonary complications after
Applied Respiratory Physiology, 8th edition. London, noncardiothoracic surgery: systematic review for the
Churchill Livingstone, 2016; 379–88. American College of Physicians. Ann Intern Med 2006;
144(8): 596–608.
A. B. Lumb. Respiratory support and artificial ventilation.
In: A. B. Lumb. Nunn’s Applied Respiratory Physiology, G. Hedenstierna. Airway closure, atelectasis and gas
8th edition. London, Churchill Livingstone, 2016; exchange during anaesthesia. Minerva Anestesiol 2002;
451–78. 68(5): 332–6.
110
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:28:16, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.029
Section 3 Cardiovascular Physiology
27
What are the functions of the heart? endocardium is in contact with blood and is
continuous with the endothelial layer of the blood
The mechanical function of the heart is to eject1 blood vessels.
into the vascular system:
The heart can be divided into right and left sides, each
The right side of the heart generates flow around
consisting of an atrium and a ventricle. The two sides
the pulmonary circulation, moving deoxygenated
of the heart are separated by the interatrial and inter-
venous blood from the heart to the lungs.
ventricular septae.
The left side of the heart generates pressure in the
arterial circulation, moving oxygenated blood The right atrium (RA) receives deoxygenated
from the heart to the other organs of the body. blood from the superior and inferior venae cavae.
Flow can then be regulated according to tissue When the RA contracts, blood passes through the
demand. tricuspid valve (a trileaflet valve) and into the right
ventricle (RV).
The heart is also an endocrine organ with a role in the
The RV has a complex shape. Viewed in the
regulation of plasma volume. Stretch receptors in the transverse plane it is shaped as a crescent, whilst it
cardiac atria and ventricles sense increases in plasma is triangular in the longitudinal plane. Because of
volume, secreting atrial natriuretic peptide (ANP) and this complex shape, the structure of the RV is
brain natriuretic peptide (BNP) in response. Both difficult to model mathematically. It is therefore
ANP and BNP act on the kidney to produce a natriur- difficult to estimate right ventricular volume by
esis, which restores plasma volume to normal. echocardiography. When the RV contracts, blood
is driven through the pulmonary valve (a trileaflet
Describe the structure of the heart valve) and into the pulmonary artery.
The heart is located in the thorax, enclosed within a The left atrium (LA). Oxygenated blood returns
fibrous sac called the pericardium. The pericardium from the lungs through four (normal variation
forms attachments to surrounding structures that from three to five) pulmonary veins and enters
hold the heart in place. the LA. When the LA contracts, blood passes
The heart is made up of three tissue layers: into the left ventricle (LV) through the mitral
The epicardium, the outer connective tissue layer. valve (a bileaflet valve)
A small amount of pericardial fluid separates the The LV has a circular transverse section and
epicardium from the pericardium, which helps a conical longitudinal section, amenable to
reduce frictional forces as the heart moves. accurate echocardiographic estimates of its
The myocardium, the middle layer, which is volume. When the LV contracts, blood is forced
composed of cardiac muscle. through the aortic valve (a trileaflet valve) and
The endocardium, a layer of epithelial cells that into the aorta.
line the inner surface of the heart. The
What is meant by the term
Technically, the heart does not operate as a true ‘pump’,
‘functional syncytium’?
1
111
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:20:42, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.030
Section 3: Cardiovascular Physiology
Oblique vein
Coronary sinus
Great cardiac vein
discs. Intercalated discs contain three different types (Figure 27.1). The aortic root has three dilatations
of cell–cell interaction: just above the aortic valve, known as the aortic sinuses
Gap junction complexes permit the direct passage (or sinuses of Valsalva). These sinuses produce eddy
of intracellular ions and larger molecules from currents, which tend to keep the valve cusps away
one cell to another. They form electrical synapses, from the aortic walls and facilitate smooth valve
allowing direct electrical spread of action closure. This is important, as the left and right coron-
potentials from cell to cell. ary arteries originate from the left posterior and
Fascia adherens anchor the actin filaments within anterior coronary sinuses, respectively, and the eddy
the sarcomere to the cell membrane. currents prevent their occlusion.
Macular adherens (also known as desmosomes) The left coronary artery (left main stem) arises
anchor cardiac cells to one another. from the left posterior aortic sinus, just above the
left cusp of the aortic valve. The left coronary
Cardiac muscle is therefore electrically, chemically
artery travels a short distance in the left
and mechanically coupled together so that it behaves
atrioventricular (AV) groove (less than 2.5 cm)
as a single coordinated unit, and it is often referred to
before bifurcating into:
as a functional syncytium.
– The left anterior descending (LAD) artery
Describe the coronary circulation (left interventricular artery). This artery
Whilst a large volume of blood passes through the descends in the anterior interventricular
cardiac chambers, the ventricular wall is too thick for groove, giving off septal and diagonal
effective diffusion of O2 to occur; only the endocar- branches. The LAD supplies most of the LV,
dium is nourished directly. The bulk of the cardiac specifically:
muscle is perfused by the coronary circulation. Cor-
▪ The anterolateral myocardium;
onary arteries are end arteries: they represent the only
▪ The apex;
source of blood for the downstream myocardium, with
▪ The interventricular septum.
few native anastomoses. Consequently, acute obstruc-
tion of a coronary artery causes myocardial infarction. The LAD often forms an anastomosis with the
The coronary circulation is divided into right posterior interventricular artery after passing
and left sides, which both originate at the aortic root over the apex.
112
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:20:42, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.030
Chapter 27: Cardiac Anatomy and Function
– The left circumflex artery. This artery The coronary sinus. Venous blood from the LV
continues in the left AV groove, giving off one (which accounts for around 85% of venous blood)
or more obtuse marginal branches. Normally, is collected by the cardiac veins, which coalesce
the terminal end of the left circumflex artery to form the coronary sinus. The sinus opens into
meets the right coronary artery in the AV the RA, between the inferior vena cava and the
groove, where the two arteries form an tricuspid valve. The cardiac veins lie in the
anastomosis. The left circumflex artery grooves between atria and ventricles. Thus, they
supplies: follow the same paths as the coronary arteries
(Figure 27.1). They are:
▪ The posterolateral LV;
▪ The sinoatrial (SA) node in 40% of – The great cardiac vein, which runs alongside
individuals. the LAD in the anterior interventricular
groove;
The right coronary artery originates from the
– The middle cardiac vein, which runs alongside
anterior aortic sinus, just above the right cusp of
the posterior interventricular artery in the
the aortic valve. It travels along the right AV
posterior interventricular groove;
groove, before dividing into:
– The small cardiac vein, which runs alongside
– The SA branch, which is present in 60% of the right coronary artery in the posterior AV
individuals and supplies the SA node; groove;
– The right marginal artery, which travels – The oblique vein, which traverses the back of
down the right margin of the heart towards the LA.
the apex and supplies the RV; it is the
right-sided equivalent of the left The anterior cardiac veins are small veins that
arise on the anterior surface of the RV and drain
interventricular artery.
into the RA.
The right coronary artery continues in the AV The Thebesian veins, the smallest of the cardiac
groove until it reaches the posterior interventricular veins, drain directly into the four chambers of the
groove. In the majority of individuals, the right heart. The Thebesian veins are predominantly
coronary artery then divides into: found in the RA and RV. Note: the few Thebesian
– The posterior interventricular artery (posterior veins that drain into the left side of the heart pass
descending artery), which supplies the deoxygenated blood directly into the stream of
posterior part of the septum and the AV node. fully oxygenated blood returning from the lungs
For this reason, occlusions of the right and thus contribute to anatomical shunt (see
coronary artery predispose to bradycardia and Chapter 14).
AV block.
The right coronary artery continues in the AV
groove, where it forms an anastomosis with the Clinical relevance: cardiac resynchronisation
therapy
left circumflex artery.
The coronary circulation has a number of recog- Cardiac resynchronisation therapy (CRT) is indi-
cated in heart failure patients in sinus rhythm where
nised variants, the most common of which is called
ejection fraction is <35% and where there is a con-
‘left dominance’. In around 15% of the population, duction defect (characterised by a widened QRS
the posterior interventricular artery is not a branch complex) resulting in asynchronous contraction of
of the right coronary artery, but is instead a branch of the left and right ventricles. A CRT device improves
the left circumflex artery. atrial and ventricular synchrony through the use of
three pacemaker wires: atrial, right ventricular and
left ventricular.
Describe the venous drainage Like standard pacemakers, the CRT leads are usu-
of the heart ally inserted through the subclavian vein, which
poses a question: how does the left ventricular wire
There are three different systems through which reach the left ventricular myocardium?
venous blood is drained from the myocardium:
113
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:20:42, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.030
Section 3: Cardiovascular Physiology
120
Dicrotic notch
110
100 Aorta
90
80
Greater coronary blood
200 flow during diastole
Coronary blood flow (mL/100 g/min)
150
Left coronary
100
20 Right coronary
114
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:20:42, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.030
Chapter 27: Cardiac Anatomy and Function
115
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:20:42, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.030
Section 3: Cardiovascular Physiology
116
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:20:42, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.030
Section 3 Cardiovascular Physiology
Cardiac Cycle
Chapter
28
What is the cardiac cycle? conducted throughout the atria, triggering
atrial contraction.
The cardiac cycle refers to the complete sequence
– As a result of atrial contraction, much of
of physiological events that occur in the heart, from
the remaining atrial blood is ejected through
the beginning of one heartbeat to the beginning of
the AV valves into the ventricles. At rest,
the next.
this atrial ‘kick’ accounts for only 10% of
The cardiac cycle consists of two phases:
ventricular filling: 90% of the blood flows
The diastolic phase, during which the ventricles into the ventricle passively. However, during
are relaxed and are filling with blood. Diastole exercise, when diastole is shortened, atrial
consists of four stages: contraction contributes up to 40% of
– Isovolumetric relaxation; ventricular filling.
– Rapid ventricular filling; – The pressure generated during atrial
– Slow ventricular filling; contraction is transmitted along the venae
– Atrial contraction. cavae and pulmonary veins as they have no
valves: atrial contraction is represented by the
The systolic phase, during which the ventricles
a-wave on the atrial pressure waveform
contract and eject blood into the aorta
(Figure 28.1).
and pulmonary artery. Systole consists of
two stages: – The volume of blood within the ventricle at the
end of atrial contraction is the end-diastolic
– Isovolumetric contraction; volume.
– Ejection.
Isovolumetric contraction. The action potential
continues through the AV node and is conducted
Describe the events making up throughout the ventricles by the His–Purkinje
the cardiac cycle system, represented on the electrocardiogram by
the QRS complex. Initially, ventricular
Traditionally, the cardiac cycle is described from late contraction causes a rapid rise in intraventricular
diastole, when the atria and ventricles are relaxed and pressure:
the atrioventricular (AV) valves are open:
– Once intraventricular pressure exceeds atrial
Slow ventricular filling. The pressure within the pressure, the AV valves close, resulting in the
atria is slightly higher than the intraventricular first heart sound, S1. The mitral valve normally
pressure. The AV valves are therefore open, closes slightly earlier than the tricuspid valve,
allowing blood to flow slowly from atrium to resulting in a ‘split’ S1.
ventricle.
– There is a period of time between the closure
Atrial contraction. of the AV valves and the opening of the aortic
– The pacemaker cells of the sinoatrial (SA) and pulmonary valves (semilunar valves)
node spontaneously depolarise, generating an during which ventricular pressure rises
action potential (see Chapter 57). The without a change in ventricular volume – this
resulting electrical impulse is rapidly is the phase of isovolumetric contraction.
117
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:18:10, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.031
Section 3: Cardiovascular Physiology
Dicrotic notch
120 Aortic valve
opens
100
Aortic valve
closes
80
Gradient
Pressure (mmHg)
reflects
60 Mitral valve contractility
closes Mitral valve
opens
40 c-wave
a-wave
x-descent
20 v-wave y-descent Right atrial
pressure
Left ventricular
0 pressure
P QRS T P
ECG
Heart sounds
S1 S2
– During isovolumetric contraction, the – Initially, the flow of blood through the
increased right ventricular pressure causes semilunar valves is rapid, but as the ventricular
the tricuspid valve to bulge into the right myocytes start to repolarise, the force of
atrium. This corresponds to the c‑wave on contraction wanes.
the atrial pressure waveform. Similarly, – In the course of ventricular relaxation, the
increased left ventricular pressure ventricular pressure falls below that of the
causes the mitral valve to bulge into the aorta and pulmonary artery; the semilunar
left atrium. valves close, resulting in the second heart
Ejection. Once ventricular pressure exceeds the sound, S2. The aortic valve usually closes
pressure in the aorta and pulmonary artery, the slightly earlier than the pulmonary valve.
semilunar valves open and blood is ejected from Inspiration can accentuate this difference,
the ventricles. particularly in young people, resulting in a
‘physiological split’ S2.
– Right ventricular contraction pulls the
– Aortic valve closure is represented on the
tricuspid valve downwards. As the length of
aortic pressure curve (Figure 28.1) by the
the right atrium increases, its pressure falls to
dicrotic notch, a positive deflection caused by
zero and it is rapidly filled with blood. This is
the elastic recoil of the aortic valve and
the origin of the x‑descent on the atrial
the aorta.
pressure waveform.
118
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:18:10, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.031
Chapter 28: Cardiac Cycle
– The volume of blood within the ventricle Ejection fraction (EF) is also commonly used. EF
following valve closure is the end-systolic is the proportion of blood ejected from the LV per
volume. heartbeat:
Isovolumetric relaxation. Following the closure
of the semilunar valves, it takes a short time Key equation: EF
for the ventricles to further relax and their
pressure to fall below that of the atria. Throughout SV
late systole and isovolumetric relaxation, atrial EF ¼
LVEDV
pressure slowly rises due to venous return from
As typical values are SV = 70 mL and LVEDV = 120 mL:
the lungs and venae cavae. This corresponds
to the v‑wave of the atrial pressure waveform 70
EF ¼ 100
(Figure 28.1). 120
Rapid ventricular filling. Once atrial pressure ¼ 58%
exceeds ventricular pressure, the AV valves open. The ‘normal range’ for EF is 55–70%.
Blood flows down its pressure gradient from the
atria to the ventricles. During the early part of
diastole, the ventricles are still undergoing
relaxation and intraventricular pressure continues Clinical relevance: cardiac output, ageing
to decrease, and blood therefore flows rapidly into and tachycardia
the ventricles. The fall in atrial pressure is Cardiac output, CO = HR SV (see Chapter 29).
represented by the y‑descent of the atrial pressure Therefore, it seems logical that as HR increases, so
waveform (Figure 28.1). does CO. However:
Ventricular filling is normally silent, but an At rest (HR = 75), a single cardiac cycle lasts
increased volume of atrial blood (e.g. in mitral for 0.8 s: the typical duration of systole is 0.3 s
regurgitation) flowing into a poorly compliant and diastole is 0.5 s. The LV fills during diastole,
left ventricle (LV; e.g. as occurs following when its pressure is low and the mitral valve
a myocardial infarction or in dilated is open.
cardiomyopathy) results in reverberation of A young athlete at maximal exercise may have an
the ventricular wall and a third heart sound, S3. HR of 200; each cardiac cycle lasts just 0.3 s:
systole lasts 0.15 s and diastole 0.15 s.
119
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:18:10, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.031
Section 3: Cardiovascular Physiology
120
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:18:10, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.031
Section 3 Cardiovascular Physiology
29
Which factors affect the – Central venous pressure provides an indication
of right ventricular preload, as it affects
cardiac output? right ventricular end-diastolic volume
The cardiac output (CO) is the volume of blood (RVEDV).
ejected by the left ventricle (LV) or right ventricle – Pulmonary capillary wedge pressure provides
(RV) per minute. an indication of left ventricular preload, as it
CO is directly dependent on two factors: heart rate affects LVEDV.
(HR) and stroke volume (SV).
Afterload is the stress developed in the
Key equation: CO left ventricular wall during ejection, and it
reflects the force opposing the shortening
CO ¼ SV HR of cardiac myocytes. As afterload increases,
both the rate and extent of sarcomere shortening
At rest, the typical SV is 70 mL and HR is 75 bpm.
decrease, resulting in a reduction in SV.
Typical resting CO is therefore 70 75 = 5.25 L/min,
Like preload, afterload is not easily measured
but CO may increase fivefold during maximal
in vivo and is assessed through surrogate
exercise.1
markers:
In turn, SV is determined by three factors: pre- – Mean arterial pressure (MAP) and systemic
load, myocardial contractility and afterload. vascular resistance (SVR) reflect left ventricular
Preload is defined as the intraluminal pressure afterload.
that stretches the RV or LV to its end-diastolic – Pulmonary vascular resistance reflects right
dimensions. Preload is therefore related to the ventricular afterload.
diastolic length of the cardiac myocyte. According Myocardial contractility is the intrinsic ability of
to Starling’s law, the force of cardiac myocyte cardiac myocytes to generate mechanical power at
contraction depends on the resting diastolic length a given preload and afterload. Factors that
of the ventricular fibres (see Chapter 30): increase myocardial contractility are said to exert
increased preload produces an increased SV. a positive inotropic effect, whilst factors that
In practice, preload is very difficult to decrease contractility exert a negative inotropic
measure. It is impossible to measure sarcomere effect. Contractility is difficult to measure directly,
length in vivo, so surrogate measurements are but an index of myocardial contractility is
used: left ventricular end-diastolic volume provided by the rate of change of pressure (i.e. the
(LVEDV; measured by echocardiography) or, gradient) during the isovolumetric contraction
more commonly, left ventricular end-diastolic phase of the cardiac cycle (see Chapter 28 and
pressure.2 Similarly: Figure 28.1).
1
2
In elite athletes, peak CO may be as high as 40 L/min. How does the body regulate CO?
Note: the relationship between end-diastolic volume and CO is not static; it varies depending on the changing
end-diastolic pressure depends on ventricular
compliance, which may vary between patients.
requirements of the body. For example:
121
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:24:24, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.032
Section 3: Cardiovascular Physiology
Age. Taking into account their proportionately diastole, SV falls with a consequent reduction
greater body surface area (BSA, m2), children have in CO (see Chapter 28).
a greater CO than adults. – When HR is rapid, as may occur with
Exercise. CO may increase up to fivefold in ventricular tachycardia, the fall in CO may
normal individuals. be sufficient to cause myocardial ischaemia,
Pregnancy is associated with an increase in resting thus further reducing myocardial contractility;
CO of up to 50% at term. a vicious cycle ensues.
Eating is associated with an increase in CO of Preload. Starling’s law ensures that the cardiac
around 25%. outputs of the RV and LV are exactly matched.
As discussed above, the main factors that influence Therefore, the main determinant of both right and
CO are HR, preload, myocardial contractility and left ventricular preloads is the venous return to the
afterload. The regulation of these four factors is com- RV; that is, RVEDV. Venous return depends on a
plex, as changes in each rarely occur in isolation. number of factors, which are discussed in detail in
However, HR may undergo a threefold increase (e.g. Chapter 37.
from 60 bpm to 180 bpm), whereas SV may only Myocardial contractility is affected by four
increase by around 50% (e.g. from 70 mL to 105 factors:
mL). Under normal circumstances, the major factor – The sympathetic nervous system. Release of
that influences CO is therefore HR. noradrenaline from cardiac sympathetic
HR is set by sinoatrial (SA) node pacemaker neurons (and to a lesser extent circulating
activity, which is in turn modulated by the noradrenaline and adrenaline) increases
autonomic nervous system (ANS): myocardial contractility through its action on
β1-adrenoceptors.
– A denervated heart has a basal HR of around
– Tachycardia. Intrinsic myocardial contractility
100–120 bpm.
is increased when the HR is high. This is
– At rest, the parasympathetic nervous system
known as the ‘Bowditch effect’.
(via the vagus nerve) is tonically active in the
– Drugs with positively inotropic effects include
heart (note: this is an exception for the ANS;
dobutamine, isoprenaline, glucagon,
elsewhere, it is the sympathetic nervous system
enoximone and digoxin. Drugs with negatively
that is tonically active). Acetylcholine is
inotropic effects include β-blockers, Ca2+
continually released from parasympathetic
channel blockers and anaesthetic agents.
nerve terminals, reducing the resting HR to
60–70 bpm through its effect at muscarinic – Disease states may reduce myocardial
M2 receptors. contractility, such as sepsis, myocarditis,
ischaemic heart disease, electrolyte and acid–
– At the onset of exercise, parasympathetic tone
base disturbance.
is withdrawn, which increases HR.
Noradrenaline is released from sympathetic Positive inotropy increases myocardial O2
nerve terminals and adrenaline is released demand. As myocardial contractility increases,
from the adrenal medulla, both of there may come a point where O2 delivery
which increase HR through activation becomes insufficient, resulting in myocardial
of β1-adrenoceptors. ischaemia. This is especially so in patients with
coronary artery disease, where atherosclerosis
CO decreases with bradycardia and increases with
limits coronary blood flow. Ischaemic
tachycardia. However, tachycardia is not always
myocardium cannot contract as effectively, and
beneficial:
this compromises SV.
– Up to around 140 bpm, CO increases with Afterload, which is governed by SVR. As
increasing HR. discussed above, an increase in afterload results in
– Above 150 bpm, the diastolic cardiac filling a reduction in SV. As less blood is ejected from the
time becomes very short (~0.15 s). As heart per beat, there is a greater volume of blood
ventricular filling can only occur during remaining in the ventricle at end-systole and
122
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:24:24, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.032
Chapter 29: Cardiac Output and Its Measurement
therefore (following the ventricular filling phase) a Likewise, SV can be standardised based on BSA,
greater LVEDV. According to Starling’s law, a resulting in the SV index (SVI):
greater LVEDV produces a greater SV. Overall,
following a sudden increase in afterload, SV Key equation: SVI
transiently decreases before gradually returning to
normal. SV
SVI ¼
In addition, an increase in afterload causes BSA
an intrinsic increase in inotropy. This ‘Anrep Normal resting SVI is 33–47 mL m–2 beat–1.
effect’ ensures that increases in afterload
cause smaller reductions in SV than would be
predicted from the Frank–Starling mechanism
How is MAP related to CO?
alone. MAP describes the average arterial pressure during a
single cardiac cycle. Pressure and flow are related by
What is the Bowditch effect? Darcy’s law:
The Bowditch effect (also known as the ‘Treppe effect’ Pressure = flow resistance
or the ‘staircase effect’) is an intrinsic autoregulatory In the case of MAP and CO:
phenomenon in which tachycardia leads to increased
myocardial contractility. The mechanism for this is Key equation: determinants of MAP
thought to be:
MAP ≈ CO SVR
As HR increases, the time period for each cardiac NB: This equation holds if right atrial pressure is
cycle falls, with the diastolic interval shortened assumed to be much smaller than MAP. The equation
more than the systolic interval. is an oversimplification – in formal terms, arterial and
At high HR, there is increased systolic Ca2+ influx venous circulations should be considered separately,
through the L-type Ca2+ channels. because pressure generation in each circulation
+
In addition, the diastolic Na efflux due to the occurs by different mechanisms.
+ +
Na /K -ATPase cannot keep pace with the systolic
influx of Na+.
+ 2+ In turn, SVR is dependent on the radius of the
The Na /Ca exchanger is normally responsible arterioles, and (to a much lesser extent) the blood
for the low intracellular Ca2+ concentration. viscosity.
However, with tachycardia, the increase in Therefore, at a given CO:
cytosolic Ca2+ and Na+ concentrations leads to an
accumulation of intracellular Ca2+, with a MAP is increased by:
consequent positive inotropic effect. This is also – Vasoconstriction, as might take place following
seen with digoxin therapy, where the Na+/K+- catecholamine release.
ATPase is blocked. – Increased blood viscosity, as occurs in patients
with paraproteinaemia or polycythaemia
What is the cardiac index? rubra vera, who are consequently often
hypertensive.
The typical resting CO in a 70‑kg adult is said to
be 5–6 L/min, but varies with body size. Cardiac MAP is decreased by:
index (CI) is a means of standardising CO based – Vasodilatation, as occurs in septic shock or
on BSA. following general anaesthesia.
– Decreased blood viscosity.
Key equation: CI
Clinical relevance: aortic stenosis
CO
CI ¼
BSA Aortic stenosis is a degenerative disease of the aortic
–1 –2 valve. Lifetime incidence is estimated at 1%. The
Normal resting CI is 3.0–3.5 L min m .
most common cause of aortic stenosis is repeated
123
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:24:24, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.032
Section 3: Cardiovascular Physiology
Classify the methods of measuring CO where Q is the blood flow to the organ per minute,
M is the number of moles of substance added or
CO is a measure of overall cardiovascular blood flow removed from the blood per minute, A is the arterial
and is therefore considered one of the most important concentration of substance and V is the venous con-
cardiovascular parameters. In 1928, Adolf Jarisch centration of substance.
wrote: ‘It is a source of regret that measurement of
flow is so much more difficult than measurement of The Fick principle can be applied in a number of
pressure. This has led to an undue interest in the ways to determine CO:
124
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:24:24, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.032
Chapter 29: Cardiac Output and Its Measurement
Using O2 as the substance, as in the direct Fick For this reason, other methods based on the Fick
method. As the entire CO passes through the principle were developed.
lungs (i.e. pulmonary blood flow equals CO) and Dye dilution method. A known amount of
the lungs add O2 to the blood, the Fick principle indicator dye is injected directly into the
can be applied to determine the CO: pulmonary artery (a PAC is therefore required)
and its concentration is continuously sampled at a
Key equation: Fick principle applied to O2 peripheral arterial line. Indocyanine green was
traditionally used as the indicator dye, as it has
V_ O2
COðmL=2pt min Þ ¼ low toxicity and a short half-life. An alternative
C a O2 C v O2 indictor is lithium, which can be measured using a
where V̇ O2 (mL/min) is the rate of O2 uptake, CaO2 lithium-sensitive electrode incorporated into an
(mLO2/mL blood) is the arterial O2 content and CvO2 arterial catheter. The change in indicator
(mLO2/mL blood) is the mixed venous O2 content. concentration over time is recorded as a graph
(Figure 29.1a). CO can then be calculated from the
– CaO2 can be determined by peripheral arterial integral of this curve (i.e. the area under the curve)
blood gas analysis (see Chapter 8). and the amount of indicator substance using a
– CvO2 can be determined by analysing a mixed modification of the Fick equation:
venous sample from a PAC.3 Some PACs are
Key equation: the Stewart–Hamilton equation
modified with a fibre-optic bundle
incorporated in the catheter to continuously
measure mixed venous haemoglobin O2 amount of indicator
saturation SvO2. CO ¼ Ð ∞
concentration of indicator dt
– V̇ O2 over 1 min can be determined by asking 0
125
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:24:24, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.032
Section 3: Cardiovascular Physiology
(a) (b)
Log10 (concentration)
Concentration
Primary passage
0 5 10 15 20 0 5 10 15 20
Time (s) Time (s)
Figure 29.1 Indicator dye technique: (a) concentration–time graph and (b) logarithmic transformation.
(a) (b)
Time (s)
0 5 10 15 20
0
–0.5
–1.0
0 5 10 15 20
Time (s)
Figure 29.2 Thermodilution method: (a) temperature–time curve and (b) logarithmic transformation.
– 10–15 mL of cold saline is injected through the The thermodilution method became the gold
most proximal lumen of the PAC (located in standard4 against which other methods of CO
the RA). assessment are compared. The thermodilution
– The change in pulmonary arterial blood method became popular as:
temperature is measured by the thermistor, – Blood sampling is not required.
resulting in a temperature–time graph – There is no second recirculation peak in the
(Figure 29.2a). temperature–time graph, the main source of
– CO is calculated using a modification of the inaccuracies with the dye dilution method.
Stewart–Hamilton equation: – It can be used accurately in the presence of
intra-aortic balloon pumps and arrhythmias.
Key equation: modified Stewart–Hamilton
equation – Inaccuracies (such as variation in the speed of
injection of the cold saline) can be reduced by
V ðT B T I ÞK 1 K 2 performing three or four measurements and
CO ¼ Ð∞
averaging the results.
0 T B ðt Þ dt
100
Area under the curve (AUC)
80
60
0 1 2
Time (s)
However, the use of the PAC is associated with a The commercially available pulse contour ana-
number of serious complications: arrhythmias, lysis systems can be classified as calibrated or non-
infection, tricuspid and pulmonary valve calibrated. An overview is provided below.
damage and pulmonary artery rupture. In 2005, Calibrated systems: PiCCO and LiDCO.
a study investigating the use of PACs in the
– PiCCO (pulse contour CO) uses a standard
management of intensive care patients (the
central line and a thermistor-tipped arterial
PAC-Man study) found no clear evidence of
line sited at the femoral, brachial or axillary
benefit or harm. Since then, the worldwide use
artery. CO is estimated by analysis of the
of the PACs has significantly reduced, as
arterial pressure waveform. The PiCCO
intensivists move towards other (arguably less
system is calibrated using a transpulmonary
accurate) methods of CO estimation or
thermodilution method in which cold saline
alternatively abandon CO monitoring entirely
is injected into the central line and the
(see Further reading).
resulting blood temperature change is
detected at the arterial line. This introduces
Methods based on pulse contour analysis an element of error when compared with the
As discussed in Chapter 35, the morphology of the thermodilution method using a PAC, as heat
arterial pressure waveform is related to SV and SVR. is dissipated as the cold injectate passes
A continuous estimate of CO is produced by means through the lungs.
of a computer-based algorithm. The commercially – LiDCO (lithium dilution CO) requires only a
available pulse contour analysis systems each use standard arterial line. The arterial pressure
their own patented algorithm for estimating CO waveform is analysed in a similar way to
(Figure 29.3). In addition to CO, a number of other PiCCO.5 The LiDCO system is calibrated by a
variables are measured or derived, including HR, SV, lithium dilution method whereby lithium
CI and SV variation (SVV). chloride is injected into a peripheral or central
SV varies throughout the respiratory cycle as a vein and the fall in its arterial concentration
result of changes in venous return to the heart with is measured by a lithium electrode sampling
changes in intrathoracic pressure. SVV is a measure the arterial line. Recalibration should be
of the difference between the maximum SV and the
minimum SV within a respiratory cycle, and it is used
as a measure of fluid responsiveness. The CO of a 5
There is a subtle difference in the analysis of the arterial
patient with an SVV 15% is likely to increase with pressure waveform using LiDCO – the algorithm is based
fluid administration, whereas a patient with an SVV on ‘pulse power analysis’ rather than ‘pulse contour
< 10% is unlikely to respond to additional fluid. analysis’.
127
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:24:24, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.032
Section 3: Cardiovascular Physiology
performed every 8 h, or whenever major mouth into the oesophagus. The tip of the probe is
haemodynamic changes occur. The use of adjusted so that it lies immediately alongside the
lithium avoids the error introduced by heat descending thoracic aorta. The ultrasound beam is
dissipation when thermodilution is used for orientated at an angle of 45° to the aortic blood
calibration. However, the LiDCO cannot be flow, where it reflects off the passing red blood
calibrated in patients who take therapeutic cells (RBCs). As the RBCs are in motion, the
lithium (e.g. bipolar disorder), and frequent ultrasound beam is reflected at a different
calibration (and therefore repeated doses of frequency – this is the Doppler principle. Using
lithium) results in inaccuracies. In addition, the Doppler equation, the velocity of blood flow
muscle relaxants may cross-react with the within the descending thoracic aorta can be
lithium electrode. calculated:
Uncalibrated systems: FloTrac/Vigileo and
Key equation: the Doppler equation
LiDCOrapid.
– FloTrac/Vigileo: this system uses a specialised Fdc
V¼
pressure sensor (FloTrac) attached to a 2F o cos θ
standard arterial line. The pressure transducer where V is the velocity of blood in the descending
is connected to a Vigileo monitor, where the thoracic aorta, F0 is the transmitted ultrasound fre-
arterial pressure waveform is analysed. The quency, Fd is the change in frequency (Doppler shift)
FloTrac/Vigileo algorithm is not externally of the reflected ultrasound, θ is the angle between
calibrated; instead, it uses an estimate of aortic the ultrasound beam and the bloodstream (45°) and
vascular compliance based on population c is the velocity of ultrasound in tissue (1540 m/s).
demographics and the patient’s age, height,
gender and weight. Blood flow in the descending thoracic aorta is
– LiDCOrapid: this system is based on the determined by multiplying the measured blood
same pulse power analysis algorithm as velocity by the cross-sectional area of the descend-
the LiDCO system. However, like the ing thoracic aorta, which is estimated from a
FloTrac/Vigileo system, LiDCOrapid is nomogram (using the patient’s height and weight)
uncalibrated, using nomograms based on based on cadaveric studies.6 CO is calculated from
demographic data. aortic blood flow on the basis that 70% of SV
In general, pulse contour analysis shows good correl- passes through the descending thoracic aorta, with
ation with PAC thermodilution methods. However, a the remainder flowing to the upper body.
number of situations may make pulse contour analy- In addition to SV, HR and CO, a number of
sis inaccurate: other cardiovascular parameters are derived from
the oesophageal Doppler waveform (Figure 29.4),
An over- or under-damped arterial line trace;
including:
Cardiac arrhythmias;
– Stroke distance (SD), the area under the
Aortic regurgitation;
velocity–time curve. SD is the distance in
An intra-aortic balloon pump.
centimetres that a column of blood moves
along the aorta with each heartbeat.
Describe the minimally invasive – Peak velocity (PV), the highest blood velocity
methods of CO estimation recorded during systole. PV is an indicator of
The proximity of the heart and great vessels to the left ventricular contractility. The normal range
oesophagus allows the use of ultrasound-based tech- of PV alters with age: 90–120 cm/s for a
niques to estimate CO. Two methods are commonly 20-year-old, decreasing to 50–80 cm/s for a
used in clinical practice: 70-year-old.
Oesophageal Doppler (CardioQ). A small
ultrasound transducer mounted on the tip of a 6
Newer machines use M-mode ultrasound to measure the
flexible probe is inserted through the nose or
diameter of the aorta.
128
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:24:24, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.032
Chapter 29: Cardiac Output and Its Measurement
0 1 2 Time (s)
Flow time
Cycle time
129
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:24:24, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.032
Section 3: Cardiovascular Physiology
N. Herring, D. J. Paterson. Assessment of cardiac methods: impact on fluid management and postoperative
output and arterial pulse. In: N. Herring, D. J. outcome. Br J Anaesth 2017; 119(1): 22–30.
Paterson. Levick’s Introduction to Cardiovascular B. Saugel, M. Cecconi, J. Y. Wagner, et al. Noninvasive
Physiology, 6th edition. Boca Raton, CRC Press, 2018; continuous cardiac output monitoring in perioperative and
113–20. intensive care medicine. Br J Anaesth 2015; 114(4): 562–75.
D. A. Reuter, S. Kalman. From ‘goal-directed S. Ghosh, B. Arthur, A. A. Klein. NICE guidance on
haemodynamic therapy’ to ‘individualised perioperative CardioQ™ oesophageal Doppler monitoring. Anaesthesia
haemodynamic management’. Br J Anaesth 2018; 120(4): 2011; 66(12): 1081–7.
615–6.
S. Jhanji, J. Dawson, R. M. Pearse. Cardiac output
F. Michard, M. T. Giglio, N. Brienza. Perioperative goal- monitoring: basic science and clinical application.
directed therapy with uncalibrated pulse contour Anaesthesia 2008; 63: 172–81.
130
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:24:24, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.032
Section 3 Cardiovascular Physiology
30
What is Starling’s law of the heart? length corresponds to an optimal point where the
number of actin and myosin crossbridges formed
The Frank–Starling law (also known as Starling’s law is high (Figure 30.2b) but there is no overlapping
of the heart) states that the strength of ventricular of the thin filaments. In a normal heart, this
contraction is dependent on the length of the resting optimal sarcomere length corresponds to an
fibres. In other words, when all other factors are kept LVEDP of approximately 10–12 mmHg.
constant, an increase in left ventricular preload causes
When the sarcomere is shorter than 2.2 μm (i.e.
stroke volume (SV) to increase, without the need
end-diastolic volume is decreased and the
for extrinsic neural or humoral regulatory mechan-
sarcomere is less stretched), overlapping of thin
isms. As left ventricular preload (i.e. left ventricular
filaments reduces the tension that may be
end-diastolic volume, LVEDV) is difficult to measure,
generated (Figure 30.2a):
left ventricular end-diastolic pressure (LVEDP) is often
used as its surrogate marker. The relationship between – Contractile energy is lost due to work against
SV and LVEDP is nonlinear (Figure 30.1). friction.
The mechanism of Starling’s law remains – The sarcomere becomes distorted.
incompletely understood. It has been traditionally When the sarcomere is stretched beyond 2.2 μm,
attributed to the degree of overlap of the actin and fewer actin–myosin crossbridges are formed; the
myosin myofilaments in diastole, which in turn deter- force of contraction is thus reduced (Figure 30.2c).
mines the extent of crossbridge formation on This situation does not occur in the normal heart,
activation. This is known as the length–tension but may occur in ventricular failure.
relationship: At 3.6 μm, there is no overlap between actin and
The maximal force of contraction occurs when the myosin myofilaments; the active tension
sarcomere is stretched to around 2.2 μm. This developed is zero (Figure 30.2d).
Normal
75
Negative inotropy
50
25
0
0 5 10 15 20
Left ventricular end-diastolic pressure (mmHg)
131
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:26:33, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.033
Section 3: Cardiovascular Physiology
(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 ( m)
The most important consequence of the Frank– suffer considerable morbidity. Systolic heart
Starling mechanism is the matching of SV between failure occurs when the strength of myocardial
the right and left sides of the heart. An increase in contraction is inadequate due to:
venous return to the right ventricle (RV) increases its – Dysfunction of myocytes as a result of
SV, resulting in a greater pulmonary blood flow, a ischaemia (coronary artery disease),
greater LVEDV and hence a greater left ventricular inflammation (myocarditis), congenital
SV. If the left ventricle (LV) ejected just 1 mL of blood disease (Duchenne muscle dystrophy) or
less than the RV per cycle, after an hour the pulmon- following myocardial infarction and scar
ary circulation would contain over 3 L of additional formation. The reduction in SV leads to an
blood. increased LVEDV, and in turn the size of the
heart is increased; this pathological dilatation
What is cardiac failure? of the heart is known as cardiomegaly.
Cardiac failure (or heart failure) is said to occur when – Chronically raised afterload; for example,
the heart is unable to provide sufficient cardiac output systemic hypertension or aortic stenosis.
(CO) to meet the demands of the tissues. Heart failure Chronically increased afterload causes a
may either be: compensatory left ventricular concentric
High-output heart failure: CO is normal, but the hypertrophy. Over time, further increases in
tissue O2 demand is high, such as in thyrotoxicosis afterload exceed the heart’s ability to
and pregnancy. compensate by hypertrophy. SV becomes
Low-output heart failure: the tissue’s O2 demand reduced and LVEDV increased.
is normal, but the CO is insufficient to meet it. Whatever the cause, the heart must then
In low-output failure, either the RV or LV may be expend more energy to achieve a normal SV. This
affected in isolation, resulting in right ventricular increases myocardial O2 demand, thus reducing
failure (RVF) or left ventricular failure, respectively. cardiac reserve. A vicious positive feedback ensues
In addition, progressive pump failure of the LV during periods of increased demand (e.g. during
may lead to RVF – this is known as congestive cardiac exercise), where increased myocardial O2 demand
failure. Heart failure may be classified as follows: in the face of low output exacerbates the failure.
Diastolic heart failure, in which ventricular
Systolic heart failure, in which the pump function
compliance is reduced, either as a result of
of the heart is impaired; that is, ejection fraction is
reduced to below 45% (Figure 30.3). At 20%, the impaired ventricular relaxation (e.g. in ischaemic
annual mortality of patients with systolic heart heart disease, restrictive cardiomyopathy) or as a
failure is higher than many cancers; patients also result of pathological ventricular hypertrophy (e.g.
132
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:26:33, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.033
Chapter 30: Starling’s Law and Cardiac Dysfunction
75
Reduced SV
Failing ventricle
50
25
Normal LVEDV of 120 mL
0
0 20 40 60 80 100 120 140 160 180 200
LVEDV (mL)
100
75
Failing ventricle with sympathetic compensation
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
LVEDV (mL)
133
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:26:33, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.033
Section 3: Cardiovascular Physiology
Sympathetic stimulation. This causes both an of smaller radius. This again increases the myocardial
increase in myocardial contractility and an work required to generate the same pressure.
increase in heart rate, thereby maintaining CO
despite the reduced SV. Over time, the heart
becomes less responsive to this sympathetic What are the clinical consequences of
nervous system activity, as β-receptors are decompensated heart failure?
downregulated. Decompensated heart failure has many effects, classified
An expansion in blood volume. A reduction in into forward heart failure and backward heart failure:
CO results in a fall in renal blood flow (RBF). The Forward heart failure. The heart is unable to
kidneys respond by increasing plasma volume pump sufficient blood to meet the metabolic
through the renin–angiotensin–aldosterone demands of the body. Consequences of left
(RAA) axis; the increase in blood volume results ventricular forward heart failure include:
in an increase in left ventricular preload. An
increase in LVEDV results in an increase in SV, – Renal failure. Reduced RBF causes kidney
according to Starling’s law. This is offset to some dysfunction and activation of the RAA axis.
extent through the production of atrial natriuretic This has the effect of further expanding plasma
peptide and brain natriuretic peptide by the heart, volume, exacerbating backward heart failure.
which causes a natriuresis. – Exercise. The LV cannot meet the increased O2
demand associated with exercise, resulting in
As the disease progresses, the heart reaches a point fatigue. As heart failure worsens, the onset of
where, despite compensatory mechanisms, it can no fatigue occurs after minimal exercise, and then
longer eject a normal SV. CO then falls, resulting in a at rest. This is reflected in the New York Heart
situation termed ‘decompensated heart failure’. Association classification of heart failure.
The cardiac sarcomeres are stretched beyond their
– Coronary circulation. Acute left ventricular
optimal length and the tension generated during con-
dysfunction may lead to cardiogenic shock:
traction is reduced (Figure 30.2). Beyond the opti-
reduced CO causes a fall in coronary blood
mum sarcomere length, increases in preload only
flow. In turn, myocardial ischaemia reduces
serve to further decrease SV, represented by the
myocardial contractility, reducing CO further
Frank–Starling curve in Figure 30.5. Additionally,
and leading to a vicious cycle.
when the heart has a large ventricular radius, it is at
a mechanical disadvantage due to Laplace’s law (see Backward heart failure. The increase in LVEDV
results in an abnormally high atrial pressure:
Chapter 20). Therefore, for the same active tension
generated in the ventricular wall, an LV of greater – Increased left atrial pressure causes an increase
radius will produce a lower pressure than a ventricle in interstitial pressure in the pulmonary
50
25
0
0 20 40 60 80 100 120 140 160 180 200
LVEDV (mL)
134
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:26:33, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.033
Chapter 30: Starling’s Law and Cardiac Dysfunction
circulation. As left atrial pressure increases, the the absorption of nutrients (leading to the
balance of Starling filtration forces (see condition of cardiac cachexia) and drugs. Gut
Chapter 36) favours fluid extravasation in the wall oedema may also facilitate the
lung bases, resulting in pulmonary oedema translocation of intestinal flora across the
and dyspnoea. Chronically increased gut wall. Bacteria may produce vasodilatory
pulmonary venous pressure increases right cytokines, which can further decompensate
ventricular afterload, which may cause RVF. heart failure.
When the patient is supine (e.g. overnight),
redistribution of blood from the legs Further reading
further increases the venous return to the
N. Herring, D. J. Paterson. Control of stroke volume and
heart. As the LV is unable to increase its cardiac output. In: N. Herring, D. J. Paterson. Levick’s
output any further, the effect of this increase Introduction to Cardiovascular Physiology, 6th edition.
in blood volume is further pulmonary Boca Raton, CRC Press, 2018; 87–112.
oedema. This leads to paroxysmal nocturnal H. Fukuta, W. C. Little. The cardiac cycle and the
dyspnoea. physiological basis of left ventricular contraction,
– Increased right atrial pressure results in an ejection, relaxation and filling. Heart Fail Clin 2008; 4
increase in central venous pressure. The (1): 1–11.
Starling filtration forces favour fluid R. Pirracchio, B. Cholley, S. De Hert, et al. Diastolic heart
extravasation, initially in the dependent areas, failure in anaesthesia and critical care. Br J Anaesth 2007;
resulting in ankle and sacral oedema. More 98(6): 707–21.
advanced RVF results in ascites and L. Groban, J. Butterworth. Perioperative management of
hepatomegaly, which may be associated with chronic heart failure. Anesth Analg 2006; 103(3): 557–75.
liver dysfunction (e.g. coagulopathy). L. Mandinov, F. R. Eberli, C. Seiler, et al. Diastolic heart
Extravasation of fluid into the intestine failure. Cardiovasc Res 2000; 45(4):
results in gut wall oedema, which can reduce 813–25.
135
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:26:33, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.033
Section 3 Cardiovascular Physiology
31
Describe the left ventricular pressure– Ventricular ejection, in which the stroke volume
(SV) is ejected into the aorta.
volume loop Isovolumetric relaxation, a vertical line
The left ventricular pressure–volume loop provides a representing the fall in intraventricular pressure
useful representation of left ventricular performance without a change in ventricular volume.
through the cardiac cycle (Figure 31.1; see also Diastolic ventricular filling, in which the ventricle
Chapter 28, Figure 28.1). fills with blood ready for the next contraction.
In a normal left ventricle (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 change when preload is increased?
representing the increase in intraventricular Preload can be thought of as the volume of blood
pressure without a change in ventricular volume. within the ventricle prior to contraction (see
120
Systolic BP
Left ventricular pressure (mmHg)
80
contraction
Isovolumetric
relaxation
60
40
0
0 20 40 60 80 100 120 140 160
Left ventricular end- Left ventricular volume (mL)
diastolic pressure Stroke volume
End-systolic volume
136
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 02 Aug 2019 at 02:00:46, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.034
Chapter 31: Cardiac Pressure–Volume Loops
Chapter 29). For the LV, it is the left ventricular end- the shortening of cardiac myocytes. As afterload
diastolic volume (LVEDV). According to Starling’s increases (e.g. due to an increase in diastolic aortic
law, an increase in preload results in a greater dia- pressure), both the rate and extent of sarcomere
stolic stretch of the contractile myocardial fibres (see shortening decrease, resulting in a reduction in SV:
Chapter 30). The stretched sarcomeres contract more As a reduced volume of blood is ejected from the
forcefully, thus increasing SV (Figure 31.2). LV, the LVESV is increased.
Figure 31.2 illustrates a number of important features: In turn, the addition of the venous return leads to
The width of the pressure–volume loop, which an increase in LVEDV.
represents SV, is increased due to the increase in According to Starling’s law, an increase in LVEDV
LVEDV. The left ventricular end-systolic volume causes an increase in myocardial contractility.
(LVESV) increases slightly due to an increase in Thus, SV increases, returning LVEDV to near
afterload (aortic pressure) caused by the greater normal.
cardiac output.
Overall, the increase in LVESV is greater than that of
The end-diastolic pressure–volume relationship LVEDV. SV is slightly decreased, and the left ven-
(EDPVR) line reflects the passive diastolic tricular pressure–volume loop looks taller and thinner
compliance of the LV. Beyond a certain preload, (Figure 31.3a).
left ventricular end-diastolic pressure (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 contractility alter the pressure–
the myocardium reaching their elastic limit.
volume loop?
Myocardial contractility may be altered extrinsically by
How does the pressure–volume loop the autonomic nervous system, circulating hormones
change when afterload is increased? or positively inotropic drugs. It is therefore independ-
Afterload is the stress developed in the left ventricular ent of preload and afterload. Graphically, increased
wall during ejection, and it reflects the force opposing contractility (positive inotropy) increases the gradient
120
Left ventricular pressure (mmHg)
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
Figure 31.2 Effect of increased preload on the pressure–volume loop (BP = blood pressure; EDPVR = end-diastolic pressure–volume
relationship; LVEDP = left ventricular end-diastolic pressure).
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 02 Aug 2019 at 02:00:46, subject to the Cambridge Core terms of use, available at137
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.034
Section 3: Cardiovascular Physiology
160 160
Increased Increased contractility
systolic and
140 140
diastolic BP
Left ventricular pressure (mmHg)
100 100
80 80
60 60
40 40 LVEDV is
EDPVR
LVESV is lower slightly lower
20 20
0 0
0 20 40 60 80 100 120 140 160 180 200 0 20 40 60 80 100 120 140 160
Stroke volume Left ventricular Stroke volume Left ventricular
is reduced volume (mL) is increased volume (mL)
Figure 31.3 Effect of (a) increased afterload and (b) increased contractility on the pressure–volume loop (BP = blood pressure).
120
Following the addition of venous return, LVEDV is
reduced. As positive inotropy decreases LVESV more 100 Area = external work
than LVEDV, overall SV is increased.
80
138
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 02 Aug 2019 at 02:00:46, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.034
Chapter 31: Cardiac Pressure–Volume Loops
The total work done – that is, the sum of external and Increased afterload may not increase external
internal work – is known as the pressure–volume area work significantly, but does increase internal work
(PVA). PVA correlates surprisingly well with the myo- (Figure 31.3a); thus, myocardial O2 demand
cardial O2 consumption for the heart. Note: whilst increases.
mechanical work accounts for most of the heart’s Increased myocardial contractility may not
energy expenditure, basal metabolism accounts for a increase internal work, but does increase external
small percentage, resulting in a small discrepancy work (Figure 31.3b). Overall, myocardial O2
between PVA and myocardial O2 consumption. consumption is increased.
Looking back at Figures 31.2 and 31.3, it can be
seen that: How does the pressure–volume loop of
Increased preload leads to increased external work
(Figure 31.2); thus, myocardial O2 demand is higher. the right ventricle compare with that of
the left?
The right ventricular pressure–volume loop has a
characteristic triangular shape (Figure 31.5). Some
Right ventricular pressure (mmHg)
120 120
Left ventricular pressure (mmHg)
Left ventricular pressure (mmHg)
100 100
Increased LVEDP,
80 80 reduced LVEDV
60 60
EDPVR
40 EDPVR 40
20 20 Reduced left
Increased
ventricular
EDV
compliance
0 0
0 20 40 60 80 100 120 140 160 180 200 0 20 40 60 80 100 120 140 160 180 200
Left ventricular Stroke volume Left ventricular
Stroke volume volume (mL) volume (mL)
reduced reduced
Figure 31.6 Left ventricular (a) systolic failure and (b) diastolic failure.
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 02 Aug 2019 at 02:00:46, subject to the Cambridge Core terms of use, available at 139
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.034
Section 3: Cardiovascular Physiology
In the RV, stroke work makes up a greater contractility (reduced gradient of the ESPVR line) and
proportion of the total work than the LV does. an increase in LVEDV. A subnormal SV is ejected
The RV is therefore more susceptible to failure from the LV, resulting in a higher than normal
in the presence of pulmonary hypertension LVESV (Figure 31.6a).
than the LV is in the presence of systemic Left ventricular diastolic failure is due to reduced
hypertension. left ventricular compliance. The EDPVR line follows
a different course, but the contractility of the LV
How does the left ventricular pressure– (the ESPVR line) is unchanged. Overall, SV is reduced
(Figure 31.6b).
volume loop change in heart failure?
As discussed in Chapter 30, left ventricular failure is Further reading
classified as systolic, diastolic or mixed. Left ventricu- R. E. Klabunde. Cardiovascular Physiology Concepts, 2nd
lar systolic failure results in a reduction in myocardial edition. Philadelphia, Lippincott Williams & Wilkins, 2011.
140
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 02 Aug 2019 at 02:00:46, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.034
Section 3 Cardiovascular Physiology
Cardiac Ischaemia
Chapter
32
How does the oxygen extraction ratio of (either troponin T or troponin I isoform) above the
upper reference range, with at least one of:
the heart compare to other organs? Typical anginal symptoms;
The oxygen extraction ratio (OER) is the ratio of New significant ST-segment or T-wave changes
oxygen consumption, V̇ O2, to oxygen delivery, ḊO2 on the electrocardiogram (ECG), which may be
(see Chapter 17). At around 60%, the OER of the dynamic in nature, or new left bundle branch
heart is near maximal. This is in contrast to the lower block (LBBB);
OERs of the liver (around 50%), the kidney (around Development of pathological Q-waves on the ECG
15%) and skeletal muscle (between 10% and 100% in established infarct;
depending on activity).
New regional wall abnormality on
During exercise, myocardial V̇ O2 increases by up echocardiography.
to fivefold. Normally, coronary blood flow increases
to match the increase in V̇ O2 through coronary vaso-
dilatation (see Chapter 27). However, when the flow Describe the typical symptoms
of blood is limited by coronary arterial stenosis, a associated with MI
mismatch between V̇ O2 and ḊO2 occurs, resulting The most common symptom of myocardial ischae-
in myocardial ischaemia. mia is severe central chest pain: tightness, pressure or
squeezing. The pain may classically radiate to the left
What is meant by the term ‘acute arm, neck or lower jaw, but also to the right arm,
coronary syndrome’? shoulder, back or upper abdomen. Other associated
symptoms include autonomic features (sweating,
Acute coronary syndrome encompasses a range of
nausea or vomiting), dyspnoea, syncope and fatigue.
conditions that are due to an acute interruption of
In a significant proportion of cases, patients experi-
myocardial perfusion. It includes:
ence no symptoms of MI – this is termed a ‘silent MI’.
ST-segment elevation myocardial Presentation in women is more likely to be atypical,
infarction (STEMI); which may delay presentation and diagnosis.
Non-ST-segment elevation myocardial infarction Anaesthetised patients cannot complain of chest
(NSTEMI); pain. The anaesthetist must instead rely on clinical
Myocardial ischaemia without evidence of signs to detect myocardial ischaemia: ECG changes,
myocyte necrosis (e.g. unstable or crescendo cardiovascular instability, arrhythmias, hypoxia and
angina). increased airway pressures due to pulmonary oedema,
as well as (if transoesophageal echo is being used)
How is a myocardial infarction regional wall abnormalities.
diagnosed? What is the physiological mechanism for
The diagnosis of myocardial infarction (MI) requires
evidence of myocardial necrosis in a clinical setting referred cardiac pain?
consistent with acute MI. In practice, this usually Visceral pain is often referred to (i.e. perceived as
means a rise in measured serum cardiac troponin coming from) the surface of the body. In addition to
141
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:14:07, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.035
Section 3: Cardiovascular Physiology
efferent sympathetic and parasympathetic neurons (see Complete occlusion of a coronary artery results in a
Chapter 59), the heart is innervated by unmyelinated full-thickness MI (with ST-segment elevation on the
afferent sympathetic neurons. Myocyte ischaemia trig- ECG), while partial occlusion of a coronary artery
gers these afferent neurons to transmit action poten- results in a partial thickness or subendocardial MI
tials, through the cardiac plexus, to synapse in the dorsal (with ST-segment depression and/or T-wave inver-
horn of the spinal cord. It is thought that when the sion on the ECG).
spinal cord is bombarded with sensory information
from a viscus, the signal is instead interpreted as pain
Clinical relevance: ECG changes with myocardial
originating from a dermatome whose afferent sensory ischaemia
neurons also synapse in the same spinal cord segment.
The ECG is a key investigation in the diagnosis of
acute myocardial ischaemia and infarction. Both the
depolarisation (Q-waves and bundle branch blocks)
Clinical relevance: silent MI
and repolarisation (ST-segment and T-wave) of
Up to half of all MIs occur either without any symp- ischaemic myocardium may be abnormal, resulting
toms or with atypical symptoms, and as a result these in characteristic changes to the ECG. These ECG
patients often miss the opportunity for early treat- changes are dependent on the extent and location
ment. Many of these patients develop pathological of ischaemic myocardium. By correlating Einthoven’s
Q-waves on their ECG. Silent MI is as significant a triangle (see Chapter 58) with the anatomical loca-
clinical event as recognised MI, and both carry a tion of injured myocardium and its arteries, the
similar mortality rate. angiographic appearance and certain complications
Two groups of patients at particular risk of silent may be predicted. As a rough guide:
MI are:
Extent of myocardial ischaemia:
Diabetics. As a result of autonomic neuropathy,
– Subendocardial ischaemia/infarction is
there may be abnormal transmission of action
associated with ST-segment depression.
potentials along the afferent sympathetic
– Subepicardial or transmural infarction is
neurons.
associated with ST-segment elevation.
Heart transplant recipients. As the donor heart
is completely denervated, there is no pathway for Location of ischaemia:
the afferent transmission of ischaemic pain
signals. This is of real significance in heart – Inferior wall ischaemia affects leads II, III and
transplant recipients, as the graft coronary aVF. This inferior portion of the heart is
arteries undergo accelerated atherosclerosis. supplied by the right coronary artery and the
posterior interventricular artery. As the right
coronary artery frequently supplies the
How is MI classified? sinoatrial (SA) and atrioventricular (AV) node,
occlusion may result in hypotension and
MI is classified into five types: bradycardia. Complete heart block is a
Type 1 refers to a primary coronary event, such as common presentation of inferior STEMI.
atherosclerotic plaque rupture or coronary – Left main stem ischaemia results in
dissection. widespread ST-depression often affecting
Type 2 is myocardial ischaemia due to either leads I, II and V4–6, with ST-elevation in aVR.
increased oxygen demand or decreased supply in – Lateral wall ischaemia affects leads I, aVL, V5
the context of another acute illness. and V6. This area of the heart is supplied by
the circumflex artery. Infarction results in left
Type 3 is unexpected cardiac death with
ventricular dysfunction.
symptoms suggestive of MI.
– Septal ischaemia affects leads V1 and V2,
Type 4 is associated with percutaneous coronary corresponding to occlusion of a septal branch
intervention (PCI). of the left anterior descending artery. As the
Type 5 is associated with cardiac surgery. interventricular septum is the site of the
The majority of cases of MI are due to spontaneous bundle of His, infarction may cause LBBB.
rupture of an atheromatous plaque. Thrombus rap- – Apical ischaemia affects leads V3 and V4,
corresponding to occlusion of a terminal
idly forms around the damaged vascular lumen.
142
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:14:07, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.035
Chapter 32: Cardiac Ischaemia
143
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:14:07, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.035
Section 3: Cardiovascular Physiology
associated with STEMI. Similar damage may also Genetic/energetic cellular changes;
occur in other organs such as the brain following a The production of ischaemic metabolites (e.g.
stroke. adenosine);
The complications of IRI are as follows: The production of paracrine factors (e.g.
Arrhythmias. Reperfusion results in atrial and endogenous opiates).
ventricular arrhythmias, likely secondary to In experimental studies, preconditioning reduces
disturbed ionic homeostasis and ROS. Accelerated infarct size and complications. Strangely, precondi-
idioventricular rhythm is commonly seen in the tioning need not be via direct occlusion of the coron-
catheter laboratory following reperfusion and is ary arteries. Occluding the brachial artery appears to
usually well tolerated. Other ventricular convey a similar benefit: this is known as remote
arrhythmias, such as ventricular ectopy and preconditioning. Ischaemic preconditioning can be
ventricular tachycardia, may be seen in the mimicked pharmacologically, such as through the
following hours. This is why patients are usually use of isoflurane during coronary bypass surgery.
monitored in a dedicated cardiac critical care unit This is known as anaesthetic preconditioning.
following primary PCI. Reperfusion arrhythmias
usually resolve spontaneously, although scar Further reading
formation may result in an anatomical substrate J. C. Kaski, D. J. Hausenloy, B. J. Gersh, D. M. Yellon (Eds.).
for persistent rhythm disturbance. Management of Myocardial Reperfusion Injury. Berlin,
Contractile dysfunction (so-called myocardial Springer, 2012.
stunning) occurs due to cytosolic Ca2+ overload. M. R. Pinski, A. Artigas, J. F. Dhainaut. Coronary
This can result in symptoms of heart failure, but Circulation and Myocardial Ischemia. New York,
these may resolve with good reperfusion and time. Springer-Verlag, 2002.
Immediate echocardiography is rarely useful for F. van Lier, F. H. I. M. Wesdorp, V. G. B. Liem, et al.
assessing long-term myocardial function. Association between postoperative mean arterial blood
Microvascular damage. Inflammation, leukocyte pressure and myocardial injury after non-cardiac
surgery. Br J Anaesth 2018; 120(1): 77–83.
debris, thrombosis, embolic events and
myocardial oedema may prevent reperfusion of A. R. Chapman, P. D. Adamson, N. L. Mills. Assessment
ischaemic tissue, even when blood flow has been and classification of patients with myocardial injury
and infarction in clinical practice. Heart 2017; 103:
restored to the blocked coronary artery. This is the
10–18.
‘no-reflow’ complication that is associated with
S. Ekeloef, M. Alamili, P. J. Devereaux, et al. Troponin
poor long-term outcomes.
elevations after non-cardiac, non-vascular surgery are
Many therapeutic interventions have been suggested predictive of major adverse cardiac events and mortality:
for IRI; however, none have a conclusive evidence a systematic review and meta-analysis. Br J Anaesth
basis. Approaches include ischaemic preconditioning, 2016; 117(5): 559–68.
therapeutic hypothermia, therapeutic hyperoxaemia, Z.-M. Zhang, P. M. Rautaharju, R. J. Prineas, et al. Race and
anti-inflammatory drugs and free radial scavengers. sex differences in the incidence and prognostic
significance of silent myocardial infarction in the
144
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:14:07, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.035
Section 3 Cardiovascular Physiology
Systemic Circulation
Chapter
33
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.
Only 15% of circulating blood volume is found within
What are the functions of the the arterial system. Most of the circulating blood
circulation? (65%) is found within the venous system due to its
Functions include: greater compliance. The veins thus act as an import-
ant reservoir for blood, with venous tone responsible
Transport of O2 from the lungs to the tissues; for maintaining venous return to the right atrium.
Transport of CO2 from the tissues to the lungs; The remainder of the circulating volume is found
Transport of metabolic waste products from the within the pulmonary circulation (10%), the cardiac
tissues to the liver and kidneys for excretion; chambers (5%) and the capillaries (5%).
Distribution of nutrients from the sites of
absorption (gut) or production (liver) to the
tissues;
What are the main differences between
Distribution of body water and electrolytes the systemic and pulmonary
between intracellular, interstitial and intravascular circulations?
body compartments; The primary function of the pulmonary circulation
Transport of immunologically active substances is the transport of blood from the right ventricle
(antibodies, leukocytes, complement); (RV) to the lungs for participation in gas exchange
Transport of hormones from their site of (see Chapter 23). The RV therefore acts as a
production (e.g. the parathyroid gland) to their flow generator around a low-resistance pulmonary cir-
target site (e.g. the kidney); culation. This is in contrast to the role of the systemic
Production of hormones (e.g. atrial natriuretic circulation, where the LV generates pressure in the
peptide); arterial system. This pressure is then used as the energy
Assisting in thermoregulation by redistributing gradient to perfuse tissues (create flow) according to
blood flow between the core organs and the demand. The transport of blood from the LV to the
the skin. rest of the body is thus determined by local tissue
The transport and distributive properties of the circu- metabolism or by stereotyped responses (e.g. an
lation are utilised by anaesthetists to distribute a increase in sympathetic outflow). The main differences
range of substances: drugs, fluids, nutrition and heat. between the two circulations stem from this pressure
difference (Table 31.1).
What are the constituent parts of the
systemic circulation? What happens to blood velocity as blood
The systemic circulation is composed of: passesthroughthesystemiccirculation?
A ‘pump’ – the left ventricle (LV) – which drives There is an important relationship between blood
blood through the vessels; velocity, flow and cross-sectional area:
145
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 21:20:57, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.036
Section 3: Cardiovascular Physiology
Table 31.1 Differences between the systemic and pulmonary circulations (PVR = pulmonary vascular resistance; SVR = systemic vascular
resistance).
Key equations: blood velocity and flow As blood passes along the arterial system, large
arteries branch into many small arteries, small arter-
Q_ ies branch into many arterioles, and so on. The
V¼
A cross-section of each individual blood vessel
where V (cm/s) is the blood velocity (the distance decreases as its radius decreases. However, the over-
travelled per unit time), Q̇ (mL/s) is the blood all cross-sectional area A summed over all of the
flow (the volume of blood passing a point per unit vessels at a given level of bifurcation increases dra-
time) and A (cm2) is the cross-sectional area of matically. The total blood flow Q̇ remains the same
the vessel. (i.e. cardiac output of 80 mL/s); so, as V = Q̇ /A, if Q̇
remains constant and A is significantly higher, then
For a typical adult, the aortic cross-sectional area the velocity of blood flow must be significantly
is 4 cm2, whilst the mean blood velocity in the aorta reduced (Figure 33.1).
is 20 cm/s. Therefore, typical aortic blood flow is The capillaries account for a combined cross-
80 cm3/s (i.e. 80 mL/s). At a heart rate of 60 bpm, sectional area of around 4000 cm2 (Figure 33.1). Total
there is one cardiac cycle per second; that is, stroke blood flow is the same, so the velocity of blood flow
volume is 80 mL. through the capillaries is:
146
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 21:20:57, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.036
Chapter 33: Systemic Circulation
20 cm/s
4000 cm2 20
Cross-sectional area (cm2)
1000
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
Figure 33.1 Changes in velocity (dotted grey line) and cross-sectional area (solid black line) across the systemic circulation.
147
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 21:20:57, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.036
Section 3 Cardiovascular Physiology
Arterial System
Chapter
34
The arterial system is the high-pressure component of maintaining the diastolic pressure. The expansion
the systemic circulation. The arterial system divides and recoil of the elastic arteries acts to dampen the
from the aorta into large arteries, smaller arteries and pulsatile arterial blood flow.
finally arterioles before joining the capillary networks. Muscular arteries: medium-sized arteries, which
Arteries normally carry fully oxygenated blood to the follow on from the large elastic arteries and, in
capillaries. The two exceptions are the pulmonary turn, divide into the smaller ‘resistance’ arterioles.
arteries and the umbilical arteries in the foetus. 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 smooth
Tunica externa (formerly known as the tunica muscle contraction (vasoconstriction), which
adventitia), the outermost layer, made up of loose narrows the vessel lumen and reduces blood flow.
connective tissue, such as collagen fibres. – Reduced sympathetic activity permits
Tunica media, a thick layer of circumferential vasodilatation, which increases the lumen
smooth muscle and elastic tissue. diameter and increases blood flow. The
Tunica intima, the innermost layer, comprising a mechanism for vasodilatation in this context is
single layer of endothelial cells. Some larger vessels an increase in sheer stress cause by higher
also have a subendothelium, made up of intravascular pressure. This results in a rise in
connective tissue and basement membrane. intracellular Ca2+, leading to increased nitric
oxide synthase activity in endothelial cells, and
Larger arteries have their own blood supply: the vasa thus increased nitric oxide production. Nitric
vasorum, a network of small blood vessels that supply oxide acts as a potent vasodilator of vascular
the outer layers of the arterial wall. smooth muscle.
148
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:30:58, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.037
Chapter 34: Arterial System
Autoregulation
Pressure
149
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:30:58, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.037
Section 3: Cardiovascular Physiology
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 via the sheer stress mechanism. The
of an arteriole to maintain a constant blood overall effect is the maintenance of a relatively
flow despite changes in intraluminal pressure constant blood flow over a range of intraluminal
(see below) (Figure 34.1). pressures. Autoregulation is an important
feature of arterioles in the brain, heart and
What are the functions of the arterioles? kidney, but does not occur in the skin.
– Metabolites. The tissues regulate blood flow in
The arterioles are the vessels with the smallest radii of
proportion to their metabolic rate. When an
the arterial tree and are therefore the main source of
organ increases its metabolic activity, the local
resistance to blood flow. Structurally, their tunica
O2 tension falls and the concentration of
media is made up of one or two layers of circumferen-
metabolites (CO2, H+ ions, lactate) increases.
tial smooth muscle. Vasoconstriction increases the
The arteriole vasodilates in response to
vessel’s resistance to blood flow; this is very sensitive
increased metabolite concentration, increasing
owing to the fourth-power relationship of the radius
blood flow and therefore O2 delivery to the
in the Hagen–Poiseuille equation. Likewise, vasodila-
tissues. This is thought to be the mechanism
tation reduces the vessel’s resistance to blood flow.
behind reactive hyperaemia: the large increase
Compared with arteries, the arterioles lack elastin in
in blood flow following temporary cessation of
their tunica media. Pulsatile blood flow is damped,
organ perfusion (e.g. critical limb ischaemia)
becoming continuous flow by the time the blood
or following deflation of an arterial tourniquet
reaches the capillaries.
in limb surgery.
In addition to conducting blood from small arter-
ies to the capillaries, the arterioles have three other Humoral factors. A number of locally and
roles: systemically produced chemical substances affect
arteriolar smooth muscle tone, including:
Control of the distribution of blood flow to
different organs by altering organ vascular – Kinins (e.g. bradykinin), which cause
resistance; vasodilatation in the salivary glands, gut and
Control of total systemic vascular skin.
resistance (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 36). allergic reactions, the systemic release of
histamine is responsible for widespread
Which factors are involved in arteriolar arteriolar vasodilatation.
– Nitric oxide (NO), previously known as
vasoconstriction and vasodilatation? endothelium-derived relaxing factor,
The control of arteriolar smooth muscle is released from the endothelium in response
complex, influenced by local, humoral and neural to shear stress. NO is a potent arteriolar
factors. vasodilator, increasing blood flow to the
Local factors: damaged area. NO also causes venodilatation;
this is the mechanism underlying a technique
– Myogenic autoregulation. This is an intrinsic
familiar to all anaesthetists: tapping the
property of the arteriolar smooth muscle in
skin overlying a peripheral vein prior to
which the vessel vasoconstricts in response to
cannulation.
increased intraluminal pressure. This occurs
150
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:30:58, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.037
Chapter 34: Arterial System
151
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:30:58, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.037
Section 3: Cardiovascular Physiology
Systole Diastole
120
Systolic BP
Pressure (mmHg)
100
Mean BP
80 Diastolic BP
60
0 1 2 3
Time (s)
152
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:30:58, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.037
Chapter 34: Arterial System
153
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:30:58, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.037
Section 3: Cardiovascular Physiology
154
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:30:58, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.037
Section 3 Cardiovascular Physiology
35
The rate and character of the arterial pulse has been aorta. The aortic wall becomes less compliant, and its
used for millennia for the diagnosis of a wide range of ability to accommodate SV without a large increase in
disorders. Perhaps more useful, however, is the direct pressure reduces. This accounts for the development
cannulation of an artery, which allows quantitative of systolic hypertension in the elderly.
information to be extracted.
Pressure increases as
SBP Systole Diastole blood flows into the aorta
120
Aortic valve closes
Pressure (mmHg)
80
Dicrotic notch
DBP Aortic valve opens
60
0 1 2 3
Time (s)
155
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 16:49:47, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.038
Section 3: Cardiovascular Physiology
120
Pressure (mmHg)
100
MAP
80
60
How does the arterial pressure Myocardial contractility. The slope of the
waveform upstroke is a reflection of myocardial
waveform differ at peripheral arteries? contractility: an increased upstroke gradient
The morphology of the arterial pressure waveform suggests a greater pressure generated per unit
differs depending on where it is measured time. However, a reduced upstroke gradient is
(Figure 35.2). As the site of measurement moves more sometimes seen in aortic stenosis (Figure 35.3a).
distally: In contrast, aortic regurgitation is usually
The arterial upstroke is steeper and SBP is associated with normal myocardial contractility,
increased. but often has a pressure wave with a bisferiens
DBP is decreased. appearance.
Crucially, mean arterial pressure (MAP) is Systemic vascular resistance (SVR). The
relatively constant wherever it is measured; this is downstroke of the arterial pressure
another reason why MAP is the most important waveform gives information about SVR: a
measure of blood pressure. steep downstroke with a low dicrotic notch
The morphology of the dicrotic notch changes: indicates a low SVR – the arterial
waveform looks thin and pointed (Figure 35.3a).
– The dicrotic notch is positioned further down
Likewise, a high dicrotic notch implies a high
the pressure curve.
SVR.
– Rather than being a sharp interruption in the
Hypovolaemia. In positive pressure-ventilated
pressure descent, the dicrotic notch becomes
patients, a respiratory swing in the arterial
more of a dicrotic wave.
pressure waveform is an indicator of
The change in shape and position of the dicrotic hypovolaemia. There is beat-to-beat variation in
wave is due to it being caused by reflections the systolic pressure of the waveform, caused by
of the arterial pressure wave rather than aortic the variation in preload throughout the
valve closure. respiratory cycle (Figure 35.3b).
Arterial pulse contour analysis. SV is
Can any other information be gathered proportional to the area under the systolic portion
of the arterial pressure waveform; arterial pulse
from the arterial pressure waveform? contour analysis allows calculation of the cardiac
Although the arterial pressure waveform is often only output (see Chapter 29). SV variation is calculated
used for measuring SBP, DBP, MAP and heart rate, it by dividing the minimum SV (Area 2) by the
has many other clinical uses: maximum SV (Area 1).
156
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 16:49:47, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.038
Chapter 35: Arterial Pressure Waveforms
100
80
Reduced pulse Increased pulse Low dicrotic High dicrotic
pressure pressure notch notch
60
‘Normal’ Aortic stenosis Aortic regurgitation Low SVR High SVR
100
80
Inspiratory phase Expiratory phase Inspiratory phase
60
0 5 10 15
Time (s)
Figure 35.3 (a) Characteristic changes of the arterial waveform and (b) variation through the respiratory cycle with positive-pressure
ventilation.
157
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 16:49:47, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.038
Section 3 Cardiovascular Physiology
36
What are the roles of the capillaries? (60–80 nm) to allow passage of all but the largest
plasma proteins (i.e. albumin).
The capillaries are tiny vessels (measuring 5–10 μm in
Sinusoidal capillaries, a particular type of
diameter) arranged in an interweaving network called
fenestrated capillary found in the bone marrow
the capillary bed. Capillaries have two main roles:
and lymph nodes. The fenestrations are large
Delivery of nutrients to and removal of enough to allow white blood cells and red blood
metabolites from the tissues; cells (RBCs) to pass through (up to 10 μm). In the
Distribution of body water between intravascular liver and spleen, even greater movement of cells is
and interstitial fluid compartments. required – in addition to large fenestrations, their
In contrast to arteries and veins, the capillary wall is sinusoidal capillaries also lack tight junctions.
almost entirely composed of endothelium and is only These vessels are called discontinuous sinusoidal
one cell thick, supported by a basement membrane. capillaries.
158
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 21:07:44, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.039
Chapter 36: Capillaries and Endothelium
capillaries. Filtration and reabsorption of fluid Forces tending to move fluid out of the capillary:
across the capillary is governed by the balance of – Capillary hydrostatic pressure Pc;
Starling filtration forces. – Interstitial fluid oncotic pressure πi.
Pinocytosis. This is an energy-consuming type of
endocytosis where substances in the capillary Forces tending to move fluid into the capillary:
lumen are enveloped by the endothelial cell – Interstitial fluid hydrostatic pressure Pi;
membrane to form a vesicle. The vesicle is then – Plasma oncotic pressure πc.
transported across the endothelial cell and its
contents released into the interstitium (see Key equation: the Starling filtration equation
Chapter 4). Pinocytosis makes only a minor Net fluid filtration pressure across capillary wall = Kf
contribution to capillary exchange. [(Pc – Pi) – σ(πc – πi)], where Kf is the filtration
Capillary exchange is facilitated by a blood flow pat- coefficient, a constant related to the permeability of
tern known as bolus flow, which is another example the capillary wall (high Kf indicates high water
of the non-Newtonian nature of blood. Capillaries permeability, whilst low Kf indicates low water
have approximately the same diameter as the RBC at permeability); σ is the reflection coefficient, a constant
around 7 μm. For this reason, the RBC only just fits that represents the permeability of the capillary to
through the capillary, often having to deform its proteins (σ = 1 implies that the capillary wall is 100%
biconvex shape. Flow therefore takes place as inter- impermeable).
mittent RBC and plasma boluses. As previously dis- As capillary walls are normally relatively
cussed, turbulence increases resistance and therefore impermeable to proteins, the Starling filtration
decreases flow; this is therefore usually avoided in the equation can be simplified as:
larger vessels. However, turbulence can be used Net fluid filtration pressure across capillary wall /
advantageously in the capillary as a method of mixing [(Pc – Pi) – (πc – πi)]
the plasma and potentially facilitating exchange at the Note: Starling pressures are usually measured
endothelium. Effective viscosity is only increased by in mmHg.
approximately 30% in bolus flow, which is much less
than would be expected from turbulent flow. Capil- Normally, three values are relatively constant:
lary bolus flow therefore allows controlled pockets of πc is 24 mmHg.
turbulence to occur for mixing whilst maintaining a Pi and πi are both low, being 2 mmHg and 3
relatively low resistance. mmHg, respectively.
Pc is therefore the main determinant of whether fluid
How do the Starling filtration forces is filtered or reabsorbed:
determine transmembrane fluid flow? At the arterial end of the capillary, Pc = 36 mmHg.
The net fluid filtration across the capillary wall results Net filtration pressure = (36 – 2) – (24 – 3) =
from the balance of the four opposing Starling filtra- 13 mmHg. Therefore, there is bulk flow out of the
tion forces (Figure 36.1): capillary; that is, filtration.
159
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 21:07:44, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.039
Section 3: Cardiovascular Physiology
At the venous end of the capillary, Pc = 10 mmHg. direction of bulk flow changes from net filtration to net
Net filtration pressure = (10 – 2) – (24 – 3) = absorption. The Starling filtration forces can be dem-
–13 mmHg. Therefore, there is bulk flow into the onstrated graphically: Area 1 represents net filtration,
capillary; that is, absorption. whilst Area 2 represents net absorption (Figure 36.2a).
As the capillary hydrostatic pressure decreases from Filtration and absorption are not exactly matched –
the arteriolar to the venous end of the capillary, the overall, there is a daily net filtration of around 4 L of
30 Area 1
24
20 Area 2
10
0
Arteriolar end Middle Venular end
Site in capillary
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
160
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 21:07:44, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.039
Chapter 36: Capillaries and Endothelium
161
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 21:07:44, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.039
Section 3: Cardiovascular Physiology
162
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 21:07:44, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.039
Section 3 Cardiovascular Physiology
Venous System
Chapter
37
Whataretherolesofthevenoussystem? increases, allowing a large amount of blood to
flow through the skin, dissipating heat to the
The venous system has a number of roles: environment.
Transport of deoxygenated blood from the
capillaries to the right side of the heart, which is How does the structure of a vein differ
the main role of the venous system. There are a
few exceptions to this rule: from an artery?
– The pulmonary veins carry oxygenated blood Arteries have three layers (see Chapter 34):
from the pulmonary capillaries to the left side The tunica externa;
of the heart (see Chapter 23). The tunica media;
– The umbilical vein carries oxygenated blood The tunica intima.
from the placenta to the foetus (see The tunica media is the thickest layer, with a much
Chapter 83). higher proportion of smooth muscle than elastin.
– A portal vein is a vein that connects two In contrast, veins:
capillary networks. For example: Have thinner walls and larger lumens than
▪ The hepatic portal vein carries equivalent-sized arteries;
deoxygenated blood between two capillary Have much less smooth muscle and more elastin
beds: from the gut to the liver (see in their tunica media;
Chapter 65). Have as their thickest layer the tunica externa,
▪ The long hypophyseal portal veins connect containing elastin and collagen;
the capillary networks of the lower Are much more distensible than arteries and are
hypothalamus and the anterior lobe of the often collapsed;
pituitary gland (see Chapter 80). Have valves formed by folds of tunica intima that
▪ The short hypophyseal portal veins prevent backflow of blood. Note that there are no
connect the capillary networks of the valves in the venae cavae, portal veins or cerebral
posterior and anterior lobes of the pituitary veins.
gland.
Storage of blood. The venous system contains
What is compliance? How does this
65% of the circulating blood volume. relate to the venous system?
Venous return to the heart. The rate at which Compliance is the change in volume caused by a unit
blood returns to the right atrium determines the change in distending pressure. The venous system is
cardiac preload and is therefore a major factor around 30 times more compliant than the arterial
determining the cardiac output (CO). system. This means that the veins can accommodate
Thermoregulation. Arteriovenous anastomoses large volumes of blood for only a small increase in
are short channels that connect arterioles to intraluminal pressure. In fact, the venous system
venules, bypassing the capillary networks. holds 65% of the circulating blood volume compared
Arteriovenous anastomoses are plentiful in the with only 15% within the arterial system, which is
skin. They are opened when body temperature under considerably higher pressure.
163
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 16:54:15, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.040
Section 3: Cardiovascular Physiology
The difference in compliance between arteries and intrathoracic pressure pulls open the distensible
veins is of critical importance to the systemic circula- venae cavae by radial traction, reducing their
tion. As previously discussed, the left ventricle acts as resistance to flow. At the same time, the increased
a pressure generator. It does this by moving a unit of intra-abdominal pressure propels blood towards
blood (the stroke volume) from the highly compliant the heart. The end result is increased venous
veins to the less compliant arteries. As compliance (C) return on inspiration. During exercise, an increase
is the change in volume per unit change in pressure, in respiratory rate produces a greater respiratory
the pressure generated is: ΔP = ΔV/C. Therefore, as pump effect, increasing venous return.
the veins have a high compliance, the same volume of The cardiac pump. During ventricular
blood gives a low pressure, whereas when it is moved contraction, the fibrous atrioventricular rings are
to the low-compliance artery the pressure is much pulled downwards, increasing the volume of the
increased. atria. Atrial pressure therefore decreases,
sometimes to below zero, which aids the flow of
Which factors are involved in blood from the venae cavae and pulmonary veins,
determiningvenousreturntotheheart? but is limited by venous collapse.
The skeletal muscle pump. Rhythmical
When standing upright, the majority of the venous contraction and relaxation of skeletal muscle,
blood is situated vertically below the level of the heart. particularly the calf, propels blood through the
This blood must therefore return to the heart against deep veins. Blood is first drawn from the superficial
the force of gravity. In addition to gravity, venous to deep veins by skeletal muscle relaxation. Skeletal
return is hindered by fluctuations in abdominal and muscle contraction then compresses the deep veins,
thoracic pressures and disease states such as congest- which propels blood forwards. Valves within the
ive cardiac failure. There are a number of mechan- veins ensure unidirectional flow towards the heart.
isms involved in venous return: This mechanism increases venous return during
Valves. One-way valves are positioned every few exercise.
centimetres along the veins – an intact valvular Body position. Standing leads to venous pooling in
system means that blood can only be propelled the lower limbs. Venous pressure increases in the
forwards. supine position, leading to an increase in venous
Venous pressure (or more correctly mean return. The Trendelenburg position (head-down
systemic filling pressure). As blood fills the venous tilt) further increases venous return to the heart.
capacitance vessels, the venous pressure increases,
thus increasing venous return to the heart. Venous Clinical relevance: venous return and anaesthesia
pressure is increased by filling the veins with a
Anaesthesia may be responsible for a fall in venous
greater blood volume or by increasing venous
return:
tone through an increase in sympathetic nervous
activity.1 Similarly, loss of blood volume (e.g. Positive-pressure ventilation increases
intrathoracic pressure during inspiration, which
haemorrhage) or loss of sympathetic tone (e.g.
reduces venous return, right ventricular preload
following central neuraxial blockade) results in a
and CO. Clinically, at induction of general
decrease in venous pressure and thus a fall in anaesthesia, patients commonly become
venous return. hypotensive; this is partly the result of propofol-
The respiratory (or abdominothoracic) pump. In or thiopentone-induced arteriolar vasodilatation,
the spontaneously breathing patient, negative but also partly the result of positive-pressure
ventilation.
1
Positive end-expiratory pressure worsens this
Like arteries, venous smooth muscle is innervated by situation, increasing intrathoracic pressure and
post-ganglionic sympathetic neurons, which act at α1- further reducing venous return.
adrenoceptors. Sympathetic stimulation results in Inferior vena cava (IVC) compression. From
venoconstriction, which reduces venous wall compliance. mid-pregnancy, the gravid uterus compresses
Owing to the relatively large radius of veins, the IVC when lying supine, reducing venous
venoconstriction causes only a small increase in the
return and thus resulting in hypotension (see
resistance to blood flow.
164
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 16:54:15, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.040
Chapter 37: Venous System
165
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 16:54:15, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.040
Section 3 Cardiovascular Physiology
38
Describe the key features of the central The y‑descent corresponds to the decrease in CVP
after the tricuspid valve opens, when blood flows
venous pressure waveform from the RA into the right ventricle (RV).
The central venous pressure (CVP) waveform is
measured using a central venous catheter positioned How can the shape of the CVP waveform
just above the right atrium (RA), within the superior
vena cava. Starting from mid-diastole, key features of help the diagnosis of arrhythmias?
the normal CVP waveform are (Figure 38.1): A number of cardiac conditions impact on the CVP
The a-wave corresponds to the increase in waveform:
pressure when the RA contracts, occurring just Atrial fibrillation. The loss of coordinated atrial
after the P‑wave on the electrocardiogram. contraction leads to the absence of a‑waves.
The c‑wave occurs in time with the carotid Third-degree heart block. Electrical impulses
pulsation. In early systole, right ventricular cannot pass through the atrioventricular node. As
contraction causes the tricuspid valve to bulge a result, atrial and ventricular contraction occur
into the RA, leading to a small increase independently. There will be times when the atria
in CVP. contract at the same time as the ventricles (i.e.
The x‑descent corresponds to atrial relaxation and when the tricuspid valve is closed), resulting in the
the downward movement of the RA during right occasional larger a‑wave on the CVP waveform;
ventricular contraction. The resultant low CVP this is called a ‘cannon a‑wave’.
leads to rapid right atrial filling. Tricuspid regurgitation. During ventricular
The v‑wave corresponds to the continued venous systole, blood is ejected from the RV into the RA,
return to the RA during ventricular systole; that is, increasing the CVP. The CVP waveform has a
right atrial filling with a closed tricuspid valve. ‘giant v‑wave’, a large positive deflection that
replaces the c‑wave, the x‑descent and the v‑wave.
T
P
6
Pressure (mmHg)
a
4 c v
x
2 y
0
0 0.5 1
Time (s)
166
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:11:46, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.041
Chapter 38: Venous Pressure Waveforms
What constitutes a normal CVP? One of the determinants of cardiac output (CO) is
left ventricular preload.
The normal mean CVP is said to be 2–8 mmHg
when measured at the level of the RA. However, CVP therefore reflects left ventricular preload and
can be used to optimise CO.
isolated CVP readings should be interpreted with
care. CVP is not purely related to central venous Even in healthy patients, there are just too many
blood volume. It is also affected by venous compli- assumptions and approximations for CVP to
ance, the compliance of the RA and RV and the provide a precise guide to fluid management. LVEDV
intrathoracic pressure. corresponds poorly with CVP, and individual CVP
Common causes of raised CVP (>8 mmHg) are: readings are of little use. However, trends of CVP
Transducer below the level of the RA; readings can be used to assess the response to a fluid
bolus:
Positive-pressure ventilation/positive end-
expiratory pressure; A transient rise in CVP implies that the RV is on
Congestive cardiac failure; the ascending part of the Starling curve; further
Isolated right ventricular failure; for example, fluid administration may be needed to optimise
following right ventricular infarction, cor preload.
pulmonale; A sustained rise in CVP implies that the RV is on
Hypervolaemia; the plateau of the Starling curve and at maximal
preload. When operating at this part of the
Pulmonary embolus;
Starling curve, the RV is already at a mechanical
Constrictive pericarditis.
disadvantage; any further increase in preload is
Common causes of low CVP (<2 mmHg) are: likely to precipitate RVF. A further increase in CO
Transducer above the level of the RA; can only be achieved by increasing myocardial
Acute hypovolaemia; for example, anaphylaxis, contractility, increasing heart rate or reducing
acute haemorrhage. afterload.
A clinical deterioration and marked rise in CVP
How can CVP be used to guide fluid implies that the RV is on the descending part of the
Starling curve, with excessive preload
management? overstretching the myocardial fibres, causing RVF.
Because of its ease of measurement, CVP has histor-
CVP is still used in clinical practice to assess adequate
ically been used to guide fluid management. The
venous filling, with a target CVP of 8–12 mmHg (12–15
physiology underlying this is as follows:
mmHg in mechanically ventilated patients) commonly
CVP provides a good approximation of right quoted. However, the Surviving Sepsis Guidelines
atrial pressure (RAP). (2016) have decreased the importance of using CVP
RAP approximately correlates with right over other methods of assessing volume status, reflect-
ventricular end-diastolic pressure (RVEDP) and ing the weakness of using CVP in this context.
right ventricular end-diastolic volume; that is,
right ventricular preload. Further reading
RVEDP approximately correlates with left M. Singer, C. S. Deutschman, C. W. Seymour, et al.
ventricular end-diastolic pressure and left The third international consensus definitions for
ventricular end-diastolic volume (LVEDV); that sepsis and septic shock (Sepsis-3). JAMA 2016; 315(8):
is, left ventricular preload. 801–10.
167
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:11:46, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.041
Section 3 Cardiovascular Physiology
Lymphatics
Chapter
39
Describe the anatomy of the lymphatic Clinical relevance: central venous cannulation
system Internal jugular and subclavian vein cannulation is a
The lymphatic system is part of the systemic circula- commonly performed procedure in major surgical
tion. Its two main components are the conducting and critical care patients. There is a long list of
system and lymphoid tissue. potential complications, including infection, air
Key aspects of the conducting system are: embolus, pneumothorax and arterial puncture.
Left-sided central venous cannulation also risks
Small lymphatic capillaries drain lymph into
damage to the thoracic duct, which is in close prox-
larger lymphatic vessels, which converge on the
imity to the junction of the internal jugular and
right lymphatic duct and the thoracic duct. subclavian veins. Puncture of the thoracic duct can
The right lymphatic duct is quite short (around lead to a chylothorax. Damage to the thoracic duct
1.5 cm). It drains lymph into the right can be prevented by using the right-sided internal
subclavian vein. jugular and subclavian veins, using a high-neck
The thoracic duct (also known as the left approach to the internal jugular vein and most
lymphatic duct) is much larger, and drains into importantly by cannulating under ultrasound
the left brachiocephalic vein. It collects lymph guidance.
from the majority of the body (everywhere except
the right arm, right chest and right side of the
head and neck) and returns it to the systemic
What are the functions of the lymphatic
circulation. system?
Lymphatic vessels are pulled opened as a result of The lymphatic system has three main functions:
radial traction by the surrounding connective Fluid balance. As blood passes through the
tissue. This permits fluid, proteins and even cells capillaries, most of the fluid filtered into the
to enter. Like veins, lymph flow is promoted by interstitium is then reabsorbed back into the
skeletal muscle activity and deep inspiration. The capillary (see Chapter 36). Overall, there is slight
larger lymph vessels have valves to ensure excess of filtration. Each day approximately 4 L of
unidirectional flow. interstitial fluid must consequently be returned to
The lymphoid tissue consists of: the circulation by the lymphatic system – this fluid
Primary lymphoid organs – thymus and bone is called lymph.
marrow. These organs are involved in the Immune. In addition to fluid, the lymph
production of lymphocytes from progenitor cells. capillaries are the only means by which filtered
Secondary lymphoid organs – these include proteins, lymphocytes and other debris (including
lymph nodes and lymphoid follicles within the cells) can leave the interstitial space. Lymph passes
tonsils, spleen, Peyer’s patches and other mucosa- through lymph nodes before passing back into the
associated lymphoid tissue. This lymphoid tissue systemic circulation. The lymph nodes are packed
contains mature lymphocytes and is the site where full of lymphocytes, which detect foreign bodies
foreign antigens activate the adaptive immune and pathogens, triggering an immune response.
response (see Chapter 75). Distribution by the lymphatic system is the most
168
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:09:21, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.042
Chapter 39: Lymphatics
169
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:09:21, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.042
Section 3 Cardiovascular Physiology
Cardiovascular Reflexes
Chapter
40
Why is it important to minimise collapse. This reflex is only usually relevant
during profound hypotension, such as during
fluctuations in blood pressure? haemorrhage or sepsis.
The organs require a fairly constant mean arterial – The CNS ischaemic response, in which CNS
pressure (MAP) to ensure adequate perfusion. Some ischaemia triggers an increase in sympathetic
organs (most notably the brain, heart and kidneys), nervous activity, thus increasing HR and
despite fluctuations in MAP, intrinsically maintain MAP.
their blood flow through autoregulation (see Chap- Reflexes triggered by stimuli external to the
ter 34), but are still unable to compensate if MAP is cardiovascular system: for example, pain,
significantly reduced or increased. emotion or temperature.
170
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:39:26, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.043
Chapter 40: Cardiovascular Reflexes
The vasodilator (depressor) area. This area acts What is the Bainbridge reflex?
on the vasoconstrictor centre, decreasing its
Low-pressure mechanoreceptors are located within
sympathetic outflow.
the great veins and the walls of the right atrium
Overall: (RA) at its junction with the superior and inferior
An increase in MAP increases the frequency of venae cavae and are activated by increased wall dis-
action potentials produced by the baroreceptors. In tension. An increase in CVP therefore stimulates
response, the vasodilator area inhibits sympathetic these low-pressure mechanoreceptors, increasing
outflow, causing peripheral vasodilatation and a their frequency of action potential generation – these
decrease in both HR and myocardial contractility, action potentials are then relayed to the CNS via the
thus returning MAP to normal. vagus nerve. In response, the vasomotor centre
A decrease in MAP reduces the frequency of increases sympathetic outflow to the sinoatrial node
action potentials produced by the baroreceptors. (but not to the cardiac ventricles or peripheral vascu-
In response, the vasoconstrictor area increases lature), resulting in an isolated tachycardia.
sympathetic outflow, causing peripheral Physiological manifestations of the Bainbridge
vasoconstriction and an increase in both HR and reflex are:
myocardial contractility, thus returning MAP to Respiratory sinus arrhythmia. This occurs in
normal. children and young adults. During inspiration,
Some important points to note about this system are: negative intrathoracic pressure leads to a transient
In addition to short-term changes in HR, increase in venous return to the RA, which
myocardial contractility and SVR, the activates low-pressure mechanoreceptors. As a
baroreceptor reflex also influences plasma volume. result, HR increases during inspiration and
Following a fall in MAP, the increased decreases during expiration.
sympathetic outflow triggers renin secretion by Uterine autotransfusion. Following delivery,
the kidney, thus increasing plasma volume sustained uterine contraction returns around
through the action of the renin–angiotensin– 500 mL of uteroplacental blood to the maternal
aldosterone (RAA) axis. Likewise, an increase in circulation. The resulting increase in CVP stretches
MAP decreases sympathetic outflow, which the right atrial wall, resulting in a tachycardia.
decreases renin secretion and thus plasma volume.
In clinical practice, this can be observed in What are the cardiovascular
patients with pre-eclampsia, where persistently
raised MAP results in a relative hypovolaemia.
consequences of chemoreceptor
There are two types of neurons involved in the activation?
baroreceptor reflex. Large myelinated A fibres are The peripheral chemoreceptors (the carotid and aortic
activated at lower pressure, whilst small bodies) are activated by low arterial O2 tension PaO2,
unmyelinated C fibres are activated at higher high PaCO2 and, in the case of the carotid bodies, low
pressure. In combination, these neurons provide a arterial pH (see Chapter 22). In addition, the peripheral
system that is sensitive over a wide range of MAP, chemoreceptors are activated by severe hypotension
from 80 to 150 mmHg. (MAP < 60 mmHg). The action potentials generated
In patients with chronic hypertension, the by the peripheral chemoreceptors are relayed to the
baroreceptors reset their working range and respiratory centre in the medulla and pons. The medul-
sensitivity. lary respiratory centre is located in close proximity to
The compliance of the arterial tree is reduced with the vasomotor centre, to which it is neurally connected;
ageing and atherosclerosis. In turn, this affects the activation of the peripheral chemoreceptors therefore
sensitivity and rapidity of the baroreceptor reflex; has a minor effect on blood pressure regulation. Hyp-
postural hypotension (i.e. a failure of the oxia, hypercapnoea and acidosis therefore trigger an
baroreceptor reflex to compensate for the postural increase in sympathetic outflow from the vasomotor
changes in MAP) is common in the elderly. centre.
171
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:39:26, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.043
Section 3: Cardiovascular Physiology
172
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:39:26, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.043
Chapter 40: Cardiovascular Reflexes
predominately through actions on the ischaemia and thus cardiac depression, resulting
distal convoluted tubule (DCT). in a rapid fall in MAP.
▪ Decreased venous return to the heart
results in decreased stretch of the atrial and Clinical relevance: classes of haemorrhagic shock
ventricular walls. As a result, atrial The physiological response to haemorrhagic shock
natriuretic peptide and brain natriuretic is proportional to the degree of haemorrhage
peptide secretion is decreased, which (Table 40.1).
ordinarily promotes Na+ and water
Table 40.1 Haemorrhagic shock divided into four classes
excretion. (HR = heart rate; SBP = systolic blood pressure; DBP = diastolic
▪ Antidiuretic hormone (ADH) is released blood pressure; RR = respiratory rate).
from the hypothalamus in response to Class 1 Class 2 Class 3 Class 4
plasma osmolarity and (to some extent)
volume changes. ADH has three effects in Blood <15 15–30 30–40 >40
severe haemorrhage: it acts as a loss (%)
vasopressor, augmenting noradrenaline- Blood <750 750–1500 1500–2000 >2000
mediated arteriolar vasoconstriction, and it loss (mL,
also acts at the renal collecting ducts, where 70‑kg
it increases water reabsorption. Finally, adult)
ADH acts at the hypothalamus to stimulate HR <100 >100 >120 >140
thirst. (bpm)
▪ Additional cortisol is released from the SBP Normal Normal Reduced Very low
adrenal gland in response to major (mmHg)
haemorrhage. Cortisol has a minor
DBP Normal Raised Reduced Very low
mineralocorticoid role, increasing the
(mmHg)
reabsorption of Na+ and water at the DCT
and collecting ducts. Cortisol also RR <20 20–30 30–40 >35
promotes gluconeogenesis. (breaths/
min)
The late response. In the longer term, plasma
volume is restored over the next 2 days by oral Urine >30 20–30 5–15 Negligible
output
intake of water and renal reabsorption of
(mL/h)
electrolytes. However, because only water and
electrolytes are returned to normal, blood has a Mental Normal Anxious Confused Drowsy or
reduced haematocrit and plasma protein status unconscious
concentration. The liver rapidly synthesises Class 1 and 2 haemorrhagic shock are referred to as
albumin, restoring plasma albumin compensated shock, as blood pressure is maintained, whilst
Class 3 and 4 haemorrhagic shock are decompensated, as
concentration to normal within 4–6 days. hypotension has occurred. Decompensated shock is associated
Haemoglobin concentration usually returns to with >50% mortality.
normal within 8 weeks if sufficient iron is Note: ‘pure’ haemorrhagic shock is unusual. Haemorrhage
usually occurs in conjunction with trauma. Following trauma,
available. tissue damage triggers a cascade of inflammatory mediators,
Decompensated shock. If blood loss is extensive resulting in the systemic inflammatory response syndrome
and organ dysfunction, further increasing mortality.
(>30%) and rapid, compensatory mechanisms
may be unable to restore MAP. This level of blood
loss reflects the change from stressed (contributes Further reading
to stretching the vessel wall) to unstressed blood N. Herring, D. J. Paterson. Cardiovascular receptors, reflexes
volume (simply fills the vessel lumen). and central control. In: N. Herring, D. J. Paterson.
Decompensated shock is characterised by a Levick’s Introduction to Cardiovascular Physiology,
paradoxical vasodilatation and decrease in 6th edition. Boca Raton, CRC Press, 2018; 303–24.
tachycardia, possibly as a result of endogenous N. Herring, D. J. Paterson. Co-ordinated cardiovascular
opioid signalling. This results in myocardial responses. In: N. Herring, D. J. Paterson. Levick’s
173
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:39:26, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.043
Section 3: Cardiovascular Physiology
174
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:39:26, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.043
Section 3 Cardiovascular Physiology
Valsalva Manoeuvre
Chapter
41
What is the Valsalva manoeuvre? effect can be gained by asking a patient to try to
blow the plunger out of a syringe.
What was it originally used for? Anaesthetised. The adjustable pressure-limiting
The Valsalva manoeuvre is performed by forced valve of the anaesthetic circuit is closed and the
expiration against a closed glottis. It is attributed to airway pressure is increased to 40 cmH2O and
Antonio Valsalva (1666–1723), who described it as a held for 10 s. This is really only possible for
test of Eustachian tube patency and as a method of intubated patients; laryngeal mask airways are
expelling pus from the middle ear. prone to leak above pressures of 20 cmH2O.
How might a patient perform a Valsalva What are the cardiovascular changes
manoeuvre? that occur during the Valsalva
The Valsalva manoeuvre involves increasing intrathor-
acic pressure to ~40 cmH2O and holding it for 10 s. The manoeuvre?
methods of achieving this depend on whether the A sudden generation of a high intrathoracic pressure,
patient is awake or anaesthetised: such as that occurring during the Valsalva manoeuvre,
Awake. The patient attempts to forcibly exhale results in dramatic changes to mean arterial pressure
whilst keeping their mouth and nose closed. This (MAP), cardiac output and heart rate (HR). The Valsalva
can be difficult to explain to a patient – the same manoeuvre is divided into four phases (Figure 41.1):
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 Positive airway
of 40 cmH2O applied pressure released
175
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:03:32, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.044
Section 3: Cardiovascular Physiology
Phase 1. At the start of the Valsalva manoeuvre, the Instead, it has found a number of other uses, both
increase in intrathoracic pressure compresses the clinical and non-clinical, including:
pulmonary vessels, squeezing blood into the left Termination of a supraventricular tachycardia.
side of the heart. This transiently increases the The intense vagal stimulation of Phase 4
stroke volume (SV), resulting in a transient slows conduction through the atrioventricular
increase in MAP. The baroreceptor reflex responds node.
to the rise in MAP by transiently reducing HR. An aid to diagnosis of a murmur. A Valsalva
Phase 2. Next, the high intrathoracic pressure manoeuvre increases the intensity of the murmur
prevents venous return to the heart. SV is reduced, of hypertrophic obstructive cardiomyopathy
which leads to a steady fall in MAP. Again, the whilst decreasing the intensity of most other
baroreceptor reflex is triggered: HR increases, murmurs, including aortic stenosis, the main
which returns MAP to near normal. differential diagnosis of an ejection systolic
Phase 3. After 10 s, the high intrathoracic pressure murmur.
is released. Venous return fills the empty Diving. During descent, a Valsalva manoeuvre
intrathoracic vessels. SV decreases, resulting in a helps the diver to open their Eustachian tubes and
further fall in MAP and a further reflex rise in HR. equalise middle-ear pressure with ambient
Phase 4. As left ventricular preload is restored, the pressure. However, it is not advisable to do this
MAP increases. However, because the HR is still during ascent – there is a risk of opening a patent
high, there is an overshoot in MAP. The foramen ovale (PFO). A PFO in combination with
baroreceptor reflex rapidly corrects this, causing a decompression illness arising from dissolved N2
reflex bradycardia through vagal stimulation. Both coming out of solution, producing gas bubbles in
MAP and HR then return to normal. the venous circulation, may result in an arterial
gas embolus.
What are the uses of the Valsalva Temporary increase in venous pressure. The
manoeuvre today? Valsalva manoeuvre is often used intraoperatively
to increase venous pressure to check for adequate
Obviously, the Valsalva manoeuvre is no longer the haemostasis following, for example, a radical neck
primary method used to expel pus from the ear. dissection.
Positive airway Phases: 1 2 3 4
pressure applied
100
90
80 No BP overshoot in Phase 4
70
No reflex tachycardia
HR (beats per minute)
90
in Phase 2
80 No reflex bradycardia
in Phase 4
70
60
50
0 5 10 15 20 25 30
Time (s)
Figure 41.2 Autonomic dysfunction and the Valsalva manoeuvre (BP = blood pressure).
176
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:03:32, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.044
Chapter 41: Valsalva Manoeuvre
100
90
80 ‘Square-wave response’
70
HR (beats per minute)
90
Little change in HR
80
70
60
50
0 5 10 15 20 25 30
Time (s)
How is the Valsalva manoeuvre used to pressure, such as congestive cardiac failure and con-
strictive pericarditis (Figure 41.3). These patients
test autonomic function? survive with the left ventricle operating on the plat-
The integrity of the autonomic nervous system (ANS) eau of the Starling curve, with a chronically raised
can be tested by demonstrating a normal cardiovas- sympathetic outflow resulting in near-maximal vaso-
cular response to the Valsalva manoeuvre. The baro- and veno-constriction. Performing the Valsalva
receptor reflex is often abnormal in conditions manoeuvre leads to an elevation of MAP throughout
affecting the ANS, such as diabetic autonomic neur- the duration of raised intrathoracic pressure, with
opathy and spinal cord injury (Figure 41.2): little change in HR and no MAP overshoot in
In Phase 2, there is no compensatory reflex Phase 4.
tachycardia – MAP continues to fall until the
intrathoracic pressure is released. Further reading
In Phase 4, there is no overshoot of MAP and no N. Herring, D. J. Paterson. Co-ordinated cardiovascular
compensatory bradycardia. responses. In: N. Herring, D. J. Paterson. Levick’s
Introduction to Cardiovascular Physiology, 6th edition.
Boca Raton, CRC Press, 2018; 325–42.
What other abnormal responses are G. Smith. Management of supraventricular tachycardia
there to the Valsalva manoeuvre? using the Valsalva manoeuvre: a historical review and
summary of published evidence. Eur J Emerg Med 2012;
A ‘square-wave response’ to the Valsalva manoeuvre 19(6): 346–52.
is seen in conditions characterised by high venous
177
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:03:32, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.044
Section 3 Cardiovascular Physiology
Exercise Physiology
Chapter
42
Exercise is a major physiological challenge to the heart rate (HR), but to a lesser extent than
body, affecting all the main body systems. An accom- dynamic exercise.
panying increase in muscle metabolic rate results in
an increase in O2 demand and a requirement for an What types of skeletal muscle fibres
increased rate of removal of CO2 and other metabolites,
including lactic acid and ketone bodies. Exercise thus
are there?
requires substantial increases in muscle blood flow with There are two main types of skeletal muscle fibre:
maintenance of mean arterial pressure (MAP). In add- Type I (slow-twitch or fatigue-resistant) fibres.
ition, despite the increased rate of energy metabolism, This type of muscle fibre derives its metabolic
normoglycaemia must be preserved. Finally, exercising energy from the oxidative metabolism of
muscle generates a large amount of heat, yet core tem- triglycerides and is therefore rich in myoglobin
perature must be controlled. (hence its red appearance), mitochondria and
capillaries. Type I fibres are found in groups of
Whatisthedifference betweendynamic muscles where sustained contraction is required,
such as the postural muscles. Type I fibres
and static exercise? contract more slowly but are resistant to fatigue.
Exercise involves the activation of skeletal muscle. It Type II (fast-twitch) fibres. There are two types:
may be classified as: – Type IIa (fast-twitch oxidative) fibres;
Dynamic (or isotonic), where muscles – Type IIb (fast-twitch glycolytic) fibres.
rhythmically contract and relax, moving joints Type IIb fibres are more reliant on anaerobic
(e.g. running); metabolism (glycolysis) for ATP generation and
Static (or isometric), where muscles contract thus have larger glycogen stores; their lack of
against a resistance but do not lengthen or shorten myoglobin leads to a white appearance. These
(e.g. weight lifting). fibres occur in muscles that require short, rapid,
Both types of exercise may involve the same muscles, powerful movements for activities such as
but they differ in their effects on muscle blood flow sprinting. Because of the limited capacity of
and metabolism: anaerobic metabolism to generate ATP, type IIb
During dynamic exercise, there is marked muscle muscle fibres are more prone to fatigue. Type IIa
capillary bed vasodilatation in response to aerobic fibres are functionally intermediate between type
metabolic activity. Accordingly, systemic vascular IIb and type I fibres. They utilise both aerobic and
resistance (SVR) falls. The baroreceptors initiate a anaerobic metabolism using large glycogen stores
tachycardia in response to the consequent and contract more slowly, but are more resistant
reduction in diastolic blood pressure (DBP). to fatigue than type IIb fibres.
During static exercise, the muscle capillaries are Individual muscles contain varying mixtures of type I,
externally compressed by sustained muscle IIa and IIb fibres, with the proportions of each fibre
contraction, with a resultant increase in anaerobic type depending on the muscle’s function. The per-
metabolism. Vessel compression results in an centage of each fibre type also differs widely between
increase in SVR, which causes an increase in DBP. individuals. Individuals genetically equipped with a
In addition, sympathetic nervous activity increases greater proportion of type IIb fibres will be better
178
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 21:05:59, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.045
Chapter 42: Exercise Physiology
sprinters than those who have a higher proportion of and therefore contributes little in the early phases
type I fibres, who make better endurance athletes. of exercise. Fat metabolism becomes more
important during sustained exercise, when muscle
Which substrates are used by skeletal and liver glycogen stores become depleted. In
muscle to generate energy for marathon running, the sudden fatigue associated
with glycogen store depletion is called ‘hitting the
contraction? wall’.
In common with other cells, skeletal muscle uses ATP
as the direct energy source to power contractions. What is muscle fatigue?
However, only a small amount of ATP is stored in Muscle contraction cannot be sustained indefinitely;
the muscles, enough for 1–2 s of muscle contraction. muscle fatigue is defined as the decline in the
It is therefore essential that ATP can be rapidly regen- ability of a muscle to generate a force. Peak muscle
erated. There are a number of means by which the tension and the velocity of contraction may be
muscles do this: reduced.
Breakdown of phosphocreatine. This is a high- Muscle fatigue is a protective mechanism; it stops
energy molecule that is used to rapidly re- the muscle from contracting to the point where it
synthesise ATP from adenosine diphosphate runs out of ATP, which would result in rigor mortis
(ADP). Despite muscles only having sufficient or even cell apoptosis. The exact mechanism under-
phosphocreatine stores for around 7 s of intense lying muscle fatigue is unknown, with a number of
exercise, it acts as an important energy buffer that factors thought to be involved:
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
Glycolysis utilises either glucose or the muscle reduce Ca2+ reuptake into the sarcoplasmic
glycogen store to generate ATP without the need reticulum (see Chapter 54) or to trigger the
for O2. Considering the number of steps involved opening of ATP-sensitive K+ channels, which
(see Chapter 77), glycolysis results in a rapid but reduces muscle membrane excitability.
relatively inefficient increase in ATP synthesis: +
Increased extracellular K . In severe exercise,
– The maximum glycolysis rate is achieved +
arterial K concentration can rise as high as 8
within a few seconds of the onset of exercise. mmol/L (the exercising heart seems to be
– The glycolytic breakdown of glucose generates protected from the effects of hyperkalaemia). The
two ATP molecules, whilst that of glycogen muscle interstitial K+ concentration rises even
generates three ATP molecules. higher, up to 12 mmol/L. Hyperkalaemia is
Lactic acid is produced as a by-product of thought to contribute to muscle fatigue.
glycolysis. In strenuous exercise, lactic acid is not Accumulation of lactate within the muscle.
cleared from the circulation as quickly as it is Intense exercise may inhibit enzymes involved in
produced, as the blood supply to the liver is aerobic metabolism.
reduced. Exhaustion of muscle glycogen stores following
Oxidative phosphorylation. This is the most prolonged exercise.
efficient mechanism of generating ATP. Complete
breakdown of glucose (through glycolysis, the What physiological changes occur in
citric acid cycle and oxidative phosphorylation by
the electron transport chain) generates 36 ATP anticipation of exercise?
molecules. Some physiological changes occur before the onset of
Fat metabolism. Metabolism of fats through β- exercise. Merely anticipating exercise results in
oxidation (see Chapter 77) generates a greater greater sympathetic outflow and parasympathetic
number of ATP molecules than an equivalent nervous system inhibition, causing:
weight of carbohydrate. However, such fat In the venous system: venoconstriction, which
mobilisation takes place over a longer time course causes an increase in the venous return to
than the corresponding carbohydrate metabolism the heart.
179
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 21:05:59, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.045
Section 3: Cardiovascular Physiology
In the heart: an increase in HR and myocardial – A large increase in CO. Resting skeletal muscle
contractility, which, in conjunction with the blood flow accounts for around 20% of CO
increased venous return, leads to an increase in (1000 mL/min). In normal individuals, CO
cardiac output (CO). may increase fivefold with strenuous exercise,
In skeletal muscle: vasodilatation of capillary from 5 L/min to 25 L/min, to match the
beds through activation of sympathetic metabolic demands of exercising muscles. At
cholinergic fibres. This is an important maximum exercise intensity, skeletal muscle
mechanism that prevents large increases in blood flow accounts for 80% of CO. The
blood pressure following the anticipatory increase in CO is mediated by the sympathetic
increase in CO. nervous system:
In the peripheries: vasoconstriction in the gut ▪ Preload is increased as a result of
and skin. venoconstriction, the skeletal muscle pump
The cardiovascular effects vary depending on the and the respiratory pump (see Chapter 37).
anticipated duration and intensity of the exercise. ▪ Afterload is reduced: SVR falls due to the
For example, anticipation of a short sprint results in release of vasodilatory metabolites from
a greater increase in HR than anticipation of an the muscle.
endurance run. This is because it would be impossible ▪ HR increases in proportion to exercise
to increase HR to near-maximal levels over the short intensity due to a reduction in
duration of a sprint distance, whereas in a marathon parasympathetic nervous activity and an
there is ample time to instigate the cardiovascular increase in sympathetic nervous activity in
response. This is an example of feedforward control. the heart. However, there is a limit to the
value of tachycardia: above a certain rate,
What are the physiological effects of the diastolic filling time is so short that
exercise on each body system? venous return is compromised and CO
falls (see Chapter 29).
Considering each system in turn:
▪ Myocardial contractility increases due to
Skeletal muscle. Exercising muscle requires a both sympathetic nervous system
substantial increase in blood flow to increase the stimulation of the cardiac myocytes and
delivery of O2 and metabolic substrates and to the Bowditch effect, where tachycardia
remove CO2 and other waste products. induces an increase in myocardial
– Resting skeletal muscle blood flow is around contractility (see Chapter 29).
2–4 mL/100 g of muscle/min. At rest, pre-
– Changes in blood pressure. Little change in
capillary sphincters are closed and blood is
blood pressure occurs in anticipation of and
diverted from the muscle capillary beds into
during early phases of dynamic exercise as the
large vessels.
increased CO is mitigated by sympathetic
– In fit, healthy adults undergoing strenuous
cholinergic arteriolar vasodilatation in the
exercise, muscle blood flow increases up to
skeletal muscle. Systolic blood pressure (SBP)
50–100 mL/100 g of muscle/min, depending
increases as cardiac contractility increases.
on the type of muscle.
– This marked increase in blood flow to muscle ▪ In dynamic exercise, DBP remains similar
is caused by the local action of vasodilatory or may even decrease due to a reduction in
metabolites (e.g. H+, AMP, K+, phosphate). the SVR caused by skeletal muscle
These metabolites are produced in proportion arteriolar vasodilatation. As the SBP
to O2 consumption; they open pre-capillary increases more than the DBP falls, MAP
sphincters, allowing blood to flow through the may slowly increase with increased exercise
muscle capillary bed. intensity or duration.
Cardiovascular system. The cardiovascular ▪ In static exercise, the DBP increases as the
system undergoes significant changes with muscle capillary beds are occluded.
exercise (Figure 42.1a): Therefore, MAP increases rapidly.
180
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 21:05:59, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.045
Chapter 42: Exercise Physiology
(a) Cardiovascular changes with dynamic exercise (b) Respiratory changes with exercise
Blood pressure (mmHg)
180
Increased
pulse
pressure
120
140
10
100 0
Fall in stroke volume
200
50
Acidosis simulates
further increase in
100 ventilation
0
Rest Mild Moderate Intense
Intensity of exercise
0
Rest Mild Moderate Intense
Intensity of exercise
Figure 42.1 (a) Cardiovascular changes with dynamic exercise and (b) respiratory changes with exercise.
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 21:05:59, subject to the Cambridge Core terms of use, available at 181
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.045
Section 3: Cardiovascular Physiology
tidal volume, VT, increase (Figure 42.1b). Thermoregulation. Skeletal muscle activity is
The respiratory centre is stimulated by two relatively inefficient: only 20–25% of the chemical
factors: increased activity of the motor energy within the metabolic substrates is converted
cortex and afferent signals from limb joint to mechanical energy, with the rest dissipated as
proprioceptors. heat energy. As discussed in Chapter 89,
▪ As CO2 is a by-product of skeletal muscle thermoregulation is controlled through a complex
metabolism, V̇ E increases in proportion to negative-feedback loop involving peripheral and
the intensity of exercise. central sensors, whose signals are integrated by the
▪ With extremely intense exercise, V̇ E hypothalamus. Effectors are:
increases disproportionately – Eccrine sweat glands in the skin: heat is lost as a
(Figure 42.1b). There comes a point where result of the latent heat of evaporation.
O2 delivery to the exercising muscle is – Cutaneous vasodilatation: heat is lost by
unable to match O2 consumption (the conduction.
anaerobic threshold) and anaerobic
Following the onset of exercise:
metabolism commences. Lactic acid is
produced as a consequence, which causes a – There is an initial transient fall in core
fall in arterial pH. The lower arterial pH is temperature of 1°C as venous return increases
sensed by the carotid bodies, resulting in from the limbs.
further stimulation of the respiratory – As exercise continues, there is net heat
centre. generation. Heat loss mechanisms (sweating
and peripheral vasodilatation) commence.
– Increased pulmonary blood flow. As discussed
Further heat is lost as a result of the large
above, exercise results in a substantial increase
increase in V̇ E (through the latent heat of
in CO; pulmonary blood flow therefore
evaporation as dry inhaled gases are
increases to the same degree. If it were not for
humidified), although this mechanism is less
the pulmonary vasculature responding by
important in humans than in animals that pant.
recruitment and distension (see Chapter 23),
– In hot, humid climates, heat loss mechanisms
mean pulmonary artery pressure (MPAP)
are impaired. When the environmental
would increase substantially. The mild
temperature is greater than body temperature,
increase in MPAP that actually occurs
there is no net gradient for heat loss by
(Figure 42.1b) is physiologically important, as
conduction; sweating becomes the only heat loss
it diminishes the effect of gravity within the
mechanism. In humid conditions, evaporation
lung: the regional V̇ /Q̇ ratio trends towards 1.0
of sweat is impaired. Thermoregulation thus
(0.8 is typical in the resting lung). Gas
fails, leading to increased core temperature. Heat
exchange therefore becomes more efficient
stroke (a core body temperature greater than
with exercise and physiological shunt is
40.6°C) may result, with a variety of symptoms,
reduced.
including confusion and syncope. Rapid
– PaO2. Despite the high O2 consumption of
external cooling is required.
exercising muscle, PaO2 remains normal, even
182
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 21:05:59, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.045
Chapter 42: Exercise Physiology
50 . consumption.
VO2 max
40
30
20
10
0
Rest Mild Moderate Intense
Intensity of exercise
measurements attained by cardiopulmonary exercise short walk, V̇ O2 may be raised for a few minutes,
testing1 (CPET) (see Chapter 43). but it may take more than a day to fully recover
metabolically after running a marathon.
What happens to oxygen consumption
after a patient stops exercising? How do elite athletes differ from the
A person continues to breathe deeply for a period of ‘normal’ population?
time after exercise has ceased. V̇ O2 remains high during Unsurprisingly, the main changes that occur with
the recovery phase – this is known as the excess post- physical training are to the cardiovascular system:
exercise O2 consumption (EPOC) or O2 debt. There are Stroke volume (SV). Physical training causes
two distinct phases to the EPOC (Figure 42.3): cardiac hypertrophy,2 which results in an increase
The alactacid phase, which is rapid and involves: in SV of up to 40%.
– Replenishment of high-energy phosphocreatine HR. Maximum HR does not change, but the
and ATP stores that were depleted in the early resting HR of athletes is often lower than that of
phase of exercise; the general population due to increased vagal
– Replenishment of O2 to myoglobin; tone. As the resting SV is increased, resting CO
– Replenishment of muscle and liver glycogen remains approximately the same. The increase in
stores. vagal tone often results in the sinus arrhythmia of
childhood extending into adulthood.
The lactacid phase, which takes much longer and CO. The increased SV means that the maximal
involves the conversion of lactate back to CO is increased in athletes.
pyruvate, mostly in the liver.
V̇ O2 max may increase by up to 25% with training.
In the longer term, high catecholamine levels and This is thought to be due to an increase in O2 delivery
raised temperature cause a global increase in meta- as a result of increased muscle vascularisation.
bolic rate. Anabolic processes (e.g. muscle fibre repair
In addition, there are changes in:
and hypertrophy) may occur over days to 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,
maximal V̇ E may increase by up to 15 L/min with
training.
1
Strictly, it is V̇ O2 peak rather than V̇ O2 max that is
measured in CPET. V̇ O2 peak is the maximum V̇ O2
2
achieved within the time period of the CPET. Many of the This is structurally and metabolically different from
patients referred for CPET never achieve the plateau pathological cardiac hypertrophy resulting from, for
shown in Figure 42.2. example, aortic stenosis.
183
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 21:05:59, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.045
Section 3: Cardiovascular Physiology
40
Oxygen consumption (mL/kg/min)
30
20 Chemical
ventilatory drive Alactacid phase
EPOC – extra O2 is needed
Lactacid phase to restore metabolic stores
10 Increase in neural
ventilatory drive
Rest
0
0 1 2 3 4 5 6 7 8 9 10
Time (min)
Skeletal muscle. Hypertrophy occurs as a result Bone mineral density. Weight-bearing exercise
of training (an effect of the resistive work done increases bone mineral density. Exercise is a
by the muscles rather than aerobic training). particularly important means of reducing the risk
Endurance training increases the diameter of of fractures in the elderly.
type I muscle fibres and encourages the formation
of muscle capillaries, increases the density of Further reading
mitochondria and increases the activity of D. A. Burton, K. Stokes, G. M. Hall. Physiological effects of
oxidative metabolic enzymes. Exercise carried exercise. Continuing Educ Anaesth Crit Care Pain 2004;
out in repetitive, intense episodes increases 4(6): 185–8.
the diameter of type IIb muscle fibres and N. Agnew. Preoperative cardiopulmonary exercise testing.
increases the activity of anaerobic metabolic Continuing Educ Anaesth Crit Care Pain 2010; 10(2):
enzymes. 33–7.
184
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 21:05:59, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.045
Section 3 Cardiovascular Physiology
Exercise Testing
Chapter
43
How can we assess a patient’s fitness activities, such as ‘How far can you walk on the flat?’
or ‘How many stairs can you climb without stopping?’
for surgery? The problem is that these questions are very subject-
Surgery places a person’s body under physiological ive, and patients often overestimate their exercise
stress: the magnitude of the stress response is propor- tolerance.
tional to the severity of the surgical trauma. The surgical
stress response increases an individual’s O2 consump- Arethereanymoreobjectivemethodsof
tion (V̇ O2). Patients who are less physiologically fit will
be less able to increase their O2 delivery and may there- assessing exercise capacity?
fore be unable to match the increase in V̇ O2. Respiratory There are a number of more objective methods
and cardiovascular co-morbidities place a major limita- available:
tion on the cardiovascular response to major surgery, Questionnaire based, such as the Duke Activity
but physical deconditioning also plays a significant role. Status Index (DASI). DASI is a 12-question self-
When a patient is assessed for a surgical proced- assessment in which patients are asked about
ure, a number of factors must be considered: whether they can complete certain physical tasks.
The invasiveness and surgical difficulty of the Each task is weighted according to its metabolic
proposed surgical procedure; cost (in metabolic equivalents, METs). A patient
The patient’s co-morbidities, which may be who is unable to complete physical tasks of at least
previously known or newly diagnosed, and may be 4 METs is at higher risk of perioperative
well controlled, poorly controlled or uncontrolled; complications.
The patient’s physical fitness, which may be Incremental shuttle walk test, in which patients
quantified using exercise testing. are asked to walk continuously between two cones
set 9 m apart, with a progressively decreasing time
Ultimately, the aim of the preoperative assessment
permitted to reach the next cone. Patients who are
process is to identify those individuals at significant
unable to walk at least 250 m are at increased
risk of perioperative complications in order to:
perioperative risk of complications. While this test
Better inform the patient of their individual risk is cheap and easy to carry out, there are groups of
so as to help them with their decision-making. patients who may be unable to perform a walk
Inform decision-making by the multidisciplinary test: lower limb amputees, those with peripheral
team; for example, an alternative, less invasive vascular disease or those with hip or knee
surgical procedure may instead be offered to a osteoarthritis.
patient (e.g. endovascular aortic aneurysm repair Cardiopulmonary exercise testing (CPET), which
in place of open repair). is considered the gold-standard exercise test.
Plan post-operative care; for example, a high- During a CPET test, the patient’s expired gases are
dependency bed may be required. measured whilst the patient carries out a
continually increasing amount of work on an
How can you clinically assess exercise electromagnetically braked cycle ergometer. Over
capacity? 5000 measurements are taken during the
10‑minute test, including:
Exercise capacity can be assessed by asking the patient
a series of questions relating to their everyday – The work rate (in Watts);
185
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 20:09:59, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.046
Section 3: Cardiovascular Physiology
186
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 20:09:59, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.046
Chapter 43: Exercise Testing
187
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 20:09:59, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.046
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 20:09:59, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.046
Section 4 Neurophysiology
44
What are the functions of the Describe the structure of a neuron
nervous system? The neuron is the functional unit of the nervous system.
The nervous system is a complex network of special- Although neurons vary in their detailed cellular struc-
ture, all include the following components (Figure 44.1):
ised cells called neurons, which coordinate and con-
trol the other organ systems. The cell body, which in common with other cell
The nervous system has three basic functions: types contains cytoplasm, a nucleus and
organelles. The cell body is involved in protein
Sensory input. Sensory receptors detect changes
synthesis and the generation of ATP. However, as
in the external and internal environments. In
mature neurons lack a centriole, which is
response to a stimulus, the sensory receptor
necessary for cell division, neurons cannot
generates an electrical signal – an action
undergo mitosis. The cell bodies form the grey
potential – which is then relayed to the brain and
matter in the brain and spinal cord. Groupings of
spinal cord (collectively known as the central
cell bodies are termed nuclei in the CNS and
nervous system, CNS).
ganglia in the peripheral nervous system (PNS).
Integration. Sensory input is received and
processed by the CNS. Decisions are made on the Dendrites are branched projections that receive
basis of this sensory integration. signals from other neurons through synapses and
propagate them towards the cell body.
Motor output. Neurons relay action potentials
from the CNS to the muscles and glands. Motor The axon is a long projection originating at the
cell body. Action potentials are generated at the
output is the only way we can interact with our
axon hillock1 and conducted along the axon, away
external environment; even salivation requires
from the cell body. The axon may be either
smooth muscle contraction. Much of the nervous
unmyelinated or myelinated. Myelin is made up of
system is therefore dedicated to producing
multiple layers of electrically insulating lipid and
movement.
protein, produced by the Schwann cells in the PNS
Neurons communicate between themselves and other or oligodendrocytes in the CNS. Lipid gives axons
organs through two forms of signalling: a white colour and therefore forms the ‘white
Neural. An action potential is conducted from the matter’ of the brain and spinal cord. Myelin
cell body of a presynaptic neuron to its terminus. increases the speed of action potential propagation
The signal is then transmitted from the (see Chapter 52).
presynaptic neuron to a postsynaptic cell (which An axon terminal, the distal end of the axon. At the
may be another neuron, a muscle cell or a gland) axon terminal, the neuron communicates with
by means of an electrical or chemical synapse. another cell through a synapse. In a motor neuron,
Whilst nerve conduction is relatively rapid (up to this synapse is the neuromuscular junction.
120 m/s in large myelinated nerves), conduction
across a chemical synapse is slower. 1
The axon hillock has the lowest threshold for action
Endocrine. The brain synthesises and releases
potential generation in the cell, owing to its high density
hormones into the circulation, which conveys of voltage-gated Na+ channels. It is usually the first site of
them to the target organ. Endocrine signalling is action potential generation, even when inputs are received
therefore much slower than neural signalling. on the dendrites.
189
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:35:07, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.047
Section 4: Neurophysiology
Axon terminal
Myelin sheath
Terminal bouton
Cell body
Dendrites
These components can be arranged to give differing Multipolar. The dendrites insert directly into the
nerve morphologies. The major neuron classes are cell body without coalescing. The classical
(Figure 44.2): example of a multipolar neuron is a motor
Unipolar. These neurons have an axon projecting neuron.
from a cell body. They are not common in Anaxonic. Dendrites and axons are
humans, but are found in the cochlear. indistinguishable, looking like a large tree of
Bipolar. These neurons have a cell body insertions into a cell body. These are exemplified
between the dendrites and the axon. Bipolar by amacrine cells in the retina.
cells are found in the retina and the olfactory Pyramidal cells. These have a triangular cell body
neurons. (hence the name), a single axon and a large
Pseudounipolar. Some bipolar neurons may look number of dendrites – through these dendrites,
unipolar – the axon is interrupted by the cell body pyramidal cells can integrate many afferent
approximately midway down. Most sensory signals. They are commonly found in the cerebral
neurons are pseudounipolar. cortex and hippocampus.
190
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:35:07, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.047
Chapter 44: Neuronal Structure and Function
How is the nervous system divided? – Autonomic neurons deal with the more
primitive ‘housekeeping’ functions of the
All of the elements of the nervous system work
viscera, as well as the body’s emergency
together holistically. However, the nervous system
responses. The autonomic nervous system is
has traditionally been divided into:
involuntary and divided into two subsystems,
The CNS, consisting of the brain and spinal cord: the sympathetic and parasympathetic nervous
– The brain is the site of higher integration of systems, discussed in more detail in
sensory inputs, motor output, thinking and Chapter 59.
learning.
– The spinal cord contains long sensory and
motor pathways that convey information
between the periphery and the CNS, as well as
What are the component tissue layers
local integrative networks. Interneurons (e.g. of peripheral nerves?
Renshaw,2 multipolar and pyramidal cells) A peripheral nerve is a bundle of many nerve axons.
provide connections between neurons within Connective tissue physically separates and electrically
the CNS. insulates the axons from one another. The result is a
The PNS, whose cell types are: layered structure, rather like an onion skin, containing:
– Sensory (afferent) neurons, which relay Schwann cells. Myelinated nerve axons are
information from the external environment surrounded by a layer of myelin produced by the
and viscera to the CNS. Most have a Schwann cells. An axon surrounded by a myelin
pseudounipolar structure with the cell body on sheath is often referred to as a nerve fibre.
a process to the side of the axon (Figure 44.2) Endoneurium. Each nerve fibre is surrounded by
located in the dorsal root ganglion. a thin layer of connective tissue called
– Motor (efferent) neurons, also known as endoneurium.
somatic motor neurons, are under voluntary Perineurium. Many nerve fibres are bundled
control. Motor neurons transmit action together into groups called fascicles. Each fascicle
potentials from the CNS to skeletal muscle. is wrapped in a layer of connective tissue called
These neurons are typically multipolar; they perineurium, which supports the fascicles.
receive many inputs through multiple Epineurium. This is the thick outer layer of the
dendrites, with the resultant action potential peripheral nerve. The epineurium encloses the
propagated through a single axon multiple fascicles, together with their blood
(Figure 44.2). vessels.
– Enteric neurons form a large network For local anaesthetic to exert its effects on the nerve
around the gastrointestinal tract. The axons, it must therefore diffuse through three layers: the
enteric nervous system is sometimes referred epineurium, the perineurium and the endoneurium.
to as a ‘second brain’, as it operates with
relative independence from the CNS. The Further reading
brain can still influence the enteric nervous E. Pannese. Neurocytology: Fine Structure of Neurons, Nerve
system through the action of autonomic Processes and Neuroglial Cells, 2nd edition. Stuttgart,
neurons. Thieme Publishing Group, 2016.
2
Renshaw cells are simple inhibitory interneurons.
191
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:35:07, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.047
Section 4 Neurophysiology
The Brain
Chapter
45
Describe the gross anatomy ridges (gyri) and troughs (sulci). Each cerebral
hemisphere has four lobes:
of the brain – Frontal lobe. The majority of the frontal
The brain performs complex sensory, motor and lobe is involved in higher functions: problem-
higher functions, coordinating the activity of other solving, reasoning, planning, language
body systems. It has a high metabolic activity, receiv- generation and complex social and sexual
ing 15% of the resting cardiac output, a much greater behaviour. The premotor and primary motor
proportion than would be predicted on the basis of its cortices, located in the posterior frontal lobe,
weight. It can be divided into five regions: are involved in the planning and initiation of
The telencephalon (cerebrum) is the largest movement.
part of the human brain, occupying the anterior – Parietal lobe, the area of the brain involved in
and middle cranial fossae. It comprises three sensory integration. The post-central gyrus –
sub-regions: the most anterior part of the parietal lobe –
– The right and left cerebral hemispheres perform contains the primary somatosensory cortex.
higher functions of memory, thinking, The left and right parietal lobes have slightly
planning and language, in addition to being different functions. The dominant hemisphere
essential for sensory perception and the (the left hemisphere in 97% of the population)
initiation of voluntary movement. is concerned with structure and order; for
– The basal ganglia, a collection of nuclei example, reading and mathematics involve
located deep within the cerebral hemispheres, ordering letters and numbers, respectively.
has classically been regarded as part The non-dominant hemisphere is concerned
of the extrapyramidal system which with spatial awareness.
coordinates fine motor control, muscle – Temporal lobe, which controls hearing,
tone and posture. language and memory. The left temporal lobe
– The limbic system, a collection of structures contains the primary auditory cortex.
located on either side of the thalamus, is Wernicke’s area – an area of cortex important
involved in a number of higher functions, in receptive language – lies between the
including long-term memory, emotion and temporal and frontal lobes of the dominant
behaviour. hemisphere.
– Occipital lobe, the area of the brain that
The right and left cerebral hemispheres are
interprets visual stimuli.
connected by a thick bundle of myelinated nerve
axons called the corpus callosum. The cerebral The diencephalon, which includes:
cortex – the outer layer of the cerebrum – is made – The thalamus, which acts as a relay station.
up of grey matter, reflecting the relatively large Sensory afferent neurons, with the exception
number of nerve cell bodies. The deeper layers of of the olfactory neurons, synapse in the lateral
the cerebrum are composed of white matter, thalamic nuclei before relaying to the cerebral
reflecting the greater proportion of myelinated cortex. The medial structures of the thalamus
nerve axons. The cerebral cortex has a large have roles in pain perception, awareness and
surface area shaped into numerous folds with the regulation of sleep.
192
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:36:16, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.048
Chapter 45: The Brain
– The hypothalamus, a specialised area of the coordinated motor control of the limbs.
brain that regulates autonomic function and Damage to the right cerebellar hemisphere
links the nervous system to the endocrine causes limb ataxia on the right side (i.e. the
system. The hypothalamus exerts control ipsilateral side) and vice versa. This is in
over the pituitary gland, a major endocrine contrast to damage to the right side of the
gland (see Chapter 80). In addition, the motor cortex, which causes a left-sided
hypothalamus has roles in appetite and satiety, hemiplegia.
thirst and control of osmolarity, On each side, afferent and efferent nerve
thermoregulation and circadian rhythm. impulses are carried between the cerebellum
– The subthalamus contains the subthalamic and the brainstem through three nerve
nucleus, which is thought to be part of the bundles:
basal ganglia.
– The superior and middle cerebellar peduncles
– The metathalamus contains the lateral
connect the cerebellum to the pons.
geniculate nucleus, which relays visual
– The inferior cerebellar peduncle connects the
information from the optic nerve to the
cerebellum to the medulla.
primary visual cortex, and the medial
geniculate nucleus, which relays auditory The rhombencephalon consists of the following
information to the primary auditory cortex. structures:
The mesencephalon (midbrain) joins the – The pons (‘bridge’) connects the cerebellum to
hindbrain to the cerebral hemispheres. The the brainstem and the medulla oblongata to
midbrain contains the cerebral aqueduct of the midbrain. The nuclei of cranial nerves V to
Sylvius, which connects the third ventricle to the VIII are also located in the pons. The
fourth ventricle (see Chapter 46). The pneumotaxic and apneustic centres – nuclei
midbrain also contains the third (oculomotor) that form part of the respiratory centre – are
and fourth (trochlear) cranial nerve nuclei and located at the border between the pons and
the red nuclei, which relay extrapyramidal tracts medulla.
from the cerebellum and cerebral cortex to the – The medulla oblongata connects the brain
spinal cord. The medulla oblongata, pons and to the spinal cord. Most descending motor
midbrain are collectively referred to as the tracts of the pyramidal system decussate
brainstem. (cross over to the contralateral side) in the
The cerebellum (meaning ‘little brain’) occupies medulla, at the bulges known as the pyramids.
the posterior cranial fossa. Although it makes up Ascending sensory tracts of the dorsal
only 10% of the brain’s volume, the cerebellum column–medial lemniscal pathway also
contains over 50% of the brain’s neurons, decussate in the medulla. The medulla
reflecting its central role in the refinement of contains the nuclei involved in the
movement. The cerebellum does not initiate physiological functions most essential to life:
movements (this is the role of the motor cortex). the respiratory and vasomotor centres and
Instead, it modifies movements to ensure they are extrinsic regulation of the heart through the
smooth, coordinated and accurate. The autonomic nervous system. The medulla
cerebellum is also responsible for learning motor controls many stereotyped reflexes, including
movements: it builds a ‘working model’ of the the vomiting, swallowing, sneezing, gag and
environment based on experience. Damage to the cough reflexes.
cerebellum therefore does not result in paralysis,
but in ataxia and poor motor learning. The
cerebellum is divided into two main parts: What are the meninges?
– The vermis, the central part, is concerned with The meninges are membranes that cover the brain
motor and postural control of the trunk. and spinal cord, providing protection to the central
– The cerebellar hemispheres, located on either nervous system (CNS). The meninges consist of three
side of the vermis, are concerned with layers:
193
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:36:16, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.048
Section 4: Neurophysiology
The dura mater, a thick outer membrane. What are the neuroglia?
The dura consists of an outer periosteal layer
The neurons of the CNS are supported by four types
and an inner meningeal layer and has four
of cell, known collectively as the neuroglia. Unlike
infoldings:
neurons, which cannot replicate, neuroglia continue
– Falx cerebri, which separates the cerebral to divide throughout life. The neuroglial cell types are:
hemispheres;
Astrocytes, the most abundant of the neuroglia.
– Tentorium cerebelli, which separates the Astrocytes anchor neurons to blood vessels and
occipital lobes from the cerebellum; form the blood–brain barrier, providing the
– Falx cerebelli, which lies inferior to the neurons with a constant external environment
tentorium, separating the cerebellar (see Chapter 47).
hemispheres; Oligodendrocytes, which have an equivalent
– Diaphragma sellae, a circular fold of dura role to that of Schwann cells in the peripheral
that envelops the pituitary gland in the sella nervous system, coating the nerve axons in
turcica. myelin, an electrical insulator (see Chapter 52).
The arachnoid mater, a thin membrane with a Ependymal cells, which form the epithelial lining
spider-like appearance. of the ventricles of the brain and the central
The pia mater, a very thin and highly vascular canal of the spinal cord.
membrane that adheres to the surface of the brain Microglia, the specialised macrophages of the
and spinal cord. Beyond the terminus of the spinal CNS.
cord, the pia continues as the filum terminale,
which (along with the dura) tethers the spinal cord Describe the cerebral arterial
to the coccyx.
blood supply
Some features of the meninges are common to both The cerebral arterial blood supply is derived from four
the brain and spinal cord: main arteries: the right and left internal carotid arter-
The subdural space is a potential space located ies (ICAs) and the right and left vertebral arteries.
between the dura and arachnoid. The two Two-thirds of cerebral blood comes from the ICAs.
meningeal layers may be separated by blood as a The unique feature of the cerebral circulation is
result of a tear in a bridging vein – this is referred the ‘circle of Willis’, an anastomosis of the following
to as a subdural haematoma. cerebral vessels (Figure 45.1):
The subarachnoid space contains cerebrospinal Right and left anterior cerebral arteries (ACAs),
fluid and is located between the arachnoid branches of the ICAs that supply the superior and
and pia. medial portions of the cerebral hemispheres.
Other features are unique to the brain or spinal Anterior communicating artery (ACom), a small
cord: artery that connects the left and right ACAs.
In the brain, venous blood drains into the dural Right and left middle cerebral arteries (MCAs),
venous sinuses (e.g. the superior and inferior which arise from the ICAs and supply the lateral
sagittal, carvernous, sigmoid and transverse), aspect of the cerebral hemispheres.
which are located between the two layers of Basilar artery, a single artery that arises from the
dura mater. amalgamation of the two vertebral arteries.
In the spinal cord, the spinal dura mater is Branches of the basilar artery supply the
separated from the ligamenta flava and the brainstem.
periosteum of the vertebral bodies, pedicles and Right and left posterior cerebral arteries (PCAs),
laminae by the epidural (or extradural) space. The which are formed when the basilar artery divides.
epidural space contains lymphatics, spinal nerve The PCAs supply the occipital lobes and the
roots, loose connective tissue and the epidural medial portion of the temporal lobes.
venous plexus. The epidural space extends from Right and left posterior communicating arteries
the sacrococcygeal membrane to the foramen (PComs), which connect the PCA to the ICA on
magnum. either side of the brain.
194
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:36:16, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.048
Chapter 45: The Brain
ICA
MCA
PCom
PCA
Basilar artery
Vertebral artery
The cerebral vessels supplied by the ICAs (ACAs, Clinical relevance: stroke
ACom and MCAs) are referred to as the anterior
circulation, whilst the cerebral vessels supplied by The Bamford classification divides ischaemic stroke
into categories based on the affected cerebral
the vertebral arteries (basilar artery, PCAs and PComs)
circulation:
are called the posterior circulation.
Anterior circulation infarct (ACI; subclassified as
195
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:36:16, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.048
Section 4: Neurophysiology
196
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:36:16, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.048
Chapter 45: The Brain
197
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:36:16, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.048
Section 4 Neurophysiology
Cerebrospinal Fluid
Chapter
46
What are the functions of and some metabolic waste products. The brain also
produces waste products that need to be cleared, but
cerebrospinal fluid? it lacks a lymphatic system. Instead, the glymphatic
Cerebrospinal fluid (CSF) is the transcellular fluid system allows CSF to circulate in paravascular
located within the cerebral ventricles and subarach- channels between the blood vessels and the astrocyte
noid space that bathes the brain and spinal cord. CSF foot processes, where it collects and removes waste
has a number of functions: products. The name ‘glymphatic’ comes from
astrocytes (a type of glial cell) performing the role of
Buoyancy and cushioning. The adult brain the lymphatic system in the CNS.
weighs around 1400 g. However, when suspended
in CSF, the brain has an effective weight of less
than 50 g. Sudden head movement produces Where is CSF produced?
potentially damaging acceleration and CSF is produced by the choroid plexus, located in the
deceleration forces – the lower effective weight of ventricles of the brain: the two lateral ventricles, third
the brain reduces its inertia, protecting it from ventricle and fourth ventricle. CSF is produced by a
damage. CSF also cushions the brain, protecting it combination of filtration and active secretion of water
from damage, especially from the ridged and solutes at a rate of 0.3 mL/min, equivalent to 500
skull base. mL/day. The choroid plexus is formed by modified
Maintenance of a constant ionic environment. ependymal cells, ciliated cells that line the surface of
Neurons are highly sensitive to changes in their the ventricles of the brain and the central canal of the
external environment; maintaining a constant spinal cord. Ciliary action propels CSF through the
ionic and osmotic environment is essential for ventricles:
normal neuronal activity. From the lateral ventricles, CSF flows through the
Buffering changes in intracranial pressure (ICP). two foramina of Monro into the third ventricle,
Displacement of CSF from the cranium is an located between the right and left thalamic nuclei.
important, but limited, compensatory mechanism CSF travels through the aqueduct of Sylvius,
that occurs following an increase in ICP (see located within the midbrain, to the fourth
Chapter 49). ventricle, located within the pons.
Control of respiration. As a small, lipid-soluble From the fourth ventricle, CSF flows into the
molecule, CO2 can freely diffuse from the blood to subarachnoid space via the two lateral foramina of
the CSF. The CSF has a much lower protein Luschka and the midline foramen of Magendie.1
concentration than plasma and therefore has a Most of the CSF flows around the cerebral
reduced buffering capacity, making the CSF pH hemispheres, whilst the remainder flows around
very sensitive to changes in blood PCO2. The the spinal cord.
central chemoreceptors detect changes in CSF pH, Overall, the total volume of CSF is 100–150 mL, around
causing the respiratory centre to make half of which is located within the ventricular system
corresponding adjustments in V̇ E (see Chapter 22). and half is located within the subarachnoid space.
Glymphatic system. Outside the central nervous
system (CNS), the lymphatic system is responsible
for removing extracellular proteins, excess fluid 1
Mnemonic: lateral = Luschka, midline = Magendie.
198
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:36:49, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.049
Chapter 46: Cerebrospinal Fluid
199
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:36:49, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.049
Section 4 Neurophysiology
Blood–Brain Barrier
Chapter
47
What are the functions of the applied to the capillaries. Astrocytes secrete
chemicals that reduce the permeability of the
blood–brain barrier? capillary endothelial cells. In contrast, the
The blood–brain barrier (BBB) is a physiological, choroid plexus is not surrounded by astrocytes,
cellular and metabolic barrier at the level of the cere- and its endothelial cells are therefore highly
bral capillaries. Their permeability properties restrict permeable.
the free movement of substances between the capil- These three layers form a virtually impenetrable
laries and the extracellular fluid (ECF) of the brain. barrier to lipophobic molecules, comparable to a con-
The BBB has several functions: tinuous capillary.
To maintain a constant extracellular environment
within the central nervous system (CNS). This is
arguably the most important feature. The
How do substances cross the BBB?
Some signalling and nutritional substances gain
concentration of solutes in blood varies
entry to the brain ECF through a number of
considerably, and neuronal function may be
mechanisms:
adversely affected if neurons are directly exposed
to this variation. For example, exercise produces Simple diffusion. Small, lipid-soluble molecules
changes in plasma pH and K+ concentration that can cross the phospholipid bilayers of the BBB by
may depress neuronal activity if transmitted to simple diffusion, in common with cellular barriers
the CNS. elsewhere in the body. Examples include O2, CO2,
To protect the brain from harmful or neuroactive ethanol and steroid hormones.
blood-borne substances. Active transport. The passage of small ions across
To prevent the release of CNS neurotransmitters the BBB, such as Na+, K+, Mg2+, Ca2+, Cl‾, HCO3‾
into the systemic circulation. and H+, is controlled by the membrane, including
transport processes. This means that blood and
CSF may differ in pH and ion concentrations. The
What are the anatomical layers high density of mitochondria in the cerebral
of the BBB? capillaries reflects the high metabolic activity of
this process.
The BBB comprises three layers:
Facilitated diffusion. Some small molecules are
Capillary endothelial cells, interconnected by transported across the BBB by facilitated diffusion
tight junctions, restricting the passage of along their concentration gradients:
substances from the capillaries to the brain ECF.
The capillaries of the BBB differ from – Glucose is transported by GLUT1 transporters,
extracerebral capillaries in having a high density whose transport function does not
of mitochondria. require ATP.
A thick basement membrane, which lies beneath – Water is transported through pores called
the endothelial cells. aquaporins.
Astrocyte foot processes. Astrocytes are a type Pinocytosis. Other molecules (e.g. insulin) are
of supportive glial cell with projections called thought to cross the BBB by pinocytosis (see
foot processes that encircle and are closely Chapter 4).
200
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:38:26, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.050
Chapter 47: Blood–Brain Barrier
201
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:38:26, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.050
Section 4 Neurophysiology
48
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, cerebral blood flow (CBF) is typically 50 mL/100 g/min across a wide range of cerebral
perfusion pressures, ranging from 50 to 150 mmHg
15% of the resting cardiac output (approximately 750
(Figure 48.1). This property of the brain is known as
mL/min). CBF is commonly expressed in terms of the
autoregulation.
weight of brain parenchyma – normal CBF is 50 mL/
Autoregulation is thought to take place through a
100 g brain tissue/min. It is determined by the ratio of
myogenic mechanism in which the cerebral arterioles
the cerebral perfusion pressure (CPP) and cerebral
vasoconstrict in response to an increase in wall ten-
vascular resistance (CVR).
sion, and they vasodilate in response to a decrease in
What is CPP? wall tension, thereby increasing or decreasing CVR
(see Chapter 34).
CPP is the net pressure gradient driving blood flow Outside the autoregulatory range:
through the cerebral circulation, resulting in the CBF. When CPP is greater than 150 mmHg,
It is dependent upon both the mean arterial pressure CBF becomes directly proportional to
(MAP) and the intracranial pressure (ICP). It is CPP.
related to the remaining key parameters as follows:
When CPP falls below 50 mmHg, CBF falls
below the ‘normal’ value of 50 mL/100 g/min,
Key equation: CPP resulting in brain ischaemia.
In relation to ICP: The autoregulation curve (Figure 48.1) is shifted to
CPP = MAP – ICP the right in patients with chronic hypertension and to
the left in neonates.
In relation to CVR:
CPP = CBF CVR
75
50
25
0
0 50 100 150 200
Cerebral perfusion pressure (mmHg)
202
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 11:29:47, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.051
Chapter 48: Cerebral Blood Flow
What happens to neurons when CBF metabolically active brain have higher concentrations
of vasodilatory metabolites (e.g. CO2, H+, K+ and
falls below 50 mL/100 g/min? adenosine), thereby increasing local blood flow and
The brain is more sensitive to even short periods of O2 delivery.
ischaemia than any other organ in the body. For
example, a reduction in CBF to 30 mL/100 g/min
for just 5 s, as may occur during a vasovagal episode,
Which other factors affect global CBF?
results in loss of consciousness. As CBF decreases, Just as local CBF is closely matched to local cerebral
there is a corresponding reduction in cerebral O2 metabolic rate (CMR), total brain CBF is matched to
delivery, which leads to cellular ischaemia: total brain metabolism. An increase in overall CMR,
as occurs in status epilepticus or pyrexia, results in a
CBF < 50 mL/100 g/min results in cellular
corresponding increase in CBF. Likewise, a decrease
acidosis.
in CMR, as occurs with general anaesthesia or hypo-
CBF < 40 mL/100 g/min results in impaired
thermia, results in a corresponding fall in CBF.
protein synthesis.
In addition to locally produced metabolites, cere-
CBF < 30 mL/100 g/min results in cellular bral vessel tone (and therefore CVR) is affected by a
oedema. number of blood constituents:
CBF < 20 mL/100 g/min leads to failure of cell
CO2. An increase in the PaCO2 results in
membrane ion pumps, with loss of
cerebral arteriolar vasodilatation. CVR is
transmembrane electrochemical gradients.
reduced, resulting in a corresponding increase
CBF < 10 mL/100 g/min results in cellular in CBF. Likewise, hypocapnoea results in
death.
cerebral arteriolar vasoconstriction and a
corresponding reduction in CBF. CBF shows an
What is meant by the term approximately linear relationship with PaCO2
‘flow–metabolism coupling’? between 3.5 and 8 kPa (Figure 48.2a). Outside
these limits:
Although the overall CBF remains close to 50 mL/
100 g/min, blood is preferentially routed to the most – PaCO2 > 8 kPa: the cerebral arteries are
metabolically active brain regions. For example, CBF already maximally vasodilated. Any further
to grey matter is 70 mL/100 g/min, whereas CBF to increase in PaCO2 has no effect on CVR
white matter is only 20 mL/100 g/min. Areas of or CBF.
75 75
‘Normal’ CBF
50 50
25 25
0 0
0 5 10 15 0 5 8 10 15 20
PaCO2 (kPa) PaO2 (kPa)
Figure 48.2 The effect of (a) PaCO2 and (b) PaO2 on CBF.
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 11:29:47, subject to the Cambridge Core terms of use, available at 203
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.051
Section 4: Neurophysiology
204
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 11:29:47, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.051
Chapter 48: Cerebral Blood Flow
brain for areas of O2-rich blood and O2-poor by a gamma-camera, giving information about
blood, whilst PET utilises a radioactive analogue regional CBF.
of glucose.
The following are primarily research methods:
Further reading
M. ter Laan, J. M. C. van Dijk, J. W. J. Elting, et al.
Kety–Schmidt technique, which applies the Fick Sympathetic regulation of cerebral blood flow in
principle using arterial and jugular venous humans: a review. Br J Anaesth 2013; 111(3): 361–7.
N2O concentrations. Only global CBF can be C. Ayata. Spreading depression and neurovascular coupling.
measured using this method. Stroke 2013; 44(6 Suppl. 1): S87–9.
Radioactive xenon-133. The radioactive decay of E. C. Peterson, Z. Wang, G. Britz. Regulation of cerebral
injected radioactive isotope 133Xe can be detected blood flow. Int J Vasc Med 2011; 2011: 823525.
205
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 11:29:47, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.051
Section 4 Neurophysiology
49
What is intracranial pressure? How is at the time of insertion and cannot be recalibrated
in situ.1 An intraparenchymal probe only
it measured? measures the pressure of the brain parenchyma
The intracranial pressure (ICP) is simply the hydro- in which it is located, which may not represent
static pressure within the skull, reflecting the pressure global ICP.
of the cerebrospinal fluid (CSF) and brain paren- Subarachnoid and subdural probes: now
chyma. At rest in a normal supine adult, ICP is considered relatively obsolete. Although
5–15 mmHg; ICP varies throughout the cardiac and associated with a low rate of infection, these
respiratory cycles. Even in a normal brain, coughing, probes are less accurate, prone to blockage and
straining and sneezing can transiently increase ICP to require regular flushing.
as high as 50 mmHg.
Unfortunately, ICP cannot be estimated, only
invasively measured. ICP may be measured by a var-
What is the Monro–Kellie hypothesis?
The Monro–Kellie hypothesis states that the cranium
iety of devices, each with their advantages and
is a rigid box of fixed volume, which contains:
disadvantages:
Brain tissue, 1400 g or approximately 80% of the
External ventricular drain (EVD): a catheter
intracranial volume;
inserted into the lateral ventricle, which is
considered the ‘gold standard’ for measuring ICP. CSF, 150 mL or approximately 10% of intracranial
In addition to ICP measurement, an EVD can be volume;
used to remove CSF for diagnostic and Arterial and venous blood, 150 mL or
therapeutic purposes (to reduce ICP – see later) approximately 10% of intracranial volume.
and for the administration of intrathecal An increase in the volume of any of these intracranial
medication. However, to measure ICP, the EVD contents will increase ICP, unless there is also a cor-
must be ‘clamped’; that is, CSF cannot be responding reduction in the volume of one or both of
simultaneously drained. An EVD may be the other contents. For example:
surgically challenging to insert, especially if the An increase in the volume of brain tissue may be
ventricles are small or displaced. Also, EVDs are localised (e.g. a brain tumour or abscess) or
frequently complicated by blockage and are generalised (as occurs with cerebral oedema).
associated with an infection risk of up to 5%. The volume of CSF may be increased in
Intraparenchymal probe: a fibre-optic-tipped hydrocephalus (see Chapter 46).
catheter placed within the brain parenchyma The volume of intracranial blood may be
through a small burr hole. An intraparenchymal increased following haemorrhage (extradural,
probe is much easier to insert than an EVD and subdural or intraparenchymal) or venous sinus
can be used in situations where the ventricles are thrombosis.
compressed or displaced. Measurement of ICP
using an intraparenchymal probe is almost as
accurate as an EVD, and infection rates are
substantially lower. However, there are concerns
about the accuracy of intraparenchymal catheters 1
However, drift has been shown to be as little as 1 mmHg
used for prolonged periods: the catheter is zeroed after 5 days’ use.
206
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:59:54, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.052
Chapter 49: Intracranial Pressure and Head Injury
60
Intracranial pressure (mmHg)
Global ischaemia
50
40
30 Focal ischaemia
20
10
Point of decompensation
0
Volume of expanding intracranial mass (mL)
When one of the intracranial contents increases in – Pupillary dilatation: caused by compression of
volume, there is a limited capacity for displacement of the oculomotor nerve (cranial nerve III).
the other contents: – Cushing’s triad:
Some CSF is displaced from the cranium into ▪ Systemic hypertension;
the spinal subarachnoid space. Whilst the rate
▪ Bradycardia;
of CSF production remains approximately
▪ Abnormal respiratory pattern.
the same, CSF absorption by the arachnoid villi
is increased.
Dural venous sinuses are compressed, displacing Can you explain Cushing’s triad?
venous blood into the internal jugular vein, As discussed in Chapter 48, cerebral perfusion pres-
thus reducing the volume of intracranial blood. sure (CPP) is related to mean arterial pressure (MAP)
After these small compensatory changes have and ICP:
occurred, ICP will rise. The only options left are then CPP ¼ MAP ICP
potentially disastrous: a reduction in arterial blood
volume or displacement of brain parenchyma According to this equation, an increase in ICP results
through the foramen magnum (Figure 49.1). in a decrease in CPP, unless MAP also increases.
The Cushing response is a late physiological
Symptoms suggesting raised ICP include:
response to increasing ICP. When CPP falls below
– A headache that is worse in the morning and is 50 mmHg, the cerebral arterioles are maximally vaso-
exacerbated by straining and lying flat; dilated and cerebral autoregulation fails. Cerebral
– Nausea and vomiting. blood flow (CBF) falls below the ‘normal’ value of
Signs of raised ICP include: 50 mL/100 g/min, resulting in cellular ischaemia
(Chapter 48, Figure 48.1).
– A bulging, tense fontanelle in infants and
In the event of brainstem ischaemia, the brain has
neonates;
an ‘emergency’ hypertensive mechanism: the vaso-
– Papilloedema;
motor area dramatically increases sympathetic ner-
– Altered consciousness. vous system outflow, triggering an intense systemic
Severe intracranial hypertension may result in arteriolar vasoconstriction that results in systemic
additional signs as a result of brain displacement: hypertension. The rise in MAP restores perfusion,
– Cranial nerve palsies: most commonly the and hence CBF, to the brainstem. In response to
abducens (cranial nerve VI) due to its lengthy systemic hypertension, the arterial baroreceptors
course through the skull. induce a reflex bradycardia.
207
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:59:54, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.052
Section 4: Neurophysiology
If ICP continues to rise, the brain parenchyma ▪ Keeping the head in a neutral position and
starts to be displaced downwards. The cerebellar removing neck collars and tight-fitting
tonsils are pushed through the foramen magnum, a endotracheal tube (ETT) ties, which
process referred to as ‘tonsillar herniation’ or ‘coning’. prevent kinking or occlusion of the internal
The cerebellar tonsils compress the brainstem, caus- jugular veins.
ing the failure of brainstem functions: ▪ Nursing the patient in a 30° head-up tilt.
Irregular breathing and apnoea through ▪ Using minimal positive end-expiratory
compression of the respiratory centre; pressure (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.
▪ Using muscle relaxants to prevent
The Cushing reflex is a desperate attempt to maintain
coughing and straining, both of which
CPP (and therefore CBF) in the face of substantially
transiently increase intrathoracic pressure.
increased ICP. Unless swift action is taken (and often
despite this being done), brainstem death is inevitable. – Arterial blood. An adequate volume of well-
oxygenated arterial blood is essential to meet
How may ICP be reduced? the metabolic demands of the brain, but CBF
in excess of that required merely serves to
The Monro–Kellie hypothesis states that an increase increase ICP. Therefore, the goal is to provide
in the volume of one of the three intracranial contents just sufficient CBF to meet the brain’s
will cause an increase in ICP, unless there is also a metabolic needs. Two main strategies are
reduction in the volume of one or both of the other employed:
components. It therefore follows that ICP may be
reduced if the volume of one or more of the intracra- ▪ Reducing cerebral metabolic rate (CMR).
nial contents is reduced: Owing to flow–metabolism coupling, CBF
Reduction in the volume of CSF by means of an is related to CMR. Seizure activity
EVD. This method can be used to reduce ICP even substantially increases CMR, which in turn
when hydrocephalus is not the cause. Even the increases CBF and consequently increases
removal of a few millilitres of CSF can result in a ICP – seizures should be rapidly treated
significant decrease in ICP. with benzodiazepines and anti-epileptic
drugs. CMR may be reduced to subnormal
Reduction in the volume of blood: if the cause of
raised ICP is a haematoma, this should be levels through the use of drugs (propofol,
urgently evacuated. Otherwise, in the context thiopentone or benzodiazepines such as
of raised ICP, intracranial venous and arterial midazolam).
blood can be considered as two entirely different ▪ Preventing hypoxaemia or hypercapnoea.
entities: As discussed in Chapter 48, hypoxaemia
and hypercapnoea both trigger cerebral
– Venous blood. Intracranial venous blood serves arteriolar vasodilatation, which increases
no useful purpose and should be permitted to CBF and consequently increases ICP. In
drain from the cranium. As ICP increases, the situations of raised ICP, PaO2 should be
dural venous sinuses are compressed, maintained above 10 kPa and PaCO2
displacing blood into the internal jugular vein, between 4.5 and 5.0 kPa.
thereby reducing the volume of intracranial
venous blood. As the dural venous sinuses Reduction in the volume of brain parenchyma:
do not have valves, venous drainage from – Severely raised ICP may be temporarily
the cranium is entirely dependent on the reduced by decreasing brain extracellular fluid
venous pressure gradient between the venous volume through osmotherapy, following
sinuses and the right atrium and is therefore intravenous administration of an osmotic
promoted by: diuretic: mannitol or hypertonic saline.
208
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:59:54, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.052
Chapter 49: Intracranial Pressure and Head Injury
– When raised ICP is caused by a brain tumour, Area of brain injury. Brain injury can be focal
the volume of surrounding oedema may be (e.g. extradural haematoma, contusions) or diffuse
reduced by using dexamethasone, or surgical (e.g. diffuse axonal injury, hypoxic brain injury),
excision may be considered. but both types of injury commonly coexist.
– The volume of a cerebral abscess may be
reduced by surgical drainage and by antibiotic What is the difference between
therapy.
primary and secondary brain injury?
Finally, if all other measures have failed to control a
Brain injury may be classified as primary or secondary:
raised ICP, then a decompressive craniectomy may be
performed. A decompressive craniectomy is a neuro- Primary brain injury is damage to the brain
surgical procedure whereby a bone flap is removed during the initial injury caused by mechanical
from the cranium and the overlying skin closed, thus forces: stretching and shearing of neuronal and
allowing the brain to herniate upwards through the vascular tissue. Neuronal tissue is more
skull defect. susceptible to damage than blood vessels; this is
why diffuse axonal injury frequently accompanies
How is head injury classified? injuries where there has been vessel disruption,
such as 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 injury). 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 blood–brain barrier;
microorganisms. Penetrating head injury is, – Cerebral oedema;
by definition, open. – Raised ICP;
Presence of other injuries. Following trauma, – Seizures;
patients may have an isolated head injury or there – Ischaemia;
may be accompanying traumatic injuries. – Infection.
Where a head injury results in a traumatic brain Once primary brain injury has occurred, it cannot be
injury (TBI), further classifications can be made: reversed. Prevention of trauma is the best method of
Severity of injury. On arrival to hospital, the reducing primary brain injury: reducing speed limits,
severity of TBI is commonly assessed using the safer driving strategies, and so on. The impact of
post-resuscitation GCS: trauma on the brain can be reduced by the use of
airbags and seatbelts in cars, and of helmets for cyc-
– Mild TBI corresponds to a GCS score of
lists and motorcyclists. Medical and surgical efforts
13–15.
are concentrated on preventing secondary brain
– Moderate TBI corresponds to a GCS score
injury: preserving as many neurons as possible.
of 9–12.
– Severe TBI corresponds to a GCS score
of 3–8. How would you approach the
Patients presenting with mild TBI have a good prog- management of a patient with TBI?
nosis with a mortality rate of 0.1%. However, patients Patients with TBI frequently present with other,
with moderate and severe TBI have much higher more immediately life-threatening injuries. The broad
mortality rates of around 10% and 50%, respectively. principles of initial trauma management are the
Many survivors are left with severe disability. same whether in the emergency department or the
209
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:59:54, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.052
Section 4: Neurophysiology
210
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:59:54, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.052
Section 4 Neurophysiology
50
Describe the anatomy of the The conus medullaris is the tapered terminal
portion of the cord.
spinal cord The cauda equina is the collection of spinal nerves
The spinal cord is part of the central nervous system that continue inferiorly in the spinal canal after
(CNS), located within the spinal canal of the vertebral the cord has ended, until they reach their
column. The spinal cord begins at the foramen respective intervertebral foramina.
magnum, where it is continuous with the medulla
oblongata. The spinal cord is much shorter than the
vertebral column, ending at a vertebral level of L1/2 in
Describe the cross-sectional anatomy
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
three layers of the meninges: pia, arachnoid and dura oval, with a deep anterior median sulcus and a shal-
mater. Cerebrospinal fluid (CSF) surrounds the spinal low posterior median sulcus. The centre of the cord
cord in the subarachnoid space and extends inferiorly contains an approximately ‘H’-shaped area of grey
within the dural sac to approximately the S2 level. matter, surrounded by white matter:
After the spinal cord terminates, the pia and dura The grey matter contains unmyelinated axons and
merge to form the filum terminale, which tethers the cell bodies of interneurons and motor
the cord to the coccyx. neurons. Located in the centre of the grey matter
The spinal cord is divided into 31 segments, each is the CSF-containing central canal. The points of
emitting a pair of spinal nerves. There are: the ‘H’ correspond to the dorsal and ventral
Eight cervical segments. Note: there is one more (posterior and anterior) horns. There are also
pair of cervical nerves emitted than there are lateral horns in the thoracic region of the cord,
cervical vertebrae. which correspond to pre-ganglionic sympathetic
Twelve thoracic segments. neurons.
Five lumbar segments. The white matter contains columns of myelinated
Five sacral segments. axons, called tracts. These tracts are organised
One coccygeal segment. into:
With the exception of C1 and C2, the spinal nerves – Ascending tracts, containing sensory axons;
exit the spinal canal through the intervertebral – Descending tracts, containing motor axons.
foramina. The most important ascending tracts are shown in
The spinal cord enlarges in two regions: Figure 50.1:
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,
At the terminal end of the spinal cord: temperature, crude touch and pressure.
211
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:43:46, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.053
Section 4: Neurophysiology
ASCENDING DESCENDING
Figure 50.1 Cross-section of the spinal cord (extrapyramidal tracts not shown).
The anterior and posterior spinocerebellar tracts cord – essentially all of the structures, with the
carry proprioceptive information from the exception of the dorsal columns. The anterior
muscles and joints to the cerebellum. spinal artery is replenished along its length by
The most important descending tracts are (Figure 50.1): several radicular arteries, the largest of which is
called the artery of Adamkiewicz. The location
The anterior and lateral corticospinal tracts, also
of this vessel is variable, but is most commonly
known as the pyramidal tracts, carry the axons
found on the left between T8 and L1.
of upper motor neurons. In the ventral horn of the
spinal cord, these axons relay to α-motor neurons Two posterior spinal arteries, which arise from
the posterior inferior cerebellar arteries (see
(or lower motor neurons) that innervate muscle.
Chapter 45, Figure 45.1). The posterior spinal
The extrapyramidal tracts: rubrospinal,
arteries are located just medial to the dorsal roots
tectospinal, vestibulospinal, olivospinal and
and supply the posterior third of the cord. Again,
reticulospinal tracts. The extrapyramidal neurons
the posterior spinal arteries are replenished by
originate at brainstem nuclei and do not pass
radicular arteries.
through the medullary pyramids. Their primary
role is in the control of posture and muscle tone. Blood from the spinal cord is drained via three anter-
ior and three posterior spinal veins located in the
Describe the blood supply to the pia mater, which anastomose to form a tortuous
venous plexus. Blood from this plexus drains into
spinal cord the epidural venous plexus.
The spinal cord is supplied by three arteries, derived
from the posterior circulation of circle of Willis (see Clinical relevance: anterior spinal artery syndrome
Chapter 45). However, the blood flow through these The artery of Adamkiewicz most commonly arises
vessels is insufficient to perfuse the cord below the from the left posterior intercostal artery, a branch of
cervical region – an additional contribution from radi- the aorta. Damage or obstruction of the artery can
cular arteries is essential. The three spinal arteries are: occur through atherosclerotic disease, aortic dissec-
One anterior spinal artery, which arises from tion or surgical clamping during aortic aneurysm
branches of the right and left vertebral artery repair. As the anterior spinal artery supplies the
(see Chapter 45, Figure 45.1). The anterior spinal anterior two-thirds of the spinal cord, cessation of
blood flow can have profound consequences
artery descends in the anterior median sulcus
(Figure 50.4).
and supplies the anterior two-thirds of the spinal
212
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:43:46, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.053
Chapter 50: The Spinal Cord
213
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:43:46, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.053
Section 4: Neurophysiology
Somatosensory
cortex
3rd-order
neurons
Thalamus
Medial lemniscal tract
3rd-order
2nd-order Gracile nucleus neurons
neurons Cuneate nucleus
Medulla
oblongata
Figure 50.2 The two major sensory pathways: (a) dorsal column–medial lemniscal and (b) spinothalamic.
214
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:43:46, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.053
Chapter 50: The Spinal Cord
Motor cortex
Internal capsule
To skeletal muscles
Most of the remaining 10% of fibres
decussate in the anterior commissure
Lower motor neurons
215
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:43:46, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.053
Section 4: Neurophysiology
posteriorly to reach the cerebellum through other than solely the anterior column) require
the middle cerebral peduncle. immobilisation to prevent further damage to the
– At the medullary pyramids, 90% of the spinal cord. The high mobility of the cervical
remaining nerve fibres decussate and descend spine makes it especially vulnerable to unstable
in the lateral corticospinal tract of the fractures; fortunately, the spinal cord has more
spinal cord. space within the spinal canal at the cervical level
– The 10% of nerve fibres that do not decussate than elsewhere.
descend in a separate ipsilateral tract: the Extent of neurological injury. Approximately half
anterior corticospinal tract.3 of spinal cord injuries involve complete
– When they have reached their intended transection of the cord, with an absence of motor
vertebral level in the spinal cord, the upper and sensory neurological function below the level
motor neurons synapse with lower motor of injury. A spinal cord injury is said to be
neurons in the ventral horn of the spinal cord. ‘incomplete’ if some neurological function
remains below the level of injury (e.g. sacral
sparing).
A lower motor neuron, which leaves the CNS to
innervate skeletal muscle. There are two types
of lower motor neuron: How does the level of a complete
– α-motor neurons leave the anterior horn, spinal cord injury affect the different
forming the spinal nerve. The spinal nerve
exits the spinal canal via the intervertebral
body systems?
The spinal cord is the exclusive relay of sensory,
foramen, becoming a peripheral nerve.
motor and autonomic (with the exception of the
Ultimately, the α-motor neuron innervates
vagus nerve) information between the CNS and the
extrafusal fibres of skeletal muscle, causing
peripheries. The level of spinal cord injury determines
muscle contraction.
whether individual organs will remain in communi-
– γ-motor neurons innervate the intrafusal fibres
cation with the brain:
of skeletal muscle (the ‘muscle spindles’),
which are involved in proprioception (see Respiratory system. Respiratory failure is
Chapter 55). common after spinal cord injury; respiratory
complications are the most common cause of
216
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:43:46, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.053
Chapter 50: The Spinal Cord
movement of the chest wall – it is drawn from the heart, allowing unopposed
inwards during diaphragmatic contraction. parasympathetic activity. Cardiac output
As a result, vital capacity reduces by up to 50%. cannot be increased by the normal
– Injury at C3 vertebral level and above will mechanism of sympathetic stimulation of
result in paralysis of all respiratory muscles. heart rate. Stroke volume must therefore
Patients have gross ventilatory impairment be maintained by adequate cardiac preload;
requiring immediate ventilatory support. hypovolaemia is poorly tolerated in high
These patients usually require long-term spinal cord injury.
mechanical ventilation or phrenic nerve Peripheral nervous system. Spinal cord injury
stimulation. results in disruption of the motor, sensory and
Spinal cord injury also alters lung mechanics autonomic fibres:
in other ways: – Initially, there is flaccid paralysis and
– Paralysis of the external intercostal muscles loss of reflexes below the level of the
and the abdominal muscles results in markedly spinal cord lesion; this is referred to as
reduced forced expiratory gas flows. Forced ‘spinal shock’.
expiratory volume in 1 s is significantly – Over the next 3 weeks, spastic paralysis and
reduced and cough is severely impaired, brisk reflexes develop.
leading to impaired clearance of respiratory – Below the level of injury, somatic and visceral
secretions. sensation is absent.
– Impaired inspiration results in basal
Gastrointestinal system. Though the enteric
atelectasis, reduced lung compliance and V̇ /Q̇ nervous system is semi-autonomous, it is still
mismatch. affected by the sudden disruption of sympathetic
– As a consequence of the lower lung volume, fibres, resulting in unopposed parasympathetic
the production of pulmonary surfactant is input via the vagus nerve:
reduced. Lung compliance is further
decreased, which increases the work of – Delayed gastric emptying and paralytic ileus
breathing. are common. Abdominal distension may
further impair ventilation.
– Rarely, neurogenic pulmonary oedema can
result from cervical cord injury, though the – In high spinal cord lesions, gastric ulceration is
mechanism for this is unclear. almost inevitable without gastric protection
(e.g. by an H2 receptor antagonist such as
Cardiovascular system. Like the respiratory ranitidine). Gastric ulceration is thought to be
system, the cardiovascular consequences of spinal due to the unopposed vagal stimulation of
cord injury are more significant with higher spinal gastric acid secretion.
cord lesions. Adverse cardiovascular effects result – Patients usually become constipated as the
from the interruption of the sympathetic nervous sensations of defecation are lost; regular
system: laxatives and bowel care regimes are important
– Injury above T6 vertebral level results in to prevent faecal impaction.
hypotension, known as ‘neurogenic shock’. Metabolic. Spinal cord injury has several
Sympathetic nervous outflow to the systemic metabolic consequences:
arterioles is interrupted, resulting in arteriolar
– Thermoregulation may be impaired due to the
vasodilatation. Similarly, venodilatation leads
loss of sympathetic outflow below the level of
to venous pooling, which increases the risk of
the spinal cord injury:
thromboembolic disease and reduces venous
return to the heart, further contributing to ▪ Arteriolar vasodilatation in the skin may
hypotension. result in heat loss.
– Lesions above T1 vertebral level can result ▪ Overzealous attempts to warm patients
in bradycardia; the sympathetic may cause hyperthermia, as sweating is
cardioacceleratory nerves are disconnected impaired.
217
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:43:46, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.053
Section 4: Neurophysiology
218
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:43:46, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.053
Chapter 50: The Spinal Cord
219
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:43:46, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.053
Section 4: Neurophysiology
prevent hypoxaemia-related secondary cord ischaemic damage of the spinal cord. In a trauma
damage. A difficult intubation should be patient, hypotension is most likely to be the result
anticipated owing to: of haemorrhage – the search for the site of
– Suboptimal positioning of the patient; bleeding is both clinical and radiological: chest
– Rapid sequence induction (RSI) with cricoid and pelvic X-rays, abdominal ultrasound and
pressure; computed tomography. Bradycardia with
hypotension may be due to spinal cord injury
– Manual in-line stabilisation of the
with unopposed parasympathetic innervation
cervical spine;
of the heart – atropine or glycopyrrolate should
– Associated maxillofacial injuries;
be given.
– Blood and debris in the oral cavity.
Disability. A basic neurological assessment should
Nasal intubation and high-flow nasal O2 include an assessment of conscious level using the
therapy should be avoided owing to the possibility Glasgow Coma Scale or the ‘alert, voice, pain,
of associated basal skull fractures. unresponsive’ (AVPU) scale, pupil size and
Induction of anaesthesia. The risk of reactivity and tendon reflexes. Patients with a
pulmonary aspiration necessitates an RSI.5 reduced level of consciousness will almost
The best intravenous induction agent is a inevitably require imaging of their brain in
matter of debate, but in the setting of trauma, addition to their spine.
a cardio-stable drug (e.g. ketamine) may be Everything else. Plasma glucose and electrolytes
required. Suxamethonium may be used as the should be tested and abnormalities corrected.
muscle relaxant for the initial RSI, but 24 h A full secondary survey should be carried out
following the injury, the use of suxamethonium when the patient has been stabilised – this
is contraindicated: a significant rise in plasma includes log-rolling the patient to examine the
K+ may occur due to the depolarisation of the spine, flanks and anal motor tone. Care should be
newly developed extra-junctional acetylcholine taken to keep the patient warm; hypothermia is
receptors (see Chapter 53). If head injury is common, due to prolonged exposure to the
suspected, some means of obtunding the environment at the scene of trauma, cold
sympathetic response to laryngoscopy should intravenous fluids and blood and removal of
be used to avoid a rise in intracranial pressure; clothes for clinical examination.
for example, by co-administering a fast-acting,
strong opioid.
Breathing. In the acute phase, PaO2 should
Further reading
J. A. Kiernan, R. Rajakumar. Barr’s The Human
be kept above 10 kPa. Oxygenation may Nervous System: An Anatomical Viewpoint,
be impaired by associated chest injuries 10th edition. Philadelphia, Lippincott Williams &
(e.g. flail chest, haemothorax), which should Wilkins, 2013.
be dealt with promptly. As discussed above, J. H. Martin. Neuroanatomy Text and Atlas, 4th edition.
the respiratory consequences of cervical spine New York, McGraw-Hill Medical, 2012.
injury make hypoxaemia particularly common; G. Hadjipavlou, A. M. Cortese, B. Ramaswamy. Spinal cord
if a conscious patient is unable to maintain injury and chronic pain. BJA Education 2016; 16(8):
adequate arterial oxygenation or becomes 264–8
hypercapnoeic, intubation and ventilation are M. Denton, J. McKinlay. Cervical cord injury and critical
indicated. care. Continuing Educ Anaesth Crit Care Pain 2009;
Circulation. Hypovolaemia should be treated 9(3): 82–6.
promptly with fluids to minimise secondary J. Šedy, J. Zicha, J. Kuneš, et al. Mechanisms of neurogenic
pulmonary edema development. Physiol Res 2008; 57:
499–506.
5 P. Veale, J. Lamb. Anaesthesia and acute spinal cord injury.
Have a low threshold for removing cricoid pressure if it is
impeding laryngoscopic view – avoiding hypoxaemia at Continuing Educ Anaesth Crit Care Pain 2002; 2(5):
induction is paramount. 139–43.
220
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:43:46, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.053
Section 4 Neurophysiology
51
How is the membrane potential Cell excitation results in an action potential (see Chap-
ter 52), a transient change in the membrane potential
produced? from the RMP to a positive value; the cell membrane
The cell membrane provides a selectively permeant has been briefly depolarised.
electrical barrier between the intracellular and extra- The RMP is particularly influenced by the con-
cellular compartments. The membrane potential of a centrations and membrane permeability of three
cell is the electrical voltage of its interior relative to its major ions:
exterior. The electrical potential across the membrane + +
K : the intracellular K concentration is normally
will be zero when there are exactly equal numbers greater (150 mmol/L) than the extracellular K+
of positively and negatively charged ions on either concentration (5 mmol/L). The phospholipid
side of the cell membrane. A non-zero membrane bilayer of the cell membrane itself is impermeable
potential arises from inequalities in the distribution to K+ ions, as they are polar. However, the cell
of charged ions across the cell membrane. membrane contains open K+ leak channels1 that
The distribution of ions across a cell membrane permit K+ to pass down its concentration gradient
results from a combined effect of: from the ICF to the ECF.
+ +
The different ionic compositions of the Na : the extracellular Na concentration is higher
intracellular fluid (ICF) and extracellular (140 mmol/L) than the intracellular Na+
fluid (ECF). concentration (20 mmol/L). Na+ ions are polar
The selective permeability of the cell membrane to and therefore do not traverse the cell membrane,
the different ions. and Na+ channels present in the membrane are
The presence of negatively charged intracellular normally closed at RMP, leaving the resting cell
proteins, whose large molecular weight and charge membrane impermeable to Na+.2
mean that they are unable to cross the cell Cl‾: membrane permeability varies with cell type:
membrane. These proteins tend to bind positively – In neurons, the cell membrane is relatively
charged ions and repel negatively charged ions. impermeable to Cl‾: permeability to Cl‾ is
Thus: about 1000 times less than that of K+, and
therefore its contribution is often ignored.
A negative membrane potential is produced – Muscle contains open membrane Cl‾ channels.
when there is a greater number of positively Cl‾ therefore distributes itself across the cell
charged ions on the outside of the cell membrane membrane passively according to its
relative to the inside. electrochemical gradient. At RMP, Cl‾
A positive membrane potential is produced when is driven out of the cell by the negatively
there is a greater number of positively charged charged cell interior. However, membrane
ions on the inside of the cell membrane relative to
the outside.
1
These are also called two-pore-domain K+ channels.
A quiescent cell typically has a negative resting mem- 2
In reality, the resting cell membrane is not completely
brane potential (RMP). RMP is more negative in exci- impermeable to Na+, as the K+ leak channels are not
table cells (–70 mV in nerve cells, –90 mV in skeletal completely specific to K+. Overall, Na+ permeability is
muscle cells) than non-excitable cells (around –30 mV). about 100 times less than that of K+.
221
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 14:31:16, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.054
Section 4: Neurophysiology
222
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 14:31:16, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.054
Chapter 51: Resting Membrane Potential
–30
Membrane potential (mV)
Threshold potential
more negative
–50 Threshold potential
RMP
–70
Depolarisation of RMP
Hyperpolarisation of RMP
–90
‘Normal’ Hypokalaemia Hyperkalaemia Hypocalcaemia
Electrolyte disturbance
Figure 51.1 Changes to resting membrane potential (RMP) and threshold potential with electrolyte disturbances.
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 14:31:16, subject to the Cambridge Core terms of use, available at 223
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.054
Section 4: Neurophysiology
Na+. As discussed above, the cell membrane is hypothesis’. Ca2+ binds to the outside of the cell
relatively impermeable to Na+ at rest. Therefore, membrane by becoming attached to
changes to the Na+ extracellular concentration glycoproteins. This increases the amount of local
would be expected to make little difference positive charge directly apposed to the
to the RMP. However, hyponatraemia alters extracellular side of the membrane, which
the distribution of water in the body hyperpolarises the membrane relative to the
(see Chapter 69). The reduced ECF osmolarity overall RMP. Hypocalcaemia increases excitability
causes cells to swell; for example, severe of the membrane, bringing the threshold
hyponatraemia leads to cerebral oedema. potential nearer to the RMP. This predisposes to
The additional intracellular water causes a fall spontaneous action potential generation, leading
in intracellular K+ concentration, which in turn to tetany, parasthesias and arrhythmia.
leads to cell membrane depolarisation towards Ca2+ may be given for cardioprotection in
threshold potential; spontaneous action hyperkalaemia, allowing time for the underlying
potentials are more likely to be generated. cause to be dealt with.
This partially explains why cerebral oedema
secondary to hyponatraemia is associated with
seizure activity. Further reading
Ca2+. As discussed above, K+ is the major R. D. Keynes, D. J. Aidley, C. L.-H. Huang. Nerve and
determinant of the RMP – Ca2+ plays no direct Muscle, 4th edition. Cambridge, Cambridge University
role, as the membrane is largely impermeable to Press, 2011.
Ca2+ at rest. However, Ca2+ has a membrane-
S. H. Wright. Generation of resting membrane potential.
stabilising effect due to the ‘surface charge
Adv Physiol Educ 2004; 28: 139–42.
224
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 14:31:16, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.054
Section 4 Neurophysiology
52
What is an action potential? Na+ influx then exceeds K+ efflux. This is
known as the ‘threshold potential’.
An action potential is a transient reversal of the mem-
brane potential that occurs in excitable cells, includ- The resulting membrane depolarisation leads to
ing neurons, muscle cells and some endocrine cells. further opening of voltage-gated Na+ channels,
The action potential is an ‘all-or-nothing’ event: if the thus further increasing the membrane
triggering stimulus is smaller than a threshold value, permeability to Na+ (Figure 52.1b). This further
the action potential does not occur. But once trig- increases the Na+ influx, which in turn produces
gered, the action potential has a well-defined ampli- further membrane depolarisation, resulting in the
tude and duration. Action potential propagation allows rapid upstroke of the action potential. This drives
rapid signalling within excitable cells over relatively the membrane potential towards the Nernst
long distances. equilibrium potential for Na+ of approximately
+50 mV. However, the action potential never
Describe the events that result in the reaches this theoretical maximum, as two further
events intervene:
nerve action potential
– Inactivation of voltage-gated Na+ channels: the
Action potentials usually begin at the axon hillock of
voltage-gated Na+ channels make a further
motor neurons or at sensory receptors in sensory affer-
transition from the open state to an inactivated
ent neurons. Events proceed as follows (Figure 52.1a):
(refractory) state; membrane Na+ permeability
As discussed in Chapter 51, the neuronal resting decreases.
membrane potential (RMP) of approximately – Delayed activation of voltage-gated K+
–70 mV is relatively close to the Nernst channels: membrane depolarisation slowly
equilibrium potential for K+ of around –90 mV. opens voltage-gated K+ channels
An initial depolarisation of a sensory receptor, (Figure 52.1b). Membrane K+ permeability
synapse or another part of the nerve results in Na+ increases and the resulting K+ efflux acts to
and K+ movements, producing a net drive the membrane potential back towards
depolarisation of the cell membrane: the Nernst equilibrium potential for K+ of
– If the stimulus is small, the Na+ influx is approximately –90 mV.
exceeded by K+ efflux through K+ leak
The membrane potential briefly becomes more
channels primarily responsible for the RMP
negative than the RMP. This after-
(see Chapter 51). The cell membrane returns
hyperpolarisation occurs because of the gradual
to –70 mV.
closure of the voltage-gated K+ channels, which
– If the stimulus is large enough, depolarising the results in the membrane being briefly more
cell membrane to approximately –55 mV1 permeable to K+ than at the RMP, thus achieving a
results in a significant activation of value closer to the EK.
transmembrane voltage-gated Na+ channels;
In summary, the action potential results from a brief
increase in membrane conductance to Na+ followed
1
Threshold potential is dependent on a number of factors, by a slower increase in membrane conductance to K+
but is commonly between –55 and –40 mV. (Figure 52.1b).
225
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 20:01:21, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.055
Section 4: Neurophysiology
Na+
+30 +30 Membrane
Voltage-gated Na+ Voltage-gated K+ channels open conductance
potential
+10 +10
100
K+ conductance
–10 Voltage-gated K+ channels start –10
Increasing number of
to close
voltage-gated Na+ 10
–30 channels open –30
Threshold stimulus
–50 Threshold potential –50
–55 –55 1
Resting membrane potential
–70 –70
Hyperpolarisation
Subthreshold stimulus 0.1
–90 –90
0 1 2 3 4 5 6 0 1 2 3 4 5
Time (ms) Time (ms)
Figure 52.1 (a) The nerve action potential and (b) changes in the membrane permeability of Na+ and K+ throughout the action potential.
How are action potentials propagated This process of local circuit propagation and action
potential generation is continued until the action
along nerve axons? potential reaches its destination (Figure 52.2).
Electrical depolarisation propagates by the formation The velocity of action potential conduction is
of local circuits (Figure 52.2): affected by several factors:
The intracellular surface of a resting portion of The axon diameter. Just like a copper wire, the
cell membrane is negatively charged. intracellular fluid within a larger-diameter nerve
Following an action potential, a portion of cell axon has a smaller resistance to the longitudinal
membrane depolarises, resulting in the flow of current, thereby permitting a higher
intracellular surface becoming positively charged. conduction velocity.
The action potential is limited to a small portion The transmembrane resistance. This determines
of cell membrane; neighbouring segments how easily current may flow out of the
remain quiescent. nerve and into the extracellular fluid (ECF).
Ion movement at the edges of the depolarised A higher transmembrane resistance reduces
cell membrane results in current flow; the the leak of current out of the cell, thereby
neighbouring quiescent portions of cell maximising the longitudinal flow of current.
membrane become depolarised. Myelination increases the transmembrane
Current decays exponentially along the length of resistance as the myelin sheath is made of
the nerve axon with a length constant of a few insulating lipids.
millimetres.2 Nevertheless, provided the The membrane capacitance. The greater
propagated depolarisation in the previously the capacitance of the membrane, the longer
quiescent cell membrane is sufficient to reach it takes to alter the membrane polarity,3
threshold potential, an action potential is
generated.
3
As τ = RC, where τ is the time constant, R the
transmembrane resistance and C is the capacitance. As
myelination actually increases transmembrane resistance
2
Longitudinal current is reduced by a deposition of charge (as this increases longitudinal flow), the decrease in
on intervening membrane, as well as its leak across the membrane capacitance offsets this effect on the overall
membrane into the extracellular fluid. time constant.
226
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 20:01:21, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.055
Chapter 52: Nerve Action Potential and Propagation
Area undergoing an
action potential _ _
+ + + + + + + + + + + + + + + +
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
+ +
Action potential is
initiated by stimulus _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
+ +
_ _
+ + + + + + + + + + + + + + + +
_ _ _ _
+ + + + + + + + + + + + + +
_ _ _ _ _ _ _ _ _ _ _ _ _ _
+ + + +
Action potential
propagation
+ + + + _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _
+ + + + + + + + + + + + + +
_ _ _ _ _ _ _ _
+ + + + + + + + + +
_ _ _ _ _ _ _ _ _ _
+ + + + + + + +
Action potential
propagation _ _ _ _ _ _ _ _ _ _
+ + + + + + + +
_ _ _ _ _ _ _ _
+ + + + + + + + + +
Wave of depolarisation
_ _ _ _ _ _ _ _ _ _ _ _
+ + + + + +
_ _ _ _ + + + + + + + + + + + + _ _
Membrane
repolarisation _ _ _ _ _ _
beings + + + + + + + + + + + +
_ _ _ _ _ _ _ _ _ _ _ _
+ + + + + +
Wave of repolarisation
227
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 20:01:21, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.055
Section 4: Neurophysiology
+ + + + + + + +
_ _ _ _ _ _ _ _
Resting neuronal
cell membrane _ _ _ _ _ _ _ _
+ + + + + + + +
Area undergoing an
action potential
_
+ + + + + + +
_ _ _ _ _ _ _
+
Action potential is
initiated by stimulus _ _ _ _ _ _ _
+
_
+ + + + + + +
_ _ _
+ + + + +
_ _ _ _ _
+ + +
Saltatory
conduction + + _ _ _ _ _
+
_ _ _
+ + + + +
_ _ _ _ _
+ + +
_ _ _
+ + + + +
Saltatory
conduction + + + + _ _ _
+
_ _ _ _ _
+ + +
Wave of depolarisation
exposed regions of membrane are densely populated 2 m/s in unmyelinated nerves to up to 120 m/s in
with voltage-gated Na+ channels. myelinated axons.
The electrical impulse propagates passively
across the internode (where the axon is covered by Clinical relevance: demyelination
the myelin sheath) by local circuit conduction, as Myelination is an extremely important determinant
in Figure 52.2. Passive propagation is rapid as it of nerve conduction velocity. The myelin sheath is
does not require protein interactions at the surface especially important in nerves that require the rapid
membrane. As discussed above, the myelin sheath conduction of action potentials for their function,
insulates the nerve axon, preventing loss of current such as motor and sensory nerves.
to the ECF and decreasing the membrane capaci- There are two important diseases in which there
tance. This ensures that the membrane is depolar- is autoimmune destruction of the myelin sheath:
ised in excess of the threshold potential at the multiple sclerosis (where CNS neurons demyelinate)
adjacent node of Ranvier. The action potential and Guillain–Barré syndrome (where demyelination
occurs in the PNS).
therefore appears to ‘jump’ from node to node; this
A demyelinated neuron differs in its disposition of
is known as saltatory conduction (Figure 52.3). Na+ channels from normally unmyelinated neurons.
Action potential conduction velocity increases from
228
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 20:01:21, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.055
Chapter 52: Nerve Action Potential and Propagation
Myelinated neurons have Na+ channels clustered at potentials being propagated. The mechanism of
high density at the nodes of Ranvier, but not in action is:
surface membrane beneath the myelin sheath. Upon
Local anaesthetics are weak bases.
demyelination, the abnormally exposed areas of cell
Only unionised local anaesthetic can diffuse
membranes do not have adequate numbers of Na+
across the phospholipid bilayer of the neuronal
channels to ensure effective action potential conduc-
cell membrane.
tion. In contrast, whilst unmyelinated axons conduct
The lower pH within the axoplasm means that as
action potentials slowly, they are reliably conducted
soon as the local anaesthetic has crossed the cell
along the entire length of the neuron.
membrane, it is protonated (becomes ionised)
The clinical features of demyelinating disease are
and therefore cannot diffuse back into the ECF.
therefore deficiencies in sensation, motor function,
The ionised local anaesthetic blocks the voltage-
autonomic function or cognition depending on the
gated Na+ channels by binding to the inner
type and location of the nerves involved.
surface of the ion channels when they are in their
inactive state.
How are nerve fibres functionally In other words, local anaesthetics indefinitely
prolong the absolute refractory period (ARP);
classified? further action potentials are prevented.
Nerves can be classified based on their diameter and Some nerves are more sensitive to local anaesthetics
conduction velocity: than others. In general:
Type A fibres are myelinated fibres of large Small nerve fibres are more sensitive to local
diameter (12–20 μm) with a conduction velocity anaesthetics than are large nerve fibres.
of 70–120 m/s. Type A fibres are subdivided into Myelinated fibres are more sensitive to local
α, β, γ and δ in order of decreasing nerve anaesthetics than are unmyelinated fibres of
equivalent diameters. This likely reflects
conduction velocity:
myelinated fibres having only small areas of cell
– Aα motor fibres supply extrafusal muscle membrane exposed (nodes of Ranvier), in which
fibres; that is, those involved in skeletal muscle the Na+ channels are densely packed.
contraction. The overall clinical effect is:
– Aβ sensory fibres carry sensory information Intermediate-sized myelinated fibres are the
from receptors in the skin, joints and muscle. easiest to block, such as Aδ fibres (which relay
– Aγ motor fibres supply intrafusal muscle fast nociceptive signals) and B fibres (pre-
spindle fibres. ganglionic autonomic fibres).
– Aδ sensory fibres relay information from fast Larger Aα, Aβ and Aγ fibres (which relay touch,
nociceptors and thermoreceptors. pressure and proprioception) are the next easiest
to block.
Type B fibres are narrow (diameter < 3 μm) Unmyelinated C fibres are the most resistant to
myelinated fibres. Their conduction velocity is local anaesthetics.
correspondingly lower, at 4–30 m/s. The
preganglionic neurons of the autonomic nervous
system (ANS) are type B fibres. What is meant by the term
Type C fibres have narrow (diameter 0.4–1.2 μm) ‘refractory period’?
unmyelinated axons with a correspondingly slow
The refractory period describes the time following
conduction velocity (0.5–4.0 m/s). Post-ganglionic
an action potential when a further action potential
neurons of the ANS and slow pain fibres are type
either cannot be triggered whatever the size of the
C fibres.
stimulus (i.e. ARP) or only with application of a
stimulus of increased size (i.e. relative refractory
period, RRP):
Clinical relevance: local anaesthetics
The ARP starts from the moment the voltage-
Local anaesthetics act by blocking fast voltage-gated gated Na+ channels open and typically lasts
Na+ channels, thereby preventing further action
around 1 ms. The basis of the ARP is:
229
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 20:01:21, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.055
Section 4: Neurophysiology
The RRP continues for 2–3 ms after the ARP has –10
ended. The mechanism behind the RRP is as
follows: –30
230
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 20:01:21, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.055
Section 4 Neurophysiology
53
What is a synapse? What are neurotransmitters?
A synapse is the functional point of contact between A neurotransmitter is a substance released by a
two excitable cells, across which a signal can be trans- neuron at a synapse, which then acts upon the post-
mitted. There are two types of synapse: synaptic cell. Neurotransmitters are classified as:
Chemical synapse, in which the signal is relayed Small molecules, of which there are three main
by means of a chemical messenger called a classes:
neurotransmitter. Arrival of an action potential
– Amines: acetylcholine (ACh), histamine,
triggers neurotransmitter release into the
serotonin (5-HT), catecholamines
synaptic cleft, a narrow (20–50‑nm) gap
(noradrenaline, adrenaline, dopamine);
between the pre- and post-synaptic membranes,
– Amino acids: γ-amino butyric acid (GABA),
which excites or inhibits the postsynaptic cell.
glycine, glutamate;
An example of a chemical synapse is the
neuromuscular junction (NMJ): the terminal – Purines: ATP, adenosine.
bouton of an α-motor neuron forms a synapse Large molecules; over 50 neuroactive peptides are
with the motor end plate of a skeletal muscle cell. known, including:
Action potential transmissions at chemical – Opioids: β-endorphin, enkephalins;
synapses are typically unidirectional: the – Tachykinins: substance P, neurokinins;
signal can only be transmitted from pre- to – Secretins;
post-synaptic cells. Transmission of an action
– Somatostatins.
potential across a chemical synapse is associated
with a synaptic delay, as it takes time for each Most neurotransmitters exert excitatory effects on the
of the processes of neurotransmitter release, target cell, which may result in the triggering of an
diffusion and combination with postsynaptic action potential (if the target cell is a nerve or muscle)
receptors to occur. or secretion (if the target cell is a gland). The most
Electrical synapse, in which the pre- and post- widespread excitatory neurotransmitter is glutamate,
synaptic cells are electrically connected by gap which is present in over 90% of synapses in the brain.
junctions that allow electric current to pass; an Some neurotransmitters are inhibitory, causing either
action potential in the presynaptic cell induces a increased K+ conductance resulting in hyperpolarisa-
local current in the postsynaptic cell, which tion or increased Cl‾ conductance at the postsynaptic
triggers an action potential. Signals are transferred membrane, thereby reducing the likelihood of an
from neuron to target cell without a synaptic action potential being generated. GABA, the second
delay, and therefore this occurs more rapidly than most prevalent neurotransmitter in the brain, is the
when the cells are connected by a chemical major inhibitory neurotransmitter. Glycine is an
synapse. This is exemplified by cardiac muscle, inhibitory neurotransmitter that is particularly wide-
where gap junctions are essential for the rapid spread in the spinal cord and brainstem.
conduction of action potentials (see Chapter 57). Occasionally, neurotransmitters have an excita-
Electrical synapses are bidirectional: the signal can tory effect at one synapse whilst having an inhibitory
be transmitted from pre- to post-synaptic cells, or effect at another. For example, ACh is an excitatory
vice versa. neurotransmitter at the nicotinic receptors of the
231
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:27:13, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.056
Section 4: Neurophysiology
Closed voltage-
gated Ca2+ channel Vesicles containing neurotransmitter
..
.. ...
... ..
... Post synaptic membrane
.. ..
... ...
Synaptic cleft
Pre-synaptic membrane
Chemically gated ion channel (closed)
..
...
Ca2+ Ca2+ Ca2+ Ca2+ Vesicles fuse with post synaptic membrane
.. ..
... ...
... . .
. . .. .
Neurotransmitters released
(c)
..
...
.. ..
... ...
. . .
. . .. . . . .
NMJ, but it produces an inhibitory response at the Exocytosis. Periodically, vesicles in the active zone
muscarinic M2 receptors of the heart. spontaneously fuse with the presynaptic
membrane, releasing their neurotransmitter
How are neurotransmitters released contents into the synaptic cleft. Axonal Ca2+ binds
into the synaptic cleft? to a vesicular membrane protein called
synaptotagmin, which, in conjunction with
Neurotransmitters are stored in packets called ves- proteins known as SNAREs,1 triggers 50–100
icles, which are docked at the active zone of the vesicles to undergo exocytosis. Thus, a very large
presynaptic membrane. When the action potential number of neurotransmitter molecules are
propagates down the axon and into the terminal bou- released into the synaptic cleft following an action
ton (Figure 53.1a), a well-defined sequence of events potential.
occurs: Diffusion across the synaptic cleft. The
2+
Increase in presynaptic Ca concentration. neurotransmitters diffuse down their
Depolarisation results in the opening of concentration gradient, travelling the short
voltage-gated Ca2+ channels (N-type). Ca2+ distance to the postsynaptic membrane.
diffuses down its electrochemical gradient from
the extracellular fluid (ECF) to the cell interior 1
SNAP (soluble N-ethylmaleimide-sensitive fusion
(Figure 53.1b). attachment protein) Receptor.
232
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:27:13, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.056
Chapter 53: Synapses and the Neuromuscular Junction
233
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:27:13, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.056
Section 4: Neurophysiology
+10
Multiple vesicles of
–10 neurotransmitter
released simultaneously When the EPSP exceeds threshold,
–30 an action potential is triggered
EPSP
–50 Threshold potential
–55
Resting membrane potential
–70
–30
Neurotransmitter release at synapse
The GABAA receptor utilises the inhibitory The exact binding site and why their effects
neurotransmitter GABA. The receptor differ from those of the benzodiazepines are
has five subunits arranged around a Cl‾ not yet known.
channel. A number of drugs act at this
receptor: The N-methyl-D-aspartate (NMDA) receptor is
a tetrameric receptor that utilises the excitatory
– Benzodiazepines: a subset of GABAA receptors neurotransmitter glutamate. A number of
bind benzodiazepines in addition to GABA. anaesthetic agents are thought to act by
The benzodiazepine binding site is located at antagonising this excitatory receptor, thus
a different site from that of GABA, between reducing neurotransmission:
the α- and γ-subunits. Following the binding
of a benzodiazepine, the GABAA receptor – Ketamine binds at a site distant to the
changes its conformation, which increases its glutamate binding site. A conformation
affinity for GABA. change occurs in the NMDA receptor that
– Propofol, thiopentone and etomidate: all of prevents the subsequent binding of
these drugs act, at least in part, at the GABAA glutamate.
receptor. Like the benzodiazepines, all bind – N2O, Xe: both are also thought to exert their
at a site distant to the GABA binding site and anaesthetic effects through antagonism of
act by increasing the conductance of Cl‾. the NMDA receptor.
234
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:27:13, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.056
Chapter 53: Synapses and the Neuromuscular Junction
Action potential
Myelin sheath
235
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:27:13, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.056
Section 4: Neurophysiology
The motor end plate (postsynaptic membrane), to the active zone of the presynaptic
which is folded into peaks and troughs; the membrane.
peaks are densely packed with ACh receptors – The AChR is composed of five subunits: two
(AChRs), whilst the troughs contain the α-, one β-, one δ- and one ε-subunit. The
enzyme AChE. There are estimated to be in subunits are arranged in a cylinder, forming a
excess of 1,000,000 AChRs at each motor central ion channel.
end plate. – To open the ion channel, two ACh molecules
Before the action potential arrives, the NMJ must be must bind to the two α-subunits. Na+ and K+
ready for neurotransmission to occur: may then diffuse along their electrochemical
gradients; the net influx of cations depolarises
ACh synthesis. In the axoplasm of the nerve the postsynaptic membrane. The AChR ion
terminal, ACh is synthesised from choline channel stays open for a very brief period,
and acetyl-CoA, a reaction catalysed by the around 1 ms.
enzyme choline-O-acetyltransferase. Choline
– Following an action potential, a significant
originates from the diet or by hepatic synthesis,
excess of ACh molecules is released; the
whilst acetyl-CoA is produced in the axon
resulting postsynaptic depolarisation (the
mitochondria.
end-plate potential) easily exceeds threshold
ACh storage. Once synthesised, ACh is packaged potential, thereby triggering an action
into vesicles. Each vesicle contains around potential in the muscle cell. This safety margin
5000 ACh molecules, known as a ‘quantum’. is clinically important: 70–80% of AChRs must
There are functionally three types of vesicle: be blocked by muscle relaxants to prevent
– Vesicles in the active zone (1% of vesicles): neurotransmission.
these vesicles are ‘docked’ at the presynaptic Termination of neurotransmission. ACh is
membrane, ready for immediate release. rapidly removed from the synaptic cleft, mainly
– Vesicles in the reserve pool (around 80% of by degradation:
vesicles): these vesicles move forward to
replace the vesicles in the active zone as they – ACh is rapidly hydrolysed by the enzyme
are used. AChE to choline and acetic acid. These
breakdown products are actively transported
– Vesicles in the stationary store (around 20%
into the presynaptic membrane for the
of vesicles): these vesicles cannot release
re-synthesis of ACh.
their ACh.
– AChE is mainly found in the junctional folds
Neurotransmission occurs as follows: of the synaptic cleft.
ACh release. When an action potential reaches the – The structure of AChE is of pharmacological
terminal bouton, it causes voltage-gated Ca2+ importance. The active site of the enzyme has
channels to open: two binding sites: anionic and esteratic.
– Ca2+ ions diffuse from the ECF to the nerve Anticholinesterases, drugs that inhibit the
axoplasm. AChE enzyme, reversibly or irreversibly bind
– An increase in intracellular Ca2+ concentration to these binding sites.
triggers the vesicles of the active zone to fuse
with the presynaptic membrane, releasing
their contents by exocytosis. Typically, 50–100 Clinical relevance: drugs acting at the NMJ
vesicles release >250,000 ACh molecules into Neurotransmission at the NMJ may be blocked by a
the synaptic cleft. number of means, not just muscle relaxants:
The AChR is a nicotinic receptor, a ligand-gated, Inhibition of ACh synthesis: hemicholinium
non-specific cation channel. It has some blocks the uptake of choline in the nerve axon,
important features: preventing ACh synthesis.
Inhibition of vesicle exocytosis may occur
– AChRs are densely packed into the peaks of through two mechanisms:
the postsynaptic membrane, directly opposite
236
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:27:13, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.056
Chapter 53: Synapses and the Neuromuscular Junction
Where else are ACh receptors found? Clinical relevance: denervation hypersensitivity
Extra-junctional AChRs are structurally different from
In addition to the postsynaptic membrane, AChRs are
those at the motor end plate: they also have five
found:
237
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:27:13, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.056
Section 4: Neurophysiology
subunits, but the adult ε-subunit is replaced by the 100 days, the risk of hyperkalaemia is thought to
foetal γ-subunit. Classic examples of acute denerva- reduce sufficiently to permit the cautious use of
tion include burns and acute spinal cord injury. How- suxamethonium. In chronic denervation, suxametho-
ever, chronic denervation also leads to proliferation nium has an unpredictable response depending on
of extra-junctional AChRs (e.g. motor neuron disease the numbers of extra-junctional AChRs formed.
and some peripheral neuropathies such as Charcot–
Marie–Tooth disease).
Extra-junctional AChRs are not just of academic Further reading
interest. Following administration of the depolarising J. M. Hunter. Reversal of residual neuromuscular block:
muscle relaxant suxamethonium, a potentially fatal complications associated with perioperative
hyperkalaemia can occur. This is due to: management of muscle relaxation. Br J Anaesth
Suxamethonium binding to both junctional and 2017; 119(Suppl. 1): i53–62.
extra-junctional AChRs, opening their non- T. Thevathasan, S. L. Shih, K. C. Safari, et al. Association
specific cation channels. Owing to the sheer between intraoperative non-depolarising neuromuscular
number of AChRs activated, the K+ efflux is blocking agent dose and 30-day readmission after
significantly greater. abdominal surgery. Br J Anaesth 2017; 119(4): 595–605.
Once open, extra-junctional AChRs remain open M. Naguib, S. J. Brull, K. B. Johnson. Conceptual and
for up to 10 ms, which is much longer than their technical insights into the basis of neuromuscular
junctional counterparts. monitoring. Anaesthesia 2017; 72(Suppl. 1): 16–37.
The combination of these two effects has the poten- R. Khirwadkar, J. M. Hunter. Neuromuscular physiology
tial for a life-threatening increase in plasma K+ and pharmacology: an update. Continuing Educ Anaesth
concentration. Crit Care Pain 2012; 12(5): 237–44.
Following acute denervation, extra-junctional
C. J. Weir. The molecular mechanisms of general
AChRs take a little time to develop – clinically signifi-
anaesthesia: dissecting the GABAA receptor. Continuing
cant hyperkalaemia is a risk from 24 h post-injury.
Educ Anaesth Crit Care Pain 2006; 6(2): 49–53.
Therefore, suxamethonium can safely be adminis-
tered for up to 24 h following the insult. After around M. Thavasothy, N. Hirsch. Myasthena gravis. Continuing
Educ Anaesth Crit Care Pain 2002; 2(3): 88–90.
238
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:27:13, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.056
Section 4 Neurophysiology
Skeletal Muscle
Chapter
54
What are the functions of skeletal At each end of the muscle, the layers of connective
tissue (endomysium, perimysium and epimysium)
muscle? merge to form a tendon or an aponeurosis, which
Locomotion: contraction of muscle reduces the usually connects the muscle to bone.
distance between its sites of origin and insertion, Myocytes have a number of unusual anatomical
thereby producing movement. features:
Maintenance of posture and joint stability: this is Size. A muscle fibre may span the entire
achieved through tonic contraction of multiple length of the muscle and have a diameter of up
synergistic and opposing muscle groups. to 50 μm.
Support of soft tissues: the muscles of the Nuclei. Myocytes are multinucleate. Nuclei are
abdominal wall and pelvic floor support and located peripherally, unlike in cardiac and smooth
protect their underlying viscera. muscle.
Sphincteric function in the gastrointestinal tract Striations. Skeletal and cardiac muscle, but not
and urinary tracts: skeletal muscle provides smooth muscle, have a striped or ‘striated’
voluntary control over swallowing, defecation and appearance due to regularly repeating sarcomeres
micturition. (see below).
Heat production: this occurs through alterations Myocytes have a number of specialised cellular fea-
in background muscle metabolic rate and tures in addition to the usual complement of Golgi
shivering (repeated muscle contraction and apparatus, mitochondria and ribosomes:
relaxation).
The sarcoplasmic reticulum (SR) is a modified
Venous return: contraction of leg muscles aids in endoplasmic reticulum (ER) that acts as an
the generation of local pressure gradients to move
intracellular store of Ca2+ and can rapidly release
venous blood towards the heart.
and sequester Ca2+.
The transverse (T)-tubules are invaginations of
Describe the macroscopic and the muscle surface membrane, or sarcolemma,
microscopic anatomy of capable of relaying action potentials deep into the
skeletal muscle myocyte interior.
Myofibrils, the contractile apparatus of the cell,
Skeletal muscles are made up of many muscle fibres are arranged in parallel with one another spanning
(myocytes). They are served by blood vessels and the entire length of the myocyte. Because
nerves and are supported by a number of connective myofibrils are anchored to the sarcolemma at
tissue layers: either end of the myocyte, the whole myocyte
Endomysium, the thin layer of connective tissue shortens when they contract.
surrounding each myocyte. Myofilaments – within the myofibrils are bundles
Perimysium – bundles of around 100 myocytes of myofilaments, containing the contractile
surrounded by perimysium are called fascicles. proteins actin and myosin.
Epimysium, the thick layer of connective tissue Glycogen stores, which release glucose to provide
that encases the entire muscle. energy for muscle contraction.
239
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:25:53, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.057
Section 4: Neurophysiology
(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
H band H band
Sarcomere
Figure 54.1 Structure of (a) the sarcomere and (b) the myofibril.
240
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:25:53, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.057
Chapter 54: Skeletal Muscle
Tropomyosin
Actin protein (note: for clarity, single strand of actin is shown instead of double strand)
Figure 54.2 Structure of (a) the thick and (b) the thin filament.
241
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:25:53, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.057
Section 4: Neurophysiology
242
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:25:53, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.057
Chapter 54: Skeletal Muscle
(a) When myosin binds ATP, its affinity for actin is low:
Actin filament
Myosin head
Myosin binding
Myosin tail ATP ATP ATP sites
Z disc
(b) ATP is hydrolysed, energising the myosin head and allowing crossbridges to form:
(c) The myosin head flexes and ADP dissociates – this is the ‘power stroke’:
Left-ward movement
(d) ATP binds, reducing the affinity of myosin for actin – the crossbridges are broken:
The Z lines move closer together – the overall means of the SR/ER Ca2+-ATPase (SERCA). As sar-
width of the sarcomere decreases. coplasmic Ca2+ concentration decreases:
The width of the I band decreases, as thin 2+
Ca dissociates from troponin C.
filaments overlap thick filaments to a greater Troponin T and tropomyosin return to their resting
extent. configurations. Tropomyosin covers the myosin
There is no change in the width of the A band, as binding sites: crossbridges can no longer form
thick filaments do not shorten. between actin and myosin. The muscle relaxes and
Actin–myosin crossbridge cycling continues until the the sarcomere returns to its original length.
intracellular Ca2+ concentration decreases. This Overall, ATP therefore has three crucial roles in skel-
occurs when Ca2+ is re-sequestered into the SR by etal muscle contraction:
243
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:25:53, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.057
Section 4: Neurophysiology
Energising the myosin head: the hydrolysis of Frequency of action potentials. The duration of
ATP energises the myosin head, providing the the refractory period in nerve and skeletal muscle
energy for the power stroke. is shorter than the time course of both the
Detachment of crossbridges: following the power relaxation of muscle tension and Ca2+ uptake into
stroke, binding of ATP causes dissociation of the the SR. Delivery of action potentials at a high
myosin head from the actin filament. frequency therefore results in a progressive
Muscle relaxation: Ca2+ is sequestered in the SR accumulation of Ca2+ in the cytoplasm and thus
by the SERCA. an increased and sustained muscle tension, or
tetanus.
After death, muscle ATP stores are rapidly depleted.
There is no longer sufficient ATP to power the SERCA. Initial muscle length. The tension generated
Ca2+ therefore remains bound to troponin C and thus within a single muscle fibre is related to the
actin–myosin crossbridges cannot detach, resulting in number of actin–myosin crossbridges formed (see
a high skeletal muscle tone known as rigor mortis. Chapter 30 and Figure 30.2):
– At the optimal sarcomere length, the myosin
What is the motor unit? heads have the greatest possible overlap with
actin filaments.
The motor unit consists of a single α-motor neuron,
– Excessive sarcomere stretch can completely
its axon and the many muscle cells that it innervates.
remove actin–myosin overlap; no crossbridges
A single action potential in an α-motor neuron results
can then form.
in the contraction of all the myocytes within the
motor unit. Motor units have some key features: – Excessive sarcomere shortening results in
filament collisions, leading to an increase in
Each motor unit innervates only one myocyte frictional forces and distortion of the
type, such as type I muscle fibres (see Chapter 42).
sarcomere, which precludes further
Groups of motor units often work together to contraction.
coordinate the contraction of a single muscle. The
force of contraction within a muscle is controlled Normally, the sarcomeres within skeletal muscles
by the number of motor units activated. are arranged near to their optimal length, so the
initial muscle length usually contributes little to
The number of muscle fibres within each motor
unit varies considerably between muscles: muscle tension.
– Large, powerful muscles, like the quadriceps Clinical relevance: disorders of skeletal muscle
femoris, perform gross movements. The
quadriceps therefore contain >1000 myocytes Skeletal muscle disorder is a broad term encompass-
ing dystrophies, myotonias, myopathies and meta-
per motor unit.
bolic disorders. The most common are:
– Some muscles require fine control and thus
have proportionally more motor units that Duchenne’s muscular dystrophy (DMD), an X-
linked recessive disorder that causes a deficiency
contain fewer myocytes. The extraocular
of dystrophin, a protein that anchors actin via a
muscles have as few as 10 myocytes per support protein to the sarcolemma. Clinically,
motor unit. patients present between the ages of 3 and 5
with proximal muscle weakness. The sarcomeres
How is the force of muscle contraction are inadequately tethered to the cell membrane
and become replaced by fibrous tissue, which
determined? clinically results in pseudohypertrophy. DMD is
Three main factors determine muscle tension: usually fatal by late adolescence from respiratory
or cardiac failure.
Recruitment of motor units. The force of Becker’s muscular dystrophy (BMD), also
contraction of a whole muscle depends on the an X-linked recessive disorder affecting the
number of contracting myocytes. Initially, the dystrophin protein. In BMD, the amount of
smallest motor units are recruited; larger motor dystrophin protein is reduced and structurally
units are additionally recruited as greater muscle abnormal. Clinically, BMD is less severe than
tension is required.
244
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:25:53, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.057
Chapter 54: Skeletal Muscle
DMD, presenting in adolescence, with death in Starvation, due to catabolism of skeletal muscle.
the fourth or fifth decade. Ageing, which is associated with a generalised
Myotonic dystrophy, is an autosomal dominant decrease in muscle mass and function known as
trinucleotide repeat disorder that may show sarcopenia.
anticipation. Mutations in either dystrophia
Intensive care unit-acquired weakness (ICUAW) is
myotonica protein kinase (DMPK, in DM1) or
common cause of morbidity in critically ill patients,
cellular nucleic acid binding protein (CNBP, in
characterised by symmetric, flaccid muscle weak-
DM2) result in the abnormal expression of Na+ or
ness, which classically affects all muscle groups with
Cl‾ channels in the muscle sarcolemma. The
relative sparing of the cranial nerves. ICUAW is classi-
myocytes exist in an abnormal hyperexcitable
fied into the overlapping syndromes of critical illness
state, resulting in repetitive action potentials and
polyneuropathy, critical illness myopathy and critical
sustained muscle contraction. The resulting
illness neuromyopathy. The pathophysiology of
clinical features include myotonia (abnormally
ICUAW is complex and includes the use of cortico-
prolonged or repetitive muscle contraction after
steroids and neuromuscular blockers, circulating
voluntary relaxation or percussion), muscle
cytokines as a result of severe sepsis and immobilisa-
wasting, insulin resistance, cardiomyopathy and
tion. Patients lose an average of 2–4% of muscle
cardiac conduction defects.
mass per day, which causes difficulty in weaning
Myotonia congenita, an autosomal dominant
from mechanical ventilation and increased risk of
disorder characterised by an abnormal
ventilator-associated pneumonia and venous
sarcolemma ClC-1 chloride channel. Like
thromboembolism.
myotonic dystrophy, the myocytes become
hyperexcitable, leading to myotonia. However,
the two conditions differ: myotonia congenita is
not associated with generalised muscle
Further reading
weakness, but may cause palatopharyngeal J. Xiao. Muscle Atrophy. Singapore, Springer Verlag, 2018.
dysfunction, leading to dysphagia. R. D. Keynes, D. J. Aidley, C. L.-H. Huang. Nerve and
Muscle, 4th edition. Cambridge, Cambridge University
Press, 2011.
P. K. Gupta, P. M. Hopkins. Diagnosis and management of
malignant hyperthermia. BJA Education 2017; 17(7):
Clinical relevance: muscle atrophy
249–54.
Muscle atrophy refers to a decrease in muscle mass, C. L.-H. Huang, T. H. Pedersen, J. A. Fraser. Reciprocal
which may be caused by: dihydropyridine and ryanodine receptor interactions in
Muscle inactivity, such as immobilisation of a skeletal muscle activation. J Muscle Res Cell Motil 2011;
fractured limb, extended bed rest and space travel. 32(3): 171–202.
Neurogenic atrophy, where muscle denervation R. Appleton, J. Kinsella. Intensive care unit-acquired
leads to atrophy. weakness. Continuing Educ Anaesth Crit Care Pain 2012;
Cachexia, which accompanies a range of 12(2): 62–6.
illnesses, including cancer, cystic fibrosis, chronic S. Marsh, N. Ross, A. Pittard. Neuromuscular disorders and
obstructive pulmonary disease and human anaesthesia. Part 1: generic anaesthetic management.
immunodeficiency virus. Cachexia is probably Continuing Educ Anaesth Crit Care Pain 2011; 11(4):
caused by inflammatory cytokines such as 115–18.
tumour necrosis factor-α, interferon-γ and
S. Marsh, A. Pittard. Neuromuscular disorders and
interleukin-6.
anaesthesia. Part 2: specific neuromuscular disorders.
Drugs, such as corticosteroids, which cause
Continuing Educ Anaesth Crit Care Pain 2011; 11(4):
preferential wasting of the proximal muscles 119–23.
though increased muscle catabolism.
245
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:25:53, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.057
Section 4 Neurophysiology
55
What is proprioception? muscle fibres, known as intrafusal fibres. Intrafusal
fibres are arranged in parallel with contractile extra-
Proprioception refers to the detection of stimuli relat- fusal fibres; stretch of the extrafusal fibres therefore
ing to body position in space and postural equilib- alters the intrafusal fibre length. An intrafusal fibre
rium. Mechanoreceptors within muscle, joints and consists of a central non-contractile elastic portion
tendons relay sensory information about joint pos- with outer contractile ends.
ition, movement, vibration and pressure to the central There are two morphologically distinct types of
nervous system. The major sensory receptors involved intracapsular muscle fibre (Figure 55.1):
include:
Nuclear bag fibres, in which the nuclei are
Muscle spindles, which detect changes in
collected in a central dilated portion of the fibre;
muscle length;
Nuclear chain fibres, in which the nuclei are
Golgi tendon organs, which detect muscle
distributed along the fibre without a dilatation.
tension.
-motor neuron
Type Ia afferent neuron
246
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:32:59, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.058
Chapter 55: Muscle Spindles and Golgi Tendon Organs
Afferent nerve supply: sensory afferent Reflex arcs may also be classified by the origin of the
neurons wind around the central portion of sensory signal:
the intrafusal fibres. There are two types: From a peripheral sensory afferent neuron – for
– Type la afferent neurons receive inputs from example, the knee-jerk.
both nuclear bag and nuclear chain fibres. From the autonomic nervous system – for
Electrical activity in type Ia fibres reflects example, the baroreceptor reflex.
changes in both static intrafusal fibre length From a cranial nerve – for example, the gag
and rate of such change. reflex.
– Type II afferent neurons receive inputs from
nuclear chain fibres only. Type II neurons Describe the knee-jerk reflex
relay information only about the static Striking the patellar tendon with a tendon hammer
intrafusal fibre length. results in a predictable response: contraction of the
Efferent nerve supply: γ-motor neurons innervate quadriceps muscle and extension of the knee – this is
the contractile outer portions of the intrafusal known as the knee-jerk or patellar reflex. The knee-
fibres. Each γ-motor neuron innervates a number jerk is classically regarded as a monosynaptic reflex1
of muscle spindles. involving (Figure 55.2):
Voluntary contraction involves the simultaneous acti- Sensory receptors – muscle spindles of the
vation of both α- and γ-motor neurons. Contraction quadriceps muscle. When the patellar tendon is
of the outer portions of the intrafusal fibres prevents struck, the quadriceps muscle is stretched along
slackening of the spindle, despite the shortening of with its embedded muscle spindles.
the extrafusal fibres. The sensitivity of the muscle An afferent neuron – type Ia afferent neurons
spindles is therefore maintained despite skeletal from the muscle spindles relay information about
muscle shortening and variations in its load. the degree of muscle stretch to the ventral horn
of the spinal cord through the dorsal root.
What is a Golgi tendon organ? A synapse – in the ventral horn of the spinal cord,
Golgi tendon organs are stretch receptors located at the afferent neuron synapses directly with an
the junction between skeletal muscle and tendon. α-motor neuron. This synapse is excitatory
Golgi tendon organs are arranged in series rather than (utilising glutamate as the neurotransmitter).
in parallel with the extrafusal muscle fibres and there- An efferent neuron – the α-motor neuron leaves
fore sense muscle tension. Each Golgi tendon organ is the ventral horn in a spinal nerve and travels to
innervated by a single type Ib afferent neuron. They the quadriceps muscle, where it innervates several
have no motor innervation. muscle fibres.
An effector organ – the quadriceps muscle
What is a reflex arc? contracts in response to α-motor neuron activity.
A reflex is an automatic, predictable response to a As the knee-jerk is a monosynaptic pathway, the
stimulus that is generally not under voluntary control. latency period between muscle spindle activation
The simplest reflexes involve a sensory receptor, an and quadriceps contraction is relatively short.
afferent neuron, one or more synapses, an efferent However, other processes contribute to the knee-
neuron and an effector organ. jerk reflex:
Reflex arcs may be classified by their number of The type Ia afferent neurons branch within the
synapses: spinal cord, synapsing through interneurons
Monosynaptic reflex arcs. The classical example with α-motor neurons of antagonistic muscles,
is the knee-jerk (see below). which in this case would oppose knee flexion
Polysynaptic reflex arcs. For example, the
withdrawal reflex: when a limb touches a hot 1
Note: although classical descriptions refer to the knee-jerk
object, the whole limb moves away through the as a monosynaptic reflex, there is also a relaxation of the
coordinated contraction and relaxation of many antagonistic hamstring muscles through a polysynaptic
muscle groups. mechanism.
247
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:32:59, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.058
Section 4: Neurophysiology
+
Type Ia afferent +
_
Inhibitory interneuron
Muscle spindle
(e.g. the hamstrings). This synapse is inhibitory, the level of action potentials firing in the type
utilising glycine as neurotransmitter. Inhibition Ia afferent fibres.
of antagonistic muscles allows the quadriceps Type Ia afferent activity in turn activates
muscle to contract unopposed (Figure 55.2). α-motor neurons through the monosynaptic
Additionally, descending inputs from the brain reflex arc, causing contraction of the extrafusal
may modulate the intensity of reflexes: fibres, thereby increasing the tone of the
– The knee-jerk reflex is lost following repeated skeletal muscle.
rapid strikes of the patellar tendon.
– The Jendrassik manoeuvre, where the patient Clinical relevance: spinal shock
clenches their teeth or pulls their interlocked
As discussed above, muscle tone is primarily deter-
hands apart, results in an increased level of mined by extrapyramidal supraspinal neurons. In
γ-motor neuron firing, thereby increasing the acute spinal cord injury, these supraspinal pathways
background stretch in the spindle, which are interrupted. The γ-motor neurons become
results in an accentuation of the knee-jerk inactive and the muscles become hypotonic or flac-
reflex. cid, which is termed spinal shock.
After around 2 weeks, the activity in the γ-motor
248
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:32:59, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.058
Section 4 Neurophysiology
Smooth Muscle
Chapter
56
Where is smooth muscle found in Multi-unit smooth muscle is found in the large
elastic arteries, the trachea and the iris. These
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 autonomic nervous system (ANS). innervate many smooth muscle cells, in a similar
In contrast to skeletal and cardiac muscle, smooth way to the motor unit in skeletal muscle.
muscle is non-striated. Smooth muscle is found
within the walls of hollow organs and tubes. The How do smooth muscle cells differ from
following are important examples:
The uterus is primarily composed of smooth
skeletal muscle cells?
muscle. Uterine smooth muscle contraction Smooth muscle and skeletal muscle have a number of
provides the driving force for parturition. Smooth anatomical and functional differences:
muscle contraction is also essential in the Size: skeletal muscle cells are large, cylindrical cells
immediate post-partum period in securing uterine that span the entire length of the muscle. Smooth
haemostasis following delivery; uterine atony is a muscle cells are much smaller, spindle-shaped
common cause of post-partum haemorrhage. cells that are arranged in sheets, or syncytia.
The arteries contain layers of vascular smooth Nuclei: skeletal muscle cells are multi-nucleate,
muscle within their tunica media. Contraction of whilst smooth muscle cells have only one nucleus.
vascular smooth muscle reduces the vessel radius, Sarcomeres: like skeletal muscle, the primary
increasing its resistance to blood flow. function of smooth muscle is contraction. In both
The respiratory tract, where bronchiolar smooth skeletal and smooth muscle, actin and myosin are
muscle contraction results in the main contractile proteins: actin is arranged in
bronchoconstriction. thin filaments and myosin in thick filaments.
The gastrointestinal (GI) tract – coordinated However, in smooth muscle, the thick and thin
contraction of longitudinal and circular smooth filaments are not organised into sarcomeres –
muscle (segmentation and peristalsis) in the smooth muscle is therefore not striated.
intestinal wall mixes and propels the luminal Troponin complex: whilst tropomyosin is present
contents along the gut. in both smooth and skeletal muscle, troponin is
absent in smooth muscle.
What are the two types of smooth Transverse (T)-tubules: the tube-like
invaginations of the skeletal muscle sarcolemma
muscle? are absent in smooth muscle. Instead, smooth
Smooth muscle is classified into two types: muscle has shallower, rudimentary invaginations
Single-unit smooth muscle occurs in the viscera known as caveolae, which increase the surface
and the blood vessels, except the large elastic area-to-volume ratio of the muscle cell.
arteries, as sheets of smooth muscle cells forming The sarcoplasmic reticulum (SR): an intracellular
syncytial units. The ANS innervates a single cell store of Ca2+. Despite the important role of the SR
within the sheet, with action potentials rapidly in skeletal muscle excitation–contraction coupling
propagated to neighbouring cells through gap (see Chapter 54), the SR is poorly developed in
junctions, leading to synchronous contraction. smooth muscle.
249
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:37:22, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.059
Section 4: Neurophysiology
Describe how smooth muscle is excited interior. Caveolae increase the surface area-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 depolarise whilst
intracellular Ca2+ concentration triggers muscle
inhibitory signals hyperpolarise the smooth muscle
contraction. But smooth muscle cells lack T-
cell membrane. If the net effect of these signals is
tubules and have an absent or poorly developed
depolarisation to threshold potential, contraction
SR. Smooth muscle cells have various mechanisms
occurs. Like skeletal muscle, multi-unit smooth
to increase Ca2+ influx:
muscle can only be stimulated by nerve impulses.
However, single-unit smooth muscle cells may be – Voltage-gated Ca2+ channels;
stimulated in a number of ways: – Ligand-gated Ca2+ channels;
Autonomic neuronal input. Single-unit smooth – Stretch-responsive Ca2+ channels.
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+.
acetylcholine). These two autonomic inputs are Calmodulin: as discussed above, the thin
usually antagonistic: one tends to excite whilst the filaments of smooth muscle do not contain
other 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 – Myosin light-chain kinase (MLCK). The
smooth muscle contraction. In the arterial system, sarcoplasmic enzyme MLCK is activated by
this is referred to as the ‘myogenic response’, the Ca2+–calmodulin complex. MLCK
responsible for the autoregulation of blood flow phosphorylates the myosin light-chains,
(see Chapter 34). In the GI tract, peristalsis may be allowing myosin to form crossbridges with
triggered when the luminal contents stretch the actin filaments.
smooth muscle of the gut wall. – Caldesmon. In skeletal muscle, the troponin
Pacemaker activity. Like the heart, the GI tract complex positions tropomyosin over the
contains pacemaker cells (the interstitial cells of myosin binding site, preventing actin–myosin
Cajal) whose cell membrane spontaneously interaction. Troponin is absent in smooth
depolarises, triggering an action potential. The muscle – this role is instead played by a
spontaneous oscillation in the pacemaker cell protein called caldesmon. The Ca2+–
membrane potential is called the ‘slow wave’. The calmodulin complex causes a conformational
frequency of slow waves differs throughout the GI change in caldesmon that leads to
tract. For example, around 12 action potentials are tropomyosin movement, unblocking the
generated per minute in the duodenum, compared myosin binding site and permitting
with only three per minute in the colon. actomyosin crossbridge cycling.
– Calponin. This protein inhibits the ATPase
Describe how excitation–contraction activity of the myosin head. It may be activated
coupling occurs in smooth muscle either by the Ca2+–calmodulin complex or
directly by Ca2+.
Smooth muscle excitation–contraction coupling
differs from skeletal muscle in several respects:
Lack of T-tubules: action potentials are There are thus more points of biochemical regulation
propagated rapidly between cells through gap in smooth muscle contraction than in skeletal muscle
junctions, but are not relayed directly to the cell contraction, reflecting the greater importance of
250
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:37:22, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.059
Chapter 56: Smooth Muscle
251
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:37:22, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.059
Section 4 Neurophysiology
Cardiac Muscle
Chapter
57
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 resting membrane potential (RMP)
into the vascular system. Individual cardiomyocytes discussed in Chapter 51, the cardiac myocyte RMP is
are specialised in the generation of spontaneous activ- due to:
ity (automaticity), transmission of the resulting excit- A large difference between intracellular and
able activity and contraction in response to such extracellular K+ and Na+ ion concentrations.
excitation. Thus: The resting cell membrane having a higher
Atrial and ventricular myocardial cells are permeability to K+ than to Na+.
capable of both contraction and conduction of – In neurons, K+ permeability is predominantly
action potentials. due to membrane K+ leak channels (two-pore-
Pacemaker and conducting cells are excitable but domain K+ channels), which are
non-contractile: constitutively open.
– Pacemaker cells, found in the sinoatrial (SA) – In cardiac myocytes, K+ permeability is due to the
and atrioventricular (AV) nodes, generate presence of inward rectifying K+ channels (Kir
spontaneous cardiac action potentials. channels), which are open at negative membrane
– Conducting cells, known as Purkinje fibres, potentials, but close with depolarisation.
spread the cardiac action potentials around the +
K diffuses down its electrochemical gradient,
ventricles. resulting in the cell interior becoming negatively
Cardiac myocytes share a number of structural fea- charged with respect to the cell exterior.
tures with skeletal muscle: The RMP varies depending on the cardiac region:
A striated appearance, owing to organised rows SA node, approximately –50 mV, but unstable;
of thick and thin filaments within the sarcoplasm. Atrial myocyte, –70 mV;
A sarcotubular system – ventricular myocytes Purkinje fibre, –90 mV;
have both T-tubules and sarcoplasmic reticulum Ventricular myocyte, –90 mV.
(SR), although they are often less developed than
in skeletal muscle.
How do cardiac and nerve action
However, cardiac myocytes also share a number of
similarities with smooth muscle: potentials differ?
Involuntary control. Like smooth muscle, the There are a number of important differences between
autonomic nervous system (ANS) and endocrine nerve and cardiac action potentials:
axes modulate the function of cardiac myocytes. RMP. As discussed above, the RMP of cardiac
Cells connected by gap junctions. These low- myocytes varies with cardiac region. Ventricular
resistance electrical connections allow the rapid myocytes and Purkinje fibres have an RMP that is
conduction of action potentials throughout the more negative (–90 mV) than the neuronal RMP
myocardium through connexin channels. Thus, (–70 mV).
the cardiac myocytes contract as a single unit or Duration. The nerve action potential is very short
functional syncytium. (1–2 ms), whilst the cardiac action potential has a
252
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:28:59, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.060
Chapter 57: Cardiac Muscle
much longer duration, depending on myocardial – Inward current: voltage-gated L-type Ca2+
cell type (200–400 ms in ventricular myocytes and channels slowly open following membrane
Purkinje fibres). depolarisation. Ca2+ ions flow down their
Shape. Morphologically, the nerve action concentration gradient from the extracellular
potential is a single spike, whilst the cardiac fluid (ECF), where the ionised Ca2+
action potential varies from having a triangular concentration is around 1.2 mmol/L, to the
waveform (atrial muscle) to having a long intracellular fluid (ICF), which has a
plateau phase (ventricular myocytes and considerably lower ionised Ca2+ concentration
Purkinje fibres). (around 500 nmol/L).
2+ 2+
The role of Ca . In cardiac cells, Ca influx – Outward current: as discussed above, Kir
prolongs the duration of the action potential, channels are predominantly responsible for
resulting in the characteristic plateau phase of generating the RMP, but close following
ventricular myocytes. Ca2+ plays no role in the membrane depolarisation. At the same time,
nerve action potential. membrane depolarisation causes slow delayed
rectifier K+ channels to open.
Outline the phases of the cardiac action Overall, there is a net inward current that
potential maintains the plateau.
Phase 3, repolarisation. A gradual inactivation of
The cardiac action potential has five phases voltage-gated Ca2+ channels reduces the inward
(Figure 57.1): Ca2+ current. Additional outward K+ currents1
Phase 0, rapid depolarisation. return the membrane to its RMP (Figure 57.2).
– The threshold potential for cardiac myocytes is Phase 4, electrical diastole. During this phase, the
around –65 mV. The threshold potential is membrane is maintained at RMP due to K+ efflux
reached by the depolarising action of local through Kir channels. There is also a correction of
currents conducted through gap junctions the small net fluxes of Na+, K+ and Ca2+ that took
from neighbouring myocytes. place during the action potential through Na+/K+-
– Stimuli that exceed threshold potential trigger ATPase and Na+/Ca2+-exchanger activity.
the opening of fast voltage-gated Na+ channels, In summary (Figure 57.2):
thereby increasing membrane Na+ Phase 0 – a brief, rapid increase in Na
+
permeability. conductance results in rapid depolarisation.
– The resultant increased Na+ influx causes a Phase 1 – K conductance increases transiently.
+
further membrane depolarisation, which
Phase 2 – the increase in Ca conductance results
+
triggers further opening of voltage-gated Na+ 2+
in an inward Ca current, which opposes the
channels; a positive-feedback loop is created. tendency of the outward K+ current to restore the
– The end result is rapid depolarisation to membrane potential, resulting in the action
approximately +20 mV. potential plateau.
Phase 1, early rapid repolarisation. Following the Phase 3 – a decrease in Ca conductance and a
2+
+
membrane depolarisation of phase 0: progressive increase in K conductance results in
– Voltage-gated Na+ channels inactivate, membrane repolarisation.
Phase 4 – Ca , Na and K conductance have
2+ + +
resulting in a rapid decrease in the membrane
Na+ permeability. returned to resting levels, with K+ conductance
– Fast voltage-gated K+ channels transiently exceeding Ca2+ and Na+ conductance, resulting in
open, resulting in a transient outward K+ the RMP.
current Ito (Figure 57.2).
The overall effect is a brief phase of 1
repolarisation. Rapid and slow delayed rectifier K+ channels produce
outward K+ currents IKr and IKs, respectively. As the cell
Phase 2, plateau. Membrane depolarisation is
membrane develops an increasingly negative potential, Kir
maintained for a prolonged period (around 200 ms) channels reopen, which further increases membrane K+
through a balance of inward and outward currents: permeability and thus K+ efflux.
253
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:28:59, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.060
Section 4: Neurophysiology
–10
Fast delayed rectifier K+ channels open
–30 0
Fast voltage-gated Na+ channels open 3
Kir channels close
–50
Kir channels re-open
Threshold potential
–65
–70
4
4 Resting membrane potential
–90
–110
0 100 200 300 400
Time (ms)
+10
Relative membrane permeability
Na+
Membrane potential (mV)
–10 Ca2+ K+ 10
–30
–50
1
–70
–90
0.1
–110
0 100 200 300 400
Time (ms)
Figure 57.2 Changes in membrane permeability to ions during the cardiac action potential.
At a heart rate (HR) of 75 bpm, the ventricular action summed activity of phase 0 and 1 across
potential lasts for around 250 ms: the septum and ventricular wall corresponds to
Phases 0 and 1 have a total duration of 1–2 ms, the QRS complex of the electrocardiogram
similar to that of the nerve action potential. The (ECG).
254
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:28:59, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.060
Chapter 57: Cardiac Muscle
–30 0 –30
40
–50 3 –50
–70 –70
20
4 4
–90 –90
–110 –110 0
0 100 200 300 0 100 200 300
Time (ms) Time (ms)
Figure 57.3 (a) The absolute refractory period (ARP) and relative refractory period (RRP) of the cardiac action potential and (b) Relationship
between the cardiac action potential and the contractile response of cardiac muscle.
Phase 2 lasts for around 200 ms and corresponds to tetany of the cardiac muscle, which would be
to the ST-segment of the ECG. incompatible with diastolic filling.
Phase 3 takes around 50 ms, and corresponds to The relative refractory period (RRP), when a
the T-wave of the ECG. further action potential can be initiated, but it
The duration of the action potential decreases with requires a greater stimulus than normal.
increasing HR: at a rate of 200 bpm, the action poten-
tial lasts for only 150 ms. This is why QT intervals Clinical relevance: antiarrhythmic drugs
must be corrected (QTc) to make values comparable The Singh–Vaughan Williams classification
across a range of HRs. (Table 57.1) categorises antiarrhythmic drugs into
four classes on the basis of their ionic mechanism.
What are the refractory periods of the Later, Class V was added to include antiarrhythmic
drugs with mechanisms dissimilar to the other four
cardiac action potential? classes. However, few antiarrhythmic drugs are spe-
In common with the nerve action potential (Chap- cific to one class. For example, flecainide (Class 1C)
ter 52), the cardiac action potential has two refractory also blocks K+ channels, amiodarone (Class III) also
periods (Figure 57.3a): blocks Na+ and Ca2+ channels and sotalol (Class III) is
also a β-blocker. It is also important to note that
The absolute refractory period (ARP), where a relatively few drugs are effective in the treatment of
further action potential cannot be initiated, no ventricular fibrillation; cardioversion is therefore
matter how large a stimulus is applied. Following indicated.
membrane depolarisation, the fast voltage-gated
Na+ channels become inactivated. Inactivated Na+
channels cannot return to their resting state until
membrane repolarisation has occurred. The
Where are action potentials generated
prolonged plateau phase of the cardiac action in the heart?
potential means that the ARP is 200 ms, which is Pacemaker cells are specialised cardiac myocytes
considerably longer than that of the nerve action whose spontaneous activity results in the regular gen-
potential. The long ARP of cardiac muscle means eration of action potentials. The rate at which action
that further action potentials cannot be triggered potentials are produced by the pacemaker cells deter-
until muscle contraction is nearly complete mines the frequency of cardiac contraction. Several
(Figure 57.3b). A short ARP could potentially lead sites within the heart may act as pacemakers:
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:28:59, subject to the Cambridge Core terms of use, available at 255
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.060
Section 4: Neurophysiology
Table 57.1 Classification of antiarrhythmic drugs (see also Vaughan Williams, 1975).
The SA node, located at the junction between the property of the pacemaker potential is called
superior vena cava and right atrium. The SA node automaticity.
generates action potentials at a higher frequency Historically, the pacemaker potential was called
than the other pacemaker cells and therefore the ‘funny’ current If. It is now known that the slow
normally sets the HR. depolarisation of the membrane potential is due to
The AV node, located between the atrial septum the intracellular movement of Na+ ions exceeding the
and tricuspid valve, just above the opening of the extracellular movement of K+ ions (see below).
coronary sinus.
The bundle of His, located within the Describe the action of the pacemaker
interventricular septum.
The Purkinje fibres, a specialised network of
currents
cardiac myocytes that conduct electrical impulses The action potential in pacemaker cells
to the ventricles. (Figure 57.4) includes contributions from
hyperpolarisation-activated cyclic nucleotide-
What is meant by the term ‘pacemaker gated (HCN) channels. These channels are
permeable to both Na+ and K+.
potential’? Following an action potential, membrane
The pacemaker potential refers to the spontaneous hyperpolarisation opens HCN channels, allowing
decay of the membrane potential of a pacemaker cell, Na+ and K+ to diffuse along their electrochemical
from a membrane potential of approximately –60 mV gradients. Overall, Na+ influx slightly exceeds K+
(in the SA node) to threshold potential (approxi- efflux, resulting in a slow depolarisation of the cell
mately –40 mV in the SA node), thereby initiating membrane from its initial voltage of –60 mV.
an action potential. The rate at which the pacemaker When the membrane potential reaches
potential decays to threshold determines the HR; this approximately –50 mV, T-type (transient) Ca2+
256
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:28:59, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.060
Chapter 57: Cardiac Muscle
0
HCN channels open 0 3
4 L-type Ca2+ 4
–60 channels open
–80
0 100 200 300 400 500
Time (ms)
channels open in the pacemaker cell membrane, fibrosus.2 The AV node delays transmission of the
resulting in inward Ca2+ current from the ECF, action potential between atria and ventricles,
where the concentration of ionised Ca2+ is allowing the atria time to contract. AV nodal delay
approximately 1.2 mmol/L, to the ICF, where is a major component of the PR interval of the
the Ca2+ concentration is ~500 nmol/L. The ECG.
influx of Ca2+ ions enhances membrane The bundle of His. Shortly after leaving the AV
depolarisation. node, the bundle of His divides into the right and
The action of both is to cause a spontaneous decay left bundle branches. The left bundle branch
of the membrane potential to the threshold divides again into the left anterior and left
potential of –40 mV. posterior fascicles.
The Purkinje fibres. The branches of the bundle
How are action potentials conducted of His divide to form the Purkinje fibres,
through the heart? which rapidly conduct action potentials
throughout the right and left ventricles, thereby
An efficient conducting system is essential to ensure synchronising ventricular contraction. The
the synchronous contraction of the ventricular Purkinje fibres terminate just below the
myocytes. Action potentials generated in the SA node endocardium; thereafter, action potential
are relayed as follows: conduction is performed by the cardiac
The internodal pathways. Action potentials are myocytes themselves.
relayed from the SA node to the AV node through The cardiac myocytes have both mechanical and
three specific internodal pathways: electrical connections. The myocytes are
– Anterior, the Bachmann pathway, which also connected end to end by intercalated discs, which
relays action potentials to the left atrium via
the Bachmann bundle;
2
The existence of congenital accessory conduction
– Middle, the Wenckebach pathway;
pathways between the atria and ventricles (collectively
– Posterior, the Thorel pathway. known as the ‘bundle of Kent’) can result in action
potential conduction bypassing the AV node, with
The AV node is the only physiological means of
arrhythmic consequences referred to as the Wolff–
transmitting action potentials between the atria Parkinson–White syndrome. Similar accessory pathways
and the ventricles; elsewhere, the junction between with the AV node itself result in AV node re-entrant
the chambers is insulated by the annulus tachycardia.
257
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:28:59, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.060
Section 4: Neurophysiology
allow them to contract as a single unit or crossbridge cycling follows a similar ATP-dependent
functional syncytium. Adjacent to the intercalated mechanism to that of skeletal muscle (see
discs are gap junctions, which allow the action Chapter 54):
potential to pass from one myocyte to the next. 2+
Binding of sarcoplasmic Ca to troponin
C causes tropomyosin to roll deeper into the
Describe the process of excitation– groove between actin filaments.
contraction coupling in a cardiac This conformation change leads to the uncovering
of myosin binding sites on the actin filament,
myocyte allowing myosin to form crossbridges with actin.
Excitation–contraction coupling in cardiac muscle is The myosin head pulls the actin filament towards
slightly different from that of skeletal muscle (see the centre of the sarcomere in the power stroke.
Chapter 54). In cardiac muscle, intracellular Ca2+ con- Crossbridge cycling continues until the
centration is increased through Ca2+-induced Ca2+ cytoplasmic Ca2+ concentration decreases during
release rather than as a result of a physical connection repolarisation.
between the T-tubule, the ryanodine receptor (RyR)
and the dihydropyridine receptor (DHPR).
The process of excitation–contraction coupling in
How is cardiac contraction terminated?
cardiac muscle is as follows: Crossbridge cycling is terminated by actively remov-
ing Ca2+ from the cell. As the sarcoplasmic concen-
Ventricular and atrial myocytes differ in the
tration of Ca2+ decreases, Ca2+ dissociates from
anatomy of their cell membranes:
troponin C. Tropomyosin re-covers the actin binding
– Ventricular myocytes have T-tubules, which site; myosin can no longer bind to actin and relax-
contain L-type Ca2+ channels (i.e. DHPRs). ation occurs.
The T-tubules conduct action potentials deep In diastole, the intracellular Ca2+ concentration is
into the myocyte interior. extremely low (around 0.1 μmol/L). This is achieved
– The atrial myocyte cell surface membrane through three mechanisms:
contains L-type Ca2+ channels. The surface 2+
The plasma membrane Ca -ATPase pump,
area of the cell membrane is increased by small which uses energy (from ATP hydrolysis) to
invaginations called caveolae. actively remove Ca2+ ions from the cell (i.e.
In both cell types, membrane depolarisation primary active transport).
causes L-type Ca2+ channels to open. Ca2+ diffuses + 2+
The Na /Ca -exchanger, which removes one
through the open Ca2+ channels from the ECF to 2+
Ca ion from the cell in exchange for the influx
the sarcoplasm. of three Na+ ions. The efflux of Ca2+ occurs
Like skeletal muscle, the SR of cardiac muscle against its concentration gradient and is driven
contain RyRs. Ca2+ influx opens the RyR, causing by the low intracellular concentration of Na+,
the SR to release Ca2+. This process is known as itself maintained by the Na+/K+-ATPase pump
Ca2+-induced Ca2+ release. (i.e. secondary active transport).
2+
Therefore, excitation–contraction coupling in cardiac Sarcoplasmic/ER Ca -ATPase pump, which uses
muscle involves both DHPRs and RyRs, but unlike in energy (from ATP hydrolysis) to sequester Ca2+
skeletal muscle, there is no physical connection in the SR.
between the two. Diastolic relaxation is therefore an ATP-dependent
process, as ATP is required to actively remove Ca2+
How does cardiac muscle contract? from the sarcoplasm by either primary or secondary
Cardiac muscle contraction starts shortly after active transport or by sequestration in the SR.
depolarisation and continues until about 50 ms after
repolarisation is complete; that is, contraction has How does the ANS influence the heart?
a duration of around 300 ms (Figure 57.3b). Once The HCN channels give the heart the property of
Ca2+ has been released from the SR, activation of automaticity: action potentials can be generated
258
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:28:59, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.060
Chapter 57: Cardiac Muscle
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) of referred to as a ventricular escape rhythm.
contraction: The sympathetic nervous system. The heart is
Parasympathetic nervous system. The right vagus innervated by post-ganglionic sympathetic fibres
nerve supplies the SA node, whilst the left vagus from the upper thoracic sympathetic chain
nerve supplies the AV node. Atrial muscle is also (mainly T1–T3). Increased sympathetic nervous
innervated by parasympathetic neurons, but system activity causes release of noradrenaline at
ventricular muscle is not (and is therefore sympathetic nerve endings and release of
unaffected). Parasympathetic nervous system adrenaline from the adrenal medulla. Both
activity therefore affects HR and conduction, but noradrenaline and adrenaline act at the cardiac β1-
has little effect on the force of contraction: adrenergic receptor, a G protein-coupled receptor
– Negative chronotropy (decreased HR). The whose activation increases the intracellular
intrinsic rate of the SA node is 90–120 bpm. At concentrations of cAMP and protein kinase A,
rest, there is continuous parasympathetic resulting in:
nervous discharge at the SA node, known as – Positive chronotropy: in the SA node, cAMP opens
vagal tone, which decreases the resting HR to HCN channels, which increases Na+ influx,
60–80 bpm. The mechanism behind this is: thereby increasing the gradient of the pacemaker
potential (Figure 57.5b). Threshold potential is
▪ Acetylcholine (ACh) is released by the
reached more quickly, which increases the HR.
presynaptic neuron (parasympathetic post-
ganglionic neuron) and binds to an – Positive inotropy (increased myocardial
inhibitory G protein-coupled receptor in contractility): in the cardiac myocytes, protein
the postsynaptic membrane. kinase A phosphorylates L-type Ca2+ channels,
which increases Ca2+ influx during the plateau
▪ The associated G protein becomes
phase. Intracellular Ca2+ concentration rises,
activated, triggering the division of its Gαi
which increases the force of contraction.
and Gβγ subunits.
– Shorter action potential duration: protein
▪ The Gαi subunit inhibits the intracellular
kinase A increases the opening of delayed
enzyme adenylate cyclase, which leads to a
rectifier K+ channels that open during phase
decrease in the intracellular concentration of
3 of the cardiac action potential, shortening
cyclic AMP (cAMP). HCN channels, as the
the repolarisation time.
name suggests, are activated by cyclic
nucleotides. Therefore, decreased cAMP leads – Increased rate of transmission through the AV
to decreased Na+ influx, and thus reduces the node: the opposite effect of parasympathetic
gradient of the pacemaker potential, resulting activity.
in a reduced HR (Figure 57.5a).
▪ The Gβγ subunit activates G protein- Clinical relevance: local anaesthetic toxicity
coupled, inwardly rectifying K+ channels. The potential for toxicity when using local anaesthet-
The resulting additional K+ efflux causes ics has been known for more than 100 years. It is
membrane hyperpolarisation hardly surprising:
(Figure 57.5a) that counteracts the Local anaesthetics are extremely effective at
pacemaker current, thereby decreasing HR. blocking the fast voltage-gated Na+ channels of
peripheral nerves.
– Decreased conduction velocity through the AV Similar fast voltage-gated Na+ channels are also
node. AV nodal delay is increased. Sometimes, found in central nervous system (CNS) neurons
marked parasympathetic nervous activity may and cardiac myocytes.
prevent transmission of electrical impulses Clinical signs and symptoms of local anaesthetic tox-
through the AV node altogether. If this occurs, icity fall into three categories:
the pacemaker cells within the bundle of His
259
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:28:59, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.060
Section 4: Neurophysiology
+20
Membrane potential (mV)
–20 Hyperpolarisation of
membrane potential
–40
–60
+20
Membrane potential (mV)
–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 57.5 The effects of (a) parasympathetic and (b) sympathetic nervous system activity on the pacemaker action potential.
Immunological. Local anaesthetics can cause – Depressive phase. This is followed by blockade
allergy, especially ester-based local anaesthetics of Na+ channels in excitatory interneurons,
whose metabolite, para-aminobenzoic acid, is resulting in global CNS depression: coma,
especially allergenic. Allergy may be local respiratory depression.
(urticaria) or systemic (anaphylaxis).
CNS toxicity. High plasma concentrations of Cardiac toxicity. In addition to Na+ channels,
local anaesthetic may result in CNS toxicity, local anaesthetics block K+ and Ca2+ channels in
which occurs in two phases: the heart. Initial signs of cardiotoxicity are those
of direct myocardial depression and bradycardia;
– Excitatory phase. Initially, blockade of Na+ higher plasma concentration may lead to
channels in inhibitory interneurons causes refractory ventricular fibrillation. Important
excitatory phenomena: tinnitus, circumoral points to note are:
parasthesias, seizures.
260
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:28:59, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.060
Chapter 57: Cardiac Muscle
– Ion channels are stereospecific: one receptors on the transplanted heart are still able
enantiomer of local anaesthetic has much to respond to the circulating catecholamines
greater toxicity than the other enantiomer. released from the adrenal medulla. There may
For example, levobupivacaine, the pure S- also be a contribution from the Bainbridge reflex.
enantiomer of bupivacaine, has a lower
Heart transplants also have pharmacological implica-
cardiac and CNS toxicity than racemic
tions, including:
bupivacaine.
– Bupivacaine is particularly cardiotoxic when Atropine and glycopyrrolate have no effect –
compared with other local anaesthetics. In these drugs are competitive antagonists of the
addition, signs of cardiac toxicity may occur muscarinic M2 ACh receptor. The transplanted
before CNS toxicity; that is, there is heart has no parasympathetic innervation and
potentially no ‘warning’ before the onset of therefore no ACh to antagonise. Instead,
cardiovascular collapse. This marked isoprenaline may be used to increase HR in the
cardiotoxicity is thought to be due to the transplanted heart.
high affinity of bupivacaine for Na+ channels Adrenaline and noradrenaline have an
in the heart and due to the fact that increased effect – sympathetic denervation
bupivacaine also binds Ca2+ channels, causes upregulation of β1‑adrenergic receptors.
inhibiting Ca2+ release from the SR. Therefore, the transplanted heart has an
exaggerated response to these catecholamines.
In addition to supportive management, a specific
treatment of local anaesthetic toxicity is administra-
tion of Intralipid®. Intralipid is thought to act as a Further reading
‘lipid sink’, drawing the lipophilic bupivacaine out of R. D. Keynes, D. J. Aidley, C. L.-H. Huang. Nerve and
the plasma and away from cardiac ion channels Muscle, 4th edition. Cambridge, Cambridge University
(though this mechanism has recently been Press, 2011.
disputed – see Further reading).
E. Litonius, P. Tarkkila, P. J. Neuvonen, et al. Effect of
intravenous lipid emulsion on bupivacaine plasma
concentration in humans. Anaesthesia 2012; 67(6): 600–5.
M. E. Stone, B. Salter, A. Fischer. Perioperative management
Clinical relevance: heart transplant of patients with cardiac implantable electronic devices. Br
J Anaesth 2011; 107(Suppl. 1): i16–26.
A transplanted donor heart is denervated – it has
neither sympathetic nor parasympathetic innerv- AAGBI Safety Guideline. Management of Severe Local
ation. In the resting state, this is relatively well toler- Anaesthetic Toxicity, Association of Anaesthetists of
ated owing to automaticity, intrinsic regulation via Great Britain and Ireland, 2010; www.aagbi.org/sites/
Starling’s law and hormonal regulation via circulating default/files/la_toxicity_2010_0.pdf.
adrenaline. However, there are a number of physio- J. Pinnell, S. Turner, S. Howell. Cardiac muscle physiology.
logical consequences: Continuing Educ Anaesth Crit Care Pain 2007; 7(3): 85–8.
Loss of resting vagal tone, resulting in a resting J. M. Dippenaar. Local anaesthetic toxicity. S Afr J Anaesth
HR of around 100 bpm. Analges 2007; 13(3): 23–8.
Loss of cardiovascular reflexes – the usual S. Rohr. Role of gap junctions in the propagation of the
cardiovascular responses to, for example, cardiac action potential. Cardiovasc Res 2004; 62(2):
laryngoscopy and peritoneal traction are lost. The 309–22.
fall in systemic vascular resistance caused by
N. J. Morgan-Hughes, G. Hood. Anaesthesia for a patient
anaesthetic drugs is poorly tolerated, with the with a cardiac transplant. Continuing Educ Anaesth Crit
potential for dramatic hypotension if cardiac Care Pain 2002; 2(3): 74–8.
preload is not maintained.
Blunted cardiovascular response to exercise – E. Vaughan. Williams classification of antidysrhythmic
the HR gradually increases with exercise, drugs. Pharmacol Ther B 1975; 1: 115–38.
followed by a gradual decrease with rest (the B. Singh. Beta-blockers and calcium channel blockers as
normal response involves rapid changes in HR – anti-arrhythmic drugs. In: D. Zipes, J. Jalife. Cardiac
see Chapter 42). This is because β1‑adrenergic Electrophysiology from Cell to Bedside. Philadelphia:
Saunders, 2004; 918–31.
261
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:28:59, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.060
Section 4 Neurophysiology
The Electrocardiogram
Chapter
58
The electrocardiogram (ECG) represents a summa- interval is 0.12–0.2 s; that is, three to five small
tion of electrical activity in the heart, derived from squares. First-degree AV nodal block is
extracellular electrode recordings obtained from the characterised by a prolonged PR interval, whilst
body surface. Although a detailed description of ECG the δ-wave of Wolff–Parkinson–White syndrome
analysis for detecting cardiac pathology is beyond the characteristically shortens the PR interval.
scope of this book, this chapter provides a simplified The QRS complex represents ventricular
outline of the electrical basis of the normal ECG. depolarisation and its propagation. The normal
QRS complex is <0.12 s; that is, three small
Describe the normal ECG squares. A widened QRS complex may occur in a
The normal ECG, as recorded using lead II, is shown bundle branch block – a conduction defect in
in Figure 58.1. Heart rate (HR) may be calculated either the right or left bundle branches.
from the ECG most simply by dividing 300 by the Pathological Q waves may result from a
number of large squares between adjacent QRS com- pulmonary embolus, which classically gives an
plexes. For example, if there are five large squares S1Q3T3 pattern, or a previous myocardial
between adjacent QRS complexes, the HR is 60 bpm infarction. Pathological Q waves have a duration
(note: this shortcut is only valid for regular heart >40 ms (one small square) or an amplitude 25%
rhythms and standard UK paper speeds). of the subsequent R wave.
The ST segment is the isoelectric segment that
The P wave represents atrial depolarisation. The
follows the QRS complex. The ST segment
smaller muscle mass of the atria compared with
corresponds to the plateau phase of the cardiac
the ventricles results in the P wave having a
action potential. Myocardial ischaemia or
smaller amplitude than the QRS complex. The
infarction may cause the ST segment to become
duration of the P wave is normally <100 ms, or
depressed or elevated respectively.
<2.5 ‘small squares’.1 P waves are absent in atrial
fibrillation, where there is uncoordinated atrial The T wave represents the wave of ventricular
depolarisation. In mitral stenosis, left atrial repolarisation. Repolarisation of cardiac myocytes
hypertrophy results in a larger, and sometimes is not nearly as rapid as depolarisation; the T wave
bifid, P wave. is therefore wider than the QRS complex. Inverted
T waves may be caused by ventricular ischaemia.
The PR interval is the time between the onset of
atrial and ventricular depolarisation, which The QT interval is the time from the onset of
represents atrioventricular (AV) nodal delay. It is ventricular depolarisation to the completion of
conventionally measured as time from the ventricular repolarisation. The QT interval
beginning of the P wave to the beginning of the therefore represents the duration of the cardiac
Q wave rather than the R wave. The normal PR action potential. As discussed in Chapter 57, the
duration of the cardiac action potential shortens
with increasing HR. The QT interval is therefore
1
At the standard UK ECG recording speed of 25 mm/s, routinely ‘corrected’ (QTc) for HR using an
each 1‑mm ‘small square’ represents 40 ms. One large algorithm, the most popular of which is Bazett’s
square contains five small squares and thus represents 0.2 formula (QT interval divided by the square root of
s. The voltage is calibrated so that +1 mV is represented the R–R interval, the time between consecutive
by a positive deflection of 10 mm.
262
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 14:44:31, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.061
Chapter 58: The Electrocardiogram
263
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 14:44:31, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.061
Section 4: Neurophysiology
Time (s)
Figure 58.2 Generation of electrical signals by the heart: (a) myocardial fibre undergoing propagation of an action potential wave and
(b) representation of a depolarising waveform and the resultant change in voltage of the recording electrode (SA = sinoatrial).
Explain the waveform of the QRS As the remaining ventricular muscle begins to
depolarise, net current flows towards the
complex electrode, resulting in a large positive deflection
The wave of cardiac depolarisation (Figure 58.3): known as the R wave (Figure 58.3b).
Starts from the sinoatrial (SA) node. The wave of depolarisation then flows towards the
Spreads through the atria to the atrioventricular bases of the ventricles, away from the electrode
(AV) node. (Figure 58.3c), returning the electrical potential
In the interventricular septum, as the wave of to zero.
depolarisation propagates towards the apex, Finally, the base of the left ventricle depolarises
cardiac myocytes depolarise from left to right. (Figure 58.3d), resulting in a small negative
Finally, the wave of depolarisation spreads from deflection known as the S wave.
the apex to the base of the ventricles.
The active electrode (lead II is shown in Figure 58.3) What is the cardiac axis?
measures the change in potential as ventricular myo- The leads that view the heart in the coronal plane (the
cytes depolarise. Positive and negative deflections six limb leads and augmented limb leads) can be used
indicate net electrical current flow towards and away to determine the cardiac axis: the net direction (or
from the electrode, respectively: vector) of the depolarisation wave (Figure 58.4).
Septal depolarisation produces a small negative Owing to the large mass of ventricular excitable
deflection known as a Q wave (Figure 58.3a). tissue, the net direction of depolarisation normally
264
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 14:44:31, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.061
Chapter 58: The Electrocardiogram
Q wave R
wave
Lead II
electrode
Depolarisation of Depolarisation towards
septum from left to right the electrode
(c) (d)
Lead II Lead II
recording recording
S
wave
Depolarisation away
from the electrode
Figure 58.3 The path of ventricular depolarisation (atrial depolarisation not shown).
265
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 14:44:31, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.061
Section 4: Neurophysiology
266
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 14:44:31, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.061
Section 4 Neurophysiology
59
What is the autonomic nervous Describe the anatomy of the ANS in
system? more detail
The autonomic nervous system (ANS) is the portion Irrespective of the ANS subdivision, action potentials
of the nervous system that innervates smooth muscle reach the viscera through two sets of neurons: pre-
and glands, thus influencing the function of internal ganglionic and post-ganglionic. The sympathetic and
organs that regulate heart rate (HR), arterial blood parasympathetic nervous systems differ in the length
pressure, digestion, micturition, defecation, sweating of these neurons, the location of their synapses (gan-
and sexual function. glia) and the neurotransmitter utilised (Figure 59.1).
Sympathetic nervous system:
Describe the two divisions of the ANS – Sympathetic pre-ganglionic neurons originate
The ANS is subdivided into two separate nervous from the lateral horn of the spinal cord
systems – sympathetic and parasympathetic – which between T1 and L2/3, the so-called
usually have antagonistic effects. Most viscera are thoracolumbar outflow of the ANS.
innervated by both divisions of the ANS. Some – Pre-ganglionic nerves emerge from the spinal
authorities separately identify the enteric nervous cord with the spinal nerves in white rami
system as a distinct ANS subdivision. The ANS communicantes,1 but separate shortly afterwards
comes under the control of the hypothalamus (see to form either paravertebral or prevertebral
Chapter 80). ganglia. The paravertebral ganglia form the
The function of the sympathetic nervous system is sympathetic chain; important named prevertebral
often summarised by fight, flight or fright. Its role is ganglia are the coeliac, the superior mesenteric
concerned with preparing the body for stressful situ- and the inferior mesenteric (Figure 59.1).
ations: increasing cardiac output (by increasing HR, – The sympathetic chain is often divided into
stroke volume and myocardial contractility), vasocon- four parts:
striction, venoconstriction, mobilising glucose stores
and pupillary dilatation. ▪ Cervical, which supplies the head and neck.
The function of the parasympathetic nervous ▪ Thoracic: the upper thoracic sympathetic
system is often summarised by rest and digest. It chain (T1–5) supplies the heart, lungs and
carries out the basic functions required for life, 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
Name some of the effects of ▪
hindgut viscera.
Sacral (or pelvic), which supplies the pelvic
sympathetic and parasympathetic viscera.
nervous system activity on the viscera
The effects of sympathetic and parasympathetic activ- 1
Referred to as ‘white’ because there are more myelinated
ity on the viscera are perhaps best described in a table fibres than unmyelinated. Pre-ganglionic fibres are type
(see Table 59.1). B neurons.
267
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 14:46:22, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.062
Section 4: Neurophysiology
268
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 14:46:22, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.062
Chapter 59: Autonomic Nervous System
T4
T5 Adrenal medulla
Coeliac ganglion
Foregut and
midgut viscera
269
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 14:46:22, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.062
Section 4: Neurophysiology
Division of ANS
– At the target organ, the post-ganglionic – M2 receptors are found in the heart.
neuron releases ACh, which acts upon – M3 receptors are found in smooth muscle of
postsynaptic muscarinic receptors. the bronchioles and arterioles.
These features are summarised in Table 59.2. – M4 and M5 receptors are found in the CNS.
Outline the types of ACh receptor What are the subtypes of adrenergic
As suggested above, there are two types of ACh receptors?
receptor: Adrenergic receptors, or adrenoceptors, are
Nicotinic ACh receptors are directly linked to G protein-coupled receptors whose ligands are cat-
an ion channel; that is, they are ionotropic. echolamines. Adrenoceptors are therefore metabotro-
Nicotinic ACh receptors are found in the pic, exerting their effects through intracellular second
postsynaptic membrane of the neuromuscular messenger systems. There are four main subtypes:
junction (NMJ) within autonomic ganglia and α1-adrenoceptors are Gq-coupled receptors found
within the brain. The receptor is referred to as in arteriolar smooth muscle and the urethral
nicotinic because, in addition to ACh, nicotine sphincter. The vasoconstrictors noradrenaline,
acts as an agonist. Nicotinic ACh receptors in metaraminol and phenylephrine are all α1-
the NMJ (foetal: α2βγδ; adult: α2βεδ) and adrenoceptor agonists. Doxazosin and tamsulosin
autonomic ganglia (α2β3) have different subunit are examples of selective α1-adrenoceptor
isoforms and are thus acted upon by different antagonists used to treat hypertension and benign
drugs. prostatic hypertrophy.
Muscarinic ACh receptors are G protein-coupled α2-adrenoceptors are presynaptic Gi-coupled
receptors and act through an intracellular second receptors found in the pancreas, arterioles and
messenger system; that is, they are metabotropic. CNS. Both noradrenaline and adrenaline activate
The fungal alkaloid muscarine also acts on these α2-adrenoceptors, resulting in vasodilatation,
receptors. There are five subtypes of muscarinic inhibition of insulin release from the pancreas,
receptors: sedation and analgesia. Clonidine, an α2-agonist,
is used as a sedative and analgesic.
– M1 receptors are commonly found in secretory
glands (e.g. the salivary glands) and the central β1-adrenoceptors are Gs-coupled receptors found
in the heart and kidney. Activation by adrenaline
nervous system (CNS).
270
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 14:46:22, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.062
Chapter 59: Autonomic Nervous System
271
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 14:46:22, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.062
Section 4 Neurophysiology
Pain Physiology
Chapter
60
What is the definition of pain? What is a nociceptor?
Pain is defined by the International Association A nociceptor is a free, unmyelinated nerve ending
for the Study of Pain as ‘an unpleasant sensory capable of generating action potentials in response
and emotional experience associated with actual or to a variety of stimuli that are generated by cellular
potential tissue damage or described in terms of such damage. For example:
damage.’ +
K is released from damaged cells.
Histamine is released from mast cells near to the
How does pain differ from nociception? site of tissue damage.
Nociception is the process by which noxious signals Bradykinin is increased at the site of injury as a
are encoded as action potentials and transmitted result of inflammation.
from the periphery to the central nervous system Leukotrienes and prostaglandins are synthesised
(CNS). Pain results from the brain’s interpretation in response to cellular damage as part of the
of these nociceptive signals, resulting in the percep- inflammatory process.
tion of an unpleasant sensory and emotional Serotonin is released by platelets in response to
experience. vascular injury.
272
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:03:57, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.063
Chapter 60: Pain Physiology
pain that often follows the early sharp pain – The mesencephalic trigeminal nucleus receives
mediated by Αδ fibres. proprioceptive information from the jaw.
Like the spinothalamic pathway, the second-order
What are the pathways by which pain neurons immediately decussate and ascend
signals are relayed to the brain? through the brainstem to the thalamus, where
they synapse with third-order neurons.
As discussed in Chapter 50, the afferent neurons that
The third-order neurons relay action potentials to
relay nociceptive impulses from the peripheries travel
the somatosensory cortex.
in the spinothalamic tract:
A first-order neuron (C or Αδ fibre) relays action
potentials from a nociceptor to the substantia
How is pain modulated?
gelatinosa (Rexed lamina II) or nucleus proprius It has long been known that the pain associated with
(Rexed laminae III, IV and V) in the dorsal horn an injury may not always correlate with the severity of
of the spinal cord. Here, the first-order neuron that injury. For example, soldiers with severe battle
synapses with a second-order interneuron, with wounds may experience little or no pain. Clearly, the
substance P as the neurotransmitter. traumatic amputation of a limb will result in acti-
The second-order interneuron decussates in the vation of peripheral nociceptors. This suggests an
anterior commissure, before ascending the length existence of mechanisms by which nociceptive signals
of the spinal cord in the spinothalamic tract. The received by the brain are modulated. Three mechan-
second-order neuron synapses with a third-order isms contribute to pain modulation:
neuron in the thalamus. Segmental inhibition. It is well known that
The third-order neuron relays nociceptive action rubbing an injured area or the external application
potentials to the somatosensory cortex. of heat or ice reduces the sensation of pain. This
led to the gate theory of pain control (1965). At
Sensation from the face is relayed to the brain
the time, it was thought that only C fibres carried
through the trigeminal pathway:
pain, whereas Αδ fibres carried touch, pressure
A first-order neuron (C or Αδ fibre) relays action and vibration sensory modalities. The gate control
potentials from the face to the trigeminal nucleus. theory hypothesised that both type C and Αδ
Most of this sensory information is relayed to the fibres converge on the same second-order neuron
brain through the trigeminal nerve, but a small and that greater activity of the Αδ fibres reduced
number of sensory afferent neurons from the the transmission of pain through C fibres
oropharynx and ear travel in the facial, (Figure 60.1).
glossopharyngeal and vagus nerves. Irrespective of Gate theory has now largely been disproved by
the cranial nerve, all sensory afferent fibres the subsequent identification of interneurons
synapse with second-order neurons in the dedicated to carrying nociceptive impulses from
trigeminal nucleus, the equivalent of the dorsal Αδ fibres alone. This does not exclude alternative
horn of the spinal cord. Again, substance P is mechanisms for segmental inhibition that may
thought to be the neurotransmitter at this synapse. explain phenomena such as transcutaneous
The trigeminal nucleus (also known as the electrical nerve stimulation, in which electrical
Gasserian ganglion) is large, extending from the stimulation of Αδ fibres using skin electrodes
medulla to the midbrain. Three parts of the reduces pain intensity in some patients.
trigeminal nucleus receive different sensory Endogenous opioid system. Opioid receptors are
modalities: located throughout the CNS, but especially in the
– The spinal trigeminal nucleus receives pain and periaqueductal grey matter, the ventral medulla
temperature information. and the spinal cord. Opioid receptors are
– The main trigeminal nucleus receives touch G protein-coupled receptors of three classes: μ, κ
and proprioception information from the face and δ. When endogenous opioids (enkephalins,
and mouth. endorphins and dynorphin) bind to opioid
273
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:03:57, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.063
Section 4: Neurophysiology
To the dorsal
columns
Inhibitory synapse
2nd-order neuron
receptors, there is reduced transmission of brainstem, where they influence the activity of
nociceptive impulses along the second-order ascending second-order nociceptive neurons
neurons; that is, activation of opioid receptors (Figure 60.2). By inhibiting neurotransmission at
inhibits pain transmission. Opioid receptors the synapse between the first- and second-order
achieve this by either: nociceptive neurons, the perception of pain is
– Opening K+ channels on the postsynaptic reduced. Serotonin and noradrenaline are thought
membrane, thus hyperpolarising the second- to be the main neurotransmitters of the
order neuronal membrane; descending inhibition pathway, which in part
– Inhibiting Ca2+ influx into the presynaptic explains the analgesic properties of selective
terminal, thus reducing neurotransmitter serotonin reuptake inhibitors and tricyclic
release (substance P). antidepressant drugs. The analgesic effects of
clonidine, an α2‑adrenergic agonist, are thought to
Descending inhibition. Neurons from the
occur through augmentation of activity in the
periaqueductal grey matter project to the dorsal
descending inhibitory pathway.
horn of the spinal cord via the raphe nuclei in the
274
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:03:57, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.063
Chapter 60: Pain Physiology
Define hyperalgesia and allodynia. How neuropathic pain may be an episodic pain, like an
do they occur?
electric shock, or a burning pain. Abnormal sensa-
tions are common, such as parasthesias and allodynia.
Hyperalgesia is defined as increased pain from a stimulus Neuropathic pain may result from a number of
that normally provokes pain. Hyperalgesia is of two types: mechanisms; for example:
Primary hyperalgesia occurs in damaged tissues. In diabetic neuropathy, ischaemia of a myelinated
For example, areas of sunburnt skin have a greater nerve fibre causes demyelination. The newly
sensitivity to pain than normal areas of skin. exposed axon fires ectopic action potentials, which
Primary hyperalgesia is due to release of substance are perceived as a shooting or burning pain.
P, bradykinin and histamine at the site of tissue Transected nerve axons attempt to regrow with the
damage, which sensitise the nociceptors, aid of nerve growth factor released from the
decreasing their threshold potential for the supporting Schwann cells. However, axon regrowth
generation of action potentials. may be disorganised: sprouting nerve endings may
Secondary hyperalgesia occurs in the tissues spontaneously generate action potentials or may
surrounding the areas of tissue damage. have altered threshold potentials.
Secondary hyperalgesia is thought to result from
the increased release of substances (e.g. substance
P, calcitonin gene-related peptide and glutamate)
How is the sympathetic nervous system
by activated second-order interneurons, which involved in the development of pain?
sensitise neighbouring second-order interneurons. Trauma to the tissues damages not only somatic
Because neurons in the brain and spinal cord are nerves, but also sympathetic nerves. For reasons as
somatotropically organised, these neighbouring yet unknown, a small number of patients develop
neurons correspond to the tissue surrounding the chronic sympathetic nervous system dysfunction
site of tissue damage. following tissue trauma, resulting in complex regional
Allodynia is defined as pain due to a stimulus that pain syndrome (CRPS). Patients with CRPS develop
does not normally provoke pain; for example, light chronic abnormalities at the site of injury:
touch or a cold breeze may be perceived as pain. Vasomotor changes – the affected limb may be
Whilst hyperalgesia can be thought of as a protective hotter or colder than the other limb.
mechanism, preventing an area of damaged tissue Sudomotor changes – reduced sweating.
becoming further damaged, allodynia serves no useful Reduced hair or nail growth.
purpose. Allodynia is often a feature of neuropathic Osteoporosis of the underlying bone.
pain, such as trigeminal neuralgia. Neuropathic pain – hyperalgesia and allodynia are
The physiological mechanism behind the develop- common.
ment of allodynia is far from clear. One possible
The significance of the sympathetic nervous system in
mechanism involves reorganisation of the circuitry
the development of acute pain is a matter of debate
of the spinal cord, so that the interneurons serving
(see Chapter 59).
nociceptors are exchanged with the interneurons
transmitting mechanoreceptor impulses. Further reading
A. R. Moller. Pain: Its Anatomy, Physiology and Treatment.
What is neuropathic pain? Dallas, Moller Publishing, 2014.
Neuropathic pain is pain caused by a lesion or disease P. Brook, T. Pickering, J. Connell. Oxford Handbook of Pain
of the somatosensory nervous system. Neuropathic Management. Oxford, Oxford University Press, 2011.
pain may originate from either the peripheral nervous E. Albrecht, K. R. Kirkham, S. S. Liu, et al. Perioperative
system (PNS) or the CNS. For example: intravenous administration of magnesium sulphate and
The PNS may be damaged by diabetes, infections postoperative pain: a meta-analysis. Anaesthesia 2013;
68(1): 79–90.
such as herpes zoster or invasion by cancer.
Central neuropathic pain may result from J. Sandkühler. Models and mechanisms of hyperalgesia and
allodynia. Physiol Rev 2009; 89(2): 707–58.
multiple sclerosis or spinal cord injury.
R. D’Mello, A. H. Dickenson. Spinal cord mechanisms of
Neuropathic pain differs from nociceptive pain. pain. Br J Anaesth 2008; 101(1): 8–16.
Whilst nociceptive pain is usually sharp or aching,
275
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:03:57, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.063
Section 4 Neurophysiology
61
Describe the anatomy of the globe – Cones primarily function in bright light. There
are three types of cones, each responding to
of the eye the wavelength of a different primary colour
The globe is an approximately spherical structure (red, green and blue), resulting in colour
made up of three layers (Figure 61.1): perception.
Sclera, the dense, fibrous outer layer that provides – Retinal ganglion cells relay signals from the
structure and protection to the eye. There are two rods and cones to the brain: their axons
gaps in the sclera – one anteriorly for the cornea form the optic nerve. The optic nerve (cranial
and one posteriorly for the optic nerve. nerve II) then transmits visual information to
Choroid, the middle vascular layer whose main the occipital lobe of the brain (via a synapse in
role is the supply of nutrients to the sclera and the lateral geniculate nucleus).
retina. An important structure within the retina is the
Retina, the inner neural layer of the globe that fovea, a small indentation with a high density of
contains the photosensitive cells – the rods and cone cells, which provides the necessary visual
cones: acuity for activities such as reading.
– Rods are the most numerous photoreceptor The globe is divided anatomically into three chambers:
and are extremely light sensitive. Rods Anterior chamber, the space between the cornea
perform their visual function mainly in dim and the iris;
light, but cannot distinguish between different Posterior chamber, the triangular space between
wavelengths of light. the iris, the lens and the ciliary body;
Vitreous chamber, the space behind the lens.
Cornea The three chambers contain two intraocular fluids:
Iris
Aqueous humour, within the anterior and
posterior chambers. Aqueous humour is a watery,
optically clear solution of water and electrolytes,
Lens
similar to extracellular fluid.
Fovea Vitreous humour, within the vitreous chamber.
Vitreous humour is a transparent gel consisting of
Ciliary body a three-dimensional collagen network, hyaluronic
acid and water.
Retina
Choroid
Sclera Describe the blood and nerve supply
to the eye
The blood supply to the globe is from a single source –
Anterior Posterior Vitreous chamber the ophthalmic artery. Arterial blood enters the globe
chamber chamber through branches of the ophthalmic artery: the
Figure 61.1 Anatomy of the globe of the eye. central retinal artery, the anterior ciliary arteries and
276
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:05:27, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.064
Chapter 61: The Eye and Intraocular Pressure
277
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:05:27, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.064
Section 4: Neurophysiology
278
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:05:27, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.064
Section 5 Gastrointestinal Tract
62
What are the functions of saliva? Neutralisation of acid: the HCO3‾-containing
saliva dilutes and neutralises gastric acid when the
A volume of 500–1000 mL of saliva is secreted by the contents of the stomach either:
parotid, submandibular and sublingual glands per day
in response to the thought, smell, taste and presence – Reflux into the oesophagus.
of food in the mouth or stomach. Saliva is 98% water, – Enter the oral cavity during vomiting. There is
with the remaining 2% made up of: a large increase in salivation immediately
before vomiting, which protects tooth enamel
Electrolytes. Saliva is hypotonic – it has a
lower Na+ concentration but a higher K+ against acid erosion.
concentration than plasma. Resting salivary Antibacterial effects: despite the many bactericidal
pH is 7.0, but when HCO3‾ secretion is constituents of saliva, there is little evidence of any
increased, the pH rises to 8.0. significant bacteriostatic action in humans.
Proteins and enzymes, including
mucin, haptocorrin, α-amylase and lingual How is saliva produced?
lipase. Salivary glands are composed of acinar cells and
Bactericidal substances, including thiocyanate, ducts surrounded by contractile myoepithelial cells.
lysozyme, lactoferrin and immunoglobulin A. Production of saliva occurs in two phases:
Unsurprisingly, the functions of saliva are reflected by The acinar cells produce the primary secretion by
its constituents: the active transport of electrolytes, followed by the
Lubrication of food: saliva protects the passive movement of H2O. The primary secretion
pharyngeal and oesophageal mucosa from damage is approximately isotonic: Na+, Cl‾ and HCO3‾
during swallowing. Mucin is primarily responsible concentrations approximately resemble those of
for the lubrication properties of saliva. plasma.
Digestion: The duct cells modify the primary secretion to
give a secondary secretion. Na+ and Cl‾ are
– α-amylase is an enzyme identical to pancreatic reabsorbed, whereas K+ and HCO3‾ are secreted.
amylase, which catalyses the breakdown of Reabsorption takes place at a greater rate than
carbohydrate polymers. It works optimally at secretion – saliva therefore becomes more
pH 7 – the pH of saliva – and manages to hypotonic as it progresses through the duct.
cleave up to 75% of starch before becoming
denatured by the acidic environment of the The rate of saliva production affects its composition.
stomach. At higher rates saliva is rich in Na+ and HCO3‾, whilst
– Lingual lipase commences the digestion of at lower rates it has a greater proportion of K+ and
dietary triglyceride. It is particularly important Cl‾. Aldosterone increases Na+ reabsorption and K+
in neonates, whose pancreatic lipase is secretion, similar to its effect in the kidney.
immature and not particularly effective at
digesting milk fats. How are the salivary glands innervated?
– Haptocorrin is a protein that binds to vitamin The basic secretory unit of the salivary gland is the
B12, protecting it from the low-pH acinus. The acini of the parotid, submandibular and
environment of the stomach. sublingual glands have both:
279
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 20:03:23, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.065
Section 5: Gastrointestinal Tract
Parasympathetic innervation – stimulation – Elevation of the hyoid (by the digastric and
produces vasodilatation of blood vessels supplying stylohyoid muscles), which moves the larynx
the acini and myoepithelial cell contraction, superiorly and anteriorly. In addition, the
resulting in the secretion of a mainly serous, epiglottis moves downwards to direct the food
electrolyte-rich saliva. bolus towards the posterior pharynx and away
Sympathetic innervation – stimulation produces from the larynx.
vasoconstriction of blood vessels supplying the The food bolus is propelled towards the oeso-
acini and myoepithelial cell contraction. This phagus by successive contractions of the superior
results in a brief increase in the secretion of and middle pharyngeal constrictor muscles. The
mainly mucous saliva that is rich in amylase, inferior pharyngeal constrictor muscle (crico-
followed by a period of decreased saliva pharyngeus), which is normally closed, relaxes to
production. allow the food bolus to pass. Cricopharyngeus is
The origin of the parasympathetic fibres differs also 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 re-
ganglionic fibres synapse at the otic ganglion. opening once the food bolus has passed. It is therefore
The submandibular and sublingual glands are impossible to breathe during the pharyngeal phase;
supplied by the facial nerve (cranial nerve VII); the respiratory centre in the medulla coordinates a
pre-ganglionic fibres synapse at the 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
(LOS) partially relaxes.
Swallowing is a complex process involving the coord-
– The food bolus is then propelled along the
ination of a number of muscles, both voluntary and
oesophagus by peristalsis. There are two types
involuntary. Swallowing involves passing a food bolus
of peristaltic waves propagated by the enteric
from the oral cavity to the oesophagus via the phar-
nervous system:
ynx, with closure of the larynx to prevent pulmonary
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. – By the time the peristaltic wave reaches the
The pharyngeal phase, which is under LOS, it has fully relaxed to allow the food
involuntary control. The medulla coordinates: bolus to pass. The smooth muscle of the LOS
– Closure of the nasopharynx by the soft palate. then contracts to prevent gastric contents
– Protection of the laryngeal inlet by adduction of refluxing into the oesophagus.
the vocal cords (lateral cricoarytenoid, oblique
and transverse arytenoid muscles) followed by Clinical relevance: aspiration pneumonia
adduction of the aryepiglottic folds
Aspiration pneumonia occurs when foreign materials
(aryepiglottic muscles). All of these laryngeal (usually vomit, food, fluids or oral or nasal secretions)
muscles are supplied by the recurrent enter the tracheobronchial tree, causing infection
laryngeal nerve.
280
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 20:03:23, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.065
Chapter 62: Saliva, Oesophagus and Swallowing
282
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 20:03:23, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.065
Section 5 Gastrointestinal Tract
63
What are the functions of the stomach? important peptidase that starts the process of
protein breakdown. Pepsinogen secretion is
The stomach has a range of functions: triggered by:
Temporary storage of large meals – releasing
– Gastrin;
ingested food slowly into the small intestine.
– Parasympathetic nervous activity through the
Secretion of digestive enzymes – for example,
vagus nerve.
gastrin.
Mixing – vigorous contraction of gastric smooth Gastrin, a peptide hormone secreted by G cells in
muscle helps mix and liquefy ingested food. the stomach in response to:
Secretion of gastric acid – in part to defend – Parasympathetic nervous activity through the
against ingested microorganisms. vagus nerve;
Secretion of intrinsic factor (IF) – which aids the – Distension of the stomach;
absorption of vitamin B12. – The presence of partially digested proteins in
Endocrine – secreting hormones to control gastric the stomach.
emptying. Gastrin has three main roles:
– Stimulation of parietal cells to secrete HCl, both
Which substances are secreted by the directly and through stimulation of histamine
stomach? release by the ECL cells;
A total of 2 L of gastric fluid is produced by the – Stimulation of chief cells to secrete pepsinogen;
stomach per day. There are five important substances – Stimulation of gastric motility.
secreted by the stomach: Gastrin secretion is controlled by negative
Hydrochloric acid (HCl). The parietal cells secrete feedback: high acid concentration releases
HCl to concentrations of up to 150 mmol/L somatostatin from δ cells, which inhibits further
(equivalent of a pH of 0.8). HCl secretion is release of gastrin from G cells.
increased by three stimuli: IF, a glycopeptide secreted by parietal cells. IF has
– Histamine, which stimulates H2 receptors – the an important role in vitamin B12 absorption:
most important stimulus for gastric acid – Vitamin B12 is released from ingested animal
secretion. proteins as they are broken down in the stomach.
– Parasympathetic stimulation through the – In the low-pH environment of the stomach, IF
vagus nerve. Acetylcholine (ACh) acts as the has a low binding affinity for vitamin B12, so
neurotransmitter at muscarinic M3 receptors. very little is bound. Released vitamin B12 is
– Gastrin, the least important direct stimulus of instead bound by haptocorrin, a vitamin B12
the parietal cells. However, gastrin has an binding protein. This protects the acid-
important indirect effect, as it triggers sensitive structure of vitamin B12.
histamine release from neighbouring – In the duodenum, vitamin B12 is re-released as
enterochromaffin-like (ECL) cells. haptocorrin is digested by trypsin. In contrast,
Pepsinogen, a proenzyme secreted by the chief IF is resistant to trypsin.
cells, is converted into pepsin by the acidic – In the higher-pH environment of the
environment of the stomach. Pepsin is an duodenum, IF avidly binds vitamin B12.
283
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 19:21:55, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.066
Section 5: Gastrointestinal Tract
– In the terminal ileum, IF receptors allow Carbonic anhydrase (CA) within the cell
absorption of the IF–vitamin B12 complex. cytoplasm.
In pernicious anaemia, autoimmune destruction The main stimulus for the secretion of gastric acid is
of parietal cells leads to an IF deficiency. Vitamin histamine, synthesised and stored by neighbouring
B12 therefore cannot be absorbed, resulting in a ECL cells that release histamine in response to gas-
megaloblastic anaemia. trin or parasympathetic stimuli. Histamine acts by
Mucus. Mucous cells secrete an HCO3 -rich increasing the cyclic AMP (cAMP) concentration
mucus that covers the gastric mucosa. It has two within the parietal cell. Gastrin and ACh also dir-
main roles: ectly stimulate the parietal cell, but to a lesser extent
– Protection of the gastric mucosa from the than histamine.
highly acidic contents of the stomach lumen; The mechanism for gastric acid secretion is:
– Lubrication of the stomach wall, protecting it CO2 diffuses into the parietal cell from the blood.
from frictional damage due to vigorous CO2 reacts with water to give H2CO3 in a reaction
peristalsis and mixing of partially digested food. catalysed by CA.
+
H2CO3 dissociates into H and HCO3. These ions
How do the parietal cells secrete then go their separate ways:
SS Secondary messengers
Stimulatory receptors
Inhibitory somatostatin receptor
284
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 19:21:55, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.066
Chapter 63: Stomach and Vomiting
285
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 19:21:55, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.066
Section 5: Gastrointestinal Tract
called ‘early’ dumping syndrome, because it In addition, there are a number of other factors that
occurs soon after ingestion of a meal. inhibit gastric emptying:
Hypoglycaemia. Rapid absorption of a large Sympathetic nervous system activity;
amount of carbohydrate triggers the β‑cells of the Pain;
islets of Langerhans in the pancreas to secrete Drugs (e.g. opioids);
large amounts of insulin. Plasma glucose is rapidly Diseases such as diabetic autonomic neuropathy,
taken up by the cells; plasma insulin concentration acute abdomen and ileus.
takes longer to fall back to normal, resulting in
hypoglycaemia. This is referred to as ‘late’
dumping syndrome, as it occurs 1–3 h after a How long does gastric emptying take?
meal. As discussed above, gastric emptying depends on
whether gastric contents are solid or liquid:
The rate of gastric emptying into the duodenum
depends on: Solids. After consuming a typical meal, there is a
20–30‑min period where there is minimal gastric
The consistency of the chyme. Liquids pass
emptying. This lag period allows time for mixing
through the stomach much faster than solids. The
of food with gastric secretions and for pepsin to
pyloric sphincter constricts when solids come
start the breakdown of proteins. After 30 min, the
close, preventing them from leaving the stomach
rate of gastric emptying is approximately linear,
until they are essentially liquefied.
resulting in a steady decrease in gastric volume
The volume of chyme. Increased gastric volume (Figure 63.2).
promotes gastric emptying.
Liquids. Unlike solids, clear liquids empty from
The content of the chyme. Protein enters the the stomach at rates showing an exponential time
small intestine the most rapidly, followed by
course, without a lag phase (Figure 63.2).
carbohydrate. High-fat meals are associated with
However, if the fluid is hyperosmolar, acidic or
the slowest gastric emptying.
contains fats, the rate of gastric emptying will be
The rate of gastric emptying is primarily controlled by slower and may mirror the non-exponential
the duodenum – chyme passes through the pylorus pattern of solid food.
and into the small bowel at an optimal rate for diges-
tion and absorption of food. The four main duodenal
factors that slow the rate of gastric emptying are: Clinical relevance: preoperative fasting
Duodenal distension. This results in a reflex
The aim of preoperative fasting is to reduce the
inhibition of the enteric nervous system, reducing
volume and acidity of gastric fluid, thereby reducing
gastric emptying. the risk of pulmonary aspiration. However, there is
Acid. Low duodenal pH triggers the release of increasing evidence of the harms of excessive starva-
secretin from the duodenal mucosa. As discussed tion periods, including:
above, secretin promotes pancreatic HCO3 and Patient discomfort;
secretion and inhibits gastrin secretion. As gastrin Dehydration;
is responsible for stimulating gastric motility, Electrolyte disturbance;
reduced gastrin concentration slows gastric Increased incidence of post-operative nausea
emptying. and vomiting (PONV);
Fat. Cholecystokinin (CCK) is secreted by the Glycaemic disturbance in patients with diabetes;
duodenal mucosa in response to the presence of Increased body muscle catabolism following
duodenal lipid. CCK increases the tone of the major surgery.
pylorus, thereby reducing gastric emptying, which The risk of pulmonary aspiration is related to the
allows the small intestine more time to digest the volume of gastric contents: at a given time after
ingestion, gastric volume is considerably less for
lipids that have already passed from the stomach.
liquids than solids. Therefore, liquids can be ingested
Hyperosmolarity. Hyperosmolar chyme passing much nearer to the time of general anaesthesia than
into the duodenum inhibits gastric emptying solids can.
through a complex enteric nervous system reflex.
286
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 19:21:55, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.066
Chapter 63: Stomach and Vomiting
100
75
50
25
Liquid meal
0
0 0.5 1 1.5 2 2.5 3
Time after consumption (h)
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 19:21:55, subject to the Cambridge Core terms of use, available at 287
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.066
Section 5: Gastrointestinal Tract
288
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 19:21:55, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.066
Section 5 Gastrointestinal Tract
64
Which gastrointestinal organs are The submucosa contains nerve cells making up
Meissner’s plexus (a secondary enteric nervous
involved in digestion? system plexus), blood vessels, lymphatic vessels
The gastrointestinal (GI) tract is a tube that extends and elastic connective tissue.
from mouth to anus and is approximately 9 m in The mucosa, the innermost layer, is divided into
length. It consists of the mouth, oesophagus, stomach, (from outermost to innermost):
small intestine and large intestine. In addition, there – Muscularis mucosae, a layer of smooth muscle
are a number of accessory organs of digestion: that provides continuous agitation of the
The teeth and tongue are involved in the initial mucosa, increasing contact with the luminal
mixing of food with saliva. contents and preventing their adherence.
The salivary glands, liver, gallbladder and – Lamina propria, which contains blood vessels
pancreas secrete substances involved in the and collections of immune cells. In the ileum,
chemical and enzymatic breakdown of food. the immune cells are organised into lymphoid
nodules called Peyer’s patches.
How is the small intestine anatomically – Epithelium: the absorptive cells of the intestine
and histologically arranged? are called enterocytes.
The small intestine is divided into three parts: Although the length of the small intestine is only 7 m,
Duodenum; the absorptive surface area of the small intestine is
Jejunum; enormous: over 250 m2. The absorptive surface area is
Ileum. increased as a result of:
Most dietary nutrients are absorbed in the jejunum, Valvulae conniventes, mucosal folds that project
but some are absorbed at other sites: into the lumen of the small intestine.
Vitamin B12 and bile salts are absorbed in the Villi, tiny finger-like projections of the intestinal
terminal ileum. wall. In between the intestinal villi are goblet cells,
Iron is absorbed in the duodenum. which secrete mucus, and intestinal crypts, which
Dietary fat and water are absorbed throughout the secrete the brush border enzymes and contain
small intestine. stem cells.
Microvilli, microscopic projections on top of the
The small intestine is made up of four layers:
villi. The fuzzy microscopic appearance of the
The adventitia, the outermost layer, is composed microvilli superimposed on the intestinal villi
of loose connective tissue. gives rise to the name brush border.
The muscularis externa consists of an outer layer
Each villus has three vessels:
of longitudinal smooth muscle and an inner layer
of circular smooth muscle. Peristalsis results from A single arteriole. This gives rise to a capillary
coordinated contraction of the smooth muscle. network at the tip of the villus.
The myenteric plexus, part of the enteric nervous A single venule. The capillary network drains into
system, lies between the muscle layers, where it a single venule, which returns blood to the liver
coordinates smooth muscle contraction. through the portal vein.
289
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 19:20:12, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.067
Section 5: Gastrointestinal Tract
A single lacteal. Each villus also has a single Within the enterocyte. Once absorbed into the
lymphatic capillary called a lacteal, which enterocyte, glucose and galactose travel down their
transports absorbed dietary fats as chylomicrons concentration gradients. They pass through the
to the thoracic duct. basolateral membrane and into the capillary by
facilitated diffusion (via the transmembrane
What are the three main classes of glucose transporter, GLUT-2). As
monosaccharides are osmotically active, their
dietary nutrients? absorption across the enterocyte also results in the
The three main dietary nutrients are carbohydrates, absorption of water.
amino acids and fats. Each is broken down and
absorbed very differently. Clinical relevance: oral rehydration therapy
Worldwide, diarrhoea is the second commonest
How are carbohydrates digested and cause of death in children under 5 years old. It is, of
absorbed? course, the complications of dehydration rather than
diarrhoea that are to blame for this high mortality.
Dietary carbohydrate polymers (e.g. starch) must be Oral rehydration therapy (ORT) is an effective
broken down into their constituent monosaccharides method of rehydration in diarrhoeal illness, reducing
before they can be absorbed: the need for intravenous fluid therapy in cases of mod-
erate and severe dehydration. Oral rehydration solution
In the mouth. Salivary amylase breaks down
is essentially just water, salt (sodium chloride) and
complex carbohydrates into smaller carbohydrate
glucose. ORT exploits the intestinal Na+–glucose co-
polymers and monosaccharides. transport system to facilitate the absorption of water:
In the duodenum. Pancreatic amylase continues
Both Na+ and glucose are osmotically active, and
the breakdown of complex carbohydrates.
their absorption into the enterocyte is
At the brush border. Specific brush border accompanied by a significant amount of water.
enzymes (e.g. sucrase, maltase and lactase) Because Na+ is also absorbed with oral
hydrolyse the smaller carbohydrate polymers into rehydration solutions, some of the Na+ lost from
their constituent monosaccharides. For example, the GI tract is replaced.
sucrase hydrolyses the disaccharide sucrose into However, ORT does not contain potassium, so hypo-
glucose and fructose. The brush border enzymes kalaemia can occur following prolonged diarrhoea
are integral membrane proteins attached to the and oral replacement.
villi. Individuals with brush border enzyme
deficiencies cannot digest certain carbohydrates.
For example, lactose intolerance is caused by How are proteins digested and
brush border lactase enzyme deficiency. Some absorbed?
carbohydrates, such as cellulose, pass through the Ingested proteins must be broken down into single
GI tract unchanged, as humans do not have the amino acids, dipeptides and tripeptides before they
brush border enzymes necessary for hydrolysis. can be absorbed:
At the enterocyte, monosaccharides are absorbed:
In the stomach, protein digestion begins. The
– Glucose and galactose can only be absorbed by proenzyme pepsinogen is released by chief cells in
secondary active transport through an Na+ co- the stomach. The low-pH environment then
transporter. This co-transporter (called the converts pepsinogen into pepsin. Pepsin cleaves
sodium-glucose linked transporter, SGLT1) the peptide bonds of dietary protein, resulting in
requires a low enterocyte intracellular Na+ shorter polypeptides.
concentration, generated as a result of In the duodenum, protein digestion continues.
basolateral Na+/K+-ATPase pump activity. The two most important peptidases are trypsin
– Fructose is absorbed by facilitated diffusion, and chymotrypsin, both of pancreatic origin.
not by Na+ co-transport. Polypeptides are progressively cleaved by these
– Pentose sugars are absorbed by simple powerful peptidases, resulting in dipeptides and
diffusion. tripeptides (but not single amino acids).
290
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 19:20:12, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.067
Chapter 64: Gastrointestinal Digestion and Absorption
At the brush border, peptidases cleave dipeptides remain in the gut lumen and are absorbed in the
and tripeptides into single amino acids. Again, terminal ileum, where they return to the liver and
these brush border enzymes are integral are recycled.
membrane proteins attached to the villi. Within the enterocyte. Monoglycerides and fatty
At the enterocyte, single amino acids are acids travel to the endoplasmic reticulum, where
absorbed in a similar way to glucose, through they are recombined to form triglyceride. The
Na+-linked co-transport. There are different co- triglyceride is packaged together with cholesterol,
transporters for neutral, basic and acidic amino phospholipid and a cellular label called
acids. Short peptides (two or three amino acids in apolipoprotein to form lipid balls called
length) are also absorbed by secondary active chylomicrons. The chylomicrons are released from
transport using an H+-linked co-transport system. the enterocytes into lacteals, the lymphatic capillaries
Inside the enterocyte, these short peptides are that service each villus. Chylomicrons flow through
broken down into single amino acids, which then the lymphatic system until they are released into
exit the enterocyte by facilitated diffusion across systemic circulation at the thoracic duct.
the basolateral membrane. Amino acids are
osmotically active: as they are transported from Clinical relevance: lipase inhibitors
the gut to the capillary, water molecules are also The weight-reduction drug Orlistat is a lingual and
absorbed. pancreatic lipase inhibitor. It prevents dietary triglycer-
ide being hydrolysed into free fatty acids and mono-
How are lipids digested and absorbed? glyceride. Dietary triglyceride therefore remains
Most dietary lipid is triglyceride (a glycerol backbone undigested and is excreted in the faeces, resulting in
steatorrhoea. Similarly, steatorrhoea is the main pre-
with three fatty acid residues attached), with smaller
senting symptom in pancreatic insufficiency.
amounts of phospholipid, cholesterol and fat-soluble
vitamins. In common with carbohydrates and pro-
teins, triglyceride must first be broken down into its What are the functions of the pancreas?
constituent parts before absorption can take place.
The pancreas has both endocrine and exocrine func-
Emulsification in the duodenum. Lipids are tions. Most of the pancreatic tissue is dedicated to the
insoluble in water. Triglyceride therefore tends to secretion of pancreatic fluid. Despite only occupying
aggregate in large droplets when exposed to the 1–2% of the pancreatic mass, the islets of Langerhans
aqueous environment of the GI tract. In a process are the sole producers of glucagon (α-cells), insulin
called emulsification, bile acids (secreted by the (β-cells) and pancreatic polypeptide (PP cells), and
liver and stored in and then released from the they are one of the main sites of somatostatin secre-
gallbladder) coat the lipid droplets, dividing them tion (δ-cells).
into smaller and smaller droplets.
Enzymatic breakdown of triglyceride. Pancreatic
lipase acts to hydrolyse each triglyceride molecule
How are pancreatic secretions involved
into two free fatty acid molecules and 2- in digestion?
monoglyceride. However, pancreatic lipase can A total of 1.5 L of pancreatic juice is produced per
only act on the surface of lipid droplets. This is day, which drains into the duodenum through the
why bile salts are required to divide large droplets pancreatic duct. The main cell types of the exocrine
into small ones, increasing the surface area upon pancreas are:
which pancreatic lipase acts. Acinar cells, which produce digestive enzymes;
Micelle formation. The free fatty acids and Ductal cells, which secrete HCO3‾ and water.
monoglycerides released from triglyceride combine
with bile salts, forming micelles consisting of small Acinar cells produce four main enzymes and
balls of mixed lipids and bile salts. proenzymes:
At the enterocyte. When a micelle makes contact Trypsinogen and chymotrypsinogen. On
with an enterocyte, the lipid contained within it is entering the duodenum, the proenzyme
absorbed by simple diffusion. The bile salts trypsinogen is cleaved by the duodenal enzyme
291
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 19:20:12, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.067
Section 5: Gastrointestinal Tract
H+ H+ + HCO3 HCO3
Na+ Na+
H 2O H 2O
Basolateral Na+/K+-ATPase
Water diffuses, following
osmotically active HCO3
292
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 19:20:12, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.067
Chapter 64: Gastrointestinal Digestion and Absorption
CO2 diffuses into the ductal cells from the blood. pancreatic acinar cells to secrete digestive
CO2 combines with water to form H2CO3, enzymes.
catalysed by CA. Secretin. This hormone is secreted by the
H2CO3 dissociates into H and HCO3‾. These two
+ duodenal mucosa in response to the presence of
ions then go their separate ways: acid-containing chyme in the duodenum. As well
– HCO3‾ ions diffuse down their concentration as slowing gastric emptying, secretin stimulates
gradient into the lumen of the pancreatic duct, the duct cells of the pancreas to secrete HCO3‾ to
crossing the luminal membrane by exchange neutralise the chyme.
with Cl‾ ions. The Cl‾ ions can then return to
the lumen of the pancreatic duct through a Howdoesintestinalmotilitydifferinthe
separate Cl‾ channel, CFTR. It is this Cl‾ fed and fasted states?
channel whose function is abnormal in cystic
In the fed state, the contractions of the small intestine
fibrosis.
are designed to:
– H+ is expelled from the ductal cell across the
basolateral membrane into the capillary by Promote mixing of chyme with digestive enzymes
exchange with Na+. As with many cellular and bile salts;
processes, the exchange of H+ and Na+ is Propel chyme along the small intestine to the large
driven by the low intracellular concentration intestine.
of Na+ generated by the Na+/K+- The two types of contractions of the small intestine
ATPase pump. reflect these two functions:
HCO3‾ is osmotically active, and so its movement Segmental contractions. Contraction of the
into the pancreatic duct is accompanied by water. circular smooth muscle in neighbouring segments
compartmentalises a section of bowel. This is
How are pancreatic secretions followed by continuous contraction and relaxation
of the longitudinal muscle, which results in the
controlled? mixing of chyme with digestive enzymes rather
Between meals, there is very little secretion of pancre- than its propulsion along the GI tract. Segmental
atic fluid. However, when food enters the stomach, contractions also bring chyme into contact with
and especially when chyme enters the duodenum, the brush border, promoting nutrient absorption.
secretion of pancreatic fluid is strongly stimulated. Propulsive contractions. Highly coordinated
Secretion of pancreatic fluid has both neural and contraction of the circular muscle behind the food
humoral control mechanisms: bolus and longitudinal smooth muscle results in
Neural. The pancreas is innervated by the vagus propulsion of chyme along the GI tract. Each
nerve; when activated during the cephalic phase of peristaltic wave lasts only a few seconds, travelling
digestion (anticipation of a meal), there is a small at only a few centimetres per second.
increase in pancreatic acinar cell activity. In the fasted state, there are infrequent, irregular con-
Gastrin. This hormone is secreted by the G cells of tractions of the small intestine. Every 90 min, there is a
the stomach in response to gastric distension. As period of intense, coordinated intestinal contraction,
well as stimulating gastric acid secretion by the spreading from the duodenum to the ileocaecal valve;
parietal cells of the stomach, gastrin also this is known as the migrating motor complex (MMC).
stimulates pancreatic acinar cells to secrete The contraction sweeps along the length of the small
digestive enzymes in preparation for the arrival of intestine, moving undigested chyme towards the colon.
carbohydrates, proteins and fats.
Cholecystokinin (CCK). This hormone is secreted
by the duodenal mucosal cells in response to fat- How is intestinal motility controlled?
or protein-rich chyme entering the duodenum. As Like nerve cells, the smooth muscle cells of the small
well as increasing the production of bile in the intestine have a negative resting membrane potential
liver, stimulating contraction of the gallbladder (–40 to –70 mV). Contraction of smooth muscle occurs
and slowing gastric emptying, CCK stimulates the when the membrane potential exceeds threshold
293
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 19:20:12, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.067
Section 5: Gastrointestinal Tract
294
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 19:20:12, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.067
Section 5 Gastrointestinal Tract
65
Describe the blood supply to the liver In contrast, the portal vein has very little smooth
muscle, so it cannot regulate blood flow in the same
The liver is the largest solid organ in the body (the way. Instead, blood flow is proportional to the pres-
skin is overall the largest organ) and receives a large sure gradient in the portal vein.
volume of blood. At rest, the liver receives around The two different sources of hepatic blood have a
25% of the cardiac output (approximately 1500 mL/ semi-reciprocal relationship, referred to as the ‘hepatic
min). Unlike other organs, the liver receives a dual arterial buffer response’. If portal vein blood flow falls,
blood supply: the hepatic arteries maintain overall liver blood flow
The right and left hepatic arteries contribute through a vasodilatation response involving adenosine
approximately a third of the liver’s blood supply as the chemical mediator. However, if hepatic arterial
(500 mL/min) and half of its O2 requirements. blood flow falls, the portal vein cannot compensate
1
The portal vein accounts for the majority of (this is why the relationship is semi-reciprocal).
blood supplied to the liver (1000 mL/min). Extrinsic mechanisms. The hepatic vessels are
Because the blood has already passed through the innervated by the sympathetic nervous system:
abdominal organs, it has a lower oxygen
saturation (SaO2): – In the hepatic artery, increased sympathetic
activity causes vasoconstriction.
– In the fasting state, portal blood has an SaO2 – More important is the effect of sympathetic
saturation of approximately 85%. nervous activity on the portal vein, portal
– In the fed state, portal blood has an SaO2 venules and hepatic veins. Around 500 mL of
saturation of approximately 70%. blood is stored within these capacitance
vessels. Sympathetic stimulation increases the
How is hepatic blood flow regulated? tone of the vessels, resulting in around 250 mL
of blood being returned to the circulation.
Because of its dual blood supply, regulation of hepatic
Together with the splanchnic capacitance
blood flow is more complicated than that of other
vessels, around 1000 mL of blood can be
organs. Hepatic blood flow is regulated by intrinsic
mobilised at times of physiological stress.
and extrinsic mechanisms:
Intrinsic mechanisms. In common with other How does the respiratory cycle affect
arterial systems, hepatic arterial blood flow
remains relatively constant despite changes in
hepatic venous blood flow?
arterial pressure as a result of autoregulation (see During spontaneous breathing, hepatic venous blood
Chapter 34). Below a mean arterial pressure of 60 flow is increased during inspiration as a result of
mmHg, autoregulation fails and blood flow negative intrathoracic pressure. During expiration,
becomes pressure dependent. the opposite occurs.
In contrast, positive-pressure ventilation causes a
decrease in hepatic venous blood flow as a result of
positive intrathoracic pressure. Likewise, positive
1
The term ‘portal’ refers to a vein that connects two
capillary systems. Blood in the portal vein flows between end-expiratory pressure (PEEP) increases intrathor-
the capillary networks of the abdominal organs acic pressure, which results in a reduced hepatic
(intestines, stomach, spleen and pancreas) and the liver. venous blood flow.
295
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 19:18:43, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.068
Section 5: Gastrointestinal Tract
Clinical relevance: intraoperative liver blood flow – An imaginary line between the gallbladder
fossa and inferior vena cava (called Cantlie’s
Intraoperatively, liver blood flow is altered by both line) separates the functional right and left
anaesthetic and surgical factors:
halves of the liver (this is not the falciform
Anaesthetic factors: ligament). The vessels of the porta hepatis
– Positive-pressure ventilation and PEEP: as divide into right and left branches at this point.
discussed above. From a surgical perspective, the Couinaud
– Drugs: volatile agents and vasopressors classification is much more useful: any given lobe
reduce hepatic arterial blood flow. can continue its normal function when
– Minute ventilation: hypocapnoea reduces neighbouring lobes are resected.
portal vein blood flow whilst hypercapnoea
increases blood flow.
Describe the microscopic anatomy of
– Regional anaesthesia: neuraxial blockade
reduces hepatic blood flow to a similar extent the liver
as general anaesthesia. Like the macroscopic anatomy, the liver microarchi-
Surgical factors: intraoperative retraction and tecture can be considered in terms of either a classical
packing of the liver reduces hepatic blood flow histological or a functional description:
significantly more than any of the above Histological approach. The liver is composed of
anaesthetic factors. tens of thousands of lobules (Figure 65.1a). These
are hexagon-shaped arrangements with a branch
Describe the macroscopic anatomy of of the hepatic vein at the centre:
– Radiating out from the central vein are
the liver columns of hepatocytes and hepatic sinusoids.
Liver anatomy is described in terms of either its – At each of the six corners of the lobule is a
morphological anatomy or its functional anatomy: hepatic triad: a portal venule, hepatic arteriole
Morphological anatomy. Based on the external and a bile duct.
appearance of the liver: However, this classical model was derived from
– The liver is divided into the right anatomical studies of pig livers; human liver microarchitecture
lobe (much larger) and the left anatomical lobe is more disorganised, with a large amount of
by the falciform ligament. connective tissue and fewer well-defined lobules.
– When viewed from beneath, two additional Functional approach. Current thinking considers
small lobes can be seen between the right and the functional unit of the liver to be the acinus.
left lobes. These are the caudate (posterior) The elliptical acinus has a terminal branch of the
and quadrate (inferior) lobes. hepatic vein at either end, with two portal triads at
This morphological anatomy is not particularly the midpoint of the flattened sides (Figure 65.1b).
useful 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
zones of oxygenation – zones 1, 2 and 3:
– Each of the eight lobes has its own blood
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 1–8 in a clockwise processes (e.g. gluconeogenesis and β-
direction, starting from the caudate lobe. oxidation of fatty acids) occur in zone 1.
– The point where the portal vein, common bile – Zone 2 is an intermediate area where
duct and hepatic artery enter the liver is hepatocytes carry out processes characteristic
known as the hilum or porta hepatis. of both zone 1 and zone 3.
296
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 19:18:43, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.068
Chapter 65: Liver: Anatomy and Blood Supply
Central vein 3 2 1 2 3
Acinus
Hepatic lobule
Zones of oxygenation
Figure 65.1 (a) The hepatic lobule and (b) the hepatic acinus.
– Zone 3 is the area of the acinus closest to the blood-filled spaces called hepatic sinusoids.
terminal vein and is therefore the area of Oxygenated blood flows from the hepatic arteriole
lowest O2 tension. The hepatocytes of zone and portal venule towards a branch of the hepatic
3 carry out the least energy-consuming vein. The sinusoidal epithelial cells have very large
processes (e.g. glycolysis and drug fenestrations and lack tight junctions, making
metabolism). them highly permeable (see Chapter 36).
Substances within the blood (nutrients, drugs,
toxins, etc.) are filtered through the sinusoidal
What are the different cell types within epithelial cells to the peri-sinusoidal space, where
they come into contact with the hepatocytes
the liver? (Figure 65.2).
The liver has two main cell types: hepatocytes (60% by Kuppfer cells are specialised macrophages that
mass) and Kuppfer cells (10% by mass). In addition, line the walls of the hepatic sinusoids
there are other non-parenchymal cells: sinusoidal, (Figure 65.2). Their role is to destroy bacteria or
peri-sinusoidal and biliary epithelial cells. other foreign material contained within the
Hepatocytes are highly specialised cells that are venous blood flowing from the gastrointestinal
arranged in columns, making up about 80% of the tract. They also remove worn-out red blood cells
volume of the liver. They perform a wide range of and leukocytes from the circulation.
metabolic, synthetic and exocrine functions (see
Chapter 66). Within the column of hepatocytes Clinical relevance: centrilobular necrosis
are small channels called bile canaliculi Centrilobular necrosis (zone 3 of the acinus) is a
(Figure 65.2). The hepatocytes secrete bile into the common histological finding in severe liver disease
canaliculi. Bile flows from canaliculi to bile due to:
ductules and then to bile ducts. Bile ducts merge Hypoxic injury. Owing to their distance from the
and exit the liver as the common hepatic duct. portal triad, the hepatocytes of zone 3 are the
On either side of the hepatocyte columns are
297
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 19:18:43, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.068
Section 5: Gastrointestinal Tract
Bile cannaliculus
Hepatic arteriole
Hepatic venule
Kuppfer cell
most susceptible to hypoxic injury. Centrilobular this is favoured by the relatively hypoxic
necrosis is often found on liver biopsy of patients environment of zone 3. This reductive pathway
with severe sepsis complicated by hepatic generates free radicals, which damage
dysfunction. hepatocytes.
Drug metabolism. Zone 3 is the main site of Type II halothane hepatitis is a rare
drug metabolism; toxic metabolites produced by complication of halothane anaesthesia with a
the cytochrome P450 enzyme system may cause mortality of 50%. The mechanism is thought to
damage to local hepatocytes. Zone 3 is the site of be autoimmune: trifluoroacetyl metabolites bind
accumulation of the toxic paracetamol to hepatocyte proteins in zone 3, forming a
metabolite N-acetyl-p-benzoquinone imine hapten complex that activates the immune
(NAPQI) in paracetamol overdose. system. Antibodies are produced that target
Halothane hepatitis exemplifies both of the above. these hepatocyte–metabolite complexes,
Following halothane exposure, a patient can develop resulting in massive centrilobular necrosis and
two types of hepatocyte injury: fulminant liver failure.
Type I halothane hepatitis is characterised by a
mild, transient post-operative rise in serum liver
enzymes. Halothane is metabolised in zones Further reading
2 and 3 by cytochrome P450, usually through an K. Barrett. Gastrointestinal Physiology, 2nd edition. New
oxidative pathway resulting in the metabolite York, McGraw-Hill Education, 2013.
trifluoroacetic acid. A small amount of J. A. Hinson, D. W. Roberts, L. P. James. Mechanisms of
metabolism occurs through a reductive pathway; acetaminophen-induced liver necrosis. Handb Exp
Pharmacol 2010; 196: 369–405.
298
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 19:18:43, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.068
Section 5 Gastrointestinal Tract
Liver Function
Chapter
66
The liver is responsible for a wide range of strategic – Glycolysis. Like all other cells, the liver
biochemical functions, synthesising and eliminating a produces energy by transforming glucose into
huge number of molecules for a variety of purposes. pyruvate.
A healthy liver has some important features: – Glycogenesis. Following a meal, plasma
A huge physiological reserve. Even if 80% of liver glucose concentration rises, which causes
is removed, it can continue to carry out all of its insulin to be released from the pancreas. In the
physiological functions. liver, insulin stimulates the polymerisation
Regeneration. In contrast to the other organs, of excess glucose into its storage form,
following resection of up to three-quarters of the glycogen. Up to 100 g of glucose can be stored
liver, active mitosis can regenerate a normal liver in this way.
mass. This amazing ability of the liver has been used – Glycogenolysis. When plasma glucose
in transplantation medicine: living donor concentration falls between meals, insulin
transplantation involves transplanting four secretion is reduced and glucagon is released
segments of the right lobe (50–60% of the liver from the pancreas. In response to glucagon
mass) from a live donor to a recipient. In the donor, secretion, the liver releases glucose by breaking
the remaining liver regenerates to full size within down its glycogen store.
6–8 weeks; in the recipient, regeneration takes a – Gluconeogenesis. When plasma glucose
little longer. Eventually, both donor and recipient concentration is low, glucagon also simulates
have fully functioning, normal-sized livers. the liver to synthesise glucose from non-
carbohydrate precursors (e.g. amino acids,
Classify the functions of the liver 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
lipid metabolism in a number of ways:
Metabolic;
Exocrine; – Lipid breakdown. Energy is extracted from free
Endocrine; fatty acids as they are metabolised in a process
Immunological; called ‘β-oxidation’ within the hepatocyte
mitochondria.
Synthetic;
– Lipid synthesis. The liver synthesises
Hepatic clearance of drugs;
triglyceride from excess glucose. Cholesterol is
A number of additional miscellaneous functions.
also synthesised in the liver. Cholesterol is
used as a structural component of cell
What are the metabolic functions of membranes and as a precursor for steroid
the liver? hormone and bile salt synthesis.
The liver has a vast array of metabolic functions (see – Lipid processing. Apolipoproteins are
Chapter 77), the most important of which are: synthesised in the liver. These are involved in
the packaging of cholesterol and triglyceride as
Carbohydrate metabolism. Many metabolic
low-density lipoprotein, very-low-density
processes occur in the liver in order to maintain a
lipoprotein and high-density lipoprotein.
normal plasma glucose concentration:
299
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 19:16:58, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.069
Section 5: Gastrointestinal Tract
300
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 19:16:58, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.069
Chapter 66: Liver Function
Globin Fe2+
(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
Conjugated bilirubin
KIDNEY
(5)
Urobilinogen
Conjugated bilirubin
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
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 19:16:58, subject to the Cambridge Core terms of use, available at 301
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.069
Section 5: Gastrointestinal Tract
302
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 19:16:58, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.069
Chapter 66: Liver Function
303
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 19:16:58, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.069
Section 5: Gastrointestinal Tract
Does the liver have any other defined as a pressure > 12 mmHg. Portal
hypertension results in:
physiological roles? – Ascites: high venous hydrostatic pressure leads
In addition to the many functions described above, to net fluid filtration into the peritoneal cavity.
the liver has a number of other functions: Ascites poses an especially high infection risk,
Storage. As well as storing glycogen, the liver is as the fluid is relatively stagnant and patients
the main site of iron, copper and fat-soluble with cirrhosis are relatively
vitamin storage. immunosuppressed.
Haematological. In the first trimester, the foetal – Splenomegaly: venous blood from the spleen
liver is the main site of erythropoiesis. In addition, drains into the portal vein. Therefore, if portal
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 65, 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
304
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 19:16:58, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.069
Chapter 66: Liver Function
– PT is a test of the extrinsic pathway of distinguishing between bone and liver as the
coagulation (see Chapter 72). PT depends on origin of a high ALP. γ-GT is often elevated by
clotting factors II, V, VII and X and alcohol ingestion: a disproportionally raised γ-
fibrinogen. The liver is responsible for the GT compared with ALP or ALT suggests
synthesis of all of these factors. The half-life of alcohol abuse.
these clotting factors is <24 h, which is – ALT is present in the cytosol of hepatocytes.
considerably shorter than that of albumin. Therefore, generalised hepatocellular injury
Therefore, PT acts as an effective measure of results in an increase in serum ALT. For
liver synthetic function in acute liver example, ALT rises as a result of centrilobular
dysfunction. necrosis in paracetamol overdose.
Tests of hepatic clearance: bilirubin (discussed
above) and NH3. Normally, NH3 is converted to
urea by the liver. In severe liver dysfunction, Clinical relevance: King’s College Criteria for liver
serum NH3 concentration rises. NH3 is implicated transplantation
in hepatic encephalopathy; as it is a small, Paracetamol overdose is relatively common, and liver
uncharged molecule, osmotically active NH3 is transplantation subjects the patient to a lifetime of
able to cross the blood–brain barrier, leading to immunosuppression. Following a paracetamol over-
cerebral oedema and encephalopathy. However, dose, it is important to be able to predict which
serum NH3 does not correlate particularly well patients are likely to deteriorate and require a life-
with the clinical severity of hepatic saving liver transplant. LFTs play a part in this predic-
encephalopathy. tion. The King’s College Criteria identify patients at
risk of poor outcome following paracetamol over-
Serum hepatic enzyme tests: alkaline phosphatase dose. Liver transplantation is considered if either:
(ALP), γ-glutamyl transpeptidase (γ-GT) and
Arterial pH is <7.3;
alanine aminotransferase (ALT). These tests are
Or all three of PT > 100 s (equivalent to an
used to aid the exact diagnosis of hepatic
international normalised ratio of >6.5), serum
dysfunction. creatinine of >300 pmol/L and hepatic
– ALP is an enzyme concentrated in the biliary encephalopathy of grade III or IV.
canalicular membrane of the hepatocyte.
Disease of the biliary system causes release of
ALP into the systemic circulation. Very high Further reading
(greater than three times normal) ALP L. R. Johnson. Gastrointestinal Physiology: Mosby Physiology
suggests either intrahepatic or extrahepatic Monograph Series, 9th edition. St Louis, Mosby, 2018.
biliary obstruction. Of note, ALP occasionally K. Barrett. Gastrointestinal Physiology, 2nd edition. New
originates from sources other than the liver: York, McGraw-Hill Education, 2013.
kidney, bone and placenta. A. Kortgen, P. Recknagel, M. Bauer. How to assess liver
– γ-GT is also raised in biliary obstruction – this function? Curr Opin Crit Care 2010; 16(2): 136–41.
is because γ-GT is found in hepatocytes B. P. Sweeney, J. Bromilow. Liver enzyme induction and
surrounding the biliary canaliculi. In fact, γ- inhibition: implications for anaesthesia. Anaesthesia
GT is found in similar tissues to ALP, except it 2006; 61(2): 159–77.
is only present in low concentrations in bone. J. K. Limdi, G. M. Hyde. Evaluation of abnormal liver
This may be diagnostically useful, function tests. Postgrad Med J 2003; 79(932): 307–12.
305
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 19:16:58, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.069
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 19:16:58, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.069
Section 6 Kidney and Body Fluids
67
What are the functions of the kidney? The blood supply to the kidneys is carried by the renal
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 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 inferior vena cava
– Control of plasma osmolarity. (IVC). The left renal vein is longer than the right
– Removal of waste products and drugs or their owing to the position of the IVC to the right of the
metabolites. midline.
– Gluconeogenesis: the kidney is a major
gluconeogenic organ. Describe the structure of the nephron
– Control of the metabolic aspects of acid-base The functional unit of the kidney is the nephron
balance. (Figure 67.1), of which there are around 1,000,000
Endocrine roles: per kidney. A nephron consists of:
– Erythropoietin synthesis, which in turn The glomerulus, a network of capillaries located
in the renal cortex whose role is the filtration
controls erythrocyte production;
of plasma (see Chapter 68). The fluid is collected
– Activation of vitamin D to
in Bowman’s capsule and passes along a series
1,25-dihydroxycholecalciferol;
of tubes.
– Secretion of renin, the first hormone of the
The proximal convoluted tubule (PCT) – a
renin–angiotensin–aldosterone axis.
twisting tubule within the renal cortex where the
majority of the filtered products are reabsorbed.
Describe the anatomy of the kidney The loop of Henle (LOH) – the tubule straightens
The kidneys are solid, ‘bean-shaped’ retroperitoneal and then enters the medulla to become the thin
organs located at vertebral levels T12 to L3. From descending limb. This undergoes a hairpin bend
inside to outside, the kidney is surrounded by the to continue as the thin and then the thick
renal capsule, perirenal fat, renal fascia and pararenal ascending limb of the LOH. The main role of the
fascia. At the midpoint of the concave medial border LOH is to generate a longitudinal osmotic
of each kidney is the hilum, the point of entry of gradient in the renal medulla, which allows
the nerves, vessels and lymphatics. In cross-section, controlled water reabsorption from the collecting
the kidney contains: ducts.
An outer renal cortex. The distal convoluted tubule (DCT) – the thick
An inner renal medulla, interrupted by renal ascending limb of the LOH returns to the renal
columns (extensions of the cortex) that penetrate cortex to form the DCT, the site of regulated
deep into the renal medulla. reabsorption.
Towards the hilum, minor calyces coalesce to The collecting duct (CD) – the DCT becomes the
form major calyces, which merge to form the CD, before forming a minor calyx. The CD is an
renal pelvis and finally the ureter. important site of water reabsorption.
307
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:11:13, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.070
Section 6: Kidney and Body Fluids
RENAL CORTEX
RENAL MEDULLA
Efferent arteriole
Collecting duct
Urine excretion
The arterial blood supply of the nephron is unique: It is important to note that this anatomy results in a
The renal arterial tree divides as usual to give well-vascularised renal cortex, but a relatively poor
afferent arterioles, which in turn divide to give rise blood supply to the renal medulla. This latter feature
to the glomerular capillaries. These capillaries prevents washout of solutes from the medullary inter-
then unite to form efferent arterioles. stitium that are required for water reabsorption.
By varying the relative resistances of the afferent and
efferent arterioles, glomerular capillary hydrostatic
pressure, which is the main driving force for What is the juxtaglomerular apparatus?
glomerular filtration, can be modified. Glomerular The DCT folds back to lie anatomically very close to its
filtration is therefore controllable (see Chapter 68). corresponding glomerulus. At this point are located a
The vasa recta are an additional set of arterioles group of specialised cells that form the juxtaglomerular
that arise from the efferent arterioles, whose role apparatus, consisting of three components:
is to supply blood to the renal medulla. The vasa Granular cells, located within the wall of the
recta also have an unusual feature: they descend afferent arteriole, whose role is renin secretion.
with the ascending limb of the LOH and ascend Macula densa cells, located at the junction of the
with the descending limb, providing a DCT and the thick ascending limb of the LOH.
countercurrent flow of blood. This countercurrent Macula densa cells sense tubular Na+ and Cl‾
arrangement is required to generate the high concentration.
solute concentration gradients of the renal Extra-glomerular mesangial cells. These interact
medulla (see Chapter 69). with the macula densa via a purinergic signalling
308
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:11:13, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.070
Chapter 67: Renal Function, Anatomy and Blood Flow
Range of autoregulation
200 capillaries and therefore increased glomerular
filtration. This in turn increases tubular flow
150 and therefore the rate of delivery of Na+ and
125 Cl‾ ions to the macula densa.
100 – The macula densa senses the Na+ and Cl‾
concentrations through its own Na+/K+/2Cl‾
50 co-transporter. The intracellular movement of
0
0 50 75 100 150 165 200 1
Stretching of the arteriolar smooth muscle opens
Mean arterial pressure (mmHg) mechanically gated non-specific cation channels, which
Figure 67.2 Renal autoregulation. causes depolarisation of the arteriolar membrane, leading
to smooth muscle contraction.
309
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:11:13, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.070
Section 6: Kidney and Body Fluids
Na+, K+ and Cl‾ ions is coupled with the angiotensinogen forms the rate-determining, regulatory
osmotic movement of H2O into the macula step in this sequence. Angiotensin II increases systemic
densa cell, causing cellular swelling in blood pressure and therefore renal perfusion pressure
proportion to the GFR. through a number of mechanisms:
– An adenosine-based secondary messenger In the kidney, angiotensin II causes
is released in proportion to the degree of vasoconstriction of both afferent and efferent
cell swelling.2 arterioles, but has a greater effect on the efferent
– The secondary messenger acts at adenosine arterioles owing to their smaller basal diameter.
A1 receptors located within the The end result is an increase in systemic blood
juxtaglomerular apparatus, resulting in a pressure due to the increased vascular resistance
reduction in RBF and GFR: of the renal arterioles, but with a relatively
preserved glomerular capillary hydrostatic
▪ Afferent arterioles vasoconstrict, which
pressure, and therefore GFR.3
increases renal vascular resistance, thereby
reducing RBF. In the systemic vasculature, angiotensin II is a
potent veno- and vaso-constrictor, thereby
▪ Glomerular mesangial cells contract, which
increasing the systemic blood pressure.
reduces the surface area for filtration,
thereby reducing GFR. In the adrenal gland, angiotensin II triggers the
release of aldosterone from the zona glomerulosa
▪ Granular cells are inhibited from secreting
in the adrenal cortex. Aldosterone acts at the DCT
renin (see below).
and CD of the kidney, promoting the reabsorption
The response to a decrease in renal perfusion of Na+ and water, thus expanding plasma volume
pressure is the opposite: the afferent arteriole (see Chapter 69).
vasodilates, the mesangial cells relax and renin In the brain, angiotensin II acts on:
secretion is increased.
– The hypothalamus, where it increases the
sensation of thirst and triggers the release of
How does the renin–angiotensin– antidiuretic hormone (ADH) from the
aldosterone axis regulate RBF? posterior lobe of the pituitary gland. ADH
Renin is released from the granular cells of the increases water reabsorption at the CD.
juxtaglomerular apparatus in response to: – The sympathetic nervous system, where it
directly increases noradrenaline release at
Decreased tubular flow, sensed by the macula
sympathetic neurons, resulting in arteriolar
densa as discussed above.
vasoconstriction.
Low afferent arteriolar pressure, which directly
stimulates the release of renin. Granular cells
effectively act as ‘intra-renal baroreceptors’. How are eicosanoids involved in the
Sympathetic nervous system stimulation regulation of RBF?
through β1-adrenoceptors. In situations where the concentrations of the circulat-
Renin, a proteolytic enzyme, does not itself affect the ing vasopressors noradrenaline and angiotensin II are
vasculature. Renin cleaves the plasma protein angioten- persistently high, including haemorrhage and sepsis,
sinogen (produced by the liver) into angiotensin I, which prolonged afferent and efferent arteriolar vasocon-
is then converted into angiotensin II by angiotensin- striction causes a significant reduction in RBF. In
converting enzyme. The renin-mediated proteolysis of response, the vasodilatory prostaglandins (PGE2 and
PGI2), which oppose the effects of the circulating
vasoconstrictors, are produced locally within the
2
It is not clear whether the secondary messenger is ATP, kidney in an attempt to increase RBF and GFR.
ADP or AMP. One potential mechanism is that, in
order to reduce cell swelling, the activity of the basolateral
Na+/ K+-ATPase must be increased to remove Na+. This 3
However, very high angiotensin II levels cause glomerular
in turn reduces the amount of intracellular ATP and mesangial cells to contract, reducing the glomerular
increases ADP and AMP, which then leak from the cell. filtration area, which leads to a significant fall in GFR.
310
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:11:13, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.070
Chapter 67: Renal Function, Anatomy and Blood Flow
311
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:11:13, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.070
Section 6: Kidney and Body Fluids
312
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:11:13, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.070
Section 6 Kidney and Body Fluids
68
How does filtration occur in the kidney? Particle charge. Most plasma proteins are
negatively charged, as their pKa is less than
The basic filtration unit of the kidney is the renal physiological pH. As a result:
corpuscle, consisting of a glomerulus surrounded by
a Bowman’s capsule. The high glomerular capillary – Plasma proteins are retained. When negatively
hydrostatic pressure forces a fraction of the plasma charged plasma proteins approach the
(i.e. water and solutes) through the capillary wall and glomerular fenestrations, they are repelled by
into the Bowman’s space. This filtration barrier is the negative charges of the glomerular
composed of three layers: basement membrane and podocyte foot
processes.
Glomerular capillary endothelium, a specialised
– Small anions are filtered. Small anions do not
endothelium with large fenestrations.
come into close enough contact with the
Glomerular basement membrane, a layer of
glomerular membrane proteins to be repelled.
supportive basal lamina.
Podocytes, the epithelial cells of a Bowman’s A final determinant of whether a particle is filtered is
capsule. These cells have foot-like projections the extent of its binding to plasma proteins: acidic
that wrap around glomerular capillary compounds bind to albumin, whilst basic compounds
endothelial cells, leaving slit-like openings bind to α-1-glycoprotein. The extent of protein bind-
between them. ing is an important determinant in the clearance of
many drugs.
It is important that filtration permits the passage of
water and solutes, but that the capillary retains blood
cells and proteins. This selectivity results from: What happens to the filtrate in the
The effective pore size of the glomerular renal tubules?
capillaries. This is determined by the size of the Filtration results in a tubular fluid that contains not
capillary wall fenestrations and the spacing only metabolic waste products, but also useful solutes
between podocyte foot processes: such as electrolytes, glucose and amino acids. The
– Particles below 7 kDa are freely filtered into the nephron reabsorbs these essential components.
Bowman’s space. Most of the reabsorption occurs in the proximal
– Particles above 70 kDa (e.g. convoluted tubule (PCT). Here, 67% of Na+, K+, Cl‾
immunoglobulins – around 150 kDa) cannot and water, 85% of HCO3‾ and (in normal subjects)
pass between through the pores. 100% of glucose and amino acids are reabsorbed.
– Between 7 and 70 kDa, partial filtration Reabsorption takes place through active or passive
occurs. processes:
Albumin (67 kDa) is just small enough to fit Active reabsorption. The reabsorption of most
through the pores, but filtration is prevented due substances is active (i.e. requires energy),
to its negative charge (see below). Haemoglobin accounting for the high metabolic activity of the
(Hb) is a 69.8‑kDa protein, and so is just small kidney. In the basolateral membrane of the
enough to be filtered. Hb must therefore be tubular cells, Na+/K+-ATPase ion pumps actively
sequestered within red blood cells to prevent extrude Na+ ions from the tubular cells into
filtration. the peritubular capillaries in exchange for K+.
313
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:13:07, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.071
Section 6: Kidney and Body Fluids
400
200
Tmax
100
0
0 10 20 30
Plasma glucose (mmol/L)
314
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:13:07, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.071
Chapter 68: Renal Filtration and Reabsorption
GFR ¼ K f ½ðPi Po Þ ðπ i π o Þ
1
In a normal glomerulus, the reflection coefficient σ,
normally appearing as the coefficient before the osmotic
where Pi and Po are the hydrostatic pressures inside pressure term, approaches 1, as proteins are almost
and outside the glomerular capillary, respectively, perfectly excluded and are therefore ignored (see
Chapter 36).
315
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:13:07, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.071
Section 6: Kidney and Body Fluids
How is clearance used in the Many researchers have tried to identify an alternative
biomarker with which to estimate GFR. Urea has pre-
measurement of GFR? viously been used, but is produced at an even more
GFR is an indicator of kidney function and is used variable rate than creatinine, being dependent on diet-
clinically to assess the degree of renal failure. If a ary protein, catabolism and hormonal status. Urea is
substance X is freely filtered at the glomerulus and also reabsorbed in large quantities in the PCT and
not secreted or reabsorbed later in the tubule, then the collecting ducts, making it a very inaccurate measure
rate at which the substance appears in the urine must of GFR. Cystatin C is a small, endogenous molecule
be equal the rate of its filtration. GFR can therefore be that is freely filtered at the glomerulus and then
indirectly measured using the clearance formula. reabsorbed and almost totally metabolised by the tubu-
A number of substances have been used for the esti- lar cells. In the future, a combination of creatinine and
mation of GFR: cystatin C may prove to be the best estimate of GFR.
Inulin (not to be confused with insulin) is a small,
exogenous polysaccharide that is freely filtered at Clinical relevance: renal replacement therapy
the glomerulus and not reabsorbed or secreted
later along the tubule. Measurement of inulin Renal failure may occur acutely or insidiously – there
are a multitude of causes, and the pathogenesis is
clearance represents the ‘gold standard’ in GFR
complex. The end result is a loss of the essential
calculation, but is relatively invasive (requiring a
functions of the kidney, most notably failure of:
continuous infusion of inulin) and is really only
used in research where very accurate Clearance of toxic substances, leading to uraemia;
Electrolyte homeostasis, leading to life-
measurements of GFR are required.
threatening hyperkalaemia;
Creatinine is an endogenous molecule produced Water excretion, leading to fluid overload;
during skeletal muscle metabolism. Its clearance Acid excretion, leading to acidaemia.
can be accurately measured using blood and 24‑h Management of renal failure involves artificially per-
urine samples. However, creatinine clearance is forming the key functions of the kidney. Methods of
only an estimate of GFR: renal replacement therapy (RRT) are:
– The rate of creatinine production is dependent Peritoneal dialysis. Hyperosmolar dialysate
on skeletal muscle mass. This in turn is solution is infused into the peritoneal cavity.
influenced by age, sex and race, amongst other ‘Filtration’ is achieved by using the peritoneum as
factors. Numerous algorithms exist to try to a semipermeable membrane. Water is
compensate for these factors; for example, the reabsorbed by making use of the osmolar
Cockcroft–Gault formula compensates for age, gradient across the peritoneum. Diffusion along
concentration gradients across the peritoneum
sex and weight.
allows clearance of toxic substances and
– Creatinine is actively secreted into the PCT, correction of electrolyte abnormalities.
accounting for 10–20% of excreted creatinine. Intermittent haemodialysis and continuous
This results in a slight overestimation of haemofiltration. Whilst conceptually simple,
creatinine clearance and therefore an these methods are inherently complex, involving
overestimation of GFR. Whilst this error is extracorporeal circuits and an artificial
tolerable in normal patients, in those with semipermeable membrane. ‘Filtration’ occurs
advanced renal impairment, the error becomes within an artificial ‘kidney’, a cellulose or
proportionally much larger: filtration reduces synthetic semipermeable membrane. Like the
with disease progression, but secretory native kidney, this membrane selectively ‘sieves’
the blood, allowing small molecules (H2O,
mechanisms are left intact.
electrolytes and waste products) to pass through,
– In clinical practice, it is not practical to collect but retaining cells and large proteins in the
24‑h urine samples to perform a formal blood. Depending on the type of RRT, simple
creatinine clearance calculation. However, by diffusion, convection or a combination of the two
measuring plasma creatinine alone, GFR may may be utilised. Reabsorption is achieved by
fall by as much as 50% (from 180 to 90 L/day) returning electrolyte-rich, pH-balanced fluid to
without being detected. the blood.
316
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:13:07, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.071
Chapter 68: Renal Filtration and Reabsorption
317
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:13:07, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.071
Section 6 Kidney and Body Fluids
69 Electrolyte Balance
318
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:15:05, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.072
Chapter 69: Renal Regulation of Water and Electrolyte Balance
319
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:15:05, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.072
Section 6: Kidney and Body Fluids
320
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:15:05, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.072
Chapter 69: Renal Regulation of Water and Electrolyte Balance
Distal convoluted
tubule
Collecting duct
Aquaporin 2
RENAL CORTEX
RENAL MEDULLA
H 2O H 2O H 2O
Area of high osmolarity
H 2O H 2O H 2O
H 2O H2O H 2O
H 2O H 2O H 2O
ions via secondary active transport involving As water leaves, the remaining filtrate becomes
luminal Na+/K+/2Cl‾ co-transporters powered by more concentrated; that is, the osmolarity
secondary active transport from the basolateral increases (3).
Na+/K+-ATPase. Filtrate moves along the LOH, until it reaches the
Figure 69.2 summarises alterations in the renal thin ascending limb (4). Here, ions move out of
filtrate as it passes along the LOH: the tubule into the interstitium down a
concentration gradient. Ions continue to move
In the PCT, water is reabsorbed in conjunction into the interstitium in the thick ascending limb,
with ions, amino acids and glucose. The but by secondary active transport (5).
osmolarity of the fluid entering the descending
This countercurrent multiplier mechanism results
limb of the LOH is therefore roughly the same as
in a medullary interstitial osmolar gradient, with
plasma osmolarity; that is, 300 mOsmol/L (1).
the tip of the LOH having the highest osmolarity
When the filtrate reaches the thick ascending limb (1200 mOsmol/L) (6).
of the LOH, the Na+/K+/2Cl‾ co-transporter
moves Na+, K+ and Cl‾ from the filtrate to the As the LOH is highly metabolically active, it requires
medullary interstitium (2). As the ascending limbs a good blood supply. However, if blood vessels were
are impermeable to water: to simply pass through the renal medulla, they would
carry solutes away, washing away the osmotic gradi-
– The filtrate entering the DCT becomes hypo- ent (Figure 69.3a). To avoid this problem, the LOH
osmolar. has a specialised blood supply. The vasa recta – arter-
– The renal medullary interstitium becomes iolar branches of the efferent arterioles – follow the
hyper-osmolar. LOH deep into the medulla, descending with the
Filtrate entering the descending limb of the LOH ascending limb of the LOH, turning a hairpin bend
now passes by the hyper-osmolar medullary and ascending with the descending limb to form a
interstitium. Because the walls of the descending ‘countercurrent’ flow of blood. The hairpin design of
limb are water permeable, water moves down its the vasa recta is important in the maintenance of the
osmotic gradient into the medullary interstitium. medullary osmolar gradient (Figure 69.3b):
321
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:15:05, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.072
Section 6: Kidney and Body Fluids
PCT DCT
(1) (2) (3)
Na+ H 2O
300 300 300 300 400 200 350 350 200
K+ H 2O
300 300 300 300 400 200 350 350 200
Cl‾ H 2O
300 300 300 300 400 200 350 350 200
Na+ H 2O
300 300 300 300 400 200 350 350 200
K+ H 2O
300 300 300 300 400 200 350 350 200
Cl‾ H 2O
300 300 300 300 400 200 350 350 200
PCT DCT
(4) (5) (6)
1200 1200
1200
(a) If blood vessels simply passed through the (b) ‘Hairpin loop’ arrangement of the vasa recta:
loop of Henle: No ‘washout’ of
‘Hypothetical’ osmotic gradient
blood vessel
300
100
300 300
300
100 100
400 200 400 200
600
600
300
600
1000
Figure 69.3 Schematic illustrating how the vasa recta avoids disturbing the medullary osmolar gradient.
322
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:15:05, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.072
Chapter 69: Renal Regulation of Water and Electrolyte Balance
As the vasa recta descend in the medulla, the Urea also makes a significant contribution to the
electrolyte content and osmolarity of their blood high osmolarity of the medullary interstitium. Urea is
equilibrates with that of the surrounding produced by the liver as the end product of nitrogen
interstitium: ions diffuse into the vessel and water metabolism. It is freely filtered at the glomerulus and
diffuses out. then reabsorbed along the tubule. The result is that
As the vasa recta ascend, their contents equilibrate around 40% of the filtered urea is cleared into the
with the surrounding interstitium: water diffuses urine. The remaining urea provides around half of the
into the vessel and solutes diffuse out. osmolarity of the medullary interstitium.
Blood flows sufficiently slowly in the vasa
recta to allow near-complete equilibration
between the blood and the medullary
How does the kidney regulate Na+
interstitium. The osmolarity of the blood excretion?
leaving the vasa recta is near normal (around As discussed in Chapter 68, the kidney filters 180 L of
320 mOsmol/L). Therefore, the interstitial Na+-containing plasma per day, significantly more than
medullary osmolar gradient is minimally the total volume of body water. Typical urine output is
disturbed. in the region of 1.5 L/day. Clearly, most of the Na+ –
and therefore water – is reabsorbed by the kidney.
Clinical relevance: clinical disorders of osmolarity Na+ excretion is controlled in two ways:
The hypothalamus is crucial to the regulation of Changes in glomerular filtration rate (GFR).
plasma osmolarity through its roles in sensing When plasma volume is high, GFR is increased.
plasma osmolarity and triggering the secretion of More Na+ is then filtered at the glomerulus and
ADH. The hypothalamus may malfunction; for delivered to the nephron, resulting in more Na+
example, following a head injury. Two important being excreted in the urine. Perhaps more
clinical syndromes are: importantly, when plasma volume is low, Na+ is
Central diabetes insipidus (DI), in which the conserved through a reduced GFR.
posterior lobe of the pituitary gland fails to +
Changes in Na reabsorption. This is the main
secrete adequate ADH. Without ADH, water mechanism in operation during euvolaemia. Na+ is
cannot be reabsorbed at the collecting ducts.
reabsorbed in two phases in the kidney (Figure 69.4):
Clinically, DI is characterised by the production of
large amounts of excessively dilute urine and – Bulk reabsorption in the PCT and LOH.
signs of hypovolaemia. Biochemically, excessive Around 60% of filtered Na+ is reabsorbed in
water excretion leads to hypernatraemia, high the PCT, driven by the basolateral Na+/K+-
plasma osmolarity and an inappropriately low ATPase pump. This ion pump keeps the Na+
urine osmolarity. Note: nephrogenic DI, which concentration within the tubular cells low. Na+
may be caused by lithium therapy, has identical is reabsorbed from the tubular lumen by a
clinical and biochemical features, but a different variety of means: passive diffusion, co-
mechanism: the collecting ducts fail to respond
transport with molecules such as glucose and
to circulating ADH.
counter-transport with H+ (see Chapter 70).
Syndrome of inappropriate ADH secretion.
Circulating ADH is in excess of that required to Approximately 30% of filtered Na+ is
maintain normal plasma osmolarity. Excess ADH reabsorbed in the LOH through the Na+/K+/
may be secreted by the posterior lobe of the 2Cl‾ co-transporter (see above).
pituitary gland or by an ectopic source, such as a – Reabsorption in the DCT and collecting duct.
small-cell lung carcinoma. Excessive ADH Around 90% of the filtered Na+ has been
secretion results in additional water reabsorption reabsorbed by the time the filtrate reaches the
at the collecting duct. The clinical features are DCT. The intracellular Na+ concentration in
those of hyponatraemia (headache, nausea, the DCT and collecting duct cells is kept low as
confusion, seizures, coma), sometimes associated
a result of the basolateral Na+/K+-ATPase. Na+
with fluid overload. Biochemically, in addition to
hyponatraemia and low plasma osmolarity, urine
transfer across the tubular cell luminal
osmolarity is inappropriately high. membrane is controlled by aldosterone
through two mechanisms:
323
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:15:05, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.072
Section 6: Kidney and Body Fluids
Site of action of
thiazide diuretics
Na+ filtered
Intercalated cells
Site of action of
loop diuretics
30% Na+
reabsorbed
in LOH
Figure 69.4 Na+ handling by the kidney and the effect of diuretics.
▪ In the DCT, 5% of filtered Na+ is thirst is stimulated and three ‘hypovolaemia hor-
reabsorbed through an Na+/Cl‾ mones’ are released: noradrenaline, ADH and renin.
cotransporter in the luminal membrane. Noradrenaline causes both afferent and efferent
Aldosterone controls the number of arterioles to vasoconstrict, reducing renal blood
transmembrane co-transporters. flow and therefore GFR. Na+ excretion is
▪ In the late DCT and collecting duct, consequently reduced.
aldosterone acts on two cell types to Renin is released in response to both sympathetic
reabsorb Na+ and water in exchange for the stimulation by the medulla oblongata and the
secretion of K+ (principal cells) or H+ reduced Na+ content of the tubular filtrate, as
(intercalated cells). detected by the juxtaglomerular apparatus. Renin
leads to the production of both angiotensin II and
Summarise the physiological response aldosterone (see Chapter 68):
to low plasma volume – Angiotensin II acts at the PCT, where it
increases Na+ reabsorption, and at the afferent
Low-pressure mechanoreceptors monitor the degree
and efferent arterioles, where it causes
of stretch within the cardiac atria and pulmonary
vasoconstriction, thus reducing GFR.
vessels. Hypovolaemia results in reduced venous
– Aldosterone acts on the DCT and collecting
return and therefore reduced stimulation of the right
ducts, where it increases the reabsorption of
atrial stretch receptors. Secretion of atrial natriuretic
Na+ and water and the secretion of K+ and H+.
peptide (ANP) and brain natriuretic peptide (BNP) is
reduced. Afferent nerve impulses relay information to ADH increases the permeability of the collecting
the medulla oblongata and hypothalamus. In turn, duct to water, allowing the renal medullary
324
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:15:05, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.072
Chapter 69: Renal Regulation of Water and Electrolyte Balance
325
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:15:05, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.072
Section 6: Kidney and Body Fluids
pressure is reduced. This changes Starling’s forces at the activity of the basolateral Na+/K+-ATPase,
the glomerular capillary, favouring an increase in fil- thus increasing cellular K+ uptake, which keeps
tration fraction. the plasma K+ concentration constant.
In addition, ANP and BNP are released from the Movement between intra- and extra-cellular
cardiac atria and ventricles, respectively, in response spaces, through a number of mechanisms:
to stretch. ANP and BNP have a number of effects on – Insulin promotes intracellular movement of
the kidney, all of which increase Na+ excretion: 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
+
Inhibition of Na channels in the DCT and part, why hypokalaemia is commonly
collecting ducts, which directly inhibits Na+ associated with the acute stress response and
reabsorption. with the use of salbutamol.
Inhibition of both renin secretion by the granular – Extracellular pH. In metabolic acidosis, much
cells and aldosterone secretion by the adrenal of the additional H+ is buffered intracellularly.
glands. Intracellular acidosis impairs the basolateral
Na+/K+-ATPase, leading to extracellular leak
How is plasma potassium concentration of K+ ions, and thus hyperkalaemia (see
regulated? Chapter 70). In metabolic alkalosis, the
opposite occurs.
K+ is predominantly an intracellular ion: +
K excretion by the kidney (Figure 69.5). K is
+
+
98% of total body K is found in the ICF, where freely filtered at the glomerulus. Almost all of the
+
the typical K concentration is 150 mmol/L. As filtered K+ is reabsorbed in the PCT (through
the major intracellular ion, K+ is responsible for diffusion) and LOH (through the Na+/K+/2Cl‾ co-
intracellular osmotic pressure. transporter), irrespective of whether body K+ is high
+
2% of total body K is found in the ECF, where or low. Instead, plasma K+ is regulated through K+
+
normal K concentration is 3.5–5.5 mmol/L. secretion in the DCT and collecting ducts:
Maintaining the large K+ concentration difference – When plasma K+ concentration is low, the
between the ICF and ECF is very important, as it is kidney tries to conserve as much K+ as
responsible for the resting membrane potential (RMP; possible. Additional K+ is reabsorbed in the
see Chapter 51). 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
its mechanisms take time. Instead, rapid changes in acts at the DCT and collecting ducts, where it
plasma K+ concentration are achieved by the move- reabsorbs Na+ and water whilst secreting K+
ment of K+ between the ICF and ECF. and H+.
+
K intake. A typical Western diet contains
70 mmol of K+ per day (10 times more than is
required), nearly all of which is absorbed in the Clinical relevance: management of hyperkalaemia
gut. One might therefore expect a surge in plasma
Significant hyperkalaemia (plasma K+ concentration
K+ concentration following a meal. This is avoided
>6 mmol/L) affects cells’ RMP; membrane depolar-
through an important effect of insulin (released in isation may cause life-threatening cardiac
response to ingested glucose), which stimulates
326
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:15:05, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.072
Chapter 69: Renal Regulation of Water and Electrolyte Balance
K+ filtered
60% K+ reabsorbed
30% K+
reabsorbed
Figure 69.5 Renal K+ handling in states of high and low total body K+.
arrhythmias such as ventricular fibrillation. Classical A sodium bicarbonate infusion may be useful
electrocardiogram (ECG) changes include tall, tented in the context of hyperkalaemia and metabolic
T-waves and, later, widened QRS complexes. Hyper- acidosis: by increasing the pH of ECF,
kalaemia is frequently the result of acute renal failure sequestered intracellular H+ moves back into the
or severe metabolic acidosis, but can also be caused ECF as K+ moves intracellularly.
by drugs (e.g. spironolactone and suxamethonium),
The latter three management options merely move K+
Addison’s disease and cellular breakdown (haemoly-
between body compartments; they do not alter total
sis and rhabdomyolysis).
body K+. In the longer term, K+ may need to be
The clinical management of hyperkalaemia
removed from the body. This can be achieved using
involves, in part, intracellular movement of plasma
calcium resonium (an ion-exchange resin) or by renal
K+ through manipulation of the mechanisms
replacement therapy: haemodialysis or haemofiltration.
described above:
Ca2+ (e.g. 10 mL of 10% calcium chloride
solution) is given for cardioprotection; it stabilises
the RMP as Ca2+ ions bind to the outer surface of Clinical relevance: hypokalaemia
the membrane. This creates a local high density Like hyperkalaemia, significant hypokalaemia (K+ < 3
of positive charge, leading to a relatively more mmol/L) alters the RMP: hyperpolarisation makes the
negative intracellular voltage (see Chapter 51). membrane more difficult to depolarise. Patients with
An insulin/dextrose infusion reduces plasma K+ hypokalaemia may therefore develop muscular
concentration by increasing cellular K+ uptake. weakness and myalgia; severe hypokalaemia may
Salbutamol promotes intracellular movement of cause flaccid paralysis and respiratory failure. The
K+ through its β2-agonist activity. classical ECG changes of hypokalaemia are flattened
327
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:15:05, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.072
Section 6: Kidney and Body Fluids
or inverted T-waves, increased PR interval, U-waves required for the Na+/K+-ATPase to function normally.
and ST-segment depression. The differential diagno- Therefore, both electrolyte disturbances require
sis of hypokalaemia is wide, including low dietary treatment.
intake, diarrhoea, alkalosis and Conn’s syndrome, an
aldosterone-secreting tumour. As anaesthetists, we
tend to become involved with severe hypokalaemia Further reading
either because patients have developed severe M. A. Glasby, C. L.-H. Huang. Applied Physiology for
weakness or because they need central venous Surgery and Critical Care. Oxford, Butterworth-
replacement of K+. Heinneman, 1995.
K+ may be replaced enterally or intravenously;
D. J. McLean, A. D. Shaw. Intravenous fluids: effects on
rapid replacement by the intravenous route risks
renal outcomes. Br J Anaesth 2018; 120(2): 397–402.
ventricular tachyarrhythmias. A safe rate of periph-
eral venous K+ replacement is 10 mmol/h, whilst B. Taylor, D. J. Chambers, N. Patel, et al. Hypokalaemia: the
central venous K+ may be administered at up to 20 dangers of a sweet tooth. J Intensive Care Soc 2012; 13(4):
mmol/h, with appropriate monitoring. It is worth 342–5.
mentioning that half of patients with significant M. Doherty, D. J. Buggy. Intraoperative fluids: how much is
hypokalaemia also have significant hypomagnesae- too much? Br J Anaesth 2012; 109(1): 69–79.
mia (the mechanisms of loss of both cations are J. P. Kokko, F. C. Rector Jr. Countercurrent multiplication
similar). Hypokalaemia is often resistant to treatment system without active transport in inner medulla. Kidney
in the presence of hypomagnesaemia, as Mg2+ is Int 1972; 2(4): 214–23.
328
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:15:05, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.072
Section 6 Kidney and Body Fluids
Acid–Base Physiology
Chapter
70
What is an acid?
The word ‘acid’ is derived from the Latin acidus, Key equation: pH
meaning sour. Early chemists defined an acid as a
chemical substance whose aqueous solution tastes pH ¼ log 10 ½Hþ
sour, changes the colour of litmus paper to red and
where log10 is the logarithm (base 10) and [H+] is the
reacts with certain metals to produce the flammable
molar concentration of H+ ions.
gas, hydrogen. Likewise, a base is a chemical sub-
Note: pH is dimensionless; that is, it has no units.
stance whose aqueous solution tastes bitter, changes
the colour of litmus paper to blue and reacts with
Because the pH scale is logarithmic, a small change
acids to produce a salt.
in pH represents a much larger change in [H+]:
The ‘normal’ body pH of 7.4 is equivalent to an
What are the Brønsted–Lowry H+ concentration of 40 nmol/L.
definitions of an acid and base? Acidaemia is defined as an arterial pH below 7.35.
Brønsted and Lowry independently recognised that Alkalaemia is defined as an arterial pH above 7.45.
acid–base reactions in aqueous solution involve the A small reduction in pH from 7.4 to 7.0 represents
transfer of an H+ from one molecule to another, and more than a doubling of the H+ concentration,
they suggested the following definitions: from 40 to 100 nmol/L.
An acid is a proton donor.
A base is a proton acceptor. What is Ka?
The generic reaction between an acid and base is: Ka is the ionisation constant for H+ from its acid in
the equilibrium:
HA þ B Ð BHþ þ A
k1
where HA is a Brønsted–Lowry acid (as it donates
HA Ð Hþ þ A
H+), B is a Brønsted–Lowry base (as it accepts H+),
k2
BH+ is referred to as the conjugate acid and A‾ is
referred to as the conjugate base. where k1 is the rate constant for the forward reaction
Acids may be classified as being either strong and k2 is the rate constant for the backward reaction.
or weak: When the rate of the forward reaction equals the
A strong acid is one that completely dissociates in rate of the backward reaction, the reaction is said to
solution. be at equilibrium. The equilibrium constant Ka can
A weak acid is one that only partially dissociates in then be written as:
solution. k1 ½Hþ ½A
Ka ¼ ¼
k2 ½HA
What is pH?
pH is a measure of the acidity of an aqueous solution. What is pKa?
pH is the negative decadic logarithm of the H+ ion pKa is defined as the negative decadic logarithm of the
concentration: ionisation constant (Ka) of an acid. It equals the pH
329
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:17:09, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.073
Section 6: Kidney and Body Fluids
330
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:17:09, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.073
Chapter 70: Acid–Base Physiology
331
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:17:09, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.073
Section 6: Kidney and Body Fluids
the most common cations and anions are measured encountered than alkalosis, these mechanisms are
by the blood gas machine, giving the formula: primarily concerned with limiting the harmful
effects of acidosis:
Buffering. A buffer is a substance that responds
Key equation: anion gap
rapidly to oppose the change in pH when an acid
Anion gap ¼ sum of cation concentrations or base is added to the plasma, according to Le
sum of anion concentrations Chatelier’s principle. Buffers are salts of weak
acids or bases, and they work by releasing or
¼ ð½Naþ þ ½Kþ Þ ½Cl þ HCO
3
absorbing H+ in response to the addition of a
stronger base or acid, respectively. Buffer systems
The normal anion gap is 10–20 mEq/L, which can be classified as:
represents unmeasured anions such as sulphates, – Extracellular buffers:
phosphates and plasma proteins. The anion gap is
used clinically to identify the cause of a metabolic ▪ The H2CO3/ HCO3‾ buffer system is the
acidosis. A raised anion-gap metabolic acidosis may most important extracellular buffer owing
be the result of: to the abundance of HCO3‾ in plasma and
to the fact that CO2 (in equilibrium with
Increased endogenous anions; for example:
H2CO3) may be eliminated by the lungs
– Lactic acid, produced during anaerobic (see below). The pKa of the H2CO3/HCO3‾
metabolism; system is 6.1; therefore, at pH 7.4, HCO3‾
– Fixed acids, which accumulate in acute kidney is a good buffer of acids but not alkalis.
injury; ▪ Haemoglobin (Hb). The histidine side
– Ketoacids, whose production is increased by chains of Hb act as a buffer by binding H+
diabetic ketoacidosis. ions. Deoxyhaemoglobin is better able to
Increased exogenous anions; for example: bind H+ than oxyhaemoglobin (see the
Haldane effect, Chapter 9).
– Salicylate;
– Ethanol; – Intracellular buffers:
– Methanol; ▪ The phosphate buffer system (H2PO4‾/
– Ethylene glycol. HPO42‾). The concentration of phosphate
A normal anion-gap metabolic acidosis, which occurs is low in extracellular fluid, making it a less
much less commonly, may be caused by chronic important buffer. Phosphate is, however,
gastrointestinal HCO3‾ loss or renal tubular acidosis. an important buffer of both intracellular
Albumin is the major unmeasured anion. Hypo- fluid and urine, where the phosphate
albuminaemia, which is common in critically ill concentration is higher.
patients, is therefore associated with a reduced anion ▪ Proteins. Amino acid side chains can
gap. It is important to note that a metabolic acidosis buffer both acids (amine side chains) and
may be missed in a hypoalbuminaemic critical care alkalis (carboxyl side chains). Whilst
patient, as the anion gap may be normal. plasma proteins play only a minor role in
buffering, intracellular proteins are present
How is body pH regulated? at higher concentrations, making them
important intracellular buffers.
pH homeostasis is very important, as the effects of
acidaemia and alkalaemia on the body are poten- Respiratory regulation. The respiratory system
tially very serious. Body pH is normally1 main- responds within minutes to correct pH
tained between 7.35 and 7.45 through three disturbances. The PaCO2 is inversely related to V̇ A
mechanisms. As acidosis is much more frequently (see Chapter 11). In turn, pH is related to PaCO2.
Therefore:
1
In pregnancy, a mild physiological alkalosis is expected
– An increase in V̇ A results in an increase in
(see Chapter 82). blood pH.
332
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:17:09, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.073
Chapter 70: Acid–Base Physiology
HCO3
Filtered HCO3
Na+/H+-countertransporter
Basolateral Na+/K+-ATPase
Figure 70.1 Mechanism of HCO3‾ reabsorption in the proximal convoluted tubule (PCT).
333
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:17:09, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.073
Section 6: Kidney and Body Fluids
▪ In the PCT cell, the reverse reaction occurs: Overall, one H+ ion is excreted into the renal
CA catalyses the reaction between CO2 and filtrate per molecule of glutamine metabolised.
water, producing H+ and HCO3‾ (4). H+ is The capacity of this system to excrete H+ is
secreted back into the tubular lumen very high, even when the tubular filtrate is
through the Na+/H+-antiporter and HCO3‾ already very acidic.
moves into the blood through a sodium
bicarbonate co-transporter (5). Overall, What are the main systemic
HCO3‾ is reabsorbed from the renal
filtrate. consequences of acid–base
In the distal convoluted tubule and collecting disturbance?
ducts, the type A intercalated cells and At a molecular level, pH affects:
principal cells control the reabsorption of the Enzyme function – outside a narrow range of pH,
remaining tubular HCO3‾. The mechanism for enzymes may become denatured and their
HCO3‾ reabsorption is similar to the PCT, function impaired.
relying on H+ secretion into the tubular The ionisation of molecules – this may alter their
lumen. Under normal conditions, nearly all of ability to cross cell membranes or affect their
the filtered HCO3‾ is reabsorbed. Alkalaemia shape and function.
leads to less HCO3‾ being reabsorbed; more Ion channel function – a pH disturbance may
HCO3‾ appears in the urine, resulting in a alter the permeability of neuronal membrane ion
higher urinary pH. channels, which in turn affects the resting
– Ammoniagenesis. In response to acidosis, the membrane potential (RMP) and action potential.
liver shifts from turning ammonium (NH4+)
The clinical effects of acid–base disturbance can be
ions and HCO3‾ into urea to producing
considered system by system:
glutamine. Glutamine travels in the blood to
the cells of the PCT, where NH4+ and HCO3‾ Cardiovascular system. It is difficult to separate the
are reproduced. NH4+ is secreted into the effects of acidosis from the effects of hypercapnoea
tubular lumen in exchange for Na+ (again, on the heart and vasculature. In general:
the process is driven by the basolateral – Sympathetic response. Hypercapnoea
Na+/K+-ATPase) and HCO3‾ is moved into stimulates catecholaminergic release from the
the blood in exchange for Cl‾. This generation adrenal medulla.
of HCO3‾ is beneficial in the correction of – Effect on cardiac output. Acidosis causes direct
the acidosis, but the kidney must now excrete myocardial depression, manifesting as a
the NH4+: decrease in stroke volume. However, in mild
acidosis, these effects are offset by
▪ In the thick ascending limb of the LOH,
catecholaminergic release from the adrenal
NH4+ is reabsorbed via the Na+/K+/2Cl‾
medulla. Below pH 7.0, the negative inotropy
transporter (NH4+ passes through the
associated with acidosis outweighs the
K+ site).
positively inotropic effects of adrenaline. In
▪ In the medullary interstitium, NH4+ loses addition, parasympathetic outflow increases,
an H+ to become NH3. which counteracts the effects of
▪ The membrane of the medullary collecting catecholamines on heart rate, resulting in
duct is permeable to NH3; therefore, NH3 bradycardia. As a result of these two effects,
diffuses into the collecting duct. cardiac output falls.
▪ In continued acidosis, H+ ions are present – Cardiac arrhythmias, including ventricular
in high concentration within the tubular ectopic beats and atrial fibrillation, are
fluid and thus bind to NH3 to reform common in acidosis, whether metabolic or
NH4+. The collecting duct membrane is respiratory in origin. This is a consequence of
impermeable to NH4+ and thus it is increased circulating adrenaline and
excreted. electrolyte disturbance (see below).
334
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:17:09, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.073
Chapter 70: Acid–Base Physiology
– Vascular tone. The effects of acidosis and decrease in plasma pH. It was previously thought
hypercapnoea on the vasculature is complex: that H+ underwent intracellular buffering through
whilst acidosis per se causes arteriolar exchange with intracellular K+, but it is now
vasoconstriction, hypercapnoea causes many thought that acidosis impairs the Na+/K+-ATPase,
vascular beds to vasodilate (thus accounting resulting in net leak of K+ into the extracellular
for the bounding pulse found in fluid. Despite the high plasma K+ concentration,
hypercapnoeic patients), such as in skin and total body K+ stores are frequently depleted. Thus,
the cerebral arterioles. the treatment of acidosis may result in
Alkalosis increases myocardial contractility hypokalaemia if K+ is not simultaneously
by increasing the responsiveness of the replaced.
myocardium to circulating catecholamines; Plasma calcium occurs in two forms:
therefore, myocardial O2 demand increases. biologically active, ionised Ca2+ and protein-
However, alkalosis also reduces myocardial bound, unionised Ca2+ (see Chapter 81). In
O2 delivery through vasoconstriction of the acidosis, H+ ions compete for the same binding
coronary circulation and by shifting the sites as Ca2+ on albumin, displacing Ca2+ and thus
oxyhaemoglobin dissociation curve to the left, increasing the fraction of ionised Ca2+.
thus impairing offloading of O2 to the Conversely, alkalosis reduces the fraction of
myocardium. ionised Ca2+. As ionised Ca2+ is the biologically
Respiratory system. As discussed above, the main active form, alkalosis results in an effective
effect of acidosis on the respiratory system is an hypocalcaemia. Hypocalcaemia increases the Na+
increase in alveolar ventilation (V̇ A). The permeability of the neuronal cell membrane,
respiratory centre in the medulla oblongata is making the RMP more unstable. Paraesthesias
stimulated by the carotid bodies in response to (spontaneous depolarisation of sensory receptors)
decreased plasma pH and by the central and tetany (spontaneous depolarisation of motor
chemoreceptors in response to hypercapnoea (see neurons) may therefore occur.
+
Chapter 22). Central nervous system (CNS). Whilst H cannot
Additional effects of acid–base disturbance on cross the blood–brain barrier owing to its charge,
the respiratory system are: the high lipid solubility of CO2 allows it to diffuse
into the brain. As discussed in Chapter 49,
– The oxyhaemoglobin dissociation curve is hypercapnoea causes vasodilatation of the cerebral
shifted to the right by acidosis and to the left vasculature. Cerebral blood flow (CBF) is
by alkalosis (see Chapter 8). therefore directly proportional to PaCO2, between
– Airway resistance. The effect of acidosis on the limits of 3.5 and 8.0 kPa. Patients with
airway calibre is complex. Hypercapnoea respiratory acidosis may therefore experience
causes bronchodilatation through a headaches (due to the increased CBF),
direct effect of CO2 on the bronchial confusion and impaired consciousness, extensor
smooth muscle. But hypercapnoea also plantar responses and asterixis (CO2 flapping
triggers an increase in parasympathetic tremor).
outflow to the bronchi, indirectly causing Respiratory alkalosis may precipitate seizures.
bronchoconstriction. In otherwise-healthy Hypocapnoea induces an alkalosis within the
hypercapnoeic patients, indirect CNS. In a similar way to the peripheral nerves, the
bronchoconstriction outweighs direct RMP of the brain’s neurons becomes more
bronchodilatation, resulting in an increase unstable, which results in neuronal excitation and
in airway resistance and consequently an spontaneous depolarisation.
increase in the work of breathing.
Bones. Chronic metabolic acidosis leads to bone
Electrolyte changes. Acidosis is commonly decalcification as bone phosphate is mobilised to
associated with hyperkalaemia, which may buffer H+ ions. In chronic renal failure, this
precipitate cardiac arrhythmias. Plasma K+ contributes to the development of renal
increases by 0.6 mmol/L for every 0.1‑unit osteodystrophy.
335
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:17:09, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.073
Section 6: Kidney and Body Fluids
336
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:17:09, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.073
Chapter 70: Acid–Base Physiology
337
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:17:09, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.073
Section 6 Kidney and Body Fluids
Micturition
Chapter
71
How is urine stored and excreted from appropriate time. Biomechanically, urine will not leak
from the bladder so long as the outlet resistance
the body? exceeds intravesical pressure. Overall control of urin-
The bladder is a hollow, muscular organ situated in ary continence is directed by two pontine centres: the
the pelvis. Its role is the storage and voiding of urine. storage centre and the micturition centre.
Urine is produced in the kidneys, enters the bladder During the storage phase of micturition, the pon-
through the ureters and exits via the urethra. tine storage centre increases sympathetic nervous
Important aspects of lower urinary tract anatomy system outflow, causing:
are: Relaxation of the detrusor muscle through
Urothelium lines the inner wall of the ureters, stimulation of β3-adrenoreceptors in the fundus
bladder and urethra, providing a highly impermeable and body of the bladder;
barrier to ion, solute and water flux. This is the same Tonic contraction of the IUS through stimulation
type of epithelium that lines the renal collecting duct of α1-adrenergic receptors at the bladder neck.
and renal pelvis (see Chapter 67). The coordinated relaxation of the bladder and con-
The detrusor muscle is the smooth muscle of the traction of the IUS allows the bladder to fill without
bladder wall and is arranged in spiral, longitudinal leakage of urine.
and circular bundles. The detrusor muscle exhibits
an unusually high compliance – as the bladder
fills, the detrusor muscle relaxes and stretches,
What happens to intravesical pressure
resulting in only a small increase in intravesical as the bladder fills?
pressure. This is known as viscoelasticity. The As the bladder fills and its radius increases, bladder wall
detrusor is innervated by both the sympathetic tension increases due to the law of LaPlace (see Chap-
(via the hypogastric nerve) and parasympathetic ter 20). Bladder wall compliance is relatively high at
(via the pelvic splanchnic nerves) nervous systems low urine volumes; above 400 mL capacity, the compli-
and is therefore under involuntary control. ance of the bladder wall decreases substantially. When
The internal urethral sphincter (IUS) surrounds intravesical pressure rises above 10 cmH2O (around
the urethra at its junction with the bladder. The IUS 200 mL stored urine):
is an extension of the detrusor smooth muscle and is Stretch receptors in the bladder wall are
under control of the sympathetic nervous system. activated. Afferent signals are relayed to the
The external urethral sphincter (EUS) is a lumbar spinal cord via the hypogastric nerve,
portion of striated muscle that surrounds the where two reflexes are triggered:
urethra distal to the internal sphincter (females)
– The micturition reflex triggers firing of
or distal to the prostate (males). Because the EUS
parasympathetic cholinergic neurons
consists of striated muscle, it is under voluntary
(originating from the S2–S4 segments of the
control via the pudendal nerve.
spinal cord), resulting in a transient
What is urinary continence? How is it contraction of the detrusor muscle. The
micturition reflex is self-regenerative; that is,
achieved? detrusor contraction results in further bladder
Urinary continence is the ability to store urine with- wall stretch receptor activation, which triggers
out leakage until the bladder can be emptied at an further detrusor contraction.
338
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:20:55, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.074
Chapter 71: Micturition
Sensation of bladder fullness: the afferent signals Acute phase of spinal shock: in the period of
produced by the stretch receptors are interpreted weeks immediately following spinal cord injury,
there is flaccid paralysis and loss of reflexes
by higher brain centres as a sensation of bladder
below the level of the injury. The bladder loses
fullness. As the bladder fills, the micturition reflex both its sympathetic and parasympathetic
occurs more frequently and the detrusor contracts inputs – the bladder becomes paralysed (atonic)
more powerfully: and conscious awareness of a full bladder is lost.
– The first desire to void occurs when the In contrast, the activity of the EUS is markedly
bladder contains around 200 mL of urine. increased. The result is acute urinary retention,
with ‘overflow’ urinary incontinence occurring
– The bladder feels ‘uncomfortably full’ at
when the bladder is very full (high intravesical
around 350–400 mL.
pressure overcoming bladder outlet resistance).
– When the bladder reaches 700 mL capacity, A urinary catheter is used for bladder
pain ensues. management to prevent acute kidney injury,
Involuntary micturition: once the micturition which historically was the leading cause of death
reflex is powerful enough, it causes reflex opening following acute spinal cord injury.
Hyperreflexia and spasticity: following the
of the EUS (unless higher centres inhibit this) and
period of spinal shock, the patient develops
micturition (voiding) occurs. This is the situation abnormally strong reflexes and spasticity. The
for babies and infants, before full maturation of detrusor is commonly hyperreflexic, developing
the pontine micturition centre has developed. powerful reflex contractions in response to
Voluntary micturition: bladder wall stretch. The result is that the bladder
– If voiding is not desired or is inconvenient, the fills and empties spontaneously, a condition
known as automatic bladder. Bladder emptying is
frontal cortex instructs the pontine control
often incomplete due to non-sustained detrusor
centres to increase sympathetic outflow and
contractions and reflex contraction of the EUS
decrease parasympathetic outflow, which (called detrusor–sphincter dyssynergia), which
relaxes the detrusor and contracts the IUS, increases the risk of urinary tract infections.
preventing leakage of urine. As the micturition
reflex becomes more powerful, the pontine
control centres also initiate tonic contraction
of the EUS to counteract the increasing Clinical relevance: post-operative urinary
intravesical pressure. Higher centres can also retention
prevent voiding when the micturition reflex is Post-operative urinary retention (POUR) is the inabil-
becoming more powerful by voluntary tonic ity to void urine following surgery in the presence of
contraction of the EUS. a full bladder, complicating approximately 15% of
– When it is convenient to urinate, abdominal surgical episodes. While there is no standard defin-
muscles contract to increase the pressure ition of POUR, it usually includes:
within the bladder, thus stretching the bladder Clinical criteria, such as the sensation of a full
walls. The pontine micturition centre bladder, suprapubic pain and palpable bladder;
simultaneously triggers a micturition reflex Evidence of a full bladder, such as an
and inhibits the EUS so that urination can ultrasound scan estimating a bladder volume of
occur. >500 mL or a post-catheterisation residual
volume of >500 mL urine.
Clinical relevance: spinal cord injury and Risk factors for POUR include:
neurogenic bladder
Patient factors: previous history of lower urinary
Sympathetic and parasympathetic nervous system tract symptoms.
input to the bladder and IUS are essential for urinary Type of surgery: anorectal and inguinal hernia
continence and complete bladder emptying. In the surgery.
339
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:20:55, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.074
Section 6: Kidney and Body Fluids
Intraoperative intravenous fluid exceeding Catheterisation, usually when the bladder volume
750 mL increases the risk of POUR. has exceeded 600 mL, is the standard treatment for
Neuraxial blockade: spinal anaesthesia, POUR in order to alleviate patient discomfort and to
particularly if combined with intrathecal opioids, prevent complications (e.g. kidney injury and urinary
significantly increases the risk of POUR compared tract infection).
to general anaesthesia. This is hardly surprising –
during spinal anaesthesia, signals from the
autonomic nervous system to the detrusor are Further reading
abolished, resulting in a situation similar to that C. Tai, J. R. Roppolo, W. C. de Groat. Spinal reflex control
following spinal cord injury. The risk of POUR is of micturition after spinal cord injury. Restor Neurol
reduced by using lower-dose or shorter-acting Neurosci 2006; 24(2): 69–78.
(e.g. prilocaine) intrathecal local anaesthetics.
G. Baldini, H. Bagry, A. Aprikian, F. Carli. Postoperative
Analgesia: opioid use increases the risk of POUR
urinary retention: anesthetic and perioperative
by 1.5 times.
considerations. Anaesthesiology 2009; 110(5): 1139–57.
340
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:20:55, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.074
Section 7 Blood and Immune System
Haemostasis
Chapter
72
What is haemostasis? (PCI2). The endothelium also produces the
enzyme adenosine diphosphatase, which degrades
‘Haemostasis’ is a collective term for the mechanisms ADP, an essential compound for platelet
that stop blood loss. Macroscopically, the most obvi- activation.
ous haemostatic mechanism is the conversion of
Anticoagulant effects result from two endothelial
liquid blood to a solid gel – a process called coagula-
membrane-bound proteins:
tion. The process of clot formation is known as
thrombosis. – Heparan sulphate, which has a similar
Haemostasis can be life-saving: when blood vessels structure to heparin, activates the plasma
have been damaged, it is important that haemostasis protein antithrombin III, which in turn
occurs rapidly to prevent excessive blood loss. How- inactivates thrombin (also known as factor IIa)
ever, it is equally important that the haemostatic and factor Xa.
response is controlled and localised to the area of – Thrombomodulin has two roles: it directly
vessel damage. Widespread coagulation could prevent binds thrombin, effectively removing
blood flow completely, damage red blood cells (RBCs) thrombin from the circulation. The thrombin–
through microangiopathic haemolytic anaemia or thrombomodulin complex also activates
lead to paradoxical bleeding due to depletion of protein C. Together with a cofactor (protein S),
clotting factors through disseminated intravascular activated protein C is a potent anticoagulant,
coagulation (DIC). Therefore, the mechanisms that inactivating factor Va and VIIIa.
promote and inhibit haemostasis are finely balanced. Fibrinolytic effects – endothelial cells also
The three main components involved in haemo- secrete the enzyme tissue plasminogen
stasis are: activator (t-PA). This potent enzyme cleaves
Platelets; the proenzyme plasminogen to form plasmin.
Endothelium; Plasmin degrades fibrin clots from the endothelial
Coagulation proteins. cell surface in a process called fibrinolysis
(see p. 348).
All three must be intact for haemostasis to be
effective.
Outline the steps involved in
How does the vascular endothelium haemostasis
prevent haemostasis? Clot formation has three key steps:
The endothelium is extremely important in the bal- Vasoconstriction;
ance between haemostasis and anti-haemostasis. Platelet aggregation;
Its normal function is to prevent haemostasis and Coagulation.
promote blood flow, but when damaged, it rapidly When a vessel is disrupted, platelets must aggregate
initiates a haemostatic response. The endothelium and plug the hole. To prevent the platelet plug being
prevents haemostasis by: washed away as it is being formed, the vessel first
Inhibition of platelet adhesion through the vasoconstricts, resulting in decreased blood flow –
secretion of nitric oxide (NO) and prostacyclin this also has the effect of minimising blood loss.
341
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 20:05:52, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.075
Section 7: Blood and Immune System
The plasma coagulation proteins then trigger a fibrin The key steps of platelet aggregation are:
mesh to form around the platelet plug, resulting in a Serotonin and thromboxane A2 are potent
stable clot. vasoconstrictors that reduce blood flow at the site
of injury.
How is haemostasis initiated? Platelets are attracted to the site of injury. Initially,
When a vessel is damaged, plasma becomes exposed platelets are activated by and bind to
to a number of substances: subendothelial collagen (via vWF); the exposed
von Willebrand factor (vWF). Endothelial cells collagen becomes coated in a layer of platelets.
are the main site of the synthesis and storage of The next cohort of platelets cannot make contact
vWF. Normally, a limited amount of vWF is with collagen. Instead, they are activated by the
secreted into the vessel lumen, where it binds to ADP molecules released from the first cohort of
factor VIII, protecting the clotting factor from platelets. Binding of ADP causes the platelets to
degradation. A damaged vessel releases a large change shape and release more chemicals from
amount of vWF from its endothelial cells; vWF storage granules.
then binds platelets to subendothelial collagen Activated platelets exhibit a glycoprotein Ilb/IIIa
fibres. receptor on their surface. Fibrinogen and vWF
Collagen fibres. Vessel damage exposes ‘glue’ platelets together through this receptor
subendothelial collagen fibres. Platelets bind to (Figure 72.1). More and more platelets become
collagen (through a bridging vWF molecule) and activated and bind to the site of injury, forming a
become activated. soft platelet plug.
Tissue factor (TF) is expressed by subendothelial The soft platelet plug formed is often not enough
cells, such as smooth muscle cells, but not to achieve haemostasis – the plug must be
normally by endothelial cells, unless they become reinforced to make a strong clot. Conveniently,
damaged. TF activates plasma coagulation the strands of fibrinogen that are interwoven in
proteins (through the extrinsic pathway), the soft platelet plug are converted to fibrin (a
culminating in the production of thrombin. strong insoluble protein) by thrombin, the end
point of the coagulation cascade.
Describe the steps involved in platelet Describe the steps of the coagulation
activation and aggregation cascade
Platelets are disc-shaped (hence the name) anuclear
cell fragments. They have a short lifespan in the The coagulation cascade is a complex biochemical
circulation, typically of 7 days. Blood vessel damage pathway involving a number of plasma proteins, cul-
exposes TF, collagen and vWF. Passing platelets are minating in the formation of thrombin. The coagula-
activated by collagen and vWF, and also by thrombin tion cascade is an example of a biological amplification
itself, produced by TF activation of the coagulation system: starting from a small number of activated
cascade. When platelets are activated, they change molecules, the sequential activation of circulating
shape from disc-like to stellate and release a number coagulation proteins results in a magnified response.
of molecules from storage granules (Figure 72.1): Classically, the coagulation cascade is initiated by
one of two distinct pathways: intrinsic or extrinsic
Serotonin (5-HT); (Figure 72.2). 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 the
Fibrinogen; classical model that have more recently led to the
Thrombin; development of a cell-based coagulation model, which
2+
Ca ions; is thought to better reflect the mechanism of in vivo
Platelet-derived growth factor (PDGF). coagulation.
342
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 20:05:52, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.075
Chapter 72: Haemostasis
Platelet activation
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
343
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 20:05:52, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.075
Section 7: Blood and Immune System
X Xa X
Va Antithrombin III deactivates
Activated protein C (with protein S)
Ca2+ Xa and thrombin
deactivates Va and VIIIa
PF3
Figure 72.2 The classical coagulation cascade. Roman numerals represent unactivated clotting factors; ‘a’ denotes activated clotting
factors (PF3 = platelet factor 3).
cells may produce new COX within hours. The Key features are:
result is a net increase in platelet inhibition. Extrinsic pathway. The extrinsic pathway is
ADP receptor antagonists; for example, so called because it is activated by TF, which is
clopidogrel, ticagrelor and prasugrel. This class not normally found within the lumen of intact
of drug specifically blocks the platelet ADP blood vessels. Blood vessel disruption exposes
receptor, which prevents further platelet circulating clotting factors to subendothelial TF:
activation and inhibits the expression of the
any factor VII passing the site of injury is
glycoprotein llb/llla complex, thus inhibiting
platelet aggregation.
activated to factor VIIa. Factor VIIa activates
Glycoprotein llb/llla inhibitors; for example, factor X, the clotting factor at the start of the final
tirofiban and abciximab. Platelet aggregation is common pathway (Figure 72.2).
inhibited by preventing platelets from binding to Intrinsic pathway. The intrinsic pathway is so
fibrinogen. called because it was recognised that initiation of
Phosphodiesterase inhibitors; for example, coagulation did not always require TF, especially
dipyridamole, which acts through a number of in vitro; plasma can clot without the addition of
possible mechanisms. One mechanism is the any extrinsic material. It has since been found that
inhibition of the platelet phosphodiesterase the intrinsic pathway is activated by contact with
enzyme, whose usual role is to break down cyclic
negatively charged substances such as
AMP (cAMP). Increased platelet cAMP inhibits
ADP release, resulting in impaired platelet
subendothelial collagen in vivo or glass in vitro.
aggregation and reduced thromboxane A2 The intrinsic pathway involves a number of
synthesis. clotting factors, culminating in the activation of
factor X at the start of the final common pathway
344
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 20:05:52, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.075
Chapter 72: Haemostasis
345
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 20:05:52, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.075
Section 7: Blood and Immune System
TF TF TF TF
X TF
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
346
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 20:05:52, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.075
Chapter 72: Haemostasis
of plasma and measuring the time of clot function. This test is rarely performed, as it does
formation. The international normalised ratio not help to predict surgical bleeding.
(INR) is the ratio of a patient’s PT compared with
the average PT of a control sample. PT mainly
assesses clotting factor VII of the extrinsic Clinical relevance: oral anticoagulants
pathway, along with clotting factors II, X and Oral anticoagulant therapy is most commonly used
fibrinogen of the final common pathway. PT is in the following clinical situations:
prolonged by: Atrial fibrillation to prevent systemic
– Decreased hepatic synthesis of the vitamin K- embolisation; for example, ischaemic stroke;
dependent clotting factors: II, VII, IX and Deep vein thrombosis and pulmonary embolus,
including following lower limb arthroplasty;
X. This may be the result of warfarin therapy
Metallic heart valves to prevent systemic
(vitamin K antagonism), vitamin K deficiency
embolisation.
(e.g. fat malabsorption) or liver disease.
Until relatively recently, only one oral anticoagulant
– DIC due to the consumption of clotting
was in common usage: warfarin. Warfarin is a couma-
factors. rin derivative that acts by inhibiting vitamin
Activated partial thromboplastin time (APTT), K synthesis and thereby reduces the production of
a test of the intrinsic pathway. The test the vitamin K-dependent clotting factors II, VII, IX and
involves adding phospholipid and an activator X and proteins C and S. Warfarin is 99% protein
(e.g. silica) to a plasma sample and measuring bound, which means that it can easily be displaced
the time taken to clot. APTT mainly assesses by other highly protein-bound drugs, leading to an
increased anticoagulant effect. Warfarin is also
clotting factors VIII, IX, XI and XII of the
metabolised by the liver cytochrome P450 enzymes;
intrinsic pathway and clotting factors II, X and variations in anticoagulant effect are due to genetic
fibrinogen of the common pathway. APTT is differences in P450 activity, as well as foods and
prolonged by: drugs that are co-metabolised by P450. Warfarin
– Unfractionated heparin therapy through must therefore be closely monitored through blood
activation of antithrombin III (which sampling and testing of the PT (or INR). Despite this,
inactivates factors Xa and thrombin). Low- there are a few remaining advantages of warfarin
therapy. Its easy reversibility means that, in the event
molecular-weight heparins are too small to
of a life-threatening bleed (e.g. intracranial haem-
activate antithrombin III effectively, instead atoma), the anticoagulant effects of warfarin can be
inactivating factor Xa directly. APTT is then rapidly reversed by administering vitamin K and a
usually not prolonged. pre-calculated dose of prothrombin complex con-
– Haemophilia (factor VIII deficiency), centrate. It is also thought to be safer in severe renal
Christmas disease (factor IX deficiency) and impairment. Warfarin is the only oral anticoagulant
von Willebrand disease (vWF deficiency). licenced for metallic heart valves.
– DIC due to the consumption of clotting Direct oral anticoagulants (DOACs) have become
factors. widely used for both short- and long-term anticoa-
gulation. DOACs are preferred because of their
In addition, there are other less commonly used tests favourable pharmacokinetics with fixed dosing,
that may be indicated in certain circumstances: decreased drug–drug interactions and lack of moni-
Thrombin time (TT), a test of the final common toring requirements. DOACs in current use are:
pathway. Thrombin is added to plasma and Direct thrombin inhibitors, such as dabigatran;
the clotting time is measured. TT tests the Direct factor Xa inhibitors, such as rivaroxaban,
interaction between thrombin and fibrinogen apixaban and edoxaban.
and is prolonged in fibrinogen deficiency (e.g. due The downside of DOACs has traditionally been their
to DIC). reversibility in the event of a life-threatening bleed
Bleeding time. A standard incision is made and when compared to that of warfarin. DOACs are asso-
time to stop bleeding is measured; that is, the time ciated with less intracranial bleeding than is warfarin,
although they may have a higher incidence of gas-
it takes for an effective platelet plug to form.
trointestinal bleeding. The anticoagulant effects of
Bleeding time is therefore a test of platelet
347
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 20:05:52, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.075
Section 7: Blood and Immune System
348
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 20:05:52, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.075
Chapter 72: Haemostasis
349
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 20:05:52, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.075
Section 7 Blood and Immune System
Transfusion
Chapter
73
What are red blood cell antigens? What is the Rh system?
As discussed in Chapter 8, red blood cells (RBCs) can The Rh blood group is the second most important in
be thought of as ‘bags of haemoglobin’ (Hb). However, transfusion medicine. It is named after the Rhesus
the composition of the ‘bag’ itself differs between monkey, the animal whose blood was used in the
patients. The RBCs have surface antigens that act as discovery of the Rh system. There are 50 different
markers, identifying the RBC to the immune system. Rh antigens discovered to date, of which the most
RBC surface antigens may be polypeptides, polysac- important are: D, C, c, E and e. By far the most
charides or glycoproteins. Which specific antigens are important Rh antigen is D – this is the antigen that
expressed is determined genetically. There are at least is present when patients are referred to as being
30 different RBC antigen systems, the most important Rhesus positive, Rh factor positive or RhD positive.
of which are: The RhD antigen is a large (30‑kDa) cell mem-
The ABO blood group system; brane protein that is thought to be a subunit of an
The Rhesus (Rh) blood group system. ammonia transport protein. As with other blood group
systems, the presence or absence of the RhD antigen on
Minor blood group systems include Kell, MNS, Lewis,
a patient’s RBCs is genetically determined – around
P and Duffy.
85% of the UK population are RhD positive.
Describe the ABO system Why does the immune system develop
As well as being the first RBC antigen system discovered,
the ABO blood system remains the most important antibodies to RBC antigens?
for blood transfusion. The ABO blood groups are The immune system develops antibodies to fragments
carbohydrate-based antigens. All patients’ RBCs have a of foreign material presented by antigen-presenting
disaccharide ‘core’ antigen, called the H antigen. Patients cells (see Chapter 75). Patients may develop anti-
then fall into one of four blood groups: bodies to non-self RBC antigens for two reasons:
Group O. These patients’ RBCs only express the Exposure to foreign RBCs, such as following a
H antigen; ‘O’ signifies that no other sugars 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 that 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.
ABO blood group system. At birth, antibodies to
Group AB. These patients’ RBCs express both non-self ABO antigens are not present: they
A and B antigens. 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
350
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:46:34, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.076
Chapter 73: Transfusion
351
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:46:34, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.076
Section 7: Blood and Immune System
immune response occurs: it takes time for new is no longer routinely performed because RBCs
IgG antibodies to be produced, leading to a delay are now transfused as packed cells and thus
before haemolysis is evident. contain an insignificant amount of donor plasma.
What is meant by the terms ‘universal How are blood products stored?
donor’ and ‘universal recipient’? The three main blood products are packed RBCs,
There are two groups of patients of particular fresh frozen plasma (FFP) and platelets:
importance in transfusion medicine – the universal Packed RBCs. Donated whole blood is spun in a
donor and the universal recipient: centrifuge and the plasma removed. The RBCs are
The universal donor is a blood group O, resuspended in the minimum amount of fluid,
RhD-negative patient. This is because: resulting in a haematocrit of >75%. Citrate, adenine
and glucose are added and the mixture stored at 4°
– Group O RBCs only express the core
C, resulting in a shelf life of 42 days. During storage:
H antigen, so are safe for donation to
recipients with anti-A or anti-B antibodies. – Some RBCs become spherical, reducing their
– RhD-negative RBCs are safe to transfuse in lifespan.
recipients with anti-RhD antibodies. – K+ concentration rises to 30 mmol/L by 28
days’ storage.
In an emergency situation where there is
– ATP and 2,3-diphosphoglycerate (2,3-DPG)
insufficient time to establish the blood type of the
levels fall. Following transfusion, it takes
recipient (e.g. trauma, ruptured aortic aneurysm,
24 h for 2,3-DPG concentrations to return
obstetric haemorrhage), it is considered safe to
to normal. Transfused blood therefore has
transfuse with O negative blood. However, there
a higher O2-binding affinity than native blood
may still be minor blood group antigen–antibody
and thus O2 offloading to the tissues
incompatibility reactions; a full crossmatch is
is impaired (see Chapter 8). Whether this is
required to ensure blood is fully compatible.
clinically significant is a matter of debate.
The universal recipient is more of academic than
clinical interest. Blood group AB, RhD-positive FFP. As the name suggests, the plasma removed
patients can receive donor blood irrespective of its from whole blood during the process of producing
ABO and Rh status: packed RBCs is cooled to –30°C within 8 h of
donation. FFP has a shelf life of 1 year. FFP is used
– Their plasma has neither anti-A nor anti-B
to replace coagulation factors and should be
antibodies, because their RBCs contain both
blood-type matched to ensure compatibility.
antigens.
Other FFP-derived blood products are:
– Similarly, their plasma does not contain
anti-RhD antibodies, because their RBCs – Cryoprecipitate: FFP is frozen to –70°C then
express the RhD antigen. thawed and centrifuged and the precipitate
collected. Cryoprecipitate is rich in factors
It is important to note that the minor blood group
VIII, XIII, fibrinogen and von Willebrand
antigens are not necessarily compatible; a
factor and is used in clotting factor deficiencies
crossmatch is still required.
and hypofibrinogenaemia.
– Freeze-dried factor VIII concentrate, which also
What is a ‘crossmatch’? contains a small amount of fibrinogen, is used
Crossmatch is a compatibility test between donor and to replace factor VIII in patients with
recipient blood. There are two types: haemophilia A.
Major crossmatch. The recipient’s serum is mixed – Freeze-dried factor IX concentrate, which also
with donor RBCs – this is a test of compatibility contains a small amount of factors II, VII and
between the recipient’s antibodies and donor X, is used to replace factor IX in patients with
antigens. If donor RBCs clump together, the blood factor IX deficiency (Christmas disease).
is incompatible. Platelet concentrate. Platelets are either pooled
Minor crossmatch. The recipient’s RBCs are from the whole blood of multiple donors or
mixed with the donor’s plasma. Minor crossmatch collected from one donor by a process called
352
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:46:34, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.076
Chapter 73: Transfusion
apheresis. Platelet concentrates are ultraviolet an immune response against the recipient’s
irradiated to reduce the risk of transmission of tissues. Following the introduction of
infectious diseases. Platelets are stored at room universal leukodepletion, this has become a
temperature as they quickly become rare but very serious complication of blood
nonfunctional at 4°C, and so only have a short transfusion. Certain high-risk
shelf life (5 days). Platelets can be transfused immunocompromised patients therefore
without crossmatch, but the platelet count rises require irradiated blood.
more if they are ABO-type specific. Non-immunological complications. These are
divided into infective and non-infective types:
What are the other serious – Septicaemia. Bacterial contamination of blood
complications of blood transfusion? products can lead to septicaemia. Platelets are
Complications of transfusion range from mild to fatal at a particular risk because they are stored at
reactions. Transfusion complications can be classified room temperature, which allows bacteria to
as immunological and non-immunological: replicate.
– Infectious disease transmission; for example,
Immunological complications. In addition to
hepatitis B, hepatitis C, HIV, cytomegalovirus,
immediate and delayed haemolytic transfusion
malaria and prion disease. Donors are
reaction, the immune system is responsible for
screened for blood-borne infectious diseases
other transfusion complications:
both by questionnaire and serology. Rarely,
– Non-haemolytic febrile reactions. Recipient disease transmission may occur in the early
antibodies react with antigens on the small stages of an infection when the donor is
number of donor leukocytes contained within infectious but has not developed antibodies:
donor blood. The antibody–antigen complex serological screening tests are therefore
activates complement and cytokines are negative. No serological tests for prion disease
released. Febrile reactions were previously exist; screening is based on questionnaire
common, but have become much rarer since alone, but the risk of transmission has been
the introduction of universal leukodepletion. reduced following leukodepletion.
Febrile reactions are usually mild, but it is – Transfusion-associated circulatory overload
important to note that fever is also an early (TACO). Rapid transfusion can lead to left
symptom of the life-threatening immediate ventricular failure in susceptible patients
haemolytic transfusion reaction. (those with heart or renal failure, the elderly,
– Allergic reactions. Foreign protein in the donor those with hypoalbuminaemia). Transfusions
blood cross-reacts with recipient IgE. Allergic in these patients are often accompanied by the
reactions are usually mild, causing urticaria administration of furosemide. The resulting
and pruritus. dyspnoea may be confused with TRALI.
– Transfusion-related acute lung injury (TRALI), – Iron overload. The body does not have a
the most common cause of death following blood disposal mechanism for excess iron; only the
transfusion. TRALI is thought to occur through absorption of iron is regulated.
both immune and non-immune mechanisms. In Haemosiderosis (iron overload) can occur in
immune TRALI, antibodies within the donor patients who require frequent blood
blood attack the recipient’s tissues. Non-immune transfusions, such as those with thalassaemia
TRALI is thought to be due to neutrophil or sickle cell disease. Excess iron deposits in
activation following release of reactive lipid the liver, heart and endocrine organs, resulting
products from the donor RBC membranes. in organ damage.
Whatever the mechanism, TRALI causes a
spectrum of lung disease indistinguishable from
acute respiratory distress syndrome. What is cell salvage?
– Graft-versus-host disease. In Cell salvage is a method of autologous blood transfu-
immunocompromised patients, sion: a patient’s own blood is collected, processed,
T-lymphocytes within the donor blood launch stored and retransfused. It is an important method
353
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:46:34, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.076
Section 7: Blood and Immune System
of reducing the requirement for allogenic transfusion, Massive transfusion carries all the risks of a single-
with all its associated risks. Cell salvage is usually unit transfusion outlined above, but also has add-
performed intraoperatively, where spilt blood is col- itional risks:
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, reduced tissue oxygenation
saline. Cell salvage has some obvious advantages, (as the oxyhaemoglobin dissociation curve is
but also has some disadvantages: shifted to the left) and a worse overall outcome.
Advantages: The risk of hypothermia can be reduced by
– Cell salvage is more cost-effective than warming all transfused blood and fluids, as well as
autologous transfusion. active warming of the patient; for example, by
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 administration
– Cell salvage is accepted by some Jehovah’s leads to dilution of plasma constituents. Of
Witnesses. particular importance are clotting factors and
Disadvantages: platelets because haemostasis will become
impossible, leading to further haemorrhage and a
– Electrolyte abnormalities may occur,
particularly in massive transfusion. requirement for more blood products. Aggressive
and pre-emptive replacement of clotting factors
– Clotting factors are lost when blood is and platelets with FFP, cryoprecipitate and platelet
processed; a dilutional coagulopathy concentrate is required.
may occur.
Hypocalcaemia. Packed cells contain only a small
– In obstetric haemorrhage, there is a risk of amount of the anticoagulant citrate; FFP and
precipitating an amniotic fluid embolus, as platelet concentrate contain much higher citrate
amniotic fluid mixed with the salvaged RBCs concentrations. The role of citrate is the chelation
may not be completely removed by the of Ca2+, preventing the coagulation of stored
washing process and subsequently be blood products. In massive transfusion, there is
reinfused. However, cell salvage is now sufficient intravascular citrate to cause a severe
considered safe if used in combination with a hypocalcaemia. Without Ca2+ replacement, this
leukocyte depletion filter. can lead to hypotension and electrocardiogram
– In cancer surgery, there is a risk that malignant changes (bradycardia, flat ST segments, prolonged
cells suctioned along with spilt blood from the QT interval). Hypocalcaemia should be treated
surgical site may not be completely removed with 10 mL of 10% calcium chloride.
by the washing process and be reinfused. Hyperkalaemia. As discussed above, when RBCs
Again, a number of studies have shown that are stored, K+ seeps out of the erythrocytes. When
the use of a leukocyte depletion filter reduces blood is transfused, K+ tends to diffuse back into
this risk significantly. the RBCs, but this process is hindered if the
patient is acidotic or hypothermic, leading to
What is massive transfusion? What hyperkalaemia.
Acidosis. A unit of packed RBCs has a lower pH
additional complications occur? (around 6.8) than plasma, mainly as a result of
Massive transfusion is the transfusion of a greater lactate accumulation due to the anaerobic
volume of stored blood than a patient’s circulating metabolism of erythrocytes during storage.
volume in a 24‑h period or transfusion of more than Massive transfusion may therefore worsen
half a patient’s circulating volume in a 4‑h period acidosis, though the additional lactate is usually
(note: there are many other similar definitions). rapidly cleared by the liver.
354
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:46:34, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.076
Chapter 73: Transfusion
Is there any alternative to using blood Human blood can only be stored for 30 days and
must be refrigerated. Blood substitutes have a
for oxygen carriage? much greater shelf life and can be stored at
There are a number of alternative O2-carrying solu- ambient temperature, which makes them an
tions (blood substitutes) currently undergoing clinical attractive prospect in military trauma medicine.
trials, which can be classified as: Alternative O2-carrying solutions are likely to be
Hb-based O2 carriers. Pure Hb from RBCs acceptable to Jehovah’s Witnesses.
cannot be used as it causes renal tubular damage.
Instead, Hb must be cross-linked, polymerised or Further reading
encapsulated. J. Overfield, M. M. Dawson, D. Hamer. Transfusion Science,
2nd edition. Banbury, Scion, 2007.
Perfluorocarbon-based O2 carriers. These man-
made chemicals are able to dissolve significant S. V. Thakrar, B. Clevenger, S. Mallett. Patient blood
quantities of gases, including O2 and CO2. management and perioperative anaemia. BJA Education
2017; 17(1): 28–34.
However, perfluorocarbons are hydrophobic and
therefore must be prepared as an emulsion to mix A. A. Klein, P. Arnold. R. M. Bingham, et al. AAGBI
guidelines: the use of blood components and their
with blood. They do not have the same complex
alternatives. Anaesthesia 2016; 71(7): 829–42.
dissociation kinetics as Hb.
D. Orlov, K. Karkouti. The pathophysiology
There are some potential advantages to using blood and consequences of red blood cell storage. Anaesthesia
substitutes over human blood: 2015; 70(Suppl. 1): 29–37.
Blood transfusion is expensive and associated with J. P. Cata, H. Wang, V. Gottumukkala, et al. Inflammatory
a number of immune and non-immune response, immunosuppression, and cancer recurrence
complications (see above). after perioperative blood transfusions. Br J Anaesth 2013;
110(5): 690–701.
355
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:46:34, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.076
Section 7 Blood and Immune System
74
What steps are involved in red blood cell differentiation of BFU-E and CFU-E progenitor cells.
A negative-feedback loop is therefore created: hypox-
production? aemia stimulates EPO production, which increases
Erythropoiesis, the production of red blood cells RBC production, which increases O2-carrying cap-
(RBCs), occurs within the bone marrow. Erythrocytes acity, counteracting the initial hypoxaemia.
differentiate through several cell types during their
development:
The starting point is the common pluripotent Why do patients become anaemic?
haemopoietic stem cell. This stem cell Anaemia is defined as an Hb concentration below
differentiates into myeloid progenitor stem cells the expected value when gender, pregnancy and
dedicated to erythropoiesis, first called burst- altitude have been taken into account. The World
forming unit erythroid (BFU-E) cells, before Health Organization defines anaemia as Hb < 130 g/L
becoming colony-forming unit erythroid (CFU- in men and Hb < 120 g/L in non-pregnant women.
E) cells. The prevalence of anaemia in the surgical population
CFU-E cells then pass through a series of has been found to be as high as 60%.
erythroblast phases in the bone marrow. Anaemia occurs when RBC loss exceeds RBC
Erythroblasts require both vitamin B12 and folate production. There are many causes of anaemia, which
for their DNA synthesis. may be classified as follows.
Erythroblasts synthesise haemoglobin (Hb) from Insufficient RBC production. Examples include:
the early stages of their maturation. Globin chains – Iron-deficiency anaemia. Deficient haem
are produced in the cytoplasm, whilst the haem synthesis results in a reduced number of
moiety, which requires iron, is synthesised in the microcytic and hypochromic RBCs.
mitochondria. – Folic acid and vitamin B12 deficiency. RBCs
The penultimate cell type is the reticulocyte. By this produced are megaloblastic.
stage of maturation, the cell has lost its nucleus. – End-stage renal disease. Insufficient EPO is
However, Hb continues to be synthesised by the produced by the kidneys; RBCs are
residual ribosomal RNA within the cytoplasm. normocytic.
At 1–2 days following their release into the – Anaemia of chronic disease. This is now
circulation, reticulocytes lose their RNA (and thought to result from cytokine-mediated
therefore their ability to synthesise Hb) and (especially interleukin-6) hepatic synthesis of a
become mature erythrocytes. protein hormone called hepcidin. Hepcidin
Erythropoiesis is controlled by the hormone erythro- blunts the response of the erythropoietic
poietin (EPO). EPO is a glycoprotein secreted mainly progenitor cells to EPO and reduces the
by the kidney in response to hypoxaemia.1 EPO gastrointestinal (GI) absorption of iron
increases erythropoiesis by stimulating the (see later).
RBC haemolysis. RBCs are haemolysed either
1
Note that around 10% of the EPO originates from the intravascularly or (more commonly)
liver; this EPO is especially important in end-stage renal extravascularly within the spleen. Examples
failure. include:
356
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:27:06, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.077
Chapter 74: Anaemia and Polycythaemia
– Inherited abnormalities of RBCs; for example, Clinical relevance: patient blood management
hereditary spherocytosis. Abnormally shaped
RBCs are taken out of circulation by the Perioperative anaemia and blood transfusion are
spleen, reducing their lifespan. both independent risk factors for poor post-operative
outcomes. Patient blood management is a multidisci-
– Inherited abnormalities of Hb; for example,
plinary approach that aims to reduce unnecessary
sickle cell disease. The spleen haemolyses perioperative blood transfusions through:
sickle-shaped cells, significantly reducing the
Preoperative optimisation of red cell mass: for
average RBC lifespan.
example, through use of intravenous iron
– RBC enzyme deficiencies; for example, glucose- therapy in iron-deficiency anaemia (the most
6-phosphate dehydrogenase deficiency causes common cause of preoperative anaemia).
some Hb in the ferrous state (Fe2+) to be The minimisation of intraoperative blood loss,
oxidised to the ferric state (Fe3+), forming which may include minimally invasive surgical
MetHb (see Chapter 8). RBCs containing techniques, the use of topical haemostatic
MetHb are haemolysed by the spleen. agents, the use of antifibrinolytic drugs
– Transfusion reactions; transfusion of ABO- (tranexamic acid) and cell salvage. Where blood
incompatible blood leads to an antibody- products are required, these should be guided
using thromboelastography.
mediated intravascular haemolysis reaction
The management of post-operative anaemia: the
(see Chapter 73). National Institute for Health and Care Excellence
– Autoimmune haemolytic anaemia; RBCs are (NICE) recommends a transfusion trigger of 70 g/L,
haemolysed by autoimmune attack. or 80 g/L in patients with cardiovascular disease.
– Mechanical trauma to RBCs; for example, A ‘single-unit’ transfusion strategy is recommended
cardiopulmonary bypass and valvular in stable patients without active bleeding.
dysfunction may result in traumatic haemolysis.
Bleeding. This may be acute (e.g. postpartum How is iron handled in the body?
haemorrhage) or chronic (e.g. colonic carcinoma,
Iron is an extremely important element in all living
menstruation). In critical care patients, repeated
organisms. In humans, iron is primarily involved in:
arterial blood sampling is a major contributor to
anaemia. O2 transport and storage – Hb and myoglobin.
Catalysis of biological reactions – the
What are the adverse consequences of cytochrome class of enzymes, catalase and
peroxidase all have iron atoms at their active site.
anaemia? Total body iron is typically 3–5 g. The majority of
In itself, mild anaemia has few consequences. How- iron in the body is found within Hb (60–70%), with a
ever, the disease underlying the anaemia may be very further 5–10% incorporated within myoglobin and
significant, such as colonic carcinoma. Therefore, it is iron-containing enzymes. The rest (20–30%) is found
important to investigate and establish the cause of in the liver, where it is stored as ferritin and its
anaemia where possible. degradation product, haemosiderin. Key features of
Patients with acute blood loss exhibit the signs of iron absorption are:
hypovolaemia: tachycardia, hypotension and oliguria. A typical Western diet contains 15 mg of iron per
Patients with chronic anaemia develop signs and day, but usually only 1–2 mg of this is absorbed.
symptoms dependent on its severity: However, iron absorption can double in
Those with mild anaemia may develop general pregnancy and iron deficiency.
malaise and dyspnoea on exertion. There are two forms of dietary iron, both of which
In severe anaemia, reduced O2-carrying capacity are absorbed in the duodenum:
necessitates an increase in cardiac output; patients
– Haem groups can be directly absorbed by the
may experience palpitations.
enterocytes through a haem transport protein.
Those with pre-existing coronary artery disease or Once inside the enterocytes, iron is released.
peripheral arterial disease may experience angina
– Dietary iron salts are found in both oxidation
or claudication, respectively; high-output heart
states: ferrous (Fe2+) and ferric (Fe3+).
failure may develop.
357
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:27:06, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.077
Section 7: Blood and Immune System
Enterocytes can only absorb iron in the ferrous Conservation of iron within the body is extremely
state; this is why iron supplements are ferrous important: iron absorption is as little as 1 mg/day, yet
rather than ferric (e.g. ferrous fumerate). Fe3+ erythropoiesis requires 20 mg of iron per day. At the
salts precipitate when the environmental pH is end of the erythrocyte lifespan, iron is liberated from
greater than pH 3 (i.e. the duodenum) and Hb and carried by transferrin to the bone marrow,
therefore cannot be absorbed. where it is recycled.
The low-pH environment of chyme entering the Hepcidin deficiency is implicated in hereditary
duodenum facilitates the enzymatic reduction of haemochromatosis, a genetic condition of iron over-
iron from Fe3+ to Fe2+, thus allowing duodenal load: hepcidin levels are inappropriately low, resulting
absorption. Drugs that reduce the acidity of the in an excess of total body iron. Exactly how hepato-
stomach (e.g. proton-pump inhibitors) cytes regulate hepcidin production and what goes
significantly decrease duodenal ferrous iron, wrong in haemochromatosis are not yet established.
leading to iron deficiency.
What is polycythaemia?
How does the body control iron Polycythaemia is a persistently increased ratio of RBCs
homeostasis? to plasma (i.e. haematocrit) – above 0.51 in men and
0.48 in women. Polycythaemia is classified as:
Iron homeostasis is tightly regulated. Unusually, the
body does not have a mechanism for iron excretion, Primary polycythaemia, where an abnormality in
the bone marrow results in the inappropriate
so control of the body’s iron content is solely through
production of an increased number of RBCs. For
regulation of iron absorption. This is why iron over-
example, polycythaemia rubra vera (PRV) is a
load can be a major problem in patients requiring
myeloproliferative condition in which the bone
regular blood transfusions.
marrow undergoes excessive erythropoiesis.
When body iron stores are low, more iron is
transported across the enterocyte basolateral Secondary polycythaemia, where increased
membrane. Conversely, when iron stores are plen- erythropoiesis is due to increased EPO secretion.
tiful, iron absorption is inhibited. Traditionally, it EPO is usually secreted in response to chronic
was thought that the GI mucosal cells somehow hypoxaemia (e.g. high altitude, smoking, chronic
inherently regulated iron absorption; this is respiratory disease, congenital heart disease), but
‘mucosal block theory’. Recently, our understand- is occasionally due to an EPO-secreting tumour.
ing of the iron absorption mechanism has pro- Patients with primary polycythaemia are at greatly
gressed: it is regulated by a liver protein hormone increased risk of thrombosis, both arterial and venous.
called hepcidin. Hepcidin binds to and inhibits This is due to:
ferroportin, the enterocyte basolateral membrane Hyperviscosity. Increased haematocrit results in
iron channel: increased blood viscosity, which, according to the
2+
When hepcidin levels are high, Fe cannot be Hagen–Poiseuille equation, increases resistance to
transported out of the enterocyte. Iron is therefore blood flow. The resultant reduction in venous
stored within the enterocyte’s cytoplasmic ferritin blood flow predisposes to venous thrombosis.
before being excreted from the body as the Cardiac work is also increased.
mucosal cell sloughs. Hypercoagulability. The coagulation cascade is
2+
When hepcidin levels are low, Fe is allowed to abnormal in patients with PRV – they are at
pass into the circulation through the enterocyte greater risk of thrombotic disease, even when their
basolateral ferroportin channels. haematocrit is normalised by venesection.
Once within the plasma, Fe2+ is oxidised to Fe3+ Thrombocytosis. Some patients with PRV also
and bound to the plasma transport protein trans- have excessive platelet production, increasing their
ferrin. Transferrin transports Fe3+ within the circu- risk of arterial thrombosis.
lation to where it is needed, such as the bone Patients with secondary polycythaemia also have
marrow. Excess iron is stored by the intracellular increased blood viscosity, but seem not to have an
protein ferritin. increased risk of thrombosis.
358
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:27:06, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.077
Chapter 74: Anaemia and Polycythaemia
359
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 15:27:06, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.077
Section 7 Blood and Immune System
Immune System
Chapter
75
What is an antigen? How does an causes bacterial cell wall lysis. Transferrin
secretion in mucosa creates a low-iron
antigen differ from a hapten and an environment, thus inhibiting bacterial
allergen? replication.
An antigen is a substance that stimulates the immune ▪ Inflammation.
system, resulting in an immune response. Antigens ▪ Complement system.
are either proteins or polysaccharides. The immune ▪ Cellular components – neutrophils,
system produces antibodies that specifically bind to macrophages, natural killer (NK) cells,
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-
– Slower response, but specific to the invading
bodies can also bind to the hapten (when not attached
microorganism. The adaptive immune
to a carrier protein).
response is slower than the innate immune
An allergen is an environmental antigen that
system, but has the advantage of ‘memory’ –
produces a vigorous immune response, even though
a much quicker response occurs if the same
the allergen is usually harmless.
microorganism invades for a second time.
– Involvement of both cellular and humoral
What are the differences between the elements:
▪ Cytotoxic T cells are responsible for cell-
innate and adaptive immune systems? mediated immunity – defence against
The role of the immune system is to defend the intracellular pathogens and abnormal host
body against microorganisms, abnormal host cells, cells.
toxins and other foreign material. The two main parts ▪ B cells and T helper cells are responsible
of the immune system are the innate and adaptive for antibody-mediated (humoral)
immune systems. immunity – defence against pathogens
Innate immune system. Key features are: within body fluids.
– Immediate line of defence.
– Rapid but non-specific response to a potential Which cells are involved in the innate
threat. No previous exposure to an invading immune response?
microorganism is required.
The innate immune response involves different
– Composed of several parts: types of white blood cells (leukocytes):
▪ Anatomical/biochemical – including skin, Neutrophils account for 60% of all leukocytes.
mucociliary escalator of the respiratory They are involved in the phagocytosis (engulfing
tract, low gastric pH, peristalsis and biliary and ingestion) of bacteria and fungi. A neutrophil
secretions of the gastrointestinal tract. can phagocytose around 5–20 bacteria before
Lysozyme secretion in saliva and tears it dies.
360
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:57:17, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.078
Chapter 75: Immune System
Monocytes migrate from blood into tissues, where infection. The body recognises these threats in
they become macrophages. Macrophages different ways:
phagocytose microorganisms and cellular debris. – Trauma. Mechanical damage causes blood
A macrophage may phagocytose up to vessel disruption and local mast cell
100 bacteria before it dies. degranulation. Blood vessel disruption
Eosinophils are involved in the killing of activates platelets and the coagulation cascade
multicellular microorganisms, such as helminths (see Chapter 72), whilst mast cells release
and parasites. Eosinophils (along with mast cells) histamine and other inflammatory mediators.
are also important in the pathogenesis of allergic – Infection. Tissue macrophages recognise the
reactions and asthma (serum eosinophil count presence of microorganisms. In addition to
increases in both conditions). phagocytosing the microorganisms,
Basophils are the least common of the leukocytes. macrophages release proinflammatory
Basophils seem to act like circulating mast cells: cytokines including interleukins-1 and -6,
they have granules that contain inflammatory and tumour necrosis factor-α (IL-1, IL-6 and
mediators, including histamine and heparin. TNF-α, respectively) that trigger local mast
Basophils are involved in allergic reactions and cells to degranulate, releasing more
defence against parasites. proinflammatory 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
– Local arterioles vasodilate in response to
destroy tumour cells and cells infected with
histamine. This increases blood flow to the
viruses. They are also thought to be involved in
area of injury, thus delivering the necessary
the suppression of a pregnant mother’s immune
quantities of leukocytes and plasma proteins.
system to prevent immune attack of the foetus.
– 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
either microorganism invasion or tissue injury. First proinflammatory cytokines, mainly TNF-α
described over 2000 years ago, the symptoms of inflam- and histamine, allowing gaps to develop
mation are redness, heat, swelling and pain. Inflam- between endothelial cells. Large volumes of
mation is characterised by the following processes: plasma, including large molecules such as
complement, coagulation proteins and, later
Vasodilatation, which increases blood flow to the
site of injury/infection, thus explaining the on in the inflammatory process, antibodies,
redness and heat associated with inflammation. pass into the interstitial space. Complement
acts in two main ways (see below): by
Increased vascular permeability, which allows
triggering further degranulation of mast cells
plasma proteins to leak from the vessels to the site
and through opsonisation (coating) of
of injury/infection. The leak of plasma to the
microorganisms to facilitate their
interstitial space accounts for the oedema
phagocytosis.
associated with inflammation.
– Recruitment of cellular components. The
Migration of phagocytes, which kill invading
increased permeability of the post-capillary
microorganisms and remove debris in preparation
venules is not in itself a sufficient signal to
for tissue healing.
induce leukocytes to migrate into the
Inflammation can be initiated by a number of insults. interstitial space. Capillaries’ endothelial cells
The mechanisms of initiation are complex and not need a way of signalling to passing leukocytes,
fully understood. A simplified sequence of events is: informing them of a pathogen threat. In
Recognition of tissue damage. The two most response to inflammatory mediators,
common causes of tissue damage are trauma and endothelial cells express cell surface adhesion
361
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:57:17, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.078
Section 7: Blood and Immune System
362
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:57:17, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.078
Chapter 75: Immune System
Once activated, complement has a number of roles: to full maturation, there are still an estimated 100 mil-
Bacterial cell lysis. Many activated complement lion different T cells, each with a unique TCR.
proteins come together to form a ‘membrane Like T cells, immature B cells are tested for reactiv-
attack complex’. This complex kills bacteria by ity against self-antigens in the bone marrow before
punching holes in their cell membranes. Water being released into the circulation. Any B‑cell receptor
diffuses along its osmotic gradient through these (BCR; which is actually a cell surface-bound antibody
holes, causing the bacteria to swell and burst. molecule) that reacts strongly with self-antigens is pre-
Opsonisation. Fragments of complement protein vented from maturing further and is eliminated
coat the microorganisms and then act as binding through apoptosis. All remaining B cells complete their
sites for neutrophils and macrophages, making maturation in the bone marrow before being released
phagocytosis more efficient. into the circulation. Once in the circulation, they are
Chemotaxis. After leukocytes migrate into the taken up by lymphoid tissue, where they are stored.
tissues from the circulation, bits of complement
act as homing beacons, guiding leukocytes
towards the site of infection.
What are antibodies? How are they
Triggering local mast cells to degranulate, produced?
releasing vasoactive mediators such as histamine, An antibody, exemplified by immunoglobulins (Ig),
thus augmenting inflammation. is a ‘Y’-shaped protein produced by the adaptive
immune system. Antibodies are produced in response
to pathogen invasion and are specific to the invading
What is lymphoid tissue? How is the pathogen; that is, they bind to specific parts of the
thymus involved in lymphocyte pathogen. The functions of antibodies are:
Opsonisation. Antibodies label pathogens, making
maturation? them easier for leukocytes to identify. The Fc region
Lymphoid tissue is a collective term for tissues that: forming the tail of the antibody points away from
Produce lymphocytes – bone marrow; the pathogen (see below) and acts as a binding site
Process lymphocytes – thymus; for leukocytes, thus facilitating phagocytosis.
Store lymphocytes – lymph nodes, spleen, tonsils, Agglutination. Antibodies all have more than one
appendix, gut-associated lymphoid tissue (Peyer’s binding site. Binding more than one pathogen
patches). causes pathogens to clump together, making them
The bone marrow produces naïve B and T lymphocytes bigger targets for leukocytes.
from common lymphoid progenitor stem cells. B cells Inactivation of the pathogen. The antigenic part
mature in the bone marrow, whilst T cells leave the bone of the microorganism may be important to its
marrow and migrate to the thymus, where they mature. function; binding of an antibody may render the
The importance of the thymus is obvious when it microorganism harmless. Alternatively, the
is absent: DiGeorge syndrome is a genetic disorder antibody may bind a toxin produced by the
that results in a midline congenital defect, which pathogen, making it innocuous.
usually includes thymic aplasia. Children born with- Activation of complement. As discussed above,
out a thymus suffer from severe immunodeficiency. when antibodies bind to an antigen (e.g. a
The thymus is very important in T‑cell maturation microorganism), the complement cascade is
as its epithelial cells are able to synthesise and express activated through the classical pathway.
all of the proteins found elsewhere in the body. Each Complement aids phagocytosis through
T cell has a receptor (the T‑cell receptor, TCR) whose chemotaxis and opsonisation, promotes
protein sequence is essentially generated at random. inflammation through mast cell degranulation
Each TCR is therefore able to bind a different antigen. and directly attacks the pathogen by forming a
In the thymus, the T cells undergo processing; any membrane attack complex.
T cell that interacts strongly with a host protein is When a pathogen invades, the adaptive immune
eliminated through apoptosis. This process results in system responds in a well-defined series of steps
the death of almost all immature T cells (around (Figure 75.1). These result in the mass production of
98%). Despite only 2% of immature T cells surviving a highly specific antibody:
363
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:57:17, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.078
Section 7: Blood and Immune System
APCs travels
Antigen-presenting cell (APC)
= bacterium to lymph node
B Th
Th Memory Th cell
Th Th
B + mTh
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
364
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:57:17, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.078
Chapter 75: Immune System
Macrophages and dendritic cells (similar to – Plasma cells are antibody production factories.
macrophages) are collectively known as antigen- The rate of antibody production is
presenting cells (APCs). astonishing: each plasma cell can produce
When APCs phagocytose pathogens, they take 2000 antibody molecules per second. They are
small parts of the microorganism (antigens) and so committed to antibody synthesis that they
express them on their cell surface. The antigens do so to the detriment of protein synthesis for
are displayed on the cell membrane by a large normal cellular function and thus only survive
protein called major histocompatibility complex for around a week.
(MHC) class II. The APCs then travel from the – Memory cells are dormant plasma cells that are
site of infection to nearby lymphoid tissue, often a ready to be reactivated if the same pathogen
lymph node. were to invade again.
The lymph nodes contain a huge number of
B cells and T helper cells, each with uniquely
different BCRs and TCRs. The APCs wander
What is the difference between the
through the lymph node, presenting their cell primary and secondary immune
surface antigen to every B and T helper cell that response?
passes. Eventually, the APCs find B and T helper The steps outlined above constitute the primary
cells whose receptors are an exact match for the immune response. The whole process from pathogen
APC antigen. invasion to antibody production takes around 5 days.
Antibodies are produced as a result of the The main Ig produced by the plasma cells is IgM, with
interaction of B and T helper cells with APCs some IgG produced later. Most of the plasma cells
(Figure 75.1): and T helper cells die within the next 5 days, after the
– T helper cells become activated when their pathogen has been destroyed.
TCR matches the APC antigen. Activated If the same pathogen were to invade again, the
T helper cells become blast cells that undergo immune response would be much faster and more
rapid proliferation, resulting in a clone of vigorous; this is the secondary immune response.
identical T helper cells, all with TCRs specific APCs transport antigen to the lymph nodes as before,
to the same antigen. A small proportion of but this time memory T helper cells and memory
activated T helper cells become memory B cells formed during the clonal expansions of the
T helper cells – these cells lie dormant, ready to primary immune response are activated. These
be rapidly reactivated if the same pathogen memory cells are primed to divide rapidly and can
invades again. T helper cells are also called produce antibodies within hours of infection. In con-
CD4+ T cells, as it is the T cell CD4+ receptor trast to the primary immune response, IgG is the main
that interacts with the APC MHC class II Ig produced by the secondary immune response, with
molecule. IgM making up the minority. The secondary immune
– B cells are also activated when their membrane response is so rapid that pathogens can be killed before
surface Ig (the BCR) binds to a matching APC they make the host ill – this is called active immunity,
antigen, but this activation process (usually) where a person is immune from a particular infection
requires help from the corresponding T helper 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 immunisation?
with a T helper cell and one with a B cell. Immunisation 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 immunisation. 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
365
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:57:17, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.078
Section 7: Blood and Immune System
Tc
Virus-infected
host cell Patrolling Tc cell’s TCR
matches the viral antigen
Tc
Tc
Clonal
Tc Tc expansion
Tc +
Tc
Tc
Phagocytosis
The cytotoxic T cell induces apoptosis in the host is triggered to degranulate. This is the mechanism
cell. The pathogen remains within the cell as it of type 1 hypersensitivity (see below). IgE is
undergoes apoptosis. Tissue macrophages then normally present in the plasma in low
ingest the dead host cell, killing the intracellular concentration, but this may be increased with
pathogen. atopy (e.g. in asthma), parasitic infections and
The cytotoxic T cell rapidly divides, producing a hypersensitivity reactions.
large number of clonal daughter cells, each with IgD is a monomer Ig, usually attached alongside
an identical TCR. These daughter cells travel in IgM to the cell membrane of naïve B cells (cells
the circulation, looking for other infected cells. not yet activated by antigen). The physiological
This is known as cell-mediated immunity, an immune purpose of IgD is a bit of a mystery – IgD
response that does not involve antibodies or comple- disappears once the B cell is activated, when it
ment. Importantly, it is not just intracellular infec- becomes entirely covered with IgM.
tions that result in foreign protein being displayed on
the cell membrane. Malignant cells also display How can immunodeficiency be
abnormal proteins on their cell membranes. Cyto-
toxic T cells are involved in inducing the apoptosis
classified?
Immunodeficiency is a disorder in which the immune
of these abnormal host cells.
system is impaired or absent. The complications of
TYPES OF IMMUNOGLOBULIN:
IgG IgA
What is hypersensitivity? What types effects depend on the location of the mast cells
and the route of entry of the allergen:
are there? – Asthma: inhaled allergens bind to mast
Hypersensitivity is an exaggerated or inappropriate cell IgE within the bronchial smooth
immune response that causes discomfort, tissue muscle, causing degranulation. Release of
damage or even death. Hypersensitivity is classified as: histamine and leukotrienes triggers
Type I or immediate hypersensitivity. This bronchospasm.
occurs in asthma, allergic rhinitis (hay fever) and – Allergic rhinitis: allergens (e.g. grass pollen)
the feared anaphylaxis. This is an allergic reaction bind to mast cell IgE in the mucosa of the
that occurs following re-exposure to an allergen. nasopharynx. Mast cell degranulation releases
On first exposure to the allergen, T helper and histamine, causing itchy eyes and
B cells interact as usual, producing IgE specific to inflammation of nasal mucosa with an
the allergen. IgE travels in the circulation and increased secretion of mucus.
coats the surface of mast cells. On subsequent – Anaphylaxis: allergens that reach the systemic
exposure, the allergen binds to the specific IgE on circulation cause widespread mast cell
mast cells, causing rapid degranulation and release degranulation, resulting in a potentially life-
of inflammatory mediators: histamine, threatening vasodilatation, bronchospasm and
leukotrienes and prostaglandins. The clinical fluid extravasation. Anaphylaxis is especially
368
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:57:17, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.078
Chapter 75: Immune System
severe when the allergen is injected directly – Tuberculosis, the classic delayed-type
into the circulation, which is why it occurs hypersensitivity. Activated macrophages fuse
most commonly in association with to form giant cells around the tuberculosis
anaesthesia. antigen, the centre of which may become
Type II or cytotoxic hypersensitivity. Antibodies necrotic – this is known as a caseating
produced by the immune system bind to antigens granuloma. The importance of T helper cells is
on the surface of the body’s own cells. The seen when they are absent: patients with AIDS
antibody–antigen complex triggers complement, are very susceptible to intracellular pathogens
which initiates inflammation and facilitates such as M. tuberculosis.
phagocytosis by macrophages. Examples of type II – Contact dermatitis, where contact with certain
hypersensitivity reactions include: allergens (e.g. nickel) causes a delayed skin
reaction.
– Idiopathic thrombocytopaenic purpura. IgG
antibodies coat platelets and their precursor
megakaryocytes, resulting in phagocytosis by Clinical relevance: immune consequences of
splenic and hepatic macrophages. The result is anaesthesia and surgery
a very low platelet count. The immune system is affected in the perioperative
– Goodpasture’s disease. IgG binds to type IV period in a number of ways:
collagen in the basement membrane of the Disruption of physicochemical barriers,
renal glomerulus and pulmonary alveolus, allowing easier access for pathogens. The most
causing acute kidney injury and pulmonary obvious route of pathogen entry is the site of
haemorrhage, respectively. surgery where the skin or mucosa has been
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 UK 6th National
particularly when the amount of antibody is small. Audit Project found the incidence of anaphylaxis
The antibody–antigen complexes float around in during general anaesthesia to be 1/10,000; 4% of
the circulation and get lodged in small blood cases were fatal. The most common precipitants
vessels, joints and glomeruli, where they cause of anaphylaxis in the perioperative period were:
inflammation. Examples include: – Muscle relaxants, most notably
– Systemic lupus erythematosus, in which suxamethonium, accounting for 33%
antinuclear antibodies complex with nuclear of cases;
antigens, causing skin, glomerulus and joint – Antibiotics, most notably penicillins and
teicoplanin, accounting for 47% of cases;
inflammation.
– Antiseptics, including chlorhexidine-
– Farmer’s lung, a hypersensitivity pneumonitis
impregnated central lines, accounting for 9%
in which inhaled mould spores trigger of cases;
antibody production. The resulting antibody– – More rarely: latex. colloids, blood products,
antigen complexes deposit in the lungs, amide local anaesthetics (esters have a very
causing inflammation. low incidence of allergy) and induction
Type IV or delayed-type hypersensitivity. Some agents.
allergens trigger a type of hypersensitivity that
Depression of the immune system. Various
involves T cells, not antibodies. The response is parts of the immune system may be suppressed
much slower, taking 2–3 days to develop. T helper in the perioperative period:
cells recognise an antigen presented by an APC.
– The stress response to surgery depresses
The activated T helper cells divide and secrete
lymphocyte function and phagocytosis.
cytokines, initiating inflammation. Cell damage is
– Opioids impair macrophage, neutrophil and
caused by the macrophages that become activated NK cell function, lymphocyte proliferation
in response to these cytokines. Examples include: and cytokine release. NK cells are particularly
369
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:57:17, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.078
Section 7: Blood and Immune System
370
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:57:17, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.078
Section 7 Blood and Immune System
Plasma Constituents
Chapter
76
What are the components of blood? – Lipoproteins transport lipids;
– Thyroxine-binding globulin transports the
The constituents of blood are:
thyroid hormone thyroxine;
Plasma (55%), consisting of: – α1-acid glycoprotein transports basic and
– Water; neutrally charged drugs.
– Electrolytes; Enzyme inhibitors; for example, α1-antitrypsin is
– Dissolved gases (O2, CO2); a protease inhibitor.
– Plasma proteins; Coagulation and anticoagulation; for example,
– Other dissolved substances, including fibrinogen, protein C and antithrombin III.
hormones, glucose, amino acids, coagulation Endocrine; for example, antidiuretic hormone
proteins, lactic acid and urea. and angiotensin II.
Cellular components (45%), consisting of: Immunological; for example, IgG and IgM.
– Erythrocytes; Mixed function; for example, albumin has major
– Leucocytes; roles in both transport and colloid oncotic
– Platelets. pressure.
371
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:41:47, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.079
Section 7: Blood and Immune System
binding sites through which it transports a variety Acid–base balance. Albumin is negatively
of substances: unconjugated bilirubin, bile salts, charged, contributing significantly to the anion
electrolytes and free fatty acids. Albumin also gap – the unmeasured anions within the plasma.
binds and transports some important drugs: In hypoalbuminaemia, the anion gap is
warfarin, digoxin, non-steroidal anti- therefore reduced. Albumin also contributes to
inflammatory drugs (NSAIDs) and thiopentone. acid–base balance: hypoalbuminaemia results in a
This is clinically important, as many of these mild metabolic alkalosis. This is why albumin
drugs compete with each other for the same concentration is included in the Stewart method
binding site, leading to an increased fraction of of acid–base analysis (see Chapter 70).
2+
free drug and potentially toxic effects. Thus, if a Plasma Ca handling. The negative charge of
patient who already takes warfarin is given an albumin also sequesters Ca2+ ions in the plasma,
NSAID, some warfarin will be displaced from reducing the amount of free Ca2+.
albumin, thus increasing the unbound fraction:
prothrombin time and international normalised Further reading
ratio will increase. C. A. Burtis, E. R. Ashwood, D. E. Bruns. Tietz Textbook of
Free radical scavenging. Sulphydryl groups Clinical Chemistry and Molecular Diagnostics, 5th
within albumin act as free radical scavengers. edition. Philadelphia, Saunders, 2012.
372
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 13:41:47, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.079
Section 8 Energy Balance
Metabolism
Chapter
77
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
olism broadly encompasses anabolism (the building series of redox reactions within the inner
up of larger molecules from smaller ones) and catab- mitochondrial matrix. The resulting NADH,
olism (their breaking down into smaller entities with FADH2 and H+ are then processed by the electron
the extraction of energy). transport chain.
The electron transport chain, located within the
What is meant by the term ‘cellular inner mitochondrial matrix, is the final step of
respiration’? aerobic metabolism. NADH and FADH2 transfer
electrons to O2, releasing energy that is used to
Cellular respiration is the series of catabolic processes
pump H+ across the inner mitochondrial
by which carbohydrates, fats and proteins are broken
membrane. The resulting electrochemical gradient
down to yield ATP through a series of redox reactions,
is used to generate ATP.
ultimately using O2 as the oxidising agent. As O2 is too
reactive to be used directly, this process employs a
series of intermediate electron carriers, including nico- Describe the important steps of the
tinamide adenine dinucleotide (NAD+) and flavin glycolytic pathway
adenine dinucleotide (FAD).
Glycolysis (also called the Embden–Meyerhof path-
How are carbohydrates, fats and way) is the metabolic pathway through which glucose
is converted into pyruvate, with the generation of
proteins metabolised to adenosine two ATP and two NADH molecules (Figure 77.1).
triphosphate? Key features of the glycolysis pathway are:
Details of the metabolic processes involved are Glycolysis occurs in the cytoplasm.
complex, but an overview remains useful for clinical The first step is the phosphorylation of glucose,
practice. Catabolism involves a number of processes: resulting in glucose-6-phosphate – the ‘active’
form of glucose. One ATP molecule is consumed
Glycolysis, the process by which glucose is and converted to ADP in this process. This
converted to pyruvate, which then enters the citric
reaction is catalysed by the enzymes glucokinase
acid cycle. Glycolysis takes place in the cytoplasm
(in the liver) or hexokinase (in the other tissues).1
and can occur in either aerobic or anaerobic
Phosphorylation of glucose maintains the low
conditions.
cytoplasmic concentration of glucose. This
Lipolysis, the process by which free fatty acids are thereby maintains the concentration gradient for
oxidised to acetyl-CoA, which then enters the glucose diffusion from the extracellular to the
citric acid cycle. intracellular space.
Protein catabolism, a process of oxidative
deamination in which amino acids have their
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. 380).
373
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:01:03, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.080
Section 8: Energy Balance
2 × 1,3-bisphosphoglycerate 2,3-diphosphoglycerate
4 × ADP
4 × ATP
Anaerobic conditions
2 × pyruvate 2 × lactate
374
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:01:03, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.080
Chapter 77: Metabolism
375
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:01:03, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.080
Section 8: Energy Balance
Pyruvate (3 carbon)
CoA-SH + NAD+
CO2 + NADH + H+
Acetyl CoA (2 carbon)
CoA-SH
6 carbon
NAD+
Oxaloacetate Isocitrate
NADH NADH
NAD+
CO2
NADH
Fumarate Succinyl-CoA
CO2
4 carbon 4 carbon
Succinate
4 carbon
FADH2 ADP
FAD+ ATP +
CoA-SH
Describe the key steps of the electron Complex IV (also called cytochrome c oxidase)
transfers the collected electrons to O2, forming
transport chain water. Complex IV is the part of the electron
The electron transport chain is the final step of carbo- transport chain that is affected by cyanide
hydrate, fat and protein catabolism. The electron poisoning: cyanide binds to the Complex IV haem
transport chain consists of five protein complexes group, preventing it from binding O2.
on the inner surface of the inner mitochondrial mem- As electrons are transferred along the electron
brane that use the electron donors NADH and transport chain and as electrons are combined
FADH2 to produce ATP (Figure 77.3). with O2, the energy released is used to pump H+
Key features of the electron transport chain are: from the inner mitochondrial matrix to the
Electrons are transferred from NADH to Complex intermembrane space. This generates an
I and from FADH2 to Complex II. electrochemical gradient between the
Coenzyme Q (also called ubiquinone) is involved intermembrane space and the inner mitochondrial
in facilitating electron transfer from Complexes matrix.
I and II to Complex III. The final stage in the electron transport chain is
Cytochrome c is involved in electron transfer ATP synthesis. Complex V (also known as ATP
between Complexes III and IV. synthase) is a pore in the inner mitochondrial
376
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:01:03, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.080
Chapter 77: Metabolism
Inner mitochondrial H+ H+ H+
membrane
Q Cyt c
I III IV
½O2 H 2O
NADH NAD+ H+
H+ H+
H+ gradient
H+
ADP + Pi
Citric acid
cycle H+ V H+
ATP H+
H+
FADH2 FAD+ H+ ½O2 H 2O
II Q ATP synthase
III IV
Cyt c
Intermembrane space
H+ H+
377
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:01:03, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.080
Section 8: Energy Balance
– Overall, one molecule of glucose thus produces Ketone bodies can be utilised by the liver, heart and
4 ATP, 10 NADH and 2 FADH2. brain:
– In the electron transport chain, each NADH The liver converts ketone bodies back into acetyl-
produces 3 ATP and each FADH2 produces CoA, which then enter the citric acid cycle.
1 ATP. In total, one molecule of glucose The heart usually favours fatty acids as its main
produces 36 ATP. energy source, but can also use ketone bodies in
times of starvation.
The brain does not normally metabolise fatty
acids; it is usually entirely dependent on glucose
How are fats metabolised? for its ATP. In times of starvation, the brain can
adapt to using ketone bodies as its energy
Fats are a useful source of energy, as they produce
source. During prolonged starvation, up to 70%
more than twice the amount of ATP than equivalent of the brain’s metabolic demands can be
masses of carbohydrate or protein. provided by ketone bodies.
Free fatty acids are catabolised by the cells in a
Red blood cells (RBCs) do not have mitochondria, so
process called β-oxidation. β-oxidation takes place in they are entirely dependent on glycolysis for their
the mitochondrial matrix and involves removing suc- metabolism and are unable to utilise ketone bodies.
cessive two-carbon units from the fatty acid, with
each event producing one molecule of acetyl-CoA
(Figure 77.4). Acetyl-CoA then enters the citric acid How are proteins catabolised?
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 for
fatty acids esterified with glycerol. When needed, energy production if amino acids are plentiful or in
triglycerides are hydrolysed by lipases to 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 metabolised: 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
the circulation, where it is taken up by cells and must 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 ammonia (NH3). The keto acid enters the citric
mitochondrial membrane. acid cycle, where it may be used for energy,
transformed into glucose (gluconeogenesis) or used
to synthesise another amino acid or a fatty acid.
Clinical relevance: ketone bodies NH3 is a toxic substance; it is converted to non-
toxic urea through a process called the urea cycle
When carbohydrates are scarce (as occurs during
starvation) or unable to enter the cell (as occurs in (or ornithine cycle). Conversion of NH3 to urea is
diabetic ketoacidosis), fat metabolism becomes the an energy-consuming process, requiring three ATP
main source of energy, and so β-oxidation results in a molecules per urea molecule formed. Unlike other
high mitochondrial acetyl-CoA concentration. When amino acids, glutamate can also be deaminated in
acetyl-CoA concentration is high, ketone bodies the kidney and its NH3 immediately excreted into
(acetone, acetoacetic acid and β-hydroxybutyric the urine. This is important, as it means NH3 can
acid) are spontaneously formed by condensation of be excreted without the need for the energy-
two molecules of acetyl-CoA. Ketone bodies are a consuming urea cycle.
normal finding during starvation, but are patho-
Transamination. The amino group of an amino
logical in diabetic ketoacidosis.
acid is transferred, through catalysis by
378
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:01:03, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.080
Chapter 77: Metabolism
Adipose tissue
O
O
O CH2 R OH HO CH2
R O
O
Lipolysis
O CH R OH + HO CH
R O
O
O CH2 R OH HO CH2
R
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 mitochondial membrane by carnitine
medium chain
CoA
Mitochondrion
CoA
379
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:01:03, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.080
Section 8: Energy Balance
380
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:01:03, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.080
Chapter 77: Metabolism
Enhanced by insulin
Glycogenesis
Glycogenolysis
Glycolysis pathway
Glucose-6-phosphate
Glucose This step only occurs in the liver: muscles lack glucose-6-
phosphatase so cannot release glucose into the bloodstream
The biguanide metformin works by inhibiting The PPP accounts for approximately 60% of the
gluconeogenesis. NADPH required by the cells, which is used to
reduce glutathione. Glutathione is an antioxidant
What is the pentose phosphate used to prevent cellular damage from reactive
oxygen species (see Chapter 24). It is also
pathway? important in RBCs, where it helps maintain Hb in
The pentose phosphate pathway (PPP; also called the its ferrous (Fe2+) state. Patients with G6PD
hexose monophosphate shunt) is an anabolic carbo- deficiency cannot utilise the PPP, which leads to a
hydrate pathway with two functions: loss of reducing power, predisposing the patient to
To produce pentose sugars for nucleic acid MetHb (Fe3+) formation (see Chapter 8).
synthesis;
To produce NADPH for intracellular reduction
Summarise the effects of insulin and
reactions (i.e. the reverse of oxidation). glucagon
Key features are: Resting plasma glucose concentration is usually
The PPP starts with the active form of glucose, tightly controlled – it is maintained between 3.5 and
glucose-6-phosphate. 5.5 mmol/L by the balance of two hormones:
Whether glucose-6-phosphate proceeds along the Insulin, which acts to reduce plasma glucose
glycolytic pathway or the PPP depends on the concentration;
activity of the enzyme that catalyses the first step Glucagon, which acts to increase plasma glucose
of the PPP: glucose-6-phosphate dehydrogenase concentration.
(G6PD). G6PD is controlled by the cellular Insulin is the body’s main anabolic hormone. Insulin
concentration of NADP+, becoming more active if is a peptide hormone produced in the β-cells of the
NADP+ levels are high. islets of Langerhans in the pancreas:
381
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:01:03, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.080
Section 8: Energy Balance
Proinsulin. This is an insulin precursor consisting Insulin also promotes the cellular uptake of amino
of an A- and B-chain joined together by two acids and K+:
disulphide bridges and a C-peptide. Increased amino acid uptake promotes protein
Insulin. This is formed when the C-peptide of synthesis.
proinsulin is cleaved by endopeptidases. Insulin +
The physiological role of increased K uptake is a
and free C-peptide are packaged together in feedforward response to prevent hyperkalaemia
vesicles, awaiting a physiological trigger for following a meal – the presence of increased
release. glucose suggests feeding and the likelihood of
Exocytosis. The primary trigger for insulin increased K+. The mechanism can be manipulated
vesicles to undergo exocytosis is an increase in in hyperkalaemic patients: plasma K+
plasma glucose concentration. concentration can be reduced through the use of
Plasma insulin secretion occurs in two phases. an insulin and dextrose infusion.
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 preformed insulin. When all of the
endogenous insulin due to autoimmune attack of
vesicles have emptied, the β-islet cells release the β-cells in the islets of Langerhans. Patients are
insulin as it is synthesised. treated with exogenous insulin.
The sympathetic nervous system inhibits the When exogenous insulin is insufficient (e.g. due
release of insulin from the β-islet cells by direct to an acute illness or patient noncompliance with
innervation through α2-adrenoceptor action. treatment), plasma glucose concentration increases
However, adrenaline, which is released in due to:
response to sympathetic nervous activity at the Reduced glucose uptake into cells;
adrenal medulla, causes an increase in insulin Increased hepatic glycogenolysis;
secretion through β2-adrenoceptor activation. Increased gluconeogenesis.
This is important during exercise: muscles require In addition, low insulin plasma concentration results
insulin for glucose uptake through the GLUT-4 in lipolysis and β-oxidation. As discussed above,
glucose transporter (see below). when the acetyl-CoA concentration in the liver is
high, ketone bodies are synthesised. Hyperglycaemia
Insulin has three main physiological effects: and ketone body formation result in adverse effects:
Facilitation of glucose uptake. The cell Osmotic diuresis. Hyperglycaemia results in an
membrane glucose transporter GLUT-4 requires osmotic diuresis, which can cause significant
insulin to facilitate cellular glucose uptake. GLUT- hypovolaemia and renal electrolyte loss. In
4 transporters are present in adipose tissue, particular, significant hypokalaemia may occur.
skeletal muscle and the heart. Note: the cells of the Acidosis. Synthesis of ketone bodies may result
brain and liver have GLUT-1 and GLUT-2 glucose in significant acidaemia. The respiratory centre is
transporters, respectively, which are not insulin stimulated by the carotid bodies, resulting in an
dependent. increased VT, known as ‘Kussmaul respiration’. In
addition, acidosis may be exacerbated by lactic
Storage of metabolic substrates. Increased
acid production in significantly hypovolaemic
plasma insulin concentration promotes substrate
patients.
storage:
The paradox in diabetic ketoacidosis is that, despite a
– Hepatic glycogenesis; 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 dependent glucose transporter GLUT-4 is inactive.
synthesise triglyceride) in adipose tissue.
Inhibition of endogenous glucose production. Glucagon is a peptide hormone produced by the
Insulin inhibits the breakdown of stored α-cells of the islets of Langerhans. Unlike the β-islet
substrates (i.e. lipolysis and glycogenolysis) and cells, α-islet cells have no glucose sensing apparatus,
gluconeogenesis. and therefore:
382
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:01:03, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.080
Chapter 77: Metabolism
383
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:01:03, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.080
Section 8 Energy Balance
Starvation
Chapter
78
Describe the changes that occur Over the next few days:
– Gluconeogenesis increases: the substrates for
during starvation gluconeogenesis are glycerol, lactate and
Starvation is defined as the failure to ingest or absorb amino acids.
sufficient dietary calories to sustain normal body – Plasma insulin concentration becomes very low,
function, resulting in behavioural, physical and meta- which increases ketone body synthesis.
bolic changes.
During starvation, the body must survive partially Over the next few weeks:
or totally on endogenous stores. As starvation pro- – Gluconeogenesis gradually declines as tissues
gresses, the balance of the hormones insulin and adapt to metabolise ketone bodies. Plasma
glucagon alters: insulin concentration decreases ketone concentration rises as high as 7 mmol/L.
to very low levels, whilst glucagon concentration – Basal metabolic rate (BMR) decreases.
increases. This, in turn, is responsible for the major
The brain still requires 100–120 g of glucose per day,
metabolic changes that occur during starvation.
and gluconeogenesis is the only means of supplying
this demand. Whilst glycerol released during lipolysis
Describe the biochemical changes remains the main substrate for gluconeogenesis,
of starvation amino acids are increasingly used; high glucagon
concentration stimulates the release of amino acids
During periods of starvation, the body’s main con-
from skeletal muscle.
cern is maintaining plasma glucose concentration;
some tissues, particularly the brain and red blood
cells, are dependent on glucose for their metabolism. What other changes occur during
During the first 24–48 h, a reduction in plasma starvation?
glucose concentration causes a fall in plasma insulin Along with biochemical changes, starvation induces
concentration and a rise in glucagon concentration: behavioural changes:
– Glycogenolysis in the liver is promoted by Initially, energy is conserved through a reduction
glucagon, releasing glucose into the circulation. in unnecessary movement.
The liver glycogen store is exhausted after 48 h. In severe starvation, all but life-saving movement
– Lipolysis is promoted by high glucagon ceases.
concentration and low insulin concentration, There are also some additional physiological changes:
resulting in the liberation of free fatty acids the activity of the sympathetic nervous system is
and glycerol from stored triglyceride. reduced in severe starvation, leading to difficulty with
– β-oxidation of fatty acids is promoted by low temperature and blood pressure control.
plasma insulin concentration. Most of the
energy produced in the early stages of
starvation comes from β-oxidation.
What is the usual mode of death
This process leads to high acetyl-CoA in starvation?
concentration within the mitochondria, Total fat stores vary between patients, but a typical
resulting in the formation of ketone bodies. 70‑kg man has enough triglyceride to survive around
384
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 19:13:48, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.081
Chapter 78: Starvation
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 cata- increase in insulin secreton by the pancreatic β-islet
bolised, 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+
and water retention (the mechanism for which is
Clinical relevance: enhanced recovery unknown), which may precipitate left ventricular fail-
Traditionally in major surgery, to protect against aspir- ure. Reintroduction of carbohydrate increases the
ation pneumonia on induction of anaesthesia, respiratory quotient: the respiratory system, already
patients are starved preoperatively for at least 6 h potentially weak from respiratory muscle catabo-
and often significantly longer. The metabolic conse- lism, must increase V̇ A to compensate for the
quences of major surgery are complex (see Chap- increased production of CO2 when carbohydrates
ter 79), including insulin resistance, hyperglycaemia are metabolised.
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 mobilisation
are incorporated into a protocol-based periopera- Clinical relevance: anorexia nervosa
tive care bundle that has been shown to reduce
the length of hospital stay and post-operative Anorexia nervosa is a psychiatric disorder character-
complications. One of the factors included in ised by strict, psychologically driven weight loss
the enhanced recovery bundle is preoperative through dietary restriction, excessive exercise and
carbohydrate loading. Allowing patients to drink purging (self-induced vomiting and laxative use).
carbohydrate-based drinks up to 2 h preoperatively Anorexia has significant physiological sequelae with
is associated with less insulin resistance and a implications for anaesthesia:
reduced loss of muscle mass without increasing the Respiratory. Purging may result in a metabolic
risk of aspiration. Glucose is said to have a protein- alkalosis. The respiratory centre may partially
sparing effect that is thought to be due to the effects compensate through bradypnoea.
of insulin preventing protein catabolism. Cardiovascular. Anorexic patients are
typically hypotensive and bradycardic as a
result of decreased sympathetic outflow.
What is refeeding syndrome? The baseline electrocardiogram may
Refeeding syndrome is the severe metabolic disturb- demonstrate abnormalities as a result of
ance that can occur following reinstitution of nutri- electrolyte disturbances; perioperative
tion to patients who have been starved or severely arrhythmias are common. Myocardial
contractility may be impaired; excessive
malnourished. It was first reported amongst survivors
fluid administration may precipitate overt
of Japanese concentration camps in World War II. cardiac failure.
Patients at risk of refeeding syndrome include Gastrointestinal. Repeated vomiting results in
those who have been starved for 5 days or longer; salivary gland hyperplasia, dental caries,
refeeding syndrome may therefore be encountered in oesophageal strictures and Mallory–Weiss tears.
emergency surgical and critical care patients. The Gastric emptying times are prolonged; all
onset of refeeding syndrome is usually within a few anorexic patients should be considered to have
days of reinstitution of food, causing: a ‘full stomach’, warranting rapid sequence
induction. Refeeding syndrome is almost
Hypophosphataemia;
universal.
Hypokalaemia; Renal. Significant electrolyte disturbances
Hypomagnesaemia; (especially K+, Mg2+, Ca2+ and Cl‾) may occur in
Increased extracellular fluid.
385
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 19:13:48, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.081
Section 8: Energy Balance
those who abuse diuretics and laxatives. and hypocalcaemia may prolong the duration of
Glomerular filtration is often impaired. neuromuscular blockade.
Thermoregulation. Decreased subcutaneous fat
and an inadequate shivering mechanism
predispose anorexic patients to perioperative Further reading
hypothermia. In addition to the usual warming W. J. Fawcett, O. Ljungqvist. Starvation, carbohydrate
methods, the ambient theatre temperature may loading, and outcome after major surgery. BJA
need to be increased. Education 2017; 17(9): 312–16.
Positioning. The lack of subcutaneous fat
C. Jones, S. A. Badger, R. Hannon. The role of carbohydrate
predisposes 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.
Pharmacological. A decrease in plasma protein A. M. Denner, S. A. Townley. Anorexia nervosa:
concentration results in a greater fraction of perioperative implications. Continuing Educ Anaesth
unbound drug – doses need to be adjusted for Crit Care Pain 2009; 9(2): 61–4.
this, as well as for the patient’s weight. In M. D. Kraft, I. F. Btaiche, G. S. Sacks. Review of the
addition, drug clearance may be reduced due to refeeding syndrome. Nutr Clin Pract 2005; 20(6):
reduced BMR and renal function. Hypokalaemia 625–33.
386
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 19:13:48, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.081
Section 8 Energy Balance
Stress Response
Chapter
79
What is the stress response? – Systemic release of noradrenaline from
postganglionic sympathetic nerve terminals,
The stress response is a complex neuroendocrine resulting in some spillover of noradrenaline
response to physiological stress. The most commonly into the systemic circulation;
encountered stressors are trauma, burns, surgery and
– Renin release by the kidney, which increases
critical illness; the magnitude of the neuroendocrine
aldosterone secretion from the adrenal cortex
response is directly related to the magnitude of the
(through the production and action of
stressor. In addition to its metabolic effects, the stress
angiotensin II);
response leads to activation of the immunological and
– Glucagon release from the α-cells of the islets
haematological systems.
of Langerhans;
The stress response, often referred to as the ‘fight
or flight’ response, was once a useful survival strategy. – Reduced insulin secretion from the β-cells of
However, in the context of modern surgery, many of the islets of Langerhans (see Chapter 77).
the physiological changes that accompany the stress Signals the pituitary to release:
response adversely affect surgical outcomes and – Adrenocorticotropic hormone, which stimulates
extend hospital stay. cortisol release from the adrenal cortex.
Cortisol is known as the ‘stress hormone’
How is the stress response initiated? owing to the multitude of effects it mediates in
What are its effects on the endocrine response to physiological stress. The
mineralocorticoid effects of aldosterone and
system? cortisol result in excess Na+ and water
The hypothalamus coordinates the stress response reabsorption.
through the secretion of pituitary hormones and the – Growth hormone (GH).
activation of the sympathetic nervous system. It is – Antidiuretic hormone (ADH). Increased ADH
stimulated to do so through two mechanisms: results in reabsorption of water at the renal
Relay of autonomic and sensory afferent nervous collecting duct.
impulses from the area of injury to the The secretion of the other pituitary hormones is
hypothalamus. not altered by the stress response.
Local activation of inflammation in the area of
injury with cytokine release, complement
activation, leukocyte attraction, platelet activation
What are the metabolic effects of the
and initiation of the coagulation cascade. hormonal changes?
Cytokines such as interleukin-6, interferons and The stress response has effects on all of the major
tumour necrosis factor spill over into the systemic metabolic substrates:
circulation, triggering the hypothalamus to Carbohydrate. Hyperglycaemia occurs in
activate the stress response. proportion to the severity of trauma due to:
Once activated, the hypothalamus: – Low insulin concentration;
Increases sympathetic nervous outflow, resulting in: – High glucagon concentration;
– Systemic release of adrenaline from the adrenal – The anti-insulin effects of catecholamines,
medulla; cortisol and, to a lesser extent, GH.
387
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 20:07:20, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.082
Section 8: Energy Balance
Protein. Protein metabolism has two phases: loss of skeletal muscle makes patients feel weak
– Initially, protein anabolism is inhibited. and contributes to post-operative immobility, thus
– After 12–14 h, skeletal muscle is catabolised: increasing venous thromboembolism risk. Loss of
amino acids are required for use as substrates respiratory muscle predisposes patients to post-
for gluconeogenesis and for the synthesis of operative respiratory failure. In the severely
acute-phase proteins. malnourished, cardiac muscle mass may be lost,
predisposing to arrhythmias. Unfortunately, no
The extent of protein catabolism is proportional to strategy has ever successfully prevented stress-
the severity of the trauma. This is referred to as related protein catabolism. However, protein
negative nitrogen balance, where the amount of catabolism does appear to be reduced by
nitrogen excreted from the body is greater than that preoperative carbohydrate loading and
ingested. The hormones involved are: perioperative low-dose glucose infusion.
– Cortisol, which promotes protein breakdown Electrolyte disturbance. A consequence of
and gluconeogenesis; increased mineralocorticoid activity (due to
– GH, which has greater anabolic than catabolic aldosterone and cortisol) is increased Na+ and
effects on body protein and thus may limit water reabsorption and increased K+ excretion.
skeletal muscle breakdown. Hypokalaemia is very common in hospitalised
Fat. Lipolysis and ketogenesis are promoted by: patients, particularly after major surgery and in
– High glucagon concentration; critical illness. Hypokalaemia may result in muscle
weakness, arrhythmias and ileus.
– Low insulin concentration;
– Increased catecholamine, cortisol and GH Fluid overload. Excess ADH and
mineralocorticoid activity, along with intravenous
concentrations.
fluid administration, can result in fluid overload,
precipitating left ventricular failure in susceptible
What are the adverse consequences of patients and contributing to wound breakdown
the stress response?
and anastomotic leak.
Thromboembolism. The stress response produces
The stress response has many adverse consequences:
a pro-coagulant state, increasing the risk of deep-
Cardiovascular. Increased levels of vein thrombosis and pulmonary embolus.
catecholamines and angiotensin II result in Immunological. Cortisol, released as part of the
peripheral vasoconstriction, hypertension and stress response, has significant effects on T cells.
tachycardia, all of which increase myocardial Cortisol stimulates the division of CD8+ cytotoxic
work, with the potential to precipitate myocardial T cells, which in turn suppresses the division of
ischaemia in susceptible patients. CD4+ T helper cells. Overall, the effect on T helper
Hyperglycaemia. Raised plasma glucose is cells results in the body being more susceptible to
associated with poor wound healing and wound invading pathogens. Cortisol also decreases
infection. In critical illness, hyperglycaemia is inflammation by decreasing capillary
associated with increased mortality, increased risk permeability, prostaglandin synthesis (through
of nosocomial infection, requirement for renal inhibition of the enzyme phospholipase), cytokine
replacement therapy and critical illness release and leukocyte migration.
polyneuropathy. The plasma glucose
concentration at which insulin therapy should be
started is controversial: tight glucose control (e.g.
How may anaesthetists reduce the
plasma glucose 4.4–6.1 mmol/L) may reduce these stress response to surgery?
adverse complications, but it carries an increased Looking through the list of adverse consequences of
risk of iatrogenic hypoglycaemia. the stress response, it is likely to be advantageous if
Protein catabolism. Negative nitrogen balance is the stress response to surgery could be reduced or
a major consequence of the stress response. Loss eliminated completely. As discussed above, the stress
of skeletal muscle mass can be significant (up to response is initiated by afferent sensory and auto-
0.5 kg/day) following major surgery. Generalised nomic neural input to the hypothalamus and by
388
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 20:07:20, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.082
Chapter 79: Stress Response
cytokine release. Methods to reduce the stress appear to have minimal influence on the stress
response include: response.
Epidural and spinal anaesthesia. This is the most Intraoperative warming. Maintaining
studied and most successful method of reducing normothermia intraoperatively has been shown to
the stress response. Preoperative neuraxial reduce the magnitude of the stress response.
blockade prevents initiation of the stress response Surgical technique. Surgeons also have a role to
by afferent neural input, but does not influence play in reducing the stress response to surgery.
cytokine release. Lumbar epidurals are more Laparoscopic and other minimally invasive
effective than thoracic epidurals at attenuating the surgical techniques are associated with reduced
stress response, as the lumbar autonomic nerves cytokine release compared with the equivalent
are less reliably blocked by thoracic epidurals. open procedures.
Neuraxial blockade also improves post-operative
pain, reduces thromboembolic risk (especially in
lower limb surgery) and reduces post-
Further reading
F. Fant, E. Tina, D. Sandblom, et al. Thoracic epidural
operative ileus.
analgesia inhibits the neuro-hormonal but not the acute
Systemic opioids. Opioids are well known to inflammatory stress response after radical retropubic
suppress the hypothalamic–pituitary–adrenal axis. prostatectomy. Br J Anaesth 2013; 110(5): 747–57.
High-dose fentanyl has been shown to abolish the M. Mikura, I. Yamaoka, M. Doi, et al. Glucose infusion
stress response to abdominal and pelvic surgery, suppresses surgery-induced muscle protein breakdown
but increases the need for post-operative by inhibiting ubiquitin–proteasome pathway in rats.
ventilation. Anaesthesiology 2009; 110(1): 81–8.
General anaesthetic agents. Etomidate is an D. Burton, G. Nicholson, G. Flail. Endocrine and metabolic
inhibitor of 11-β-hydroxylase in the adrenal response to surgery. Continuing Educ Anaesth Crit Care
cortex: an induction dose of etomidate reduces Pain 2004; 4(5): 144–7.
aldosterone and cortisol synthesis for up to 8 h J. P. Desborough. The stress response to trauma and
(see Chapter 81). Other general anaesthetic agents surgery. Br J Anaesth 2000; 85(1): 109–17.
389
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 20:07:20, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.082
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 20:07:20, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.082
Section 9 Endocrine Physiology
80
What is a hormone? into the circulation; neither is stored. The high
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 into the blood, allowing it to exert its signalling exert their effects by binding to cytosolic
effects on tissues elsewhere in the body. receptors. The steroid hormone–receptor complex
then travels to the cell nucleus, where it influences
What types of hormone exist? gene transcription. The eicosanoids have a wide
Hormones are classified on the basis of their chemical range of functions in the body and their
structure: mechanisms of action are complex.
Peptide hormones, the most common type, may Monoamine derivatives; that is, hormones
be subclassified as: derived from a single amino acid. For example:
– Short peptide chains; for example, thyrotropin- – Catecholamines are synthesised from
releasing hormone (TRH), antidiuretic phenylalanine or tyrosine.
hormone (ADH), adrenocorticotrophic – Serotonin is derived from tryptophan.
hormone (ACTH) and insulin; – Thyroxine is derived from tyrosine.
– Longer protein chains; for example, growth The monoamine-derived hormones behave
hormone (GH) and prolactin (PRL); very differently:
– Glycopeptides: a protein chain with – Catecholamines and serotonin are stored in
carbohydrate groups attached; for example, granules prior to release, whilst thyroxine is
luteinising hormone (LH), follicle-stimulating incorporated within thyroglobulin (see
hormone (FSH) and thyroid-stimulating Chapter 81).
hormone (TSH). – 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: hypothalamus?
– Steroid hormones; for example, aldosterone, 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
thromboxanes and leukotrienes. control over a large number of body functions, acting
as the link between brain, autonomic nervous system
The steroid hormones are all derived from
and endocrine system. The functions of the hypothal-
cholesterol, whilst the eicosanoids are derived
amus may be classified as:
from the phospholipid bilayer of cell membranes.
Both types of lipid-derived hormone are Autonomic. The hypothalamus receives inputs
synthesised as required and immediately released from the limbic system and relays them to the
391
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:17:51, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.083
Section 9: Endocrine Physiology
medulla oblongata. Thus, emotional stress (e.g. base of the skull. The pituitary gland is situated dir-
fear) triggers a sympathetic nervous system ectly below the hypothalamus, to which it is con-
response. nected by the pituitary stalk. The pituitary gland is
Thermoregulation. The hypothalamus integrates almost entirely covered superiorly by a fold of dura
signals from peripheral and central mater called the diaphragma sella; a gap allows the
(hypothalamic) thermoreceptors and controls the pituitary stalk to pass through.
balance of activities of the two hypothalamic The pituitary gland lies close to some key structures:
centres: the heat loss centre and the heat gain Superiorly, the pituitary stalk, optic chiasm and
centre (see Chapter 89). 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
feeding and satiety centres. These centres are internal carotid artery (ICA).
influenced by hypothalamic glucose
The pituitary gland itself comprises two main lobes,
concentration, gastrointestinal hormones
anterior (larger) and posterior, which are separated by
(cholecystokinin and glucagon) and leptin (a
a small pars intermedia. These lobes have different
hormone released from adipose tissue).
embryological origins:
Regulation of body water. As discussed in
Chapter 69, the hypothalamus regulates body The anterior lobe, or adenohypophysis, develops
from a depression of oral ectoderm in the
water through two mechanisms:
embryo’s pharynx, known as Rathke’s pouch.
– The thirst centre controls water intake. The posterior lobe, or neurohypophysis, develops
– Osmoreceptors control renal water excretion, from a downgrowth of neural ectoderm from the
in conjunction with ADH secretion by the hypothalamus. The posterior lobe never separates
pituitary gland. from the hypothalamus; the downgrowth persists
Control of sleep–wake cycles. Stimulation of the as the pituitary stalk.
anterior hypothalamus leads to sleep, whilst The pars intermedia is a very thin layer of cells
stimulation of the posterior hypothalamus causes located between the anterior and posterior lobes
wakefulness. Circadian rhythms are thought to that also develops from Rathke’s pouch. It is often
originate in the hypothalamus. considered to be part of the anterior lobe and is
Control of pituitary function. The hypothalamus not well developed in humans.
exerts control over the pituitary gland through
two mechanisms: Describe the blood supply to the
– The anterior lobe is controlled by the secretion pituitary gland
of hypothalamic hormones into the long The blood supply to the pituitary gland is complex.
portal vein. The anterior lobe receives blood from:
– The posterior lobe is controlled by direct neural
– The superior hypophyseal artery, a branch of
connections from the hypothalamus.
the ICA.
Behaviour. The hypothalamus contains – The long portal veins, which supply the
‘punishment’ and ‘reward’ centres, which anterior lobe with the majority of its blood.
moderate behaviour. A portal vein connects two capillary networks.
Regulation of sexual function. The hypothalamus The long portal veins connect the capillary
controls the pulsatile release of gonadotropins and network of the lower hypothalamus and
the surge of gonadotropins that leads to ovulation. pituitary stalk to the capillary network of the
anterior lobe. Thus, hormones released by the
Describe the anatomy of the neurosecretory cells of the hypothalamus are
delivered directly to the anterior lobe.
pituitary gland – The short portal veins, which transport some
The pituitary gland is a pea-sized gland located in the capillary blood from the posterior lobe to the
sella turcica, a depression in the sphenoid bone at the capillary networks of the anterior lobe.
392
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:17:51, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.083
Chapter 80: Hypothalamus and Pituitary
The posterior lobe receives blood from the Stimulating hormones – TSH, FSH, LH and
inferior hypophyseal artery, a branch of the ICA. ACTH. These hormones act at their respective
Venous blood from both anterior and posterior lobes endocrine glands, stimulating them to release
drains into the cavernous sinuses. thyroid hormones, oestrogen, testosterone and
cortisol, respectively. Their endocrine axes are
Which hormones does the named:
– The hypothalamic–pituitary–thyroid axis;
hypothalamus secrete? – The hypothalamic–pituitary–gonadal axis;
The hypothalamus secretes six hormones into the – The hypothalamic–pituitary–adrenal axis.
long portal vein, which exert control over the anterior
lobe of the pituitary gland: Taking each anterior lobe hormone in turn:
TRH, which stimulates the release of TSH; TSH is a glycoprotein hormone that acts on the
Gonadotropin-releasing hormone (GnRH), which thyroid gland, promoting the synthesis and release
causes the release of FSH and LH; of the biologically active thyroid hormone T3 and
Corticotropin-releasing hormone (CRH), which its precursor T4. TSH release is promoted by
triggers the secretion of ACTH; hypothalamic TRH release and inhibited by
GH-releasing hormone (GHRH), which stimulates negative feedback from circulating T3.
the release of GH; LH is a glycoprotein hormone. In females, a rapid
Somatostatin, which inhibits GH release and also increase in LH stimulates ovulation; following
moderately inhibits TSH release; ovulation, LH promotes the development of the
corpus luteum. In males, LH stimulates the synthesis
Dopamine, which inhibits the release of PRL.
and secretion of testosterone by Leydig cells.
FSH is also a glycoprotein hormone. In females,
What is meant by the term FSH promotes oestrogen synthesis and the
‘hypothalamic–pituitary axis’? development of ovarian follicles. In males, FSH
The hypothalamic–pituitary axis refers to the set of aids sperm maturation. FSH and LH are
complex endocrine interactions between the hypo- collectively known as gonadotropins. FSH and LH
thalamus, the anterior lobe of the pituitary gland secretion is promoted by the pulsatile release of
and the target organ. Hormone secretion by the hypo- hypothalamic GnRH and is inhibited by negative
thalamus and anterior lobe is controlled by two feedback from circulating testosterone or
negative-feedback loops (Figure 80.1): oestrogen.
Short-loop feedback – hormones secreted by the ACTH is a small peptide hormone that exerts its
anterior lobe inhibit the release of their respective effects on the adrenal gland. In response to
hypothalamic hormones. ACTH, cortisol is released from the zona
fasiculata. ACTH release is promoted by CRH
Long-loop feedback – the peripheral endocrine
release from the hypothalamus and is inhibited by
glands secrete hormones in response to anterior
feedback from circulating cortisol. Of interest,
lobe hormones (e.g. cortisol is secreted by the
ACTH is degraded over time to produce α-
adrenal cortex in response to ACTH). The
melanocyte-stimulating hormone (α-MSH),
resulting peripheral hormones then inhibit further
which accounts for the pigmentation of skin that
secretion of both pituitary and hypothalamic
occurs in Addison’s disease when ACTH levels are
hormones.
high.
GH is a protein hormone that has anabolic effects
Which hormones are secreted by the on tissues throughout the body. GH has two types
anterior lobe? of effect:
The anterior lobe secretes six hormones, classified as: – Direct effects. GH stimulates lipolysis through
Directly acting hormones – PRL and GH. These its action on adipose cell GH receptors, thus
hormones exert their effects through PRL and GH increasing the concentration of circulating
receptors at their target tissues. fatty acids.
393
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:17:51, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.083
Section 9: Endocrine Physiology
− −
Hypothalamus
Hypothalamic hormone
−
Anterior lobe
Short-loop feedback
Target tissue
– Indirect effects. The majority of GH effects are concentration also rises following sexual
mediated through insulin-like growth factor 1 intercourse and as part of the stress response; PRL
(IGF-1), a hormone secreted by the liver in concentration is raised following an epileptic
response to circulating GH. IGF-1 promotes seizure. Tumours may also increase prolactin
cell growth and development. concentration both as a direct result of increased
GH is released from the pituitary gland in a secretion (adenomas) and from compression of
pulsatile fashion, particularly at night. Regulation the pituitary stalk, which prevents dopamine from
of pituitary GH secretion is complex: GH travelling to the anterior pituitary.
secretion is promoted by the release of In addition, the pars intermedia secretes a seventh hor-
hypothalamic GHRH, but is inhibited by mone: α-MSH. Increased α-MSH secretion is respon-
hypothalamic secretion of somatostatin. In sible for the skin pigmentation of pregnancy and in
addition, GH secretion is part of a negative- Addison’s disease.
feedback loop in which IGF-1 inhibits pituitary
secretion of GH. Overall, plasma GH Which hormones are released by the
concentration is usually very low, but it is
increased at times of physiological stress, posterior lobe?
hypoglycaemia and exercise. The posterior lobe of the pituitary gland releases two
PRL is a protein hormone that has an important hormones: ADH and oxytocin. It is important to note
role in lactation, where it promotes breast that these hormones are not synthesised in the posterior
development during pregnancy and induces milk lobe. Instead, the two hormones are synthesised in the
production following delivery. Regulation of PRL hypothalamus, packaged into tiny vesicles, transported
release is different from that of the other anterior to the posterior lobe through nerve axons and stored in
lobe hormones: there is no hypothalamic granules within the nerve terminals. Following an action
stimulating hormone. Instead, the hypothalamus potential from the hypothalamus, the storage granules
controls PRL secretion through tonic dopamine are released into the systemic circulation.
release, which in turn inhibits pituitary PRL The two posterior lobe hormones are:
release. In the context of breastfeeding, PRL ADH, a small peptide hormone with two main
secretion is stimulated by suckling. PRL physiological effects:
394
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:17:51, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.083
Chapter 80: Hypothalamus and Pituitary
395
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:17:51, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.083
Section 9 Endocrine Physiology
81
The thyroid gland Metabolism. T3 affects the activity of a wide range
of metabolic processes, such as lipolysis and
Which hormones are synthesised by the gluconeogenesis. Hyperthyroidism results in an
increase in basal metabolic rate (BMR) and an
thyroid gland? increased availability of metabolic substrates, such
The thyroid gland is located in the anterior neck and as free fatty acids and glucose. In hypothyroidism,
consists of two lobes connected by an isthmus. It the opposite occurs.
secretes two hormones: Growth and development. Hypothyroidism in
Triiodothyronine (T3), the strongly biologically childhood causes growth retardation. T3 is
active thyroid hormone. T3 comprises only 10% especially important in the development of the
of the hormones released by the thyroid gland. central nervous system (CNS), where it stimulates
In the circulation, T3 is very highly protein neuronal myelination and nerve axon growth.
bound (99.7%), mainly to albumin, and has a Respiratory system. In hyperthyroidism, O2
short half-life (24 h). Only the unbound fraction consumption and CO2 production are increased
of T3 is able to diffuse into the tissues to exert due to the increase in BMR. In turn, V̇ E increases.
its effects. Cardiovascular system. In hyperthyroidism, T3
Thyroxine (T4), a weakly biologically active increases the number of β-adrenergic receptors in
hormone, is the main hormone synthesised by the the heart. The result is an increase in heart rate
thyroid gland (90%). T4 is also very highly protein (HR) and myocardial contractility, leading to an
bound, but mainly to a specific carrier protein: increase in cardiac output.
thyroxine-binding globulin. At 7 days, the half-life CNS. T3 has an important effect on mood: in
of T4 is much longer than that of T3. Around half hypothyroidism, depression and psychosis may
of the weakly active T4 is converted to the active occur, whilst hyperthyroidism is associated with
form, T3, in the peripheral tissues. The other half anxiety.
is converted to an inactive hormone called reverse Musculoskeletal system. In hyperthyroidism, T3
T3. Bound T3 and T4 provide a large reservoir of induces protein catabolism, which predominantly
thyroid hormone, which delays the onset of affects proximal muscles, resulting in proximal
symptoms in hypothyroidism. myopathy.
What are the physiological effects of How are triiodothyronine and thyroxine
triiodothyronine? synthesised?
T3 is able to diffuse across cell membranes to reach The thyroid gland is made up of multiple follicles:
the cell nucleus, where it regulates gene transcription. spheres of follicular cells surrounding a core of thyro-
T3 therefore has physiological effects on most tissue globulin, a large protein containing many tyrosine resi-
types in the body, with the exception of the spleen and dues. T3 and T4 are synthesised as follows (Figure 81.1):
the thyroid gland itself. The main physiological effects Iodide (I‾) uptake. I‾ is actively transported from
of T3 are perhaps best illustrated when T3 concen- the circulation to the follicular cells through a
tration is either abnormally high or low, as occurs in Na+/I‾ co-transporter. As a result of this
hyperthyroidism and hypothyroidism, respectively: secondary active transport, 25% of the body’s I‾ is
396
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:09:42, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.084
Chapter 81: Thyroid, Parathyroid and Adrenal
Na+ co-transporter
Na+ Na+
I2
2 O2
Thyroglobulin Thyroglobulin
T3 + T4 T3 + T4
T3 T3 DIT MIT
Thyroglobulin Thyroglobulin Thyroglobulin
T4 T4 DIT DIT
stored within the thyroid. The uptake of I‾ is the follicular cells. Within the follicular cell, T3 and
stimulated by thyroid-stimulating hormone T4 are separated from thyroglobulin and released into
(TSH). I‾ diffuses through the follicular cell and the circulation.
into the follicular lumen.
I‾ oxidation. As I‾ is relatively inert, it must be How is the plasma concentration of thyroid
oxidised to the more reactive iodine (I2) by
thyroid peroxidase involving hydrogen peroxide hormones regulated?
(H2O2), a reaction that is promoted by TSH. TSH has multiple roles in both the synthesis and
I2 reaction with tyrosine. Once synthesised, I2 release of thyroid hormones. TSH is released by the
reacts with the tyrosine residues of the anterior lobe of the pituitary gland in response to
surrounding thyroglobulin protein. Tyrosine may hypothalamic secretion of thyrotropin-releasing hor-
be iodinated at one or two positions, resulting in mone (TRH; see Chapter 80). In turn, TRH release is
mono-iodotyrosine (MIT) or di-iodotyrosine controlled through a negative-feedback loop: T3, the
(DIT), respectively. biologically active thyroid hormone, inhibits the
Oxidative coupling. Two of the iodinated tyrosine release of TRH at the hypothalamus. T3 is highly
molecules are then coupled together. If two DIT protein bound; only the unbound fraction is able to
molecules join, the resulting compound is T4; if inhibit the hypothalamus.
MIT is coupled to DIT, the result is T3. This Disturbances in the hypothalamic–pituitary–thyroid
oxidative coupling of tyrosine residues is axis usually result from thyroid gland dysfunction:
promoted by TSH. Hypothyroidism most commonly results from
Hashimoto’s thyroiditis, an autoimmune disease
The end result of this process is small T3 and T4
of the thyroid gland in which antibodies are
molecules dispersed throughout the large thyroglobu-
directed against thyroid peroxidase or
lin protein.1 It is estimated that the thyroid gland
thyroglobulin. The result is a reduction in T3 and
contains a sufficient store of T3 and T4 to meet the
T4 secretion. In response, the hypothalamus and
body’s requirements for 1–3 months. In response to
anterior lobe of the pituitary gland increase their
TSH, droplets of thyroglobulin are endocytosed by
secretion of TRH and TSH, respectively; a high
measured TSH normally implies hypothyroidism.
1
This is why thyroglobulin is often called a colloid; that is, Hyperthyroidism is most commonly due to
a substance dispersed within another substance. Graves’ disease, an autoimmune condition that
397
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:09:42, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.084
Section 9: Endocrine Physiology
results in increased synthesis and secretion of T3 severe Graves’ eye disease may be treated with corti-
and T4. The hypothalamus and anterior lobe of costeroids or by surgical debulking.
the pituitary gland respond by decreasing their
secretion of TRH and TSH. A low measured TSH Clinical relevance: anaesthesia for thyroid surgery
normally implies hyperthyroidism. There are many indications for thyroid surgery: thy-
roid malignancy, hyperthyroidism and goitre with
What is Graves’ disease? associated complications, such as tracheal compres-
Graves’ disease is an autoimmune disease: autoantibo- sion. Anaesthesia for thyroid surgery may be particu-
larly challenging owing to the proximity of the
dies stimulate TSH receptors in the thyroid gland, caus-
thyroid gland to the trachea.
ing excessive synthesis and release of T3 and T4. The Prior to thyroid surgery, the patient should be
clinical effects of Graves’ disease can be divided into: rendered euthyroid by one of the medical methods
Those due to hyperthyroidism. Symptoms above. In addition to the usual clinical assessments of
include palpitations, heat intolerance, weight loss the airway, a computed tomography scan of the neck
despite increased appetite, fine tremor, diarrhoea may be used to assess the size and position of any
and excessive sweating. Clinical signs include goitre. It is also important to identify compression or
sinus tachycardia, atrial fibrillation, lid lag and a invasion of the structures surrounding the thyroid
smooth, diffusely enlarged thyroid gland (a gland: the trachea (resulting in stridor), superior vena
cava (obstruction), sympathetic chain (Horner’s syn-
‘goitre’).
drome) and recurrent laryngeal nerve (hoarse voice).
Those caused by the autoantibodies. Graves’ eye Induction of anaesthesia may require a gaseous
disease is caused by the same TSH receptor or awake fibre-optic technique if the trachea is com-
autoantibodies that also target fibroblasts in the pressed or the anatomy significantly distorted. Occa-
extraocular muscles. The resulting inflammation sionally, the only airway option is a tracheostomy
causes exophthalmos (upper lid retraction), performed under local anaesthesia. Intraoperative
proptosis (bulging eyes) and conjunctivitis. electrophysiological testing of the recurrent laryn-
geal nerve may preclude the use of muscle relaxants
following induction – a remifentanil infusion is there-
What are the management options in fore commonly used.
Graves’ disease? A number of serious post-operative complica-
There are three treatment options in hyperthyroidism: tions may occur:
398
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:09:42, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.084
Chapter 81: Thyroid, Parathyroid and Adrenal
2+
The mass of Ca in an adult is approximately 1 kg.
have long-standing or very large goitres are at 2+
Almost all Ca is located in bone (99%). This
much greater risk of tracheomalacia. Prior to
Ca2+ cannot be rapidly mobilised. The remaining
extubation, it is useful to deflate the
endotracheal tube cuff to check for air leak. 1% is located in teeth and soft tissues.
2+
Only 0.1% of body Ca is located in the
extracellular fluid (ECF) and only a third of this is
Regulation of calcium homeostasis located in the plasma.
The normal range of plasma Ca2+ is 2.2–2.6 mmol/L.
What are the physiological functions of Only around 45% of plasma Ca2+ is in the biologically
calcium? active ionised form. The remaining 55% is either pro-
Ca2+ has numerous biological roles, the most import- tein bound or associated with various anions, such as
ant of which are: HCO3‾, citrate and phosphate. It is important to note
Structural – calcium phosphate gives bone its that whilst the total amount of plasma Ca2+ falls when
rigidity. albumin is low, the ionised portion of Ca2+ remains the
same. Plasma Ca2+ can be mathematically corrected for
Haemostasis – Ca is an essential cofactor in the
2+
coagulation cascade. Blood samples are prevented hypoalbuminaemia2 or, alternatively, ionised Ca2+ can
from clotting through the addition of EDTA or be measured by arterial blood gas analysis. The normal
range for ionised Ca2+ is 1.1–1.4 mmol/L.
citrate, which irreversibly binds Ca2+ (see
Chapter 72).
Resting membrane potential (RMP) – How is plasma calcium concentration
extracellular Ca2+ concentration affects the cell regulated?
membrane Na+ permeability, which in turn affects Logically, plasma Ca2+ concentration may be altered
the RMP of excitable cells. Hypocalcaemia acts to by:
depolarise the cell membrane towards the
threshold potential. Thus, nerves may undergo An increase or decrease in intestinal absorption
of dietary Ca2+;
spontaneous depolarisation, resulting in tetany
(see Chapter 52). Clinical signs of hypocalcaemia An increase or decrease in renal excretion of
include Trousseau’s sign (carpal spasm following Ca2+ salts;
2+
inflation of a blood pressure cuff ) and Chvostek’s Movement of Ca between body compartments.
sign (inducing facial spasm when tapping over the Three hormones are involved in Ca2+ homeostasis.
zygoma). Parathyroid hormone (PTH) and vitamin D act to
Neurotransmitter release – Ca influx into the
2+
increase plasma Ca2+ concentration, whilst calcitonin
terminal bouton triggers the exocytosis of vesicles acts to decrease plasma Ca2+ concentration:
filled with neurotransmitter into the synaptic cleft PTH is a protein hormone secreted by the
(see Chapter 53). parathyroid glands. There are usually four
Excitation–contraction coupling – Ca influx
2+
parathyroid glands, located on the posterior
into skeletal, cardiac or smooth muscle is essential surface of the thyroid gland. Plasma Ca2+
for the binding of myosin to actin (see concentration is sensed by parathyroid Ca2+-
Chapters 54, 56 and 57). sensing receptors (CaSRs). Low plasma Ca2+
Cell signalling – Ca is an important second
2+
triggers PTH secretion, which acts at:
messenger. For example, G proteins that act via – The kidney. Here, it increases Ca2+
inositol triphosphate use Ca2+ as the intracellular reabsorption and decreases phosphate
messenger. reabsorption.
399
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:09:42, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.084
Section 9: Endocrine Physiology
– Bone. Here, it increases the activity of the biologically active form of vitamin D.
osteoclast cells (the cells that resorb bone), The enzyme that catalyses this process is 1-α-
releasing stored Ca2+. hydroxylase, which is upregulated by PTH.
– The intestine. This is an indirect effect: PTH Vitamin D increases plasma Ca2+ concentration
upregulates the renal enzyme 1-α-hydroxylase, through its actions on:
which is responsible for activating vitamin
– The intestine, where the absorption of dietary
D (see below). Vitamin D increases the
Ca2+ and phosphate is increased.
intestinal absorption of dietary Ca2+ and
– The kidney, where Ca2+ and phosphate
phosphate.
reabsorption is increased.
Vitamin D, a steroid hormone. Vitamin D must
In addition, vitamin D acts on the bone, where it
go through a series of modifications before it can
increases bone calcification.
exert its effects (Figure 81.2):
It is important to note that, under normal
– In the skin: cholecalciferol (vitamin D3) is circumstances, the rate-determining step in the
synthesised through the effects of sunlight on synthesis of calcitriol is 1-α-hydroxylation. PTH
7-dehydrocholesterol in the skin. controls the activity of the enzyme involved in this
Cholecalciferol also originates in the diet; step; PTH therefore directly controls the plasma
vitamin D is not a vitamin in the strictest concentration of calcitriol.
sense: individuals who have adequate exposure Calcitonin is a peptide hormone secreted by the
to sunlight do not require dietary parafollicular C cells of the thyroid gland.
supplementation. Calcitonin has a minor role in Ca2+ homeostasis
– In the liver: vitamin D3 is 25-hydroxylated by in humans, only being secreted when plasma Ca2+
the enzyme 25-hydroxylase, resulting in rises above 2.4 mmol/L. Calcitonin decreases
calcidiol (25-hydroxy vitamin D3). plasma Ca2+ concentration through its actions on:
– In the kidney: calcidiol is 1-α-hydroxylated – The intestine, where it decreases the absorption
to give calcitriol (1,25-dihydroxy vitamin D3), of dietary Ca2+ and phosphate;
– The kidney, where it decreases the
7-dehydrocholesterol reabsorption of Ca2+ and phosphate and
decreases the activity of the enzyme 1-α-
hydroxylase, thereby decreasing the effects of
SKIN UVB radiation
vitamin D.
– Bone, where osteoclast activity is decreased,
Cholecalciferol Diet thereby decreasing bone resorption.
Other hormones such as gonadal steroids (increase
LIVER 25-hydroxylase bone density), glucocorticoids (decrease bone density)
and growth hormone (increase bone density) also
affect Ca2+ homeostasis.
Calcidol
In summary:
2+
Low plasma ionised Ca concentration:
KIDNEY 1- -hydroxylase
– Increases parathyroid PTH secretion, which,
in turn, increases the rate of vitamin
Calcitriol D activation.
Rate-determining step:
upregulated by PTH – The combined effects of vitamin D and PTH
increase intestinal absorption and renal
reabsorption of Ca2+. The effect on bone is
negligible, as the increase in bone resorption
Bone effects Intestinal effects
Renal effects by PTH is cancelled out by the bone
calcification effect of vitamin D.
Figure 81.2 Vitamin D metabolism.
400
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:09:42, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.084
Chapter 81: Thyroid, Parathyroid and Adrenal
2+
High plasma ionised Ca concentration: surrounded by a protective fat pad and renal fascia.
– Decreases PTH secretion and, in turn, The adrenal gland consists of two distinct parts that
decreases the rate of activation of vitamin differ in their embryological origins:
D. In addition, the parafollicular C cells release The (outer) adrenal cortex makes up 70% of the
calcitonin. adrenal glands’ weight. The adrenal cortex is
– The combined effect of reduced PTH, reduced derived from mesoderm and is composed of three
vitamin D and increased calcitonin results in a layers:3
decrease in intestinal Ca2+ absorption and – Zona glomerulosa, the outermost layer, is the
renal Ca2+ reabsorption. main site of aldosterone production.
– Zona fasciculata, the middle layer, is the main
Clinical relevance: kidney and liver dysfunction site of glucocorticoid synthesis.
As discussed above, 25-hydroxylation of vitamin – Zona reticularis, the inner layer, produces
D occurs in the liver and 1-α-hydroxylation occurs androgens. The main androgens produced are
in the kidney. dehydroepiandrosterone and androstenedione.
In chronic kidney disease (CKD), 1-α-hydroxyla- These are weak androgens that are converted
tion of calcidiol is impaired – activated vitamin to testosterone by the peripheral tissues.
D cannot be synthesised. Without vitamin D, renal
excretion of Ca2+ exceeds intestinal absorption, The (inner) adrenal medulla is innervated by
resulting in hypocalcaemia. PTH secretion increases T5–T9 pre-ganglionic sympathetic neurons; the
as the parathyroid glands attempt to normalise adrenal medulla can be considered to be a
plasma ionised Ca2+ concentration. This is referred modified sympathetic ganglion. Sympathetic
to as secondary hyperparathyroidism. PTH causes nervous system activity stimulates the chromaffin
extensive demineralisation of the bones as Ca2+ is cells to release granules containing adrenaline
redistributed to the ECF, resulting in renal osteody- (approximately 80%) and noradrenaline
strophy. Patients with CKD are treated with a pre- (approximately 20%).
activated form of vitamin D, alfacalcidol, thereby
bypassing the renal 1-α-hydroxylation mechanism.
The aetiology of bone disease in cirrhosis patients Discuss the physiology of aldosterone
is more complex than in CKD; for example, alcoholism Aldosterone is a steroid hormone produced by the
is associated with a dietary Ca2+ deficiency and hae- zona glomerulosa. It accounts for 95% of the miner-
mochromatosis is complicated by gonadal failure, alocorticoid activity in the body, with cortisol con-
which is associated with osteoporosis. Severe liver tributing much of the remainder. It therefore
dysfunction may also cause impaired 25-hydoxylation
promotes Na+ and water reabsorption, along with
of cholecalciferol: activated vitamin D levels are low,
K+ and H+ excretion. Aldosterone therefore plays an
which contributes to bone disease.
important role in the regulation of blood volume and
consequently blood pressure.
There are four main triggers to aldosterone
Clinical relevance: hyperparathyroidism
secretion:
Other than surgery, hyperparathyroidism may also Angiotensin II is the most important factor in
be treated using the ‘calcimimetic’, cinacalcet. Cina- aldosterone release. The renin–angiotensin–
calcet increases the sensitivity of the CaSR, resulting
aldosterone axis is a complex feedback loop that
in decreased PTH secretion. It has been used in
helps regulate blood volume. As discussed in
primary, secondary and tertiary hyperparathyroidism.
Chapter 67, the main trigger for renin release is a
reduction in renal blood flow (RBF). Renin
The adrenal glands converts angiotensinogen to angiotensin I.
401
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:09:42, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.084
Section 9: Endocrine Physiology
402
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:09:42, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.084
Chapter 81: Thyroid, Parathyroid and Adrenal
Tyrosine
L-DOPA
DOPA decarboxylase
Dopamine
Dopamine -hydroxylase
COMT
Noradrenaline Normetanephrine MAO
Tyrosine is taken up into the cytoplasm of pre-ganglionic sympathetic nerves that terminate
chromaffin cells, where it is converted to l-3,4- on the chromaffin cells of the adrenal medulla.
dihydroxyphenylalanine (l-DOPA). This is the Like other pre-ganglionic sympathetic neurons
rate-determining step of catecholamine synthesis. (see Chapter 59), acetylcholine (ACh) is released
l-DOPA is converted into dopamine. from the terminal bouton.
Dopamine is converted into noradrenaline. ACh activates nicotinic receptors on the
Noradrenaline is converted into adrenaline by the chromaffin cell membrane, increasing cell
enzyme phenylethanolamine N-methyl transferase membrane Na+ and K+ permeability, which
(PNMT). This enzyme is only present in the results in net depolarisation.
chromaffin cells of the adrenal medulla. Membrane depolarisation opens voltage-gated
Therefore, whilst noradrenaline may be Ca2+ channels; the influx of Ca2+ into the
synthesised elsewhere (e.g. sympathetic nerve chromaffin cells triggers exocytosis of the
terminals), adrenaline can only be synthesised catecholamine-containing granules, releasing
within the adrenal medulla. adrenaline and noradrenaline into the circulation.
Noradrenaline and adrenaline are then packaged It is important to note that catecholamine release
into granules, which also contain ATP, from the adrenal medulla does not take place in
chromogranin A and opioid peptides such as isolation – it is part of a wider sympathetic nervous
metenkephalin. response that includes extensive noradrenaline release
at sympathetic nerve terminals.
How is catecholamine secretion controlled?
Whilst the hormones of the adrenal cortex are con-
trolled by negative-feedback loops, the catechol-
What are the physiological effects of
amines of the adrenal medulla are secreted in adrenaline and noradrenaline?
response to sympathetic nervous system activity; The most important physiological effects of adrena-
there is no negative-feedback control of catechol- line are:
amine secretion. Metabolic. Adrenaline stimulates glycogenolysis,
Secretion of catecholamines takes place as follows: which in turn increases plasma glucose
In response to various stimuli (exercise, trauma, concentration. Free fatty acids are liberated from
pain, hypovolaemia, hypoglycaemia, hypothermia adipose tissue and amino acids are released from
and anxiety), action potentials are generated in the skeletal muscle.
403
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:09:42, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.084
Section 9: Endocrine Physiology
Heart. Adrenaline has positive chronotropic and (MAO), two enzymes distributed widely throughout
positive inotropic effects on the heart, increasing the body. Metanephrine is an intermediate in this
HR and myocardial contractility, respectively, process, with vanillylmandelic acid produced after
through stimulation of β1-adrenergic receptors. both enzymes have exerted their effects. Phaeochro-
Vasculature. Adrenaline causes peripheral mocytoma, a tumour of chromaffin cells associated
vasoconstriction, except in skeletal muscle with excessive secretion of catecholamines, may be
capillary beds, where it causes vasodilatation. diagnosed through raised plasma metanephrine
Lungs. Adrenaline relaxes bronchial smooth concentrations.
muscle through β2‑adrenergic receptors, resulting
in bronchodilatation. Further reading
P. E. Molina. Endocrine Physiology, 5th edition. New York,
Noradrenaline causes peripheral vasoconstriction McGraw-Hill, 2018.
through the activation of α1‑adrenoceptors, with
D. E. Kerr, T. Wenham, J. Newell-Price. Endocrine
baroreceptor-mediated reflex bradycardia. Noradren-
problems in the critically ill 2: endocrine emergencies.
aline promotes gluconeogenesis and lipolysis. In add- BJA Education 2017; 17(11): 377–82.
ition, noradrenaline plays an important role in the
T. Miller, B. Gibbison, G. M. Russell. Hypothalamic–
normal functioning of the CNS. pituitary–adrenal function during health, major
surgery, and critical illness. BJA Education 2017;
How are catecholamines metabolised? 17(1): 16–21.
The plasma half-life of catecholamines is very short: D. S. Ross. Radioiodine therapy for hyperthyroidism.
both noradrenaline and adrenaline have plasma half- N Engl J Med 2011; 364(6): 542–50.
lives of around 2 min. Noradrenaline and adrenaline S. Malhotra, V. Sodhi. Anaesthesia for thyroid and
are both sequentially metabolised by catechol-O- parathyroid surgery. Continuing Educ Anaesth Crit Care
methyltransferase (COMT) and monoamine oxidase Pain 2007; 7(2): 55–8.
404
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:09:42, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.084
Section 10 Developmental Physiology
82
How does endocrine function alter – After 10 weeks’ gestation, the placenta slowly
takes over oestrogen and progesterone
during pregnancy? synthesis from the corpus luteum. β-hCG
It comes as no surprise that there are major endocrine concentration then falls and the corpus luteum
changes during pregnancy. These endocrine changes degenerates.
are the driving force for many of the other physio- β-hCG is also thought to be involved in
logical and anatomical changes associated with suppressing the maternal immune response,
pregnancy. protecting the placenta and embryo from immune
The main hormones involved are: destruction.
β-human chorionic gonadotropin (β-hCG), a Human placental lactogen (hPL), a polypeptide
glycoprotein hormone with a structure similar to hormone whose structure is similar to that of
that of luteinising hormone, follicle-stimulating growth hormone. Like β-hCG, hPL is secreted by
hormone and thyroid-stimulating hormone the syncytiotrophoblast cells of the placenta.
(TSH). It is secreted by the placenta shortly after Throughout pregnancy, hPL concentration
implantation of the embryo and can be detected in increases in proportion to foetal and placental
the maternal circulation from the second week of growth, peaking near term. Its function is to
pregnancy. β-hCG levels rise rapidly, doubling ensure adequate provision of nutrients for the
every 2 days until a peak is reached at 10 weeks’ growing foetus through manipulation of maternal
gestation. Its main role is to prolong the life of the metabolism:
corpus luteum: – Increased maternal lipolysis increases the
– In the second half of the menstrual cycle, the availability of free fatty acids.
corpus luteum secretes progesterone and a – Decreased maternal peripheral insulin
small amount of oestrogen. sensitivity results in decreased peripheral
– After 14 days, in the absence of an implanted utilisation of glucose and thus increased
embryo, progesterone secretion stops and the maternal plasma glucose concentration. It is
corpus luteum degenerates into the corpus important that the foetus has access to ample
albicans. The decline in progesterone triggers glucose, as this is its primary source of energy.
sloughing of the uterine lining (the hPL is implicated in the development of
endometrium). gestational diabetes.
– If an embryo implants in the endometrium (or – Stimulation of breast growth and development.
fallopian tube in the case of an ectopic As the name suggests, hPL mimics the action
pregnancy), the syncytiotrophoblast cells of of prolactin (PRL); whilst it has a much weaker
the newly formed placenta produce effect than PRL, the high concentration of hPL
progressively increasing amounts of β-hCG, is thought to be partly responsible for breast
which stimulates the corpus luteum to development during pregnancy.
continue secreting progesterone. This prevents
Progesterone, a steroid hormone often referred to
sloughing of the endometrium, which would as the ‘pregnancy hormone’, reflecting its many
cause miscarriage. important roles. Progesterone is secreted by the
405
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:11:15, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.085
Section 10: Developmental Physiology
corpus luteum in early pregnancy and by the the pituitary. Increased TSH stimulates the
placenta in the second and third trimesters. The thyroid to secrete additional T3 and T4, bringing
main functions of progesterone are: the free fractions of thyroid hormones back to
– Preparing the endometrium for implantation normal.
and promoting growth of the endometrium PRL. Oestrogen stimulates a dramatic increase in
following implantation; the pituitary secretion of PRL, whose role is the
– Uterine muscle relaxation, suppressing preparation of the breasts for lactation. The
myometrial contractions and preventing pituitary gland doubles in size to accommodate
miscarriage; the number of extra lactotrophs required. Because
– Formation of a cervical mucus plug, thus of the increased metabolic demands of the
protecting the developing foetus from enlarged pituitary gland, it becomes vulnerable to
ascending infection; ischaemia. Pituitary infarction can occur if the
patient suffers prolonged hypotension, as may
– Development of milk glands in preparation for
result from post-partum haemorrhage – this is
lactation.
known as Sheehan’s syndrome.
In addition, progesterone is responsible for many 2+
Parathyroid hormone (PTH). Ca is transferred
of the other physiological changes associated with across the placenta to meet the requirements of
pregnancy, which are discussed in more detail the growing foetus. As maternal absorption of
below. dietary Ca2+ cannot meet this placental loss, one
Oestrogen. Three oestrogens are synthesised by might expect maternal ionised Ca2+ concentration
the placenta: oestradiol, oestrone and oestriol. to fall. However, the maternal parathyroid
Each oestrogen comes from a different precursor, glands sense the fall in plasma Ca2+ and
and the amount of each oestrogen produced is respond by increasing secretion of PTH. PTH
proportional to the amount of each precursor increases plasma Ca2+ concentration by increasing
delivered to the placenta. The main oestrogen bone resorption, renal tubular Ca2+ reabsorption
produced in pregnancy is oestriol, whose main and activation of vitamin D. Of clinical
role is to increase uteroplacental blood flow (in significance, pregnant patients at high
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-
foetal adrenal precursor called molecular-weight heparin (LMWH). LMWH has
dehydroepiandrosterone sulphate. Consequently, the undesirable effect of worsening the PTH-
uteroplacental blood flow is under the control of related reduction in bone mineral density,
the growing foetus. Other roles of oestrogens potentially leading to osteopenia.
include:
– Stimulation of uterine growth;
– Sensitisation of the myometrium to oxytocin in
Which other physiological changes of
preparation for labour. pregnancy are of interest to
In addition, oestriol is responsible for the anaesthetists?
increased risk of thromboembolic disease This is best answered using a system-by-system
associated with pregnancy. approach:
Other pregnancy-related endocrine changes include: Respiratory system. Changes to the respiratory
Thyroid hormones. In pregnancy, oestriol system begin by as early as 4 weeks’ gestation, but
stimulates the liver to synthesise additional the most significant changes occur from 20 weeks’
thyroxine-binding globulin. Therefore, one might gestation:
expect unbound triiodothyronine (T3) and Airway. Pregnancy-related capillary engorgement
thyroxine (T4) concentrations to decrease. causes oedema of the oropharyngeal mucosa
However, thyrotropin-releasing hormone and larynx. In pre-eclampsia, the change in
secretion increases as a result of the negative- capillary dynamics can significantly worsen
feedback loop, which increases TSH secretion by airway oedema.
406
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:11:15, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.085
Chapter 82: Maternal Physiology during Pregnancy
407
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:11:15, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.085
Section 10: Developmental Physiology
Blood volume. Total blood volume increases during uterine contractions. Epidural analgesia
gradually throughout pregnancy, by around 40% reduces the secretion of catecholamines in
for a singleton pregnancy and even more for a response to pain, which can lessen the impact of
multiple pregnancy: labour on the heart. Following delivery, the
– Red cell mass increases by 20–30% due to an autotransfusion of 500 mL of uterine blood to the
increase in erythropoietin secretion. Plasma venous system increases cardiac preload, resulting
volume increases by 45% due to oestrogenic in a 60–80% increase in CO. This is a moment of
stimulation of the renin–angiotensin– great danger to parturients at risk of cardiac
aldosterone system. The discrepancy between failure.
the increases in red cell mass and plasma Aortocaval compression. From 20 weeks’
volume results in the physiological anaemia of gestation, the enlarging uterus can compress the
pregnancy. Haemoglobin (Hb) concentration inferior vena cava (IVC) and the descending aorta
falls from a typical pre-pregnancy when the parturient is supine. This has serious
concentration of 150 g/L to around 120 g/L at implications:
term; haematocrit falls to around 0.35. – Reduced maternal venous return. Reduced
– Each uterine contraction squeezes 300–500 mL cardiac preload causes a fall in CO, leading to a
of blood from the uterus to the systemic feeling of nausea, pallor, hypotension or
circulation during labour. cardiovascular collapse when supine.
– Blood loss at delivery is typically 300 mL for Symptoms and signs resolve in the lateral
vaginal delivery and 500 mL for caesarean position, where IVC compression is relieved.
section. The mother is protected from the – Reduced placental blood flow. Blood flow to the
impact of this haemorrhage by placenta is not autoregulated; instead, blood
‘autotransfusion’, in which around 500 mL of flow is directly proportional to perfusion
blood is returned to the systemic circulation pressure (see Chapter 83). IVC compression
during uterine involution. by the gravid uterus reduces CO, which
impairs placental perfusion. In addition,
Cardiac output (CO). The increase in CO starts in
early pregnancy, from the fourth week of compression of the descending aorta further
gestation. CO increases by up to 50% by the third reduces uteroplacental blood flow. Impaired
trimester. The factors involved are: placental blood flow may result in inadequate
foetal gas exchange, sometimes with fatal
– A reduction in afterload. Systemic vascular consequences.
resistance (SVR) falls by 20% due to
progesterone-induced vasodilatation. As a Most non-anaesthetised parturients are able to
result, systolic blood pressure falls by 5% and compensate, at least partially, for aortocaval
diastolic blood pressure falls by 10%. compression through two mechanisms:
– Increased heart rate (HR). In response to – Sympathetic outflow increases, which in turn
decreased blood pressure, there is a reflex increases SVR and HR.
increase in HR of 25% over the course of the – Some blood bypasses the compressed IVC,
pregnancy. returning from the lower limbs to the heart
– An increase in preload. Increased circulating through collateral pathways: the azygos,
blood volume results in an increase in cardiac paravertebral and epidural veins.
preload. As a result, stroke volume (SV) General anaesthesia and neuraxial blockade
increases by 30%. Much of the increase in SV abolish the sympathetic response to aortocaval
occurs during the first trimester. compression; severe hypotension or even cardiac
– Myocardial contractility is unchanged by arrest may develop rapidly when the patient is
pregnancy. supine. It is therefore very important that the
During labour, CO is increased further (25–50%) parturient is never supine and that the uterus is
in response to catecholamine secretion. In always displaced from the great vessels.
addition, CO increases by an additional 20–30% Aortocaval compression is usually relieved by a
408
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:11:15, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.085
Chapter 82: Maternal Physiology during Pregnancy
lateral tilt (on the operating table or with a wedge), universally accepted, but is often taken as
but relief can only be guaranteed in the full lateral 6000–16,000/mm3 from the 12th gestational week.
position. Lateral tilt with a wedge is especially WCC may increase to as much as 30,000/mm3
important to remember during cardiopulmonary during labour.
resuscitation of pregnant patients. Platelet count falls gradually throughout
Gastrointestinal (GI) system. The changes in GI pregnancy; at term, the lower limit of a normal
physiology are of particular importance to the anaes- platelet count is 115 109/L. The decreased
thetist. There is a significantly increased risk of platelet count is due to both haemodilution (a
gastro-oesophageal reflux in pregnancy due to: relatively increased plasma volume) and shorter
platelet lifespan.
Decreased lower oesophageal sphincter (LOS)
tone. Progesterone-induced smooth muscle Hypercoagulable state. Pregnant patients are at
relaxation decreases the tone of the LOS, leading significantly increased risk of venous
to sphincter incompetence. thromboembolism due to:
Mechanical changes at the gastro-oesophageal – An increase in fibrinogen and clotting factors
junction. The gravid uterus displaces the stomach VII, X and XII;
and diaphragm upwards, reducing the acute angle – Decreased fibrinolysis.
of the oesophagus as it passes through the Renal physiology. Pregnancy induces both
diaphragm. anatomical and physiological changes to the
Increased intra-gastric pressure. In the third kidneys and ureters:
trimester, the gravid uterus increases gastric
– Dilatation of the ureters and renal pelvis as a
pressure. This further reduces the lower
result of both mechanical obstruction by the
oesophageal barrier pressure.
gravid uterus and progesterone-induced
Delayed gastric emptying. Gastric emptying is
smooth muscle dilatation. These changes make
unaffected by pregnancy. However, in labour,
urinary tract infection and pyelonephritis more
there is a significant delay in gastric emptying,
common in pregnancy.
which may be further worsened by opioids.
– Increased glomerular filtration rate (GFR).
Gastric pH. The hormone gastrin is secreted by
Renal blood flow increases by 50%, reflecting
the placenta from the 15th week of gestation.
the increase in CO. GFR is increased by a
Compared with non-pregnant patients, gastric
similar amount; pregnant patients have lower
volume is increased and gastric pH decreased;
serum creatinine and urea concentrations.
aspiration causes a greater degree of lung injury.
– Uric acid levels. In early pregnancy, increased
Gastro-oesophageal reflux commonly causes heart- GFR results in a lower uric acid concentration.
burn in pregnancy, but its main anaesthetic implica- In the third trimester, uric acid concentration
tion is an increased risk of Mendelson’s syndrome steadily increases above the pre-pregnancy level
(see Chapter 63), a pneumonitis resulting from pul- due to increased tubular reabsorption of uric
monary aspiration of acidic gastric contents under acid. Hyperuricaemia in pregnancy is
general anaesthesia. Rapid sequence induction and associated with pre-eclampsia and has been
non-particulate antacids are indicated for general suggested (controversially) to correlate with its
anaesthesia in pregnant patients beyond the first tri- severity.
mester; the exact gestational week is a matter of – Glycosuria. Tubular reabsorption of glucose
controversy. cannot keep pace with the increase in GFR. The
Haematological physiology. In addition to the result is glucose passing into the urine, making
physiological anaemia of pregnancy described above, urinary dipstick testing an unreliable test for
there are other important pregnancy-induced haem- diabetes mellitus in pregnancy.
atological changes: – Proteinuria. In a similar way to glucose, tubular
White cell count (WCC) is elevated in pregnancy protein reabsorption mechanisms are
due to an increase in neutrophils and monocytes. insufficient to match the 50% increase in GFR.
The normal range of WCC in pregnancy is not Proteinuria is therefore more common in
409
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:11:15, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.085
Section 10: Developmental Physiology
pregnancy; the upper limit of the normal range fluid pressure undergoes a significant increase in
is generally taken as 300 mg of protein in a 24‑h the second stage of labour, up to 70 cmH2O.
urine collection (compared with 150 mg per Hepatic physiology. Levels of the hepatic enzymes
24‑h period in the non-pregnant state). Pre- glutamyltransferase, alanine aminotransferase and
eclampsia causes a pathological increase in lactic acid dehydrogenase are slightly elevated, and
proteinuria. some clinical signs usually associated with chronic
Central nervous system (CNS). The endocrine liver disease (e.g. palmar erythema, spider naevi)
changes of pregnancy have a significant effect on the may occur normally in pregnancy. Alkaline phosphat-
CNS. The minimum alveolar concentration (MAC) of ase (ALP) levels are also increased; ALP originates
volatile anaesthetics needed to prevent movement in from both the liver and the placenta. Hepatic protein
50% of subjects in response to surgical stimulus is production does not keep pace with the increase in
reduced by 30–40%. This is thought to be due to: plasma volume, leading to decreased plasma protein
concentration. Thus:
Progesterone. This is known to have sedative
effects and reduce the MAC of volatile anaesthetic Albumin concentration decreases throughout
agents in both male and female animal models. pregnancy, from around 35 g/L to 25 g/L.
β-endorphins. These are secreted by the placenta Plasma cholinesterase concentration decreases
throughout pregnancy, but especially in labour. by 25% due to both decreased hepatic synthesis
Their exact role is unknown, but β-endorphins are and increased plasma volume. This is of particular
thought to be analgesic in labour, to contribute to interest to anaesthetists, as suxamethonium is
the reduction in MAC and possibly to increase metabolised by plasma cholinesterase; decreased
neural sensitivity to local anaesthetics, which enzyme activity leads to prolonged
partially explains why lower doses of local suxamethonium action.
anaesthetic are required for regional anaesthesia Musculoskeletal. Ligaments become increasingly
in pregnancy. lax as pregnancy progresses due to placental secretion
Pregnancy also causes changes to the epidural and of the hormone relaxin. During general anaesthesia, it
subarachnoid spaces: is important to pay close attention to positioning in
order to minimise the risk of post-operative back and
Epidural pressure is increased to around
joint problems.
+1 cmH2O, compared with –1 cmH2O in the non-
pregnant state.
The higher epidural pressure is due to
Further reading
D. Katz, Y. Beilin. Disorders of coagulation in pregnancy. Br
engorgement of the epidural veins secondary to J Anaesth 2015; 115(Suppl. 2): ii75–88.
mechanical compression of the IVC by the gravid
A. T. Dennis, C. B. Solnordal. Acute pulmonary oedema in
uterus. In the first stage of labour, epidural pregnant women. Anaesthesia 2012; 67(6): 646–59.
pressure increases to +4–10 cmH2O. Bearing
E. Reitman, P. Flood. Anaesthetic considerations for
down in the second stage of labour can increase
nonobstetric surgery during pregnancy. Br J Anaesth
epidural pressure to +60 cmH2O. Epidural vein 2011; 107(Suppl. 1): 172–8.
engorgement means accidental venous
B. H. Heidemann, J. H. McClure. Changes in maternal
cannulation is more common when introducing physiology during pregnancy. Continuing Educ Anaesth
an epidural catheter. Crit Care Pain 2003; 3(3): 65–8.
Cerebrospinal fluid pressure is unchanged from
its pre-pregnancy value. However, cerebrospinal
410
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:11:15, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.085
Section 10 Developmental Physiology
Foetal Physiology
Chapter
83
What are the functions of the placenta? projections into the blood-filled cavities and
then become vascularised.
The placenta has the following functions:
– When the foetal heart becomes active at 5
Exchange of nutrients between the foetal and weeks’ gestation, foetal blood supplies the
maternal circulations; placenta through the two umbilical arteries.
Endocrine; The umbilical arteries give rise to chorionic
Immunological. arteries, which branch over the foetal surface
of the placenta until the capillaries of the
How does the anatomy of the placenta chorionic villi are reached. The capillaries of
relate to these functions? the chorionic villi converge and return blood
to the foetus through a single umbilical vein.
Exchange of nutrients. The placenta is an unusual
The foetal and maternal blood are thus separated
organ because it is derived from the tissues of two
only by the foetal endothelium and two
different organisms: endometrial cells (known as
(syncytiotrophoblastic and cytotrophoblastic)
decidual cells in pregnancy) from the mother and
chorionic cell layers. Nevertheless, there is
trophoblastic cells from the foetus. The foetus is
normally no mixing of maternal and foetal blood.
entirely reliant on exchange with the maternal
The placenta grows to match the increasing
circulation for nutrition (supply of O2, glucose,
nutritional demands of the developing foetus. As a
amino acids, etc.) and excretion (elimination of
result, at term, uterine blood flow has increased
CO2, urea, creatinine, uric acid, etc.). Key features
10-fold over its pre-gestational value to 750 mL/
of placental development are:
min, with placental blood flow accounting for
– The foetal cells form a ball of cells – the approximately 85% of this flow.
blastocyst – which implants within the Endocrine function. The placenta is an important
endometrium. endocrine organ during pregnancy, producing
– The placenta develops from trophoblast cells, both peptide and steroid hormones. Hormone
derived within the outer cell layer of the production takes place in syncytiotrophoblast
blastocyst. cells. The hormones produced are:
– The trophoblastic cells develop into two layers,
– β-human chorionic gonadotropin;
which together form the chorion. The outer
– Human placental lactogen;
chorionic layer consists of syncytiotrophoblast
cells, whilst the inner layer is made up of – Oestrogen;
cytotrophoblast cells. – Progesterone.
– The chorion invades the maternal decidua, The roles of these four hormones in pregnancy is
releasing enzymes that produce cavities within more fully discussed in Chapter 82.
the decidua. When the maternal spiral arteries
(which supply the decidua) are invaded, their
Clinical relevance: pre-eclampsia
blood fills these cavities.
– Projections called chorionic villi form an Pre-eclampsia is a potentially life-threatening compli-
extensive network of finger-like chorionic cation of pregnancy characterised by hypertension
411
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:13:06, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.086
Section 10: Developmental Physiology
412
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:13:06, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.086
Chapter 83: Foetal Physiology
413
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:13:06, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.086
Section 10: Developmental Physiology
60 Uterine artery
40
20
0
0 3.5 5 5.3 10 13.3 15 20
Oxygen tension (kPa)
414
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:13:06, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.086
Chapter 83: Foetal Physiology
PO2 3.5 kPa (sats 65%) 90% of blood passes through the DA,
Aortic arch
only 10% passes through the lungs
L PA
SVC
DA
PO2 2.5 kPa R PA
(sats 40%)
RA PV
P LA
FO
PA
LV
RV
PO2 3 kPa (sats 50%)
DV
D
UV = umbilical vein
60% Liver
UA = umbilical artery
40%
IVC = inferior vena cava
SVC = superior vena cava
IVC DV = ductus venosus
FO = foramen ovale
DA = ductus arteriosus
RA = right atrium
UV
LA = left atrium
PO2 4−5 kPa RV = right ventricle
(sats 80−90%) LV = left ventricle
UA UA PV = pulmonary vein
PA = pulmonary artery (L and
R denote left and right)
Placenta
Maternal factors – hypotension; for example, as a The presence of the umbilical vessels;
result of sepsis or aortocaval compression; Two vascular shunts: the ductus venosus and
Foetal factors – for example, malpresentation; ductus arteriosus;
Placental factors – for example, placenta praevia, A defect in the atrial septum, the foramen ovale.
placental abruption; As a result, patterns of foetal blood flow differ from
Umbilical cord factors – for example, those of an adult:
entanglement around the foetus, true knots.
Blood in the umbilical vein flowing from the
placenta is oxygenated. The umbilical vein PO2 is
How does the foetal circulation differ 4.0–5.0 kPa, equivalent to Hb O2 saturations of
from the adult circulation? around 80–90%.1
The foetal circulation is shown in Figure 83.2.
1
The foetal circulation differs from the adult circu- Note: the HbF oxyhaemoglobin dissociation curve is
lation in the following respects: shifted to the left in relation to HbA, so SaO2 is higher for
a given O2 tension.
415
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:13:06, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.086
Section 10: Developmental Physiology
Of the blood flowing from the placenta, 40% The foetal HR is under autonomic control:
enters the foetal liver, whilst 60% bypasses the – The parasympathetic nervous system is
liver and flows into the inferior vena cava (IVC) responsible for the normal baseline variability
through the ductus venosus. in HR.
Blood from the IVC flows into the right atrium – The sympathetic nervous system is responsible
(RA). A flap of tissue called the Eustachian valve for the accelerations in HR seen with foetal
directs the flow of the freshly oxygenated blood activity.
from the ductus venosus through the foramen
ovale and into the left atrium (LA). From here, Clinical relevance: labour and foetal cardiovascular
blood flows into the left ventricle (LV) and then reflexes
into the ascending aorta (PaO2 of around 3.5 kPa,
During labour, foetal HR may be measured by cardi-
equivalent to saturations of 65%). The ascending otocography (CTG). The CTG records the baseline
aorta supplies the upper half of the body, foetal HR and the response to uterine contractions.
including the heart and brain, the organs most in During uterine contractions, maternal spiral arter-
need of fully oxygenated blood. ies are compressed, resulting in a transient fall in
Deoxygenated blood (PO2 of around 2.5 kPa, O2 delivery to the placenta. A healthy foetus may
equivalent to saturations of 40%) from the exhibit an early deceleration on the CTG trace – a
superior vena cava, the coronary sinus and the parasympathetic-mediated fall in HR shortly after the
remaining blood from the IVC (the blood onset of a uterine contraction due to mild hypox-
returning from the lower limbs) flows through the aemia or compression of the foetal head.
A late deceleration is more sinister. In response
RA and into the right ventricle (RV). When the
to severe foetal hypoxaemia, the peripheral chemo-
RV contracts, blood is ejected into the pulmonary receptors trigger peripheral vasoconstriction to redir-
artery. However, only 10% of this blood enters the ect blood to vital organs. The resulting hypertension
pulmonary circulation – pulmonary vascular stimulates the baroreceptor reflex, resulting in a
resistance (PVR) is high owing to the effects of bradycardia. The deceleration in HR is late relative
hypoxic pulmonary vasoconstriction (HPV) (see to the onset of uterine contractions because of the
Chapter 23). Instead, the majority of blood flows time taken in this two-step reflex response.
through the lower-resistance ductus arteriosus to
the descending aorta, which perfuses the lower
half of the body. In this way, the least oxygenated
blood flows back to the placenta for re-
What are the physiological changes
oxygenation. that occur at birth?
The foetal heart shows many differences from the In utero, the foetus is dependent on the placenta for
adult heart: gas exchange and nutrition. Following birth, the neo-
nate must fend for itself, with its lungs as the newly
The LV pumps half of the venous return to the
upper half of the body, whilst the RV pumps the established gas-exchange organ and a circulation of
remaining blood to the lower half of the body. adult configuration. Key changes are as follows:
Unlike the adult heart, both ventricles pump Respiratory system:
blood into high-pressure systems – the foetal RV – The newly delivered neonate is bombarded with
and LV are therefore of similar sizes and wall tactile, thermal, visual and auditory stimuli.
thicknesses. – Along with sensory stimulation, the falling
The foetal myocardium is immature, with a high PaO2, rising PaCO2 and falling pH stimulate
proportion of non-contractile protein. It cannot both central and peripheral chemoreceptors,
increase its wall tension in response to increased triggering the neonate to take its first breath.
preload, in contrast to the adult heart. The stroke – The first breath requires a large amount of
volume (SV) is therefore fixed: cardiac output inspiratory work; the lungs are entirely fluid
(CO) is consequently dependent on heart rate filled and poorly compliant, though some of
(HR; remember CO = SV HR). The normal the fluid is squeezed out of the lungs as a result
foetal HR at term is 110–160 bpm. of thoracic compression during labour.
416
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:13:06, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.086
Chapter 83: Foetal Physiology
– As O2 enters the alveoli, PVR rapidly falls ▪ Bradykinin released from the lungs
as HPV is reversed, permitting pulmonary following the first breath is also implicated
blood flow. in ductus arteriosus closure.
Cardiovascular system: the circulation changes
from foetal to adult configurations.
– Immediately following birth, the umbilical Clinical relevance: transitional circulation
arteries vasoconstrict in response to The physiological changes that follow birth are
mechanical stimulation and exposure to cold not irreversible. In certain circumstances they may
air. Delaying the clamping of the umbilical be reversed, resulting in a transitional circulation
arteries for 40–60 s allows additional venous that often has disastrous consequences for the neo-
return from the placenta to the foetus. The nate. The main causes for reversion to a transitional
circulation are hypoxia, hypercapnoea, acidosis and
removal of the low-resistance placenta from
hypothermia.
the arterial and venous circulations results in
For example, in hypoxaemic neonates, HPV
an increase in systemic vascular resistance and results in high PVR. Right atrial pressure is increased
a reduction in right atrial venous return, whilst left atrial pressure is reduced, resulting in the
respectively. Reduced blood flow through the foramen ovale reopening. Hypoxaemia also prevents
ductus venosus results in its closure within closure of the ductus arteriosus. The right-to-left
1–3 h. shunting of blood through a patent foramen ovale
– Following the first breath, PVR decreases and and the patent ductus arteriosus exacerbates hypox-
blood flows into the lungs. Left atrial blood aemia and acidosis, further increasing PVR: a vicious
flow increases; when left atrial pressure cycle ensues.
Treatment aims to reverse hypoxaemia using
exceeds right atrial pressure, a flap-like valve
specific therapies like exogenous surfactant (for
closes the foramen ovale.
infant respiratory distress syndrome) and general
– Physiological closure of the ductus arteriosus supportive therapies: O2 administration, continuous
occurs over the next 10 h through a number of positive airway pressure and mechanical ventilation.
mechanisms: PVR may be reduced using inhaled nitric oxide as a
pulmonary arterial vasodilator.
▪ Following birth, the higher PaO2 stimulates
vasoconstriction of the ductus arteriosus (the
mechanism for this is not known). There is a Further reading
higher incidence of failed ductus arteriosus S. Blackburn. Maternal, Fetal, and Neonatal Physiology,
closure in neonates with significant 5th edition. Philadelphia, Saunders, 2017.
hypoxaemia and those born at altitude. S. Guller. Role of the syncytium in placenta-mediated
▪ Vasodilatory prostaglandins are produced complications of preeclampsia. Thromb Res 2009;
in foetal life by the ductus arteriosus. 124(4): 389–92.
Following birth, prostaglandin production P. J. Murphy. The fetal circulation. Continuing Educ
is reduced. Anaesth Crit Care Pain 2005; 5(4): 107–12.
417
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:13:06, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.086
Section 10 Developmental Physiology
Paediatric Physiology
Chapter
84
Children are not simply ‘small adults’. The anatomical bronchus is as likely as the right, as the angle at
and physiological differences between children and the carina is similar. This is in contrast to the
adults have a significant impact on their anaesthetic situation in the adult, where the left bronchus
management. takes a more acute angle than the right,
Childhood is classified into the following age making the right bronchus more susceptible to
groups. endobronchial intubation. The endotracheal
Neonate: the first 28 days of life (or, more tube (ETT) should be positioned at least 1 cm
precisely, a baby under 44 weeks in terms of post- above the carina and should be fixed to the
conceptual age); maxilla (otherwise accidental endobronchial
Infant: 28 days to 1 year; intubation may occur with intraoperative head
Child: 1–12 years; and jaw movement).
Adolescent: 13–17 years. – The narrowest part of the trachea is the cricoid
ring in prepubescent children. The mucosa
Describe the main anatomical and here is loosely bound, pseudostratified ciliated
epithelium that, following airway trauma, is
physiological differences between very prone to developing oedema.
children and adults
The differences between children and adults are most Clinical relevance: choice of ETT in children
evident below the age of 1 year. System by system, key In young children, the trachea is very narrow. Even a
features are as follows. small amount of oedema will have a significant
Airway. impact on the radius of the trachea and therefore
the resistance to airflow: the Hagen–Poiseuille equa-
– Relatively large head with a prominent occiput;
tion indicates that resistance to flow is inversely
relatively short neck and large tongue. Optimal proportional to the fourth power of the radius (see
head position is ‘neutral’ rather than the Chapter 21).
‘sniffing the morning air’ position of the adult. Traditionally, smaller versions of the adult high-
– Neonates and infants are obligate nasal pressure, low-volume cuff ETTs were used in children.
breathers. Nasal obstruction with secretions or Pressure on the tracheal mucosa caused oedema,
nasogastric tubes can significantly impact which had the potential to cause airway obstruction
breathing. This risk diminishes beyond the age following extubation. Therefore, uncuffed ETTs were
of 4 months. used for children below the age of 10, whose tra-
cheas were the narrowest, with the ETT size calcu-
– Large ‘U’-shaped epiglottis. A straight-bladed
lated using the following formula: (age/4) + 4. When
laryngoscope may be required.
inserted, a correctly sized, uncuffed ETT should not
– A more cephalad larynx. The larynx is at feel tight and there should be an air leak when
vertebral level C3 in the neonate and C4 in the positive pressure is applied. However, getting the
child, compared with C5 or C6 in adults. right-sized ETT for a particular patient sometimes
– A short trachea (as little as 4 cm). This required multiple changes of ETT in order to find
increases the risk of accidental endobronchial one that was not too tight and did not have a large
intubation. Intubation of the left main air leak.
418
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:14:27, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.087
Chapter 84: Paediatric Physiology
419
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:14:27, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.087
Section 10: Developmental Physiology
420
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:14:27, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.087
Chapter 84: Paediatric Physiology
421
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:14:27, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.087
Section 10 Developmental Physiology
Physiology of Ageing
Chapter
85
What makes surgery and anaesthesia in Respiratory system:
– Airway. The elderly are often edentulous,
older people higher risk? making bag–valve–mask ventilation more
Ageing involves processes not only of physical 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 post-operative compli- at night: partial obstruction (snoring) and
cations being more common in the older population. arterial hypoxaemia are common. Decreased
It is 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 being 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 both ▪ The thoracic cage becomes more rigid due
more important and more difficult to measure. to calcification of the coastal cartilages,
Ageing is associated with a decline in the physio- leading to reduced thoracic wall
logical reserve of every organ system. The mechanism compliance.
of this decline is either loss of cells from an organ or ▪ Vertebral column deformity leads to
reduced function of the remaining cells. The decline kyphosis, which adversely affects lung
in organ function often begins early in adult life, but mechanics.
is often not clinically evident until almost all of the ▪ The diaphragm and intercostal muscles
organ reserve is lost. Organ failure occurs either when atrophy. At times of high respiratory
organ function declines to a level that can no longer workload, this makes the elderly more
support life or when a disease state requires an susceptible to respiratory muscle fatigue.
increase in organ function that cannot be met due to
– Degeneration of the elastic fibres of the alveolar
insufficient reserve.
septae, leading to:
Older patients often have chronic diseases that may
impact the development or progression of an acute ▪ Loss of support for alveoli and small airways,
illness. The polypharmacy that commonly accompan- resulting in airway collapse in expiration (i.e.
ies chronic illness may also influence the medical and an increased closing capacity, CC). This is a
anaesthetic management of an acute illness. major cause of V̇ /Q̇ mismatch and
hypoxaemia in the elderly (see Chapter 15).
Describe the physiological and ▪ Increased lung compliance, which partially
anatomical changes of interest to offsets the reduced thoracic wall
compliance. Overall, the combined
anaesthetists respiratory compliance is lower in older
The physiological and anatomical changes associated patients; that is, the gradient of the
with ageing can be classified according to organ pressure–volume curve is reduced
system: (Figure 85.1).
422
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:03:27, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.088
Chapter 85: Physiology of Ageing
70-year-old
Lung volume (L)
Residual
volume
4 VC CC
3 FRC
Residual
volume
2
0
20 30 40 50 60 70 80
Age (years)
423
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:03:27, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.088
Section 10: Developmental Physiology
▪ Hypoxic pulmonary vasoconstriction being ▪ The baroreceptors are less able to rapidly
less active, which further exacerbates V̇ /Q̇ reflexively modify HR in response to
mismatch. changes in blood pressure, predisposing
the elderly to postural hypotension.
Cardiovascular system:
– Cardiac output (CO) falls with age at a rate of
– Arteries stiffen with age, leading to systolic approximately 1% per year. This is due to
hypertension. This has two effects: reduced contractility of the LV as a result of
▪The walls of the aorta normally distend to both the reduced response to β-adrenergic
accommodate the blood ejected from the stimuli and reduced myocyte function with
left ventricle (LV). With ageing, the LV advancing age.
must generate a greater pressure to eject – Conduction system abnormalities. There is an
the stroke volume into a stiff aorta. increased tendency to supraventricular
▪ Normally, ejection of blood into the aorta arrhythmias, particularly atrial and ventricular
causes a pressure wave that passes along the ectopic beats, and AF. This is thought to be
aorta and is reflected back towards the heart. due to fibrosis of the atria and sinoatrial node,
The reflected wave reaches the heart after as well as a large reduction in the number of
ejection of blood is complete and is pacemaker cells.
responsible for the bump after the dicrotic – Cardiac valve degeneration. Calcification of the
notch in the arterial waveform. In the elderly, aortic valve is more common in older patients,
stiffened arteries cause an increase in the leading to aortic sclerosis and aortic stenosis.
speed of the pressure wave. The reflected
wave consequently reaches the heart in late Central nervous system:
systole, which further increases the pressure – Loss of brain cells. A generalised loss of cells
against which the ventricle must pump. leads to a reduced brain weight and the
– Left ventricular hypertrophy. As a consequence appearance of cerebral atrophy on computed
of the increase in afterload, the LV undergoes tomography scan. The remaining neurons
hypertrophy. Ventricular hypertrophy increases compensate by forming longer dendrites and
the stiffness of the LV, which impairs diastolic making more connections to other neurons.
relaxation (see Chapter 30). This diastolic Loss of dopaminergic neurons results in
dysfunction worsens with age. The heart Parkinson’s disease, whilst loss of cholinergic
becomes progressively more dependent on neurons in the hypothalamus is implicated in
atrial contraction for ventricular filling. This is the development of dementia. The reduction
why development of atrial fibrillation (AF) can in cell number results in a lower cerebral
so easily result in LV failure in the elderly. metabolic O2 demand; cerebral blood flow is
– Veins stiffen with age. Normally, veins act as a reduced by 10–20% as a result of the lower
reservoir of blood to buffer changes in venous metabolic demand.
pressure, maintaining a constant right – Sensory impairment is common. Deafness is
ventricular preload. With increasing age the very common in older people, and visual
veins stiffen, reducing their compliance and impairment affects around a third of the
impairing the buffering mechanism. This is elderly population.
why the elderly are more likely to become – Cognitive impairment becomes more common
hypotensive with mild hypovolaemia. with advancing age, affecting 20% of patients
– Decreased response to β-adrenergic stimulation aged over 80.
with ageing, causing:
Renal physiology:
▪ Reduced responsiveness of heart rate (HR) – Decrease in glomerular filtration rate. Young
to catecholamines during exercise, adults have a significant reserve in renal
resulting in a reduced maximum HR. function. From the age of 30 years, there is a
Resting HR is unchanged. progressive loss of glomeruli and reduced
424
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:03:27, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.088
Chapter 85: Physiology of Ageing
425
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:03:27, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.088
Section 10: Developmental Physiology
426
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:03:27, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.088
Section 10 Developmental Physiology
Physiology of Obesity
Chapter
86
What is the definition of obesity? – Lung volume: reduced functional residual
capacity (FRC) due to weight of chest wall;
The World Health Organization classifies obesity based closing capacity may exceed FRC, causing
in the patient’s body mass index (BMI); their weight (in atelectasis and ventilation–perfusion (V̇ /Q̇ )
kilograms) divided by the square of their height (in mismatch; decreased thoracic compliance,
metres): leading to an increased work of breathing (see
Chapter 21).
• <18.5 Underweight
– Gas exchange: increased O2 consumption and
• 18.5–24.9 Healthy weight CO2 production due to the increased tissue
• 25.0–29.9 Overweight mass – minute ventilation, V̇ E, must increase
to maintain normocapnoea.
• 30.0–34.9 Obesity class I (formerly known simply as
‘obesity’) – Obstructive sleep apnoea (OSA): obesity
increases the risk of OSA, which manifests as
• 35.0–39.9 Obesity class II (formerly known as repeated cycles of overnight hypoxaemia and
‘morbid obesity’ if associated with an
hypercapnoea (see Chapter 6).
obesity-related comorbidity)
– Asthma: obese patients are twice as likely to
• >40.0 Obesity class III (formerly known as develop asthma as the non-obese population.
‘morbid obesity’) The cause is unclear, but may be related to the
chronic inflammation associated with obesity
What are the physiological or decreased airway calibre as a result of
consequences of obesity of relevance to reduced lung volumes.
427
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:59:25, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.089
Section 10: Developmental Physiology
428
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:59:25, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.089
Chapter 86: Physiology of Obesity
LBM should be used when dosing. Exceptions are input weight = IBW + 0.4 (TBW – IBW)). This
suxamethonium, which should be dosed on TBW, modification accurately predicts plasma propofol
and remifentanil, whose pharmacokinetics are concentration in the early part of an anaesthetic,
similar in obese and lean patients. but increasingly underdoses patients after 40
Metabolism: hepatic clearance may be affected min, risking accidental awareness.
(may be increased or decreased) by fatty liver The Schnider model uses the inputs of age,
infiltration. height and TBW and calculates LBM1 for use in its
Elimination may be affected by obesity-related algorithm. The LBM calculation is accurate up to a
co-morbidity, such as nephropathy secondary to BMI of 42 kg/m2 in males and 37 kg/m2 in females,
diabetes or hypertension. Volatile anaesthetics but when patients exceed this BMI, the calculated
show a similar time to recovery in obese and LBM paradoxically decreases. As the Schnider
non-obese patients, with desflurane (least model uses LBM to correct the rate constant for
lipophilic) having only a minor advantage over drug elimination from the central compartment,
isoflurane (most lipophilic). the clinical effect of this error is a higher
maintenance infusion and anaesthetic overdose.
The Minto model also uses the same LBM
formula as the Schnider model and therefore
Clinical relevance: obesity and target controlled suffers from inaccuracies at high BMI. The clinical
infusions effect here, however, is an underdosing of
remifentanil during the maintenance infusion.
Total intravenous anaesthesia (TIVA) is challenging in
Despite the flaws of the above pharmacokinetic
morbidly obese patients. TIVA is most commonly
models in the morbidly obese, TIVA can still be used
delivered using target controlled infusion pumps
safely in this patient group. Arguably, the best strat-
programmed with either the Marsh (propofol), Schni-
egy is to use the Schnider and Minto models titrated
der (propofol) or Minto (remifentanil) pharmacoki-
to surgical depth of anaesthesia using processed
netic models. However, there is controversy over
electroencephalogram monitoring.
which pharmacokinetic model to use in the morbidly
obese and which weight to input:
Vd and rate constants of all models were Further reading
derived from normal-weight subjects – the
L. E. C. De Baerdemaeker, E. P. Mortier, M. M. R. F. Struys.
pharmacokinetic models are therefore not Pharmacokinetics in obese patients. Continuing Educ
formally validated in the morbidly obese. Anaesth Crit Care Pain 2004; 4(5): 152–5.
The Marsh model uses TBW to calculate the
induction dose and maintenance infusion rates S. Lotia, M. C. Bellamy. Anaesthesia and morbid obesity.
Contuing Educ Anaesth Crit Care Pain 2008; 8(5): 151–6.
of propofol. However, in the morbidly obese, an
induction bolus of propofol based on TBW is J. Ingrande, H. J. M. Lemmens. Dose adjustment of
likely to represent a significant overdose and anaesthetics in the morbidly obese. Br J Anaesth 2010;
result in unwanted cardiovascular side effects. To 105(Suppl. 1): i16–23.
prevent overdosing, pump manufacturers limit A. R. Absalom, V. Mani, T. De Smet, M. M. R. F. Struys.
the input weight to the Marsh model at 150 kg. Pharmacokinetic models for propofol – defining and
Anaesthetists may choose instead to use a illuminating the devil in the detail. Br J Anaesth 2009;
modified input weight (e.g. Servin’s formula: 103(1): 26–37.
1
Using the formulae LBMmen = 1.1 TBW – 128 (TBW/height (in cm))2; LBMwomen = 1.07 TBW – 148 (TBW/
height (in cm))2.
429
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:59:25, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.089
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:59:25, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.089
Section 11 Environmental Physiology
Altitude
Chapter
87
High altitude has no consensus definition. It is most As alveolar gas is in equilibrium with the arterial
commonly defined as corresponding to >2500 m gas, PaO2 will fall.
above sea level, where most individuals begin to show A fall in PaO2 results in lower haemoglobin (Hb)
physiological adaptations. Long-term habitation at saturation (see Chapter 8), with the result that O2
high altitude is possible – 100 million people live at carriage is reduced.
altitudes >2500 m. Extreme altitude is defined as O2 delivery becomes insufficient for the tissues to
>6000 m – Mount Everest is 8848 m high. Humans maintain their normal metabolic processes; that is,
are able to adapt their physiology to survive for short hypoxaemic hypoxia develops.
periods of time at extreme altitude, but long-term
Saturated vapour pressure of water is unchanged by
habitation is impossible.
altitude (6.3 kPa at 37°C), so it has a proportionally
greater effect on PAO2 at higher altitudes, when PB is
What are the problems associated with reduced.
high altitude?
High altitude presents a number of problems to the How does the body adapt to survive at
body, classified as: altitude?
Reduced barometric pressure (PB): during ascent, Survival at altitude depends on a coordinated
the PB decreases exponentially. response by the respiratory, cardiovascular, haemato-
Temperature: the environmental temperature logical and renal systems. No physiological
falls by 1°C for every 150 m elevation above changes are seen below 2500 m in a healthy adult,
sea level. probably because PaO2 is above the threshold for
Reduced relative humidity: this results in activation of the peripheral chemoreceptors (around
increased evaporative losses from the skin and 8 kPa).
respiratory tract. The acute response to altitude produces a com-
Increased solar radiation: due to reduced cloud pensatory increase in PaO2 by hyperventilation, but
cover. its action is limited by the resulting respiratory alkal-
osis. This is followed by the chronic adaptive
response, in which a further increase in ventilation
How is alveolar oxygen tension PAO2 is permitted as the kidney corrects the pH disturb-
affected by altitude? ance. System by system:
PAO2 is calculated using the alveolar gas equation Respiratory system. Important aspects are:
(AGE) (see Chapter 18): Hyperventilation. The peripheral chemoreceptors
(but not the central chemoreceptors) are sensitive
Pa CO2
PA O2 ¼ ½F i O2 ðP B PSVPwater Þ to changes in PaO2 (see Chapter 22). When PaO2
R falls below 8 kPa, the peripheral chemoreceptors
As the height above sea level increases, PB decreases stimulate the respiratory centre in the medulla,
exponentially, but the inspired fractional oxygen con- resulting in increased V̇ A. The consequent fall in
centration remains the same (21%); PAO2 will also PaCO2 leads to an increase in PAO2, according to
therefore decrease. In turn: the AGE (see above).
431
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:55:10, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.090
Section 11: Environmental Physiology
‘Braking effect’. The unwanted consequence of HPV is a useful mechanism to optimise V̇ /Q̇
hyperventilation is an increase in arterial pH; that matching when a region of the lung is
is, a respiratory alkalosis. Hypocapnoea is detected hypoxic (e.g. due to a lobar pneumonia).
by the central chemoreceptors, whilst alkalosis is However, the generalised hypoxia that occurs
detected by the carotid bodies; both act to limit the at altitude results in a potentially harmful
increase in V̇ A.1 global pulmonary arteriolar vasoconstriction.
Diffusion limitation. Transfer of O2 across the Pulmonary vascular resistance increases by
alveolar–capillary barrier may become diffusion 50–300%, resulting in pulmonary hypertension.
limited at altitude (see Chapter 10), especially The increase in pulmonary capillary
in association with exercise (where the pulmonary hydrostatic pressure may cause fluid transudation,
capillary transit time is reduced) and in known as high-altitude pulmonary
patients with high-altitude pulmonary oedema oedema (HAPE). In addition, the sudden
(interstitial fluid thickens the alveolar–capillary onset of pulmonary hypertension may
barrier). precipitate right heart failure in susceptible
Cardiovascular system. Key features are: individuals.
Increased heart rate (HR) as a result of increased Haematological system. The sigmoid shape of the
sympathetic outflow triggered by the peripheral oxyhaemoglobin dissociation curve is important:
chemoreceptors. SaO2 remains >90% at elevations of up to 3000 m in
Reduced plasma volume. Haematocrit normal patients. At higher altitudes, compensatory
increases due to a 20% reduction in plasma mechanisms occur:
volume. This is the combined result of a Leftward shift of the oxyhaemoglobin
pressure diuresis (an increase in renal perfusion dissociation curve. Hyperventilation-induced
driven by the increase in sympathetic activity), alkalosis shifts the P50 of the oxyhaemoglobin
increased fluid loss (hyperventilation and dissociation curve to the left. This aids the loading
reduced relative humidity) and decreased oral of scarce O2 onto the Hb molecule in the lungs,
intake (loss of appetite). Stroke volume falls as a but prevents offloading of O2 to the tissues (see
result of the reduction in preload, but overall Chapter 8).
cardiac output remains the same owing to Increased 2,3-diphosphoglycerate (DPG). To
tachycardia. compensate for the leftward shift of the
Increased myocardial work. The high oxyhaemoglobin dissociation curve, erythrocytes
haematocrit of the blood (up to 0.6 with chronic produce a greater amount of 2,3-DPG. This
acclimatisation) increases the viscosity of the causes a rightward shift of the curve in order
blood. The work required to move blood in the to facilitate O2 offloading from Hb, returning
circulation (i.e. the left ventricular work) is the P50 to the normal sea-level position within
increased. a week.
Hypoxic pulmonary vasoconstriction (HPV). Increased red cell mass. The kidney responds to
The pulmonary arterioles vasoconstrict in chronic hypoxaemia within hours of ascent by
response to low PAO2 (see Chapter 23). Normally, increasing the secretion of erythropoietin, which
stimulates erythrocyte production by the bone
marrow. Over time, red cell mass increases,
1 restoring the blood’s O2-carrying capacity to near
It was previously thought that over the following days the
alkalaemia is partially corrected as a result of increased normal.
renal HCO3‾ excretion: the ‘brakes’ are then taken off, Increased risk of thrombotic events. This is as a
allowing a further increase in V̇ A. However, more recent result of both the increase in haematocrit (which
studies show that the braking effect is decreased before increases the viscosity of the blood) and the
renal HCO3‾ excretion begins. This suggests that a faster activation of platelets due to hypoxaemia.
central mechanism is involved in acclimatisation. This
may be due to a decrease in cerebrospinal fluid HCO3‾ Thermoregulation. Continuous exposure to a
concentration, although the mechanism for this is not cold environment causes a number of metabolic
completely elucidated. changes:
432
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:55:10, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.090
Chapter 87: Altitude
Acute high-altitude illness is a maladaptive physio- Vaporisers. Saturated vapour pressure is not
affected by changes in PB. Therefore, the partial
logical response to altitude occurring in unacclima-
pressure of a volatile agent within a plenum
tised people who ascend too quickly. The rate of
vaporiser is the same at high altitude as at sea
acclimatisation has significant interpatient variability: level. At altitude, the lower atmospheric pressure
some people acclimatise much more slowly than results in a higher concentration of volatile agent
others, making them more susceptible to acute high- being delivered to the patient than that ‘dialled’
altitude illness. Three high-altitude syndromes are (i.e. percentage when calibrated at sea level).
classically described: However, it is the alveolar partial pressure of the
Acute mountain sickness (AMS) is a neurological agent that determines its clinical effect, and this
syndrome whose cardinal feature is remains constant. Therefore, an isoflurane
vaporiser set at 1% will have the same clinical
headache, combined with a number of other
effect at high altitude as at sea level.
non-specific features: nausea, anorexia,
Flowmeters. Variable-orifice flowmeters are
dizziness and insomnia. Symptoms usually calibrated at sea level and are under-read at high
improve after 3–4 days at the same altitude; that altitude owing to a reduction in gas density.
is, allowing additional time for acclimatisation. However, since it is the number of molecules (e.g.
High-altitude cerebral oedema (HACE) is similar of O2) and not the volume of gas that matters
to AMS, but at the severe end of the disease clinically, flowmeters can be used as normal.
spectrum. The cardinal features of HACE are Venturi-type O2 masks. At altitude, these deliver
headache combined with ataxia or cognitive a slightly higher percentage of O2 than at
impairment. This is a serious condition, which may sea level.
progress to seizures, coma and death. The Cuff pressures. Pressures within cuffed
endotracheal tubes or laryngeal mask airways may
mechanism by which HACE develops is unknown.
increase significantly with rapid acute changes in
HAPE is thought to occur as a result of changes to altitude, such as may occur during an aeromedical
the Starling forces in the alveolus following HPV. transfer of a critically ill patient. Unchecked, the
Early symptoms are exertional dyspnoea and a increased cuff pressure may cause ischaemic injury
persistent dry cough; patients later develop to the tracheal or pharyngeal mucosa.
haemoptysis and orthopnoea. HAPE is the most
serious of the acute high-altitude illnesses,
accounting for the majority of mortality. Further reading
J. B. West, R. B. Schoene, A. M. Luks, J. S. Milledge. High
The only definitive treatment for the acute high- Altitude Medicine and Physiology, 5th edition. Boca
altitude illnesses is descent. Other treatments buy time: Raton, CRC Press, 2012.
Supplemental O2: the fastest way to increase PAO2, J. P. R. Brown, M. P. W. Grocott. Humans at altitude:
thereby counteracting the most harmful effects of physiology and pathophysiology. Continuing Educ
high altitude. Anaesth Crit Care Pain 2013; 13(1): 17–22.
Hyperbaric chamber: reduces the effective altitude K. B. Leissner, F. U. Mahmood. Physiology and
of the patient, simulating descent. A portable pathophysiology at high altitude: considerations for the
hyperbaric chamber (the Gamow bag) is available. anaesthesiologist. J Anesth 2009; 23(4): 543–53.
433
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:55:10, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.090
Section 11 Environmental Physiology
Diving
Chapter
88
You may wonder what a chapter entitled ‘diving’ is on a frozen lake) – this is in part due to the diving
doing in a book for anaesthetists – only the few who reflex maximising cerebral blood flow by intense
work in coastal areas will ever be required to anaes- peripheral vasoconstriction. Children are more
thetise patients with decompression sickness. How- likely to survive prolonged immersion than adults
ever, the primitive diving reflex is of clinical interest, owing to:
and the physiology and physics associated with des- – A stronger diving reflex;
cent are not infrequently tested in postgraduate – A greater surface area-to-bodyweight ratio,
examinations. resulting in a faster fall in body temperature,
which reduces cerebral metabolic rate and
What is the diving reflex? protects against cerebral ischaemia.
434
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:52:37, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.091
Chapter 88: Diving
(Boyle’s law). With deeper dives, the volume of the exposure time: divers calculate their maximum
lungs may fall below residual volume, risking time underwater based on the depth of the dive.
negative-pressure pulmonary oedema.
As the breath-hold diver ascends, the air within the What is decompression sickness?
lungs re-expands. However, as metabolic processes
Decompression sickness is a consequence of breathing
continue during the course of the dive, alveolar O2 will
N2 at high partial pressures. N2 is usually poorly soluble
have been consumed and CO2 produced. On reaching
in blood, with very little dissolved in the circulation at
the water’s surface, the lung volume will be reduced
sea level. However, SCUBA divers breathing com-
slightly due to O2 consumption being slightly higher
pressed air mixtures inhale higher partial pressures of
than CO2 production (see Chapter 18). The fraction of
N2. According to Henry’s law, the amount of N2 dis-
O2 within the lung will be decreased: rapid ascent from
solved in solution is proportional to the partial pressure
a deep-water dive therefore results in a rapid fall in the
of N2 above the solution. Therefore, additional N2
alveolar partial pressure of O2, potentially resulting in
crosses the alveolar–capillary membrane into the circu-
cerebral hypoxia and unconsciousness.
lation, where it deposits into the body’s tissues.
The problem comes at ascent:
How does breath-hold diving compare Slow, staged ascent allows a steady reduction in
with SCUBA diving? the partial pressure of inspired N2. Allowing time
SCUBA stands for ‘self-contained underwater for equilibration facilitates N2 removal from the
breathing apparatus’. Compressed air is delivered at body’s tissues.
ambient pressure from a tank to the diver via a During rapid ascent, the sudden change in
demand valve (bear in mind that the ambient pressure ambient pressure causes N2 to come out of
depends on underwater depth). Breathing air at ambi- solution, with N2 bubbles forming in (amongst
ent pressure avoids the problem of reduced lung other organs):
volume experienced by breath-hold divers, but intro- – Joints, causing pain (‘the bends’);
duces a number of other complications: – The pulmonary circulation, causing dyspnoea
Increased gas density. As the diver descends, the (‘the chokes’) and retrosternal pain;
partial pressure of the inspired air increases. – The arterial circulation, resulting in gas
The density of the inhaled gases is therefore also embolism.
higher. Increased gas density results in an increase
In addition to slow ascent, decompression sickness
in turbulent gas flow (see Chapter 21), especially
can be prevented by breathing O2–He gas mixtures.
during inspiration, resulting in an increased work
Once symptoms of decompression sickness have
of breathing. N2 in air can be replaced by the
developed, the most effective treatment is recompres-
lower-density helium (He) in a mixture known as
sion in a hyperbaric chamber. This forces the N2
Heliox in order to counteract this problem.
bubbles back into solution. This is then followed by
Nitrogen narcosis. Very high pressures of N2 can a slow, controlled decompression.
directly affect the central nervous system (CNS),
leading to a feeling of euphoria, incoordination, Further reading
loss of concentration and eventually coma. Again, A. O. Brubakk, T. S. Neuman. Bennett and Elliotts’
N2 can be replaced by He, which has no effect on Physiology and Medicine of Diving, 5th edition.
CNS function at equivalent pressures. Philadelphia, Saunders, 2002.
O2 toxicity. As discussed in Chapter 24, breathing M. Castellini. Life under water: physiological adaptations to
O2 at high partial pressures is potentially harmful, diving and living at sea. Compr Physiol 2012; 2:
causing acute lung injury, seizures and loss of 1889–919.
consciousness. The latter two have profound A. S. Blix, B. Folkow. Cardiovascular adjustments to diving
consequences in the context of diving. The risk of in mammals and birds. Compr Physiol 2011; (Suppl. 8):
O2 toxicity is prevented by limiting the O2 917–45.
435
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 17:52:37, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.091
Section 11 Environmental Physiology
Temperature Regulation
Chapter
89
How is body temperature regulated? – Temperature-conserving and -generating
mechanisms involving vasoconstriction,
Core body temperature is one of the most tightly shivering, non-shivering thermogenesis,
controlled physiological parameters. Normal core behavioural changes (e.g. putting on more
body temperature ranges from 36.5 to 37.5°C. Periph- clothes or turning up the central heating) are
eral body temperature, involving the skin and sub- controlled by the posterior hypothalamus.
cutaneous tissues of the trunk and limbs, is less well
controlled – the difference between core and periph- Whilst basal metabolic rate (BMR) cannot be
eral temperatures is usually around 2–3°C, but can be increased to boost heat production, shivering is
as much as 20°C in extreme circumstances. extremely effective, producing up to a sixfold increase
Body temperature is determined by a balance of in heat production.
heat loss and production:
Heat loss occurs due to radiation, convection, How does general anaesthesia disturb
evaporation (sweat and respiration), conduction
and loss in urine and faeces.
the normal thermoregulatory
Heat is produced by basal metabolic processes, mechanisms?
exercise, shivering and non-shivering Mild hypothermia (34.0–36.5°C) is common during
thermogenesis (in neonates and infants). general anaesthesia – the cause is often multifactorial:
Temperature is regulated by both feedforward and Patients may arrive at theatre cold; for example,
negative-feedback loop control. Feedforward control following a prolonged wait in a cold preoperative
is mediated by the central nervous system (CNS) ward whilst wearing a thin hospital gown.
involving interpretation and prediction of the exter- The hypothalamic set-point is lowered during
nal environment. If it is snowing, you are likely to put general anaesthesia. Normally, the hypothalamus
on a coat before going outside. This prevents any responds to a core temperature below 36.5°C with
temperature change from occurring. vasoconstriction, and shivering commences at
Negative-feedback control contains the usual elem- 36.0°C. Under general anaesthesia, these threshold
ents for sensing and correcting the internal environment: temperatures are lowered by 2–3°C.
Temperature sensors. These are a large family of Behavioural changes are (obviously) lost under
temperature-gated ion channels known as general anaesthesia. The patient is no longer able
transient receptor potential channels. Peripheral to put on additional layers of clothes.
and core temperature sensors send information to Muscle paralysis prevents shivering.
the hypothalamus. Most anaesthetic drugs cause vasodilatation,
A control centre. The hypothalamus analyses the counteracting the normal vasoconstriction
afferent temperature signals, checks them against response to hypothermia.
a set-point and controls the efferent response. The reduction in core body temperature associ-
Effector system. ated with general anaesthesia normally follows a tri-
– Temperature-losing mechanisms involving phasic pattern (Figure 89.1):
sweating and skin vasodilatation are controlled Redistribution phase. A decrease in core
by the anterior hypothalamus. temperature of 1.5–2.0°C over 30–45 min. This is
436
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 11:28:35, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.092
Chapter 89: Temperature Regulation
37
36
Core temperature (oC)
35
Plateau
Neuraxial blockade alone
34
General anaesthesia (GA)
33
437
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 11:28:35, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.092
Section 11: Environmental Physiology
438
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 11:28:35, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.092
Index
abciximab, 344 adrenergic receptors, 270–1 amino acids, 201, 300, 332, 378–80, 391
ABO blood group system, 350–1 adrenocorticotropic hormone (ACTH), aminoglycosides, 237, 311
acetazolamide, 325, 433 393, 402 amiodarone, 255–6
acetylcholine (ACh), 231–2, 235–6, aerobic metabolism, 74, 374, 377–8 ammonia, 201, 305
268–70 afferent neurons. See sensory neurons ammoniagenesis, 334
acetylcholine receptors (AChRs), afterload, 121–3, 137–8, 180 amylase, 279, 292
235–8, 270 ageing, 119–20, 422–6 anaemia, 75, 356–8
acetylcholinesterase (AChE), 20, 235–6 airway anaemic hypoxia, 63
acid-base balance changes of pregnancy, 406–7 anaerobic metabolism, 32–3, 74, 81,
albumin, 372 closure of small, 51 374–5, 377–8
anion gap, 331–2 lower (See lower airways) anaesthetic agents
base excess, 331 obesity effects, 427 effects on CBF, 204
Brønsted-Lowry acids and bases, 329 paediatric, 418–19 effects on thermoregulatory
complex disturbances in critical care spinal cord injury patients, 219–20 mechanisms, 436–7
patients, 337 thyroid surgery complications, hepatic blood flow effects, 296
definition of acid, 329 398–9 immune system depression, 370
disorders of, 330–1 upper, 21–3, 60, 62, 89 inotropic effects, 122
Haldane and Bohr effects, 38 airway devices, 91, 108 intravenous, 107, 204, 413, 426
HCO3‾/H2CO3 buffer system, 330, airway obstruction, 60–2 mechanism of action, 229, 233–4
332 airway resistance, 88–92 obesity effects, 428–9
hypothermic cardiopulmonary albumin, 304, 332, 371–2 pharmacokinetic differences between
bypass, 336 alcohol, 303, 332 children and adults, 421
Ka, 329 aldosterone, 310, 401–2 physiological changes with ageing,
pH (See pH) alkalosis, 330–1, 333–5 426
pKa, 329–30 allele, 11 reduced stress response, 389
Stewart approach, 336–7 allergen, 360, 369 respiratory system effects, 107–8
systemic consequences of allergic reactions, 260, 353, 368–9 spinal cord injury patients, 220
disturbances, 334–5 allodynia, 275 TCI programs, 429
acidosis, 330–5, 354, 375, 382 allogenic blood transfusion, 351 transport across placenta, 413
actin, 241–4 allopurinol, 311 ventilation control effects, 96
action potential, 4, 225, 244. See also alteplase, 348 volatile (See volatile anaesthetic
cardiac action potential; nerve altitude physiology, 42–3, 77–9, 100, agents)
action potential 431–3 anaphylaxis, 368–9
active immunisation, 365–6 aluminium hydroxide, 285 anatomical dead space, 25, 45, 47–8
active transport, 15–16, 200, 413–17 alveolar dead space, 45–6 angina, 162
acute coronary syndrome (ACS), 141 alveolar diffusion, 40–3, 63–4 angiotensin II, 151, 310, 401–2
acute high-altitude illness, 433 alveolar gas equation (AGE), 77–9, 431 angiotensin-converting enzyme (ACE)
acute kidney injury (AKI), 311 alveolar partial pressure of oxygen inhibitors, 29
acute mountain sickness (AMS), 433 (PAO2), 77–80, 431 anion gap, 331–2
acute pancreatitis, 292 alveolar ventilation (V̇ A), 46–7, 68–9, anorexia nervosa, 385–6
adaptive immune system, 2, 360 77, 86–7, 104, 419. See also Anrep effect, 123
adenosine, 256 ventilation–perfusion mismatch; antacids, 285, 409
adenosine diphosphate (ADP) receptor ventilation–perfusion ratio anterior spinal artery syndrome,
antagonists, 344 alveolar volume (VA), 45 212–13, 218
adenosine triphosphate (ATP), 179, alveolar–arterial (A–a) gradient, 78 anti-anginal drugs, 162
242–4, 373, 377–8 alveolar–capillary barrier, 27, 40, 42–3, antiarrhythmic drugs, 255–6
adrenal glands, 310, 401–4 81 antibiotics, 369
adrenaline, 122, 151, 153, 261, 270–1, alveoli, 26–7, 77, 80, 83–4 antibodies, 350–1, 363–9, 412
382, 402–4 amiloride, 325 anticholinesterases, 236, 281
439
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:22:49, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.093
Index
anticoagulant therapy, 347–8 balloon-tipped flow-directed PAC, 101, cell salvage, 353–4
anti-diuretic hormone (ADH), 151, 125–7 complications, 353
173, 310, 320–1, 323, 325, 394–5 Bamford classification, 195–6 cross-match, 352
antiemetic drugs, 288 barbiturates, 421 haemolytic transfusion reaction,
antifibrinolytic drugs, 348–9 barometric pressure, 77–9, 431 351–2
antigens, 350–1, 360 baroreceptors, arterial, 170–1 massive, 354
antioxidants, 102 barotrauma, 51 O2-carrying solutions, 355
antiplatelet drugs, 115, 143, 343–4 basal ganglia, 192 RBC antigens, 350–1
anti-RhD immunoglobulin, 351 basal metabolic rate (BMR), 383, 420–1 Rhesus blood group system, 350–1,
antiseptics, 369 base, 329. See also acid-base balance 412
anti-thyroid drugs, 398 base excess (BE), 331 Rhesus disease, 351
aorta, 155 basophils, 361 storage of blood products, 352–3
aortic stenosis, 120, 123–4 Bazett’s formula, 262–3 universal donors and recipients,
aortocaval compression, 408–9 Becker’s muscular dystrophy (BMD), 352
apixaban, 347–8 244–5 blood velocity, 145–7
apneustic centre, 93 bendroflumethiazide, 325 blood–brain barrier (BBB), 158, 200–1,
apnoea, 30, 39, 51, 434 benzodiazepines, 107, 201, 234, 426 420
appetite, 428 β-blockers, 115, 122, 255–6 body
aqueous humour, 276–8 β-human chorionic gonadotropin control mechanisms, 3–5
arginine vasopressin. See anti-diuretic (β-hCG), 405 general organisation, 1–5
hormone β-oxidation, 378–9, 384 homeostasis, 2–3
arrhythmia, 144, 166, 171, 255–6, 419 bicarbonate (HCO3‾) organs, 1–2
arterial baroreceptor reflex, 170–1 CO2 transport as, 37–9 systems, 1–2
arterial pressure waveform, 152–3, controlled reabsorption, 333–4 body fluid compartments, 318, 421
155–7 HCO3‾/H2CO3 buffer system, 330, body plethysmography, 53–4
arterial system, 146–53, 194–6, 424 332 Bohr effect, 32, 38, 414
arterial tension of carbon dioxide hyperkalaemia management, 327 Bohr equation, 48–9
(PaCO2), 46–7, 65, 104, 203–4, 407 pancreatic synthesis of, 292–3 bone mineral density, 184
arterial tension of oxygen (PaO2), 63, bile, 297, 300–1 botulinium toxin, 237
67, 81, 182, 203–4 bilirubin, 300–2, 305 Bowditch effect, 123
arteries, 148, 163–4, 249 birth, 416–17 Boyle’s law, 53–4
arterioles, 150–2, 172 bisoprolol, 256, 270–1 brain, 191
arteriovenous malformation (AVM), bladder, 338–9 angiotensin II effects, 310
64 bleeding. See haemorrhage blood flow (See cerebral blood flow)
aspiration pneumonia, 280–1 bleomycin, 103 cerebral arterial blood supply,
aspirin, 314, 343–4 blood. See also haemostasis 194–6
asthma, 43, 56–8, 72, 368–9, 427 changes of pregnancy, 408 changes with ageing, 424
asthma-COPD overlap syndrome CO2 transport in, 37–9 EEG, 196–7
(ACOS), 56–8 components, 371 glucose requirement, 384
astrocytes, 194 foetal and maternal, 411 gross anatomy, 192–3
atelectasis, 108–9 management, 357 meninges, 193–4
atheroma, 115 O2 transport in, 30 metabolism, 203, 208
athletes, exercise physiology, 183–4 reducing volume to manage neuroglia, 194
ATPases, 14, 16, 223 increased ICP, 208 pain signal pathways to, 273
atracurium, 107, 426 blood pressure. See also mean arterial proportion of cardiac output
atrium, 111 pressure directed to, 202
atrophy, muscle, 245 changes with ageing, 424 reducing volume to manage
atropine, 261, 281, 413, 420 exercise effects, 180 increased ICP, 208–9
autologous blood transfusion, 351 factors determining, 153 stroke, 195–6
autonomic nervous system (ANS), 1, importance of minimising venous drainage, 195
115, 176–7, 191, 204, 250, 258–60, fluctuations, 170 brain injury, 209–10
267–71, 294, 420 manipulation, 153 breath-hold diving, 434–5
autosomal dominant inheritance, measurements, 152–3 bronchi, 26, 249
11–12 blood products, 352–3 bronchial circulation, 97
autosomal recessive inheritance, 11–12 blood substitutes, 355 bronchioles, 26
axons, 189, 226–7 blood transfusion, 33 Brown-Séquard syndrome, 214, 219
ABO blood group system, 350–1 buffering, 330, 332
Bain circuit (Mapleson D), 47 allogenic and autologous, 351 bumetanide, 325
Bainbridge reflex, 170–1 antibodies to RBC antigens, 350–1 bupivacaine, 261, 421
440
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:22:49, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.093
Index
441
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:22:49, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.093
Index
442
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:22:49, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.093
Index
ejection fraction (EF), 119 O2 consumption after exercise, Frank–Starling law, 131–2, 134
electrocardiogram (ECG), 142–3, 183–4 fresh frozen plasma (FFP), 352
262–6 skeletal muscle energy sources, 179 frontal lobe, 192
electroencephalogram (EEG), 196–7 skeletal muscle fibre types, 178–9 functional residual capacity (FRC), 27,
electrolytes, 2. See also specific static, 178 50–5, 82, 108, 419
electrolytes exercise testing, 185–6 functional syncytium, 111–12
disturbances, 223 expiratory flow–volume curve, 58–60 furosemide, 325
effects of acid-base disturbances, 335 expiratory reserve volume (ERV), 50
stress response effects, 388 external ventricular drain (EVD), 199, ganglia, 267–70
electron transport chain, 36, 373, 376–7 206, 208 gas dilution technique, 52–3
Embden-Meyerhof pathway. See extracellular fluid (ECF), 2–3, 318–20 gastric acid, 283–5
glycolysis extrapyramidal tracts, 212 gastric acid inhibitors, 285
emphysema, 51–2 eye, 276–8 gastric dumping syndrome, 285–6
endocrine signalling, 189 gastric emptying, 285–7
endocrine system, 2. See also facilitated diffusion, 15–16, 200 gastrin, 283, 293
hormones; specific glands factors, clotting, 341, 344–5. See also gastrointestinal (GI) system, 2
changes with ageing, 425 thrombin changes of pregnancy, 409
effects of pregnancy, 405–6 Fahraeus–Lindqvist effect, 149 liver (See liver)
intestinal motility, 294 farmer’s lung, 369 obesity effects, 428
obesity effects, 428 fasting, 286–7, 293 oesophagus, 280–1
stress response, 387 fat, 179, 291, 299, 373, 378–81, 388 organs involved in digestion, 289
endoplasmic reticulum (ER), 8 fed state, 293 pacemaker cells, 250
endoscopic third ventriculostomy, 199 fentanyl, 29, 389, 428–9 pancreas, 291–3
endothelin (ET), 162 foetal haemoglobin (HbF), 33–4, 420 saliva, 279–80
endothelium, 162, 341 foetal physiology small intestine, 289–90, 293–4
endotracheal tubes (ETTs), 26, 91, 108, changes at birth, 416–17 smooth muscle, 249
418–19 circulation, 99, 415–17 spinal cord injury effects, 217
enflurane, 107 crossing of substances through stomach, 283–7
enhanced recovery, 385 placenta, 412–13 swallowing, 280–1
enoximone, 122 differences between foetal and adult gastro-oesophageal reflux, 281, 409,
enteric nervous system, 1, 294 circulation, 415–16 428
enzymes, 14, 18–20 double Haldane effect, 414 gene mutations, 11
eosinophils, 361 drug transport across placenta, 413 general anaesthesia
ependymal cells, 194 labour and foetal cardiovascular aortocaval compression response,
ephedrine, 426 reflexes, 416 408–9
epidural anaesthesia, 389, 408, 410 O2 delivery, 413–14 aspiration of gastric contents, 281
erythromycin, 294, 303 oxygenation during labour, 414–15 EEG monitoring, 196–7
erythropoiesis, 356 placenta anatomy and functions, effects on thermoregulatory
erythropoietin (EPO), 356, 358 411–12 mechanisms, 436–7
esmolol, 20, 153 transitional circulation, 417 at high altitude, 433
ether, 107 fibrinolysis, 348–9 mechanism of action, 233–4
ethylene glycol, 332 Fick principle, 124–7 post-operative visual loss, 278
etomidate, 204, 234, 389, 402 Fick’s law, 40 pregnancy and, 407
excess post-exercise O2 consumption filtration fraction, 317 pre-oxygenation for, 52
(EPOC), 183–4 flecainide, 255–6 reduced stress response, 389
excitation-contraction coupling, 4–5, flow-directed balloon-tipped PAC, 101, respiratory system effects,
241–2, 250–1, 258, 399 125–7 108–10
exercise physiology, 178 flow–metabolism coupling, 203 genetics, 9–12
alveolar diffusion effects, 42–3 flow–volume curve, 58–60 global O2 consumption (V̇ O2), 74–6,
body system effects, 180–2 flow–volume loop, 60–2 181–6
changes in anticipation of exercise, fluid management, CVP guidance, 167 global O2 delivery (ḊO2), 74–6
179–80 follicle-stimulating hormone (FSH), glomerular filtration rate (GFR),
changes in elite athletes, 183–4 393 309–10, 314–16, 409
dynamic, 178 forced expiratory volume in 1 second glomerulus, 307, 313
heart rate, 122 (FEV1), 56–8, 61 glucagon, 122, 381–4
in heart transplant patients, 261 forced vital capacity (FVC), 56–8 gluconeogenesis, 299, 380–1, 384
lung perfusion, 68 Fowler’s method, 47–8 glucose
meaning of V̇ O2 max, 182–3 fraction of inspired oxygen (FiO2), 43, amount of ATP generated from,
muscle fatigue, 179 67, 77 377–8
443
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:22:49, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.093
Index
444
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:22:49, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.093
Index
445
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:22:49, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.093
Index
446
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:22:49, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.093
Index
447
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:22:49, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.093
Index
one-lung ventilation, 100 oxygen partial pressure (PO2) parasympathetic nervous system, 1,
opioids alveolar (See alveolar partial pressure 151, 250, 259–60, 267–70, 277,
effects on CBF, 204 of oxygen) 280, 294
endogenous, 273–4 arterial (See arterial tension of parathyroid hormone (PTH), 399–401,
immune system depression, oxygen) 406
369–70 along O2 cascade, 80–1 parietal cells, 284–5
oesophageal effects, 281 oxygen toxicity, 102–3, 435 parietal lobe, 192
overdose, 78 oxygen transport passive immunisation, 365–6
PONV, 288 blood transfusion and, 33 passive transport, 14–16
post-operative urinary retention, carbon monoxide poisoning and, Pasteur point, 81
340 35–6 patellar reflex, 247–8
reduced stress response, 389 cyanide poisoning and, 36 patency, upper airway, 21
respiratory system effects, 107 haemoglobin, 30–2, 34 peak expiratory flow rate (PEFR), 56–8
spinal cord injury patients, 220 methaemoglobin and, 34–5 penetrating eye injury, 278
transport across placenta, 413 minimal flow anaesthesia and, 30–1 penicillins, 311, 314
ventilation control effects, 96 myoglobin, 36 pentose phosphate pathway (PPP), 381
optic disc, 277 O2 storage and consumption, 30–1 perfluorocarbons, 355
optic neuropathy, 278 oxyhaemoglobin dissociation curve, perfusion. See also
oral anticoagulant therapy, 347–8 32–3, 432 ventilation–perfusion mismatch;
oral contraceptive pill, 303 plasma, 30 ventilation–perfusion ratio
oral rehydration therapy (ORT), 290 red blood cells, 31 gravity effects on, 68–9
organelles, 7–8 sickle cell disease and, 34–5 problems with, 69
organs oxygenation West zone variations, 71–3
development, 1 distinction from ventilation, 104 peripheral arteries, 156
systems, 1–2 foetal, 413–15 peripheral nerves, 191
Orlistat, 291 intensive care and, 103 peripheral nervous system (PNS), 1,
osmolality, 319 oxygen-carrying solutions, 355 190–1, 217
osmolar gap, 319 oxyhaemoglobin dissociation curve, peripheral oedema, 160–1
osmolarity, 319–23, 325 32–3, 432 pethidine, 413
osmotic diuretics, 208, 325 oxymyoglobin dissociation curve, 36 pH, 329
oxidative phosphorylation, 179, 376–7 oxytocin, 4, 394–5 Henderson-Hasselbalch equation,
oxygen (O2) 330
alveolar diffusion of, 40–3 pacemaker cells, 250, 252, 255–7 regulation of, 2, 332–4
binding, 31–2, 35–6 pacemakers, 113–14 temperature dependence, 336
buffer, 51 packed RBCs, 352 phagocytes, 361
dissociation, 32–3, 36 paediatric physiology, 418 phagocytosis, 17, 302
effects on CBF, 203–4 choice of ETT for children, pharmacokinetics
Fick principle applied to, 125 418–19 differences between children and
harmful levels of, 102–3 differences between children and adults, 421
regulation, 2 adults, 418–21 obesity effects, 428–9
storage and consumption, 30–1 pharmacokinetic differences between physiological changes with ageing,
oxygen administration children and adults, 421 426
at different shunt fractions, 67 pain, 272 pharynx, 21–2
shunt response, 65 allodynia, 275 phenotype, 11–12
for V̇ /Q̇ mismatch, 65, 69–70 classification, 272 phenylephrine, 153, 270, 426
oxygen cascade, 80–1 distinction from nociception, 272 phenytoin, 201, 421
oxygen consumption, 30–1 hyperalgesia, 275 phosphodiesterase inhibitors, 344
changes of pregnancy, 407 modulation mechanisms, 273–4 phospholipid bilayer, 13
global (See global O2 consumption) neuropathic, 275 physiological dead space, 45, 48–9
paediatric, 419 nociceptive, 272 physiology, 1
oxygen content equation, 30 nociceptors, 272 pia mater, 194
oxygen delivery postoperative, 110 pineal gland, 201
foetal, 413–14 role of sympathetic nervous system, pinocytosis, 17, 159, 200
global, 74–6 275 pituitary adenoma, 395
HFNO therapy, 23 signal pathways to brain, 273 pituitary gland, 201, 387, 392–5
minimal flow anaesthesia, 30–1 types of nociceptor fibres, 272–3 pKa, 329–30
oxygen demand, 114–15 pancreas, 291–3 placenta
oxygen extraction ratio (OER), 75, 141 pancreatitis, 292 anatomy and functions, 411–12
oxygen flux equation, 74 paracetamol, 298, 305 drug transport, 413
448
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:22:49, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.093
Index
449
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:22:49, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.093
Index
renal filtration, 309–10, 313, 315–16 right ventricular failure (RVF), 132 stress response effects, 388
renal medulla, 320–3 right ventricular pressure–volume loop, thick and thin filaments, 240–1
renal replacement therapy, 316–17 139–40 tone, 248
renin-angiotensin-aldosterone axis, rivaroxaban, 347–8 skeletal system, 2
310, 408 rocuronium, 278 skin, 2, 425
reperfusion injury, 143–4 sleep, 21–2, 392
reproductive system, 2 salbutamol, 270–1, 327 sleep apnoea, 22–3, 427
residual volume (RV), 50, 52 salicylate, 332 small intestine, 289–90, 293–4
respiratory acidosis, 330–1 saliva, 279–80 smooth muscle
respiratory alkalosis, 331 sarcomere, 131–2, 240, 244, 249 adaptation to function, 251
respiratory centre, 93–5, 104–5, 107–8, Schnider model, 429 differences from skeletal muscle,
171 SCUBA diving, 435 249
respiratory compliance, 82–3, 407 secondary brain injury, 209 excitation-contraction coupling,
respiratory cycle, 295–6 secretin, 293 250–1
respiratory failure, 104 sedatives, 22–3, 76 excitatory inputs, 250
development in myasthenia gravis, segmental inhibition of pain, 273–4 intestinal, 293–4
105 selective serotonin reuptake inhibitors locations in body, 249
type 1, 104 (SSRIs), 235, 274 mechanism of contraction, 251
type 2, 104 sensory afferent pathways, 213–15 types, 249
respiratory quotient (R), 77–8 sensory nerve fibres, 229 sodium (Na+), 2, 221–4, 252, 318–19,
respiratory sinus arrhythmia, 171, 419 sensory (afferent) neurons, 190–1, 213, 323–4
respiratory system, 1 247 sodium channel blockers, 255–6
altitude adaptations, 431–2 septic shock, 153 sodium channels, 225–6, 229, 253–5
anaesthetic drug effects, 107–8 septicaemia, blood transfusion, 353 sodium citrate, 285
changes at birth, 416–17 serotonin, 151, 235, 274, 391 sodium nitroprusside, 153
changes of pregnancy, 406–7 sevoflurane, 107, 204 sotalol, 255–6
changes with ageing, 422–4 shunt equation, 65–7 spinal anaesthesia, 340, 389
difference between oxygenation and shunts, 64–5, 67, 199 spinal cord, 191
ventilation, 104 sickle cell disease, 11, 34–5 anatomy, 211
effects of acid-base disturbances, 335 silent myocardial infarction, 142 anterior spinal artery syndrome,
elite athletes, 183 simple diffusion, 14–15, 158, 200–1 212–13, 218
exercise effects, 181–2 Singh-Vaughan Williams classification, blood supply, 212–13
general anaesthesia effects, 108–10 255–6 corticospinal tract, 212, 215–16
lower airways, 24–9 skeletal muscle cross-section, 211–12
obesity effects, 427 anatomy, 239 meninges, 193–4
paediatric, 418–19 arteriolar vasoconstriction and paediatric, 420
regulation of pH, 332–3 vasodilatation, 151 sensory afferent pathways, 213–15
spinal cord injury effects, 216–17 atrophy, 245 sensory loss, 214–15
upper airways, 21–3 changes with ageing, 425 spinal cord injury
resting membrane potential (RMP) differences from smooth muscle, classification, 216
Ca2+ role in, 399 249 effects related to level of complete
cardiac muscle cells, 252 disorders, 244–5 injury, 216–18
contribution of Na+/K+-ATPase, 223 dynamic compared with static initial management, 219–20
effects of electrolyte disturbances, activation, 178 neurogenic bladder, 339
223 elite athletes, 184 patterns of incomplete, 218–19
electrolyte disturbances, 223 energy sources for contraction, 179 spinal shock, 248, 339
Goldman–Hodgkin–Katz equation, excitation-contraction coupling, spinocerebellar tract, 212
222–3 241–2 spinothalamic tract, 211, 213–15
Nernst equation, 222 exercise effects, 180 spirometry
production, 221–2 fatigue, 179 clinical uses and equipment, 56
restrictive lung disease, 56–61, 90–1 fibre types, 178–9 dynamic, 56
retina, 102, 276 force of contraction, 244 expiratory flow–volume curve,
reverse Fick principle, 74 functions, 239 58–60
Reynolds number, 89 malignant hyperthermia, 242 FEV1, FVC and PEFR
Rhesus blood group system, 350–1, 412 mechanism of contraction, 242–4 measurements, 56–8
Rhesus disease, 351 motor units, 244 flow–volume loop, 60–2
rhinitis, allergic, 368–9 physiological changes in anticipation Guillain–Barré syndrome and, 57–8
rhombencephalon, 193 of exercise, 180 lung resection preoperative work-up,
ribonucleic acid (RNA), 9–10 sarcomeres, 240, 244 61
450
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:22:49, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.093
Index
lung volume measurements, 50, 52, distinction from pulmonary tissue plasminogen activator (t-PA),
56 circulation, 145–6 341, 348–9
stridor and, 62 endothelium, 162 tonsillectomy, 24
variables measured, 56 foetal, 99, 415–17 total intravenous anaesthesia (TIVA),
spironolactone, 325 functions, 145 429
stagnant hypoxia, 63 lymphatic system, 168–9 total lung capacity (TLC), 50, 52
staircase effect, 123 systemic inflammatory response trachea, 80, 418–19
Starling filtration equation, 159, 315 syndrome (SIRS), 362 tracheobronchial tree, 25–6
Starling filtration forces systemic lupus erythematosus, 369, 412 tracheomalacia, 398–9
in capillaries, 159–61 systemic vascular resistance (SVR), trait, 11
in kidney, 315 97–8, 121, 151–3, 156–7 tranexamic acid, 348–9
Starling’s law of the heart, 131–2, 134 systole, 117 transcranial Doppler ultrasonography,
starvation, 384–6 systolic blood pressure (SBP), 152–3 204
static compliance, 84–7 transfer factor of the lung for carbon
static exercise, 178 tachycardia, 119–20, 122–3, 172 monoxide (TLCO), 42–3, 61
static lung volumes. See lung volume tamsulosin, 270 transfusion. See blood transfusion
statins, 115–16 target controlled infusion (TCI), 429 transfusion associated circulatory
stellate ganglion blockade, 268, 277 telencephalon, 192 overload (TACO), 353
steroid hormones, 391 temperature regulation, 3 transfusion-related acute lung injury
Stewart approach to acid-base adverse effects of hypothermia, (TRALI), 353
physiology, 336–7 437–8 transfusion-related
Stewart-Fencl-Story approach, 336–7 adverse effects of intraoperative immunomodulation (TRIM), 370
Stewart–Hamilton equation, 125–6 hypothermia, 438 transitional circulation, 417
stomach, 283–8 altitude adaptations, 432–3 trans-oesophageal echocardiography
streptokinase, 348 changes with ageing, 425 (TOE), 129
stress response, 387–9 effects of anaesthesia on normal transverse (T)-tubules, 239, 242,
stridor, 62 mechanisms, 436–7 249–50
stroke, 195–6 exercise effects, 182 traumatic brain injury (TBI), 209–10
stroke volume (SV), 119, 131–2, 153, hypothalamus role in, 392 Treppe effect, 123
183 mechanisms, 436 tricarboxylic acid cycle. See citric acid
stroke volume index (SVI), 123 paediatric, 421 cycle
subarachnoid space, 194 venous system role in, 163 tricyclic antidepressants (TCAs), 274
subcutaneous drug administration, 169 temporal lobe, 192 triglycerides, 291, 380
subdural space, 194 tetanus Ig, 366 triiodothyronine (T3), 396–8, 406
subthalamus, 193 thalamus, 95, 192 troponin, 141, 143, 241–2, 249
sulphonamide antibiotics, 35 thiazide diuretics, 325 tuberculosis, 369
surfactant, lung, 83–4 thick filaments, 240–1 turbulent gas flow, 88–90
suxamethonium, 20, 107, 220, 237–8, thin filaments, 240–1
242, 278, 281, 369, 410, 421, 426, thiopentone, 201, 204, 234, 281, 371–2, unfractionated heparin therapy, 347
428–9 413, 421, 428–9 universal donors, 352
swallowing, 280–1 thoracic cage compliance, 82–3 universal recipients, 352
Swan–Ganz catheter, 101, 125–7 thrombin, 162, 341–6 upper airways, 21–3, 60, 62, 89
sympathetic blockade, 268–9, 277 thrombin time (TT), 347 urea, 300, 316, 323
sympathetic nervous system, 1, 151, thromboelastography, 348 uric acid, 409
250, 259–60, 267–70, 275, 277, thrombolysis, 348 urinary continence, 338
280, 294–5, 310, 382, 387, thrombosis, 341, 358–9, 388. See also urinary retention, 339–40
391–2 clotting urinary system, 2
synapse, 231–5. See also neuromuscular thymus, 363 urine, 338
junction thyroid gland, 396–9, 406 uterine autotransfusion, 171
synaptic cleft, 232–3 thyroid-stimulating hormone (TSH), uterine contractions, 4
syndrome of inappropriate ADH 393, 397–8, 406 uterus, 249
secretion, 323 thyrotropin-releasing hormone (TRH),
syringomyelia, 214–15 397, 406 vaccination, 365–6
systemic circulation. See also arterial thyroxine (T4), 396–8, 406 Valsalva manoeuvre, 175–7
system; venous system ticagrelor, 344 valvular heart disease, 120
blood velocity and flow, 145–7 tidal breathing, 27–8 varicella zoster Ig, 366
capillaries, 146–7, 158–61 tidal volume (VT), 50–1 vasoconstriction, 150–1, 172, 341–2,
components, 145 tirofiban, 344 434
cross-sectional area, 145–7 tissue factor (TF), 342, 344–5 vasoconstrictors, 162
451
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:22:49, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.093
Index
vasodilatation, 150–1, 361 visual loss, post-operative, 278 warfarin, 347, 371–2
vasodilators, 162 vital capacity (VC), 50 waste product removal, 2
vasopressin, 153 vitamin B12, 283–4 water. See also diving
vasopressors, 153, 426 vitamin D, 400–1 distribution in body, 318
veins, 163–4 vitamin K, 347, 420 physiological changes during head-
vena cava, 164–5 vitreous humour, 276 out immersion, 434
venous pressure, 71–2, 164–5, 176. See V̇ O2 max, 74, 182–3 water balance, 2
also central venous pressure volatile anaesthetic agents, 153 ADH actions at kidney, 320–1
venous pressure waveforms, 166–7 airway resistance, 91 body fluid compartments, 318, 421
venous return, 163–5, 173 alveolar diffusion of, 41 disorders of osmolarity, 323
venous system, 147, 163–5, 424, 428 effects on CBF, 204 diuretic effects, 324–5
ventilation at high altitude, 433 high osmolarity of renal medulla,
alveolar (See alveolar ventilation) HPV effects, 100 320–3
dead-space, 46 immune system depression, 370 hypothalamus role in, 392
distinction from oxygenation, 104 malignant hyperthermia, 242 osmolality, 319
mechanical, 51 obesity effects, 428–9 osmolarity, 319
minute, 46, 181–2, 407 oesophageal effects, 281 physiological response to high
West zone variations, 71–3 pharmacokinetic differences between plasma volume, 325–6
ventilation control, 93–6, 198 children and adults, 421 physiological response to low plasma
ventilation–perfusion (V̇ /Q̇ ) mismatch, physiological changes with ageing, volume, 324–5
65, 69–70, 109 426 plasma osmolarity, 319–20, 325
ventilation–perfusion (V̇ /Q̇ ) ratio, PONV, 288 regulation of plasma volume,
68–70 pregnancy considerations, 410 318–19, 325
ventilatory failure, 104–5 respiratory system effects, 107 West zones, 71–3
ventral respiratory group (VRG), 93 transport across BBB, 201 Windkessel effect, 155
ventricle, heart, 111, 117–19 volutrauma, 51 work of breathing, 88–92, 108
ventricular contraction, 117–18, 131–2 vomiting, 287–8
ventricular septal defect (VSD), 64 von Willebrand disease, 345 xenon-133, 205
verapamil, 256 von Willebrand factor (vWF), 162, 342, X-linked recessive inheritance, 12
vertebral arteries, 194–5 345
452
Downloaded from https://www.cambridge.org/core. Nottingham Trent University, on 01 Aug 2019 at 18:22:49, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108565011.093