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Textbook of
Anaesthesia
Commissioning Editor: Michael Parkinson
Project Development Manager: Sarah Keer-Keer
Project Controller: Frances Affleck
Designer: Erik Bigland
Textbook of
Anaesthesia
EDITED BY

Alan R Aitkenhead BSC MD

Professor of Anaesthesia
University Department of Anaesthesia and Intensive Care
Queen's Medical Centre
Nottingham
UK

David J Rowbotham MDMRCPFRCA

Professor of Anaesthesia and Pain Management
University Department of Anaesthesia, Critical Care and Pain Management
Leicester Royal Infirmary
Leicester
UK

Graham Smith BSc (Rons) MD FRCA

Professor of Anaesthesia
University Department of Anaesthesia, Critical Care and Pain Management
Leicester Royal Infirmary
Leicester
UK

FOURTH EDITION

CHURCHILL
LIVINGSTONE

EDINBURGH LONDON NEW YORK OXFORD PHILADELPHIA ST LOUIS SYDNEY TORONTO 2001
Churchill Livingstone
An imprint of Elsevier Science Limited

© Harcourt Publishers Limited 2001

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First published 1985

Second edition 1990
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Fourth edition 2001

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ISBN 0443063818
Reprinted 2002, 2003

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 Preface

This fourth edition of Textbook of Anaesthesia has been designed immunology, the kidney, metabolism, and endocrinology. In addi-
with the same objectives as those underlying former editions; the tion, we have rearranged chapters throughout the book in an
aim has been to provide a readable, comprehensive, and concise attempt to produce a more logical structure. In the second section
text to satisfy the needs of new recruits into anaesthesia during the on Practice of Anaesthesia, we have retained much of the content
first two years of training and also present this clinical discipline as of previous editions but following the policy introduced in the
an integrated development from basic sciences. We hoped that this third edition, we have changed approximately one third of the
approach in the first edition would also provide a satisfactory authors. We again emphasise that this is not a reflection of the
primer for trainees in those countries where examinations feature quality of the contributions of the previous authors, to whom we
in the early stages of training. The response to the first edition are extremely grateful; our intentions are simply to ensure that
clearly demonstrated that it did provide suitable reading for anaes- fresh minds are applied to the subject matter and to avoid the risks
thetists studying for the Part I FFARCS (later Part 1 FRCA) which could be associated with asking authors merely to update
examination, the European Diploma of Anaesthesiology, and their contributions. As in past editions, we are grateful to the
equivalent examinations in other parts of the world. The book also authors of all our chapters for the quality of the revisions which
proved to be useful for a wider audience including medical practi- they have made in this edition and we are also indebted to the
tioners giving occasional anaesthetics in rural areas or developing many reviewers and readers of the book who have been sufficiently
countries and non-medical staff involved full-time in anaesthesia interested to provide helpful comments and draw our attention to
such as operating department practitioners, anaesthetic assistants, mistakes and typographical errors.
and nurse anaesthetists. We are grateful to all our contributors for allowing us to under-
In 1990, the Royal College of Anaesthetists changed the syl- take widespread revision of manuscripts in an attempt to achieve
labus for its FRCA examination by reverting to a two-part exami- uniformity of style. In addition we are indebted to the publishers
nation. The Primary, intended to be taken twelve to eighteen who have arranged for redrawing of all figures and incorporation
months after commencing training, has a very broad syllabus of a large number of new additional figures in a standardised for-
encompassing both basic science and clinical practice of anaesthe- mat. Our gratitude must be recorded to Mrs Christine Gethins in
sia, whilst the Final FRCA examination is designed to examine Leicester and Ms Lynne Chapman in Nottingham for substantial
knowledge and practice in clinical measurement and more spe- secretarial assistance. Because of the additional work involved in
cialised aspects of clinical anaesthesia. this larger fourth edition and to provide some youth to the
In order to achieve our basic objective of producing within a editorial team, we have also invited David Rowbotham to join the
single book a text suitable as both an introduction to the clinical editors.
practice of anaesthesia and also one which is appropriate reading We hope that this fourth edition will continue to be as popular
for the Primary FRCA examination, we have made substantial as the previous editions of Textbook, and that it will continue to
changes to this fourth edition of Textbook, most noticeably serve as a useful introductory text for those beginning a career in
by increasing the basic science content. The changes produced, anaesthesia. Our aim has been to try to encompass, as far as is
in comparison with the third edition, are evident most ostensibly possible within a readable text, the syllabus for the new Primary
by a marked increase in size by incorporation of an additional FRCA examination, and hopefully this aim will also have been
19 chapters. For editorial convenience we have divided the book achieved. Previous anaesthetic trainees have also found our book
into two main sections: Principles of Anaesthesia and Practice of useful as a revision manual for the Final FRCA examination;
Anaesthesia. This is not intended to separate or compartmentalise although that is not the primary purpose of this text, nonetheless
basic science and clinical practice; indeed both basic science and it may be helpful in this context. The incorporation of useful
clinical practice are intertwined in most chapters. appendices and practical information on the conduct of anaesthe-
In the section on Principles of Anaesthesia, we have incorpo- sia within most specialist areas of anaesthesia should ensure that it
rated most of the new chapters in order to cover areas which remains useful both as a practical guide in the operating theatre
were not addressed in previous editions and which are now part of and also a foundation of theoretical knowledge.
the syllabus for the Primary FRCA examination. There are new
chapters on statistics, cellular physiology and pharmacology, three Alan R Aitkenhead, Nottingham
additional chapters on the cardiovascular system, three on the Graham Smith and David J Rowbotham, Leicester
nervous system, three on the gastrointestinal tract, and others on 2001

Vll
This page intentionally left blank
 Contributors

Alan R Aitkenhead BSc MD FRCA John Curran PhD FRCA

Professor of Anaesthesia, University Department of Consultant Anaesthetist, Department of Anaesthesia,
Anaesthesia and Intensive Care, Queen's Medical Centre, Nottingham City Hospital, Nottingham, UK
Nottingham, UK
Eric de Melo FRCA
John I Alexander FRCA Consultant Anaesthetist, Department of Anaesthesia,
Consultant Anaesthetist, Department of Anaesthesia, University Hospitals of Leicester NHS Trust,
Bristol Royal Infirmary, Bristol, UK Leicester Royal Infirmary, Leicester, UK
Robert Atcheson MD FRCA David R Derbyshire FRCA
Consultant Anaesthetist, Department of Anaesthesia, Consultant Anaesthetist, Department of Anaesthesia,
Royal Hallamshire Hospital, Sheffield, UK Warwick General Hospital, Warwick, UK
Bryn R Baxendale FRCA Christopher Dodds FRCA
Consultant Anaesthetist, Department of Anaesthesia, Consultant Anaesthetist, Department of Anaesthesia,
Queen's Medical Centre, Nottingham, UK South Cleveland Hospital, Middlesbrough, UK
Jennifer Benton FRCA David J R Duthie MD FRCA
Associate Specialist in Anaesthesia, Department of Consultant Anaesthetist, University Department of
Anaesthesia, Derriford Hospital, Plymouth, UK Anaesthesia, Critical Care and Pain Management,
Glenfield General Hospital, Leicester, UK
Tim Bourne FRCA
Consultant Anaesthetist, Department of Anaesthesia, Neil D Edwards FRCA
University Hospitals of Leicester NHS Trust, Consultant Anaesthetist, Department of Anaesthesia,
Leicester Royal Infirmary, Leicester, UK Royal Hallamshire Hospital, Sheffield, UK
Donal Buggy MSc MRCPI (Dublin) DME FFARCSI Christopher D Elton FRCA
Senior Lecturer, University Department of Anaesthesia, Consultant Anaesthetist, Department of Anaesthesia,
Critical Care & Pain Management, Leicester General Hospital, University Hospitals of Leicester NHS Trust,
Leicester, UK Leicester Royal Infirmary, Leicester. UK
Aiden Byrne FRCA David Fell FRCA
Consultant Anaesthetist, Department of Anaesthesia, Consultant Anaesthetist, Department of Anaesthesia,
Morriston Hospital, Swansea, UK University Hospitals of Leicester NHS Trust,
Leicester Royal Infirmary, Leicester, UK
D Paul Cartwright FRCA
Consultant Anaesthetist, Department of Anaesthesia, Helen F Galley PhD
Derby City General Hospital, Derby, UK Senior Lecturer, Academic Unit of Anaesthesia,
University of Aberdeen, Aberdeen, UK
Paul R Clarke MRCP FRCA
Consultant Anaesthetist, Academic Unit of Anaesthesia, Keith J Girling FRCA
St James's University Hospital, Leeds, UK Consultant Anaesthetist, Department of Anaesthesia,
Queen's Medical Centre, Nottingham, UK
Beverley J Collett FRCA
Consultant Anaesthetist, Department of Anaesthesia, Neville W Goodman FRCA
University Hospitals of Leicester NHS Trust, Consultant Anaesthetist, Department of Anaesthesia,
Leicester Royal Infirmary, Leicester, UK Southmead Hospital, Bristol, UK

IX
 CONTRIBUTORS

Ian S Grant FRCP (Edin-Glasg) FRCA Anne E May FRCA

Consultant Anaesthetist and Medical Director, Intensive Consultant Anaesthetist, Department of Anaesthesia,
Therapy Unit, Western General Hospital, Edinburgh, UK University Hospitals of Leicester NHS Trust,
Leicester Royal Infirmary, UK
Andrew P Hall MRCP FRCA
Consultant Anaesthetist, Department of Anaesthesia, Rosemary McDonald PhD FRCA
University Hospitals of Leicester NHS Trust, Formerly Consultant Obstetric Anaesthetist, St Jame's
Leicester Royal Infirmary, Leicester, UK University Hospital, Leeds; Postgraduate Dean (Yorkshire),
Department of Postgraduate Medical Education,
Christopher D Harming BSc MD FRCA
Seacroft Hospital, Leeds, UK
Consultant Anaesthetist, Department of Anaesthesia,
University Hospitals of Leicester NHS Trust, Mary C Mushambi FRCA
Leicester General Hospital, Leicester, UK Consultant Anaesthetist, Department of Anaesthesia,
University Hospitals of Leicester NHS Trust,
Anne M Heffernan FFARCSI
Leicester Royal Infirmary, Leicester, UK
Clinical Research Fellow, University Department of
Anaesthesia, Critical Care and Pain Management, Michael H Nathanson FRCA
Leicester Royal Infirmary, Leicester, UK Consultant Anaesthetist, Department of Anaesthesia,
Queen's Medical Centre, Nottingham, UK
Greg Hobbs DipRACOG FRCA
Consultant Anaesthetist, Department of Anaesthesia, Martin Nicol FRCA
Queen's Medical Centre, Nottingham, UK Consultant Anaesthetist, Department of Anaesthesia,
Queen's Medical Centre, Nottingham, UK
Philip M Hopkins MD FRCA
Senior Lecturer, Academic Unit of Anaesthesia, Graham R Nimmo MD MRCP (UK) FFARCSI
St James's University Hospital, Leeds, UK Consultant Physician, Emergency Medicine and Intensive Care,
Western General Hospital, Edinburgh, UK
Jennifer M Hunter MD FRCA
Professor of Anaesthesia, University of Liverpool, Andrew J Ogilvy FRCA
Royal Liverpool University Hospital, Liverpool, UK Consultant Anaesthetist, Department of Anaesthesia,
University Hospitals of Leicester NHS Trust,
Gareth W Jones BSc MRCP FRCA
Leicester General Hospital, Leicester, UK
Consultant Anaesthetist, Department of Anaesthesia,
University Hospitals of Leicester NHS Trust, Susan R Pavord MRCP MRC Path
Leicester Royal Infirmary, Leicester, UK Consultant Haematologist, Department of Haematology,
Leicester Royal Infirmary, Leicester, UK
Michael J Jones BSc MRCP FRCA
Consultant Anaesthetist, Department of Anaesthesia, Ian Power MD FRCA
University Hospitals of Leicester NHS Trust, Professor of Anaesthesia
Glenfield General Hospital, Leicester, UK University Department of Anaesthesia, Critical Care and
Pain Management, Royal Infirmary, Edinburgh, UK
Nisha Kumar MRCP FRCA
Consultant Anaesthetist, Department of Anaesthesia, Charles S Reilly MD FRCA
University Hospitals of Leicester NHS Trust, Professor of Anaesthesia, Department of Surgical and
Leicester Royal Infirmary, Leicester, UK Anaesthetic Sciences, Royal Hallamshire Hospital, Sheffield, UK
Jo M Lamb FRCA Bernard Riley FRCA
Consultant Anaesthetist, Department of Anaesthesia, Consultant Anaesthetist, Department of Anaesthesia,
Queen's Medical Centre, Nottingham, UK Queen's Medical Centre, Nottingham, UK
David G Lambert BSc (Hons) PhD David J Rowbotham MD MRCP FRCA
Senior Lecturer in Anaesthetic Pharmacology, University Professor of Anaesthesia and Pain Management,
Department of Anaesthesia, Critical Care and Pain University Department of Anaesthesia, Critical Care &
Management, Leicester Royal Infirmary, Leicester, UK Pain Management, Leicester Royal Infirmary, Leicester, UK
Jeremy A Langton MD FRCA Colin J Runcie FRCA FRCP (Glas)
Consultant Anaesthetist, Department of Anaesthesia, Consultant Anaesthetist, Department of Anaesthesia,
Derriford Hospital, Plymouth, UK Western Infirmary, Glasgow, UK
Ravi P Mahajan MD FRCA Andrew R A Rushton FRCA
Senior Lecturer, University Department of Anaesthesia and Consultant Anaesthetist, Department of Anaesthesia,
Intensive Care, Nottingham City Hospital, Nottingham, UK Derriford Hospital, Plymouth, UK
 CONTRIBUTORS

Peter J Simpson MD FRCA John Walls FRCP

Consultant Anaesthetist, Department of Anaesthesia, Professor of Nephrology, Department of Nephrology,
Frenchay Hospital, Bristol; Senior Clinical Lecturer in Leicester General Hospital, Leicester, UK
Anaesthetics, University of Bristol, Bristol, UK
Jennifer Warner FRCA
Graham Smith BSc (Hons) MD FRCA Consultant Anaesthetist, Department of Anaesthesia,
Professor of Anaesthesia, University Department of Nottingham City Hospital, Nottingham, UK
Anaesthesia, Critical Care and Pain Management,
Leicester Royal Infirmary, Leicester, UK Nigel Webster PhD FRCA
Professor of Anaesthesia, Institute of Medical Sciences,
Justiaan C Swanevelder FRCA University of Aberdeen, Aberdeen, UK
Consultant Anaesthetist, Department of Anaesthesia,
University Hospitals of Leicester NHS Trust, John A W Wildsmith MD FRCA
Glenfield General Hospital, Leicester, UK Professor of Anaesthesia, Department of Anaesthesia,
Ninewells Hospital and Medical School, Dundee, UK
Jonathan P Thompson FRCA
Senior Lecturer, University Department of Anaesthesia, Sheila M Willatts MD FRCA FRCP
Critical Care & Pain Management, Leicester Royal Infirmary, Clinical Reader in Anaesthesia, University of Bristol,
Leicester, UK Bristol, UK

Douglas A B Turner FRCA J Keith Wood FRCP FRCPE FRCPath

Consultant Anaesthetist, Department of Anaesthesia, Formerly Consultant Haematologist, Leicester Royal Infirmary,
University Hospitals of Leicester NHS Trust, Leicester, UK
Leicester Royal Infirmary, Leicester, UK
David A Zideman BSc FRCA
Peter G M Wallace FRCA Consultant Anaesthetist and Honorary Senior Lecturer,
Consultant Anaesthetist, Division of Anaesthesia, Department of Anaesthesia, Hammersmith Hospital,
Western Infirmary, Glasgow, UK London. UK

XI
This page intentionally left blank
 Contents

PART I PRINCIPLES OF ANAESTHESIA 13. Inhalation anaesthetic agents 152

M. C. Mushambi, G. Smith
Basic considerations
14. Intravenous anaesthetic agents 169
1. Clinical trials and statistics 1 A. R. Aitkenhead
N. W. Goodman
15. Local anaesthetic agents 184
2. Cellular physiology/pharmacology relevant to
/. A. W. WildsmithJ. Kendall
anaesthesia 13
D. G. Lambert 16. Sedative and anticonvulsant drugs 192
3. General principles of pharmacology and /. M. Lamb
pharmacokinetics 21 17. Physiology and measurement of pain 201
D. J. Rowbotham R. Atcheson
Cardiovascular systems 18. Analgesic drugs 211
4. Anatomy of the cardiovascular system 31 /. Alexander
N. Kumar 19. Muscle function and neuromuscular blockade 223
5. The heart 42 /. M. Hunter
N. Edwards
Gastrointestinal tract
6. Peripheral circulation and control of cardiac output
and arterial pressure 54 20. Gastrointestinal physiology 236
K.J. Girling A. M. Heffernan, D. J. Rowbotham
7. Drugs acting on the cardiovascular and autonomic 21. Nausea, vomiting and their treatment 244
nervous systems 65 D. J. Rowbotham
/. P. Thompson
22. The liver 250
Respiratory system A.J. Ogilvy
8. Anatomy of the respiratory tract 101
Haematology and immunology
A. P. Hall
9. Respiratory physiology 109 23. Haematology 259
C. D. Hanning S. R. Pavord, J. K. Wood

10. Drugs acting on the respiratory system 119 24. Immunology and body defences 270
R. P. Mahajan N. R. Webster, H. Galley

Nervous system Kidney

11. Anatomy of the nervous system 130 25. Renal physiology 279
M. H. Nathanson A.J. OgilvyJ. Walls

12. Physiology of the nervous system 136 26. Drugs used in renal disease 289
S. Willatts /. C. Swanevelder

Xlll
 CONTENTS

Metabolism 44. Anaesthesia for gynaecological and genitourinary

surgery 576
27. Metabolism, the stress response to surgery and
/. Warner
perioperative thermoregulation 297
D. Buggy 45. Anaesthesia for orthopaedic surgery 582
/. Cur ran
Endocrinology 46. Anaesthesia for ENT surgery 590
28. Endocrine function 309 G. W.Jones
P. R. Clarke, P. M. Hopkins 47. Anaesthesia for opthalmic surgery 594
M. Nicol
Pregnancy
48. Anaesthesia for radiology and radiotherapy 606
29. Maternal and neonatal physiology 323 T. Bourne
C. D. Elton, R. MacDonald
49. Anaesthesia and psychiatric disease 611
M. J. Jones
Physics and clinical measurement
50. Day-case anaesthesia 614
30. Basic physics for the anaesthetist 336
/. Benton, J. A. Langton
M. C. Mushambi, G. Smith
51. Emergency anaesthesia 619
31. Clinical measurement 353 D. A. B. Turner
A. R. A. Rushton, J. A. Langton
52. Obstetric anaesthesia and analgesia 629
32. Anaesthetic apparatus 373 A. E. May, D. Buggy
G. Smith, A. R. Aitkenhead, M. C. Mushambi
53. Paediatric anaesthesia and intensive care 650
PART II PRACTICE OF ANAESTHESIA E. de Melo
54. Dental anaesthesia 664
33. The operating theatre environment 409 C. S. Reilly
A. R. Aitkenhead
55. Anaesthesia for plastic, endocrine and vascular
34. Preoperative assessment and premedication 417 surgery 672
B. Baxendale, G. Smith /. P. Thompson
35. Intercurrent disease and anaesthesia 429
56. Hypotensive anaesthesia 682
I. S. Grant, G. R. Nimmo
C. Dodds
36. Preoperative checking of equipment and
57. Neurosurgical anaesthesia 688
environment 455
P. J. Simpson
P. Cartwright
58. Anaesthesia for thoracic surgery 699
37. The practical conduct of anaesthesia 460
D. J. R. Duthie
D. Fell
59. Anaesthesia for cardiac surgery 711
38. Monitoring 470
C. /. Runcie, P. G. Wallace
A. Byrne
39. Fluid, electrolyte and acid-base balance 489 60. The intensive care unit 722
D. A. B. Turner B. Riley

40. Complications during anaesthesia 501 61. Management of chronic pain 738
G. Hobbs B. J. Collett

41. Postoperative care 524 62. Cardiopulmonary resuscitation 748

A. R. Ait D.A.

42. Postoperative pain 544

I. Power, G. Smith Appendices 759
D. R. Derbyshire
43. Local anaesthetic techniques 555
A. Lee Index 787

XIV
1 Clinical trials and
statistics

'A clinical trial is a carefully and ethically designed experiment for any research, even if only a loose one, otherwise the research is
with the aim of answering some precisely framed question.' This likely to lack discipline.
definition by Sir Austin Bradford Hill, a pioneer of clinical trials, is Because this chapter is largely about clinical trials, it is helpful to
worth remembering: careful, ethical, precisely framed. There are use simple practical examples: a study of a new antiemetic in the
many types of research that provide information on which medical treatment of postoperative nausea and vomiting; the effect of an
practice is based. The clinical trial is one of these types, but the intravenous induction agent on systolic arterial pressure; a com-
one known to most practising anaesthetists. Statistics are impor- parison of the effect of two intravenous induction agents on art-
tant in the interpretation of clinical trials and pragmatically candi- erial pressure; and a study of the effect of duration of surgery on
dates for examinations in anaesthesia know they must 'learn some patients' body temperature. These examples are used to illustrate
statistics'. But it is a knowledge of good study design, not of sta- principles and tests. Because the purpose of clinical trials is in
tistics, that is the key to good clinical research. some way to improve the management of patients, underlying
most aspects of study design is the need to be as sure as possible
that the improvement was indeed due to the investigators' inter-
vention, and not to confounding factors. The purpose of good
TERMINOLOGY
study design is the avoidance of bias.
There is some confusion and overlap of terms. Scientific research
may be observational or experimental. Although a clinical trial is, BACKGROUND
as Bradford Hill defines, an experiment, there are undercurrents
Good study design starts long before the first patient is recruited,
to the word that make 'experiment' better avoided. A clinical trial
with a comprehensive survey of previous similar studies. Even in
is better described as a series of experiments: each patient is the
these days of electronic databases, the best starting place is a
subject of an experiment, providing a set of observations. If those
recent textbook or review. There are several reasons why investi-
observations are numerical, they are often termed data. The noun
gators need to know what has been done before: to know what
'data' is in the plural ('the data are shown in the table...'),
remains unknown; to frame their question precisely; to improve
although many now accept that modern usage allows the singular
the chances of the study providing valid answers; and to prevent
('the data is shown in the table...'). Measurements and findings
needless repetition. Even after their study has started, investiga-
are other words applied to the outcomes of a clinical trial.
tors must remain aware of new relevant work, but any alteration
The words trial and study may be synonymous - a 'clinical trial'
to study design at that stage may affect the validity of the findings.
or a 'clinical study' - and synonymous also with 'research project'.
This meaning is implied in 'study design' and 'study protocol'.
'Study' is the better word here: 'trial' is applicable only to some SPECIFIC OBIECTIVES
types of experimental clinical research, whereas design and proto-
After the initial survey, the specific objectives of the study should
col are important in all scientific research. But a term is needed for
be clear: postoperative nausea after laparoscopic cholecystectomy
each episode (i.e. each patient) in a clinical trial, and 'study' is
in women; induction arterial pressure in patients already taking a
often used in that sense ('the study period started at induction of
(3-blocking drug for hypertension; temperature changes during
anaesthesia and lasted until the patient left the recovery ward...').
elective aortobifemoral reconstruction.

PATIENT SELECTION CRITERIA

STUDY DESIGN
For some studies, any patient presenting for the chosen operation is
The study design is the framework ensuring that, as far as possible, suitable, but that is unusual. Almost always, some unsuitable patients
difficulties have been sorted out before the study starts. Formally, have to be excluded, if only on grounds of extremes of age. A study
for any research involving humans or human material or patient of postoperative nausea might exclude patients with a history of hia-
records, a study design is needed for submission to an ethics or tus hernia; one of arterial pressure changes might exclude patients
grant-awarding committee. Informally, there should be a design with a defined degree of hypertension; and one of temperature

1
 CLINICAL TRIALS AND STATISTICS

changes might exclude patients who have had amputations of the The terms control and baseline are sometimes confused. A
lower limb. Exclusions must be defined in the study design; some placebo group is a control group; in a two-group study of standard
study designs contain long lists of both inclusion and exclusion and new antiemetics, the standard group is the control group. In
criteria. Exclusions (patients predetermined as ineligible) differ from the study of the effect of anaesthetic induction on arterial pressure,
eligible patients refusing consent and differ again from withdrawals readings taken before induction are not control readings but base-
(eligible patients who failed to complete the study). All three cate- line readings with which post-induction readings are compared.
gories of patients not included in the study must be admitted in the Patients act as their own controls if they receive both treatments
final report, and remembered when drawing conclusions from the in a trial. In practice, this is rarely feasible in a study of antiemetics,
findings. Generalization of the findings may be unsafe if only and uncommon in anaesthetic studies. In a crossover trial, patients
women aged less than 65 years are studied, if half the patients refuse receive first one and then the other drug, blinded and in random
consent, or if equipment failure forces withdrawal of patents. order. These trials may be complicated, including placebo periods
and also periods of receiving one or other test drug. There may
also be wash-in periods to establish drug effect and wash-out
TREATMENT SCHEDULES periods to remove that effect before the next drug is given. These
The only difference between the groups in a clinical trial should be trials are expensive, and unlikely without the backing of the
the study treatment. Everything else should be standardized: pre- pharmaceutical industry.
medicant drugs, induction agents, neuromuscular blocking agents,
infusion fluids, and use of techniques such as epidurals. Clearly, the
PATIENT EVALUATION
degree of standardization depends on the trial: in almost all anaes-
thetic studies, the induction of anaesthesia is standardized; but the In a clinical trial, investigators measure variables (such as arterial
size and site of an intravenous cannula may not be important if it pressure and temperature) and seek outcomes (such as postopera-
can have no influence on the outcome of the study. tive nausea). The techniques and scales must be standardized as
Study treatment is best given so that neither clinician nor patient rigorously as the treatments, even for variables and outcomes that
is aware of which treatment the patient is receiving: a double-blind can be measured objectively, such as arterial pressure (but see
trial. Sometimes the clinician knows but not the patient, which is measurement bias below). In a study of postoperative nausea,
termed a single-blind trial. If different anaesthetists are giving the investigators need to decide, for example, whether to record
anaesthetics and making the observations in a study, all those nausea and vomiting separately, whether to record vomiting as
involved should remain unaware. If it is not possible to blind all yes/no or as number of vomits, whether to use a visual analogue
those involved, care should be taken to avoid implicit or explicit score, and for how long and over what periods to record observa-
clues being leaked to the supposedly blinded investigators. Many tions from each patient. The best way to decide how to evaluate
simple drug trials are easy to make blind, but blinding is less easy patients is from reports of previous similar studies, because using
if the interventions are more complex. Sometimes investigators similar methods makes comparison with those studies easier. But
get clues even though technically the study is blind; it is easy to it is wise first to check that those methods are feasible in the inves-
prepare and inject from masked syringes that may contain either tigators' own circumstances.
thiopental or propofol, but patients complaining of pain during When there are few patients to study and research is difficult,
the injection may be presumed to be receiving propofol. Study such as in intensive care, the temptation is to record as much
design might include a questionnaire for the investigators, to as possible from each patient. The danger is of ending up with a
determine to what extent blinding was successful. welter of figures and overcomplicated analyses, which obscure
A non-blinded study is not invalid; some studies are impossible instead of clarifying. Investigators should refine and simplify their
to blind. But non-blinded studies tend to overestimate treatment question to define a primary outcome variable, and not become
effects - in other words, these studies are inevitably biased. Put distracted by collecting data.
simply, investigators find what they want to find; patients feel how
they expect to feel. This is part of human nature.
TRIAL DESIGN
Other terms to mention under this heading are placebo, control
and baseline. In a comparison of a new treatment with the The examples of the antiemetic and induction arterial pressure
accepted standard treatment, the control group receives the stan- studies are both experimental studies in which the investigators
dard treatment. If there is not yet an effective treatment for a con- are looking for the effect of interventions; that of operative tem-
dition - prophylaxis of postoperative nausea and vomiting is a perature is an observational study, although that term is reserved,
good example - there is a place for a placebo group; the best study more correctly, for epidemiological research in which the investi-
design would be for three groups: placebo, established drug and gators study factors outside their control, such as the effects of
new drug. A placebo does not contain active drug but should smoking. All are prospective studies: the investigators define the
otherwise be the same, e.g. in appearance and taste, as the test conditions and the observations come after the question. In a
treatments. Placebos are a way of trying to negate the effect of retrospective study, observations are sought from pre-existing
simply doing something: the non-specific effect of medical treat- records, such as patients' notes; the investigators cannot define
ment. Placebos are an obvious ethical issue (see below). the conditions. In general, the greatest value of retrospective
Prophylaxis for postoperative nausea and vomiting is in general studies is in defining rather than in answering questions.
ineffective and not everyone prescribes it, so it can be argued that Studies may be longitudinal, in which patients are studied over
giving a placebo does not deprive patients of effective treatment. time, or cross-sectional, of which a simple example is a snapshot post-
However, treatment of established nausea and vomiting is more operative survey of satisfaction. A cohort study is a long-term, longi-
effective and a placebo may be considered unethical. tudinal, prospective study, e.g. of a group of patients who all have

2
 CLINICAL TRIALS AND STATISTICS

the same disease. A cohort is a special type of sample (see below). A which is kept with the study paperwork; ideally there should also
case-control study is a retrospective study in which patients with a be a copy filed in patients' notes.
disease are compared for pre-existing risk markers with people who Much of the work of ethics committees (see below) is con-
do not have the disease. These definitions are sometimes used rather cerned with the what and how of information provided to
loosely, and studies may use more than one form of design. patients.

RANDOMIZATION REQUIRED SIZE OF STUDY

Allocation to treatments by randomization is an important way of The size of the study (i.e. the number of patients that need to be
avoiding bias. Randomized double-blind controlled trials (RCTs) recruited) determines the power of the study (i.e. the likelihood
are probably the best way of determining which of two treatments, of obtaining an answer). This is discussed in some detail below
on average, gives the better outcome. It must be stressed, however, (see type II error), but is mentioned now because these power cal-
that just because a trial is randomized and double-blind does not, culations are part of study design and are an important ethical
of itself, mean that the conclusions are justified or generalizable. issue. The notation for size of study group is n.
Randomization ensures that neither investigators nor patients
know which treatment they receive until the time comes to give
DESIGN DEVIATIONS
that treatment: there is no pre-selection. Randomization makes
it less likely that, in an anaesthetic study, preoperative factors Sometimes investigators discover faults with the collection of
determine which treatment is given. Another important reason information in a trial which imply that the patient can no longer
for randomization is that much of medical statistics is based on be included. There are serious risks of introducing bias if patients
the assumption that the samples are random and that differences are withdrawn from a study after randomization. Data from with-
between them therefore behave similarly to the differences drawn patients must always be admitted, but it may not be possi-
between truly random samples. ble to include those data in the general calculations. It is always
Randomization by flipping a coin is random but is open to the best, before the trial begins, to think very carefully about how
manipulation, sometimes subconscious, of saying that the coin protocol violations may arise, and to have some plans for what to
'wasn't flipped properly'. Random number tables or a computer's do in that eventuality. If it is important that a particular number of
random number generator (all statistical computer programs patients are recruited, one plan is to have some extra randomized
include these) are better methods of true randomization: an odd envelopes available to replace patients who have dropped out. It
number denotes treatment A, an even number treatment B. infringes randomization and blinding simply to replace patients
Clearly, the investigators must not see the next number in the who drop out of one treatment group with additional patients
table until the next patient is ready for treatment. This is usually having the same treatment. It is better to include enough patients
managed by putting codes into sealed envelopes, taken sequen- in the original design, so that a few withdrawals do not matter.
tially by the investigators. Patients sometimes start in one group and, for clinical reasons,
Simply using a coin or random numbers causes problems in are transferred to a different treatment. A patient whose epidural
small studies because of the likelihood of generating unequal is ineffective and who is prescribed intramuscular analgesia must,
groups, which cause statistical difficulties. The usual remedy is for the purposes of analysis, remain in the epidural group; this is
block randomization. In an intended study of 40 patients, which is known as analysis by intention-to-treat.
probably an average-sized clinical study but in statistical terms is
small, block randomization ensures two groups of 20 receive each
PLANS FOR STATISTICAL ANALYSIS
treatment. If there are known important preoperative factors that
affect outcome, e.g. smoking in a study of postoperative chest A medical statistician should be contacted early. The more complex
infections, randomization can be stratified, so that smokers and the analysis - the more treatments being compared, the more
non-smokers are allocated by separate randomization. groups of patients, the less well known the intended statistical test
Investigators should always describe their method of random- - the more important is good statistical advice. It is not a good
ization, or, if they have not randomized treatments, they should idea to make casual inquiries of non-specialized statisticians. A stat-
explain why. Randomization is difficult when patients or investi- istician will advise about randomization and n, as well as plans for
gators have clear views about which treatment they think is better. analysis, which must be drawn up before the data are generated.
The fewer measurements that are made, and the fewer compar-
isons that are made between them, the easier is the statistical
PATIENT CONSENT
analysis. Investigators must be especially wary of making subgroup
Patients must be given all the information necessary to make the analyses not set out in the original design. An example would be
decision as to whether to give freely their fully informed consent to looking for different nausea scores between men and women, or
enter the study. The information must be given in a non-coercive in people above or below a certain weight, when all that was orig-
way, in words they understand. For all except the simplest of stud- inally intended was to compare the two treatments. Subgroup
ies, patients are given a written information sheet. Discussion of analyses after the event ('post hoc') risk type I errors (see below).
possible risks of the study include far smaller risks than customar-
ily discussed before non-research clinical procedures (although
ADMINISTRATION
customs and attitudes change, and informed consent to treatment
and to research are converging as informed consent to treatment Each investigator's job during the study must be defined: who gives
demands more and more detail). Patients sign a consent sheet, the anaesthesia, who makes the measurements or observations, who

3
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