Topical Analgesia Before Inhalational Anaesthesia: A Retrospective Observational Study
Conditions: Anesthesia, Pediatric ALL
Sponsor: Nottingham University Hospitals NHS Trust

 
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LONG TITLE OF THE STUDY: 
TOPICAL ANALGESIA BEFORE INHALATIONAL ANAESTHESIA: A 
RETROSPECTIVE OBSERVATIONAL STUDY 
 
SHORT STUDY TITLE / ACRONYM: 
TOPICAL ANALGESIA BEFORE INHALATIONAL ANAESTHESIA? 
 
RESEARCH REFERENCE NUMBERS 
 
IRAS Number: 
281394 
 
SPONSORS Number: 
20AN008 
 
FUNDERS Number: 
 
SPONSOR 
Not applicable 
 
Nottingham University Hospitals NHS Trust 
 
 
PROTOCOL VERSION NUMBER AND DATE: 
1.0 
07-APR-2020 
 
This protocol has been designed to ensure regard for the HRA guidance 
 
 

 
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SIGNATURE PAGE 
The undersigned confirm that the following protocol has been agreed and accepted and that the Chief 
Investigator agrees to conduct the study in compliance with the approved protocol and will adhere to 
the principles outlined in the Declaration of Helsinki, the Sponsor’s SOPs, and other regulatory 
requirement. 
I agree to ensure that the confidential information contained in this document will not be used for 
any other purpose other than the evaluation or conduct of the investigation without the prior written 
consent of the Sponsor 
I also confirm that I will make the findings of the study publically available through publication or 
other dissemination tools without any unnecessary delay and that an honest accurate and 
transparent account of the study will be given; and that any discrepancies from the study as planned 
in this protocol will be explained. 
 
For and on behalf of the Study Sponsor: 
 
Signature:   
 
 
Date: 
03/06/2021 
Name (please print): Maria Koufali 
 
 
Position: Managing Director 
 
 
 
Chief Investigator: 
Signature:  
 
 
Date: 
07/04/2021 
Name (please print): 
MATTHEW JAMES BILLINGHAM  
 
 
 
 
 

 
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KEY STUDY CONTACTS 
 
Chief Investigator 
MATTHEW BILLINGHAM 
Department of Paediatric Anaesthesia 
Nottingham University Hospitals NHS Trust 
Queen’s Medical Centre, Derby Road, Nottingham, NG7 2UH 
07856 246425 
mbillingham@doctors.org.uk  
matthew.billingham@nuh.nhs.uk  
Sponsor 
JENNIFER BOSTON 
Head of Governance, Research and Innovation 
Nottingham University Hospitals NHS Trust 
Nottingham Health Science Partners 
C Floor South Block, Queen’s Medical Centre, Derby Road, 
Nottingham, NG7 2UH 
0115 970 9049 
researchsponsor@nuh.nhs.uk   
 
 
 
 
 
 
 
 
STUDY SUMMARY 
 

 
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Study Title 
Topical Analgesia before Inhalational Anaesthesia: A 
Retrospective Observational Study 
Internal ref. no. (or short title) 
Topical Analgesia before Inhalational Anaesthesia? 
Study Design 
Retrospective Observational Study (Cohort design) 
Study Participants 
Children from 1 month to 18 years of age undergoing elective 
or urgent inhalational induction of anaesthesia at 
Nottingham University  Hospitals NHS Trust over a six month 
study period (August 2020 to January 2021) 
Planned Size of Sample (if applicable) 
1,323 
Follow up duration (if applicable) 
Not applicable 
Planned Study Period 
August 2020 to January 2021  
Research Question/Aim(s) 
To determine whether topical analgesia application prior to 
receiving inhalational induction of anaesthesia has any 
beneficial effects for paediatric patients 

 
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FUNDING AND SUPPORT IN KIND 
FUNDER(S) 
(Names and contact details of ALL organisations 
providing funding and/or support in kind for this 
study) 
DETAILS OF FINANCIAL AND NON FINANCIAL 
SUPPORT GIVEN 
 
KATE FROST 
Head of Patient and Public Involvement and 
Engagement 
Nottingham University Hospitals NHS Trust 
Nottingham Biomedical Research Centre 
C Floor South Block, Queen’s Medical Centre, 
Derby Road, Nottingham, NG7 2UH 
07812 268 438 
kate.frost@nuh.nhs.uk  
 
DOYO ENKI 
Senior Medical Statistician 
RDS East Midlands 
Faculty of Medicine 
University of Nottingham 
Nottingham, NG7 2UH 
0115 924 9924 (ext 80717) 
doyo.enki@nottingham.ac.uk 
 
 
Non-financial support 
Patient and Public Involvement strategic support 
Liaison for Nottingham University Hospital 
Young Person Advisory Group (YPAG) 
 
 
 
 
 
 
Non-financial support 
NIHR (National Institute for Health Research) 
RDS (Research Design Service) East Midlands 
support advisor 
 
 
 
 
 

 
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ROLE OF STUDY SPONSOR AND FUNDER 
The study sponsor will monitor the study conduct against applicable regulatory standards. The study 
sponsor and study funder will have no role in the design, data analysis, interpretation, manuscript 
writing and dissemination of the results. The sponsor and funders will be consulted for the final 
decision/s regarding any aspects of this study.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
KEY PHRASES: 
Topical analgesia 
Inhalational anaesthesia 
Retrospective observational study 
 
 
 

 
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Protocol contributors 
 
CONTRIBUTOR(S) 
(Names and contact details of ALL individuals 
providing contribution to the protocol) 
DETAILS OF CONTRIBUTION GIVEN 
 
MATTHEW BILLINGHAM 
Department of Paediatric Anaesthesia 
Nottingham University Hospitals NHS Trust 
Queen’s Medical Centre, Derby Road, 
Nottingham, NG7 2UH 
07856 246425 
mbillingham@doctors.org.uk  
matthew.billingham@nuh.nhs.uk 
 
 
PAULINE HYMAN-TAYLOR 
Senior Research Governance Facilitator 
Nottingham University Hospitals NHS Trust 
Nottingham Health Science Partners 
C Floor South Block, Queen’s Medical Centre, 
Derby Road, Nottingham, NG7 2UH 
0115 970 9049 
pauline.hyman-taylor@nuh.nhs.uk 
 
KATE FROST 
Head of Patient and Public Involvement and 
 
Study conceptualisation, design and 
construction of original protocol 
Protocol amendments 
Application for protocol support from 
Nottingham University Hospitals NHS Trust 
Patient and Public Involvement and Engagement 
Team 
Application for protocol support from 
Nottingham University Hospitals NHS Trust 
Research and Innovation department 
Final protocol completion and authorisation 
 
 
Protocol reviews, suggestions and amendments 
 
 
 
 
 
 
 
 
Protocol review, suggestions and amendments 
(section 8.4 (Patient & Public Involvement)) 

 
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Engagement 
Nottingham University Hospitals NHS Trust 
Nottingham Biomedical Research Centre 
C Floor South Block, Queen’s Medical Centre, 
Derby Road, Nottingham, NG7 2UH 
07812 268 438 
kate.frost@nuh.nhs.uk 
 
DOYO ENKI 
Senior Medical Statistician 
RDS East Midlands 
Faculty of Medicine 
University of Nottingham 
Nottingham, NG7 2UH 
0115 924 9924 (ext 80717) 
doyo.enki@nottingham.ac.uk 
 
CHRISTOPHER TENCH  
Senior Medical Statistician 
Faculty of Medicine and Health Sciences 
Room S/C2711 Medical School 
University of Nottingham 
Nottingham, NG7 2UH 
0115 823 1419 
christopher.tench@nottingham.ac.uk  
TIM CARD 
 
 
 
 
 
 
 
 
 
NIHR (National Institute for Health Research) 
RDS (Research Design Service) East Midlands 
support advisor 
Protocol review and suggestions 
 
 
 
 
 
 
Protocol reviews, suggestions and amendments 
(sections 5 and 7 (Study Design and Methods of 
Data Collection and Data Analysis, Sample and 
Recruitment)) 
Peer review (external) 
 
 
 
 
 

 
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Associate Clinical Professor 
Nottingham Digestive Diseases Centre 
National Institute for Health Research (NIHR) 
Biomedical Research Unit  
Nottingham University Hospitals NHS Trust 
Queen’s Medical Centre, Derby Road, 
Nottingham, NG7 2UH  
and 
Division of Epidemiology and Public Health 
Faculty of Medicine & Health Sciences  
University of Nottingham 
Room B114 Clinical Sciences Building, 
Nottingham City Hospital, Hucknall Road, 
Nottingham, NG5 1PB 
0115 823 1346 
tim.card@nottingham.ac.uk 
 
JOYCE YEUNG 
Associate Clinical Professor in Anaesthesia and 
Critical Care 
Warwick Clinical Trials Unit 
Warwick Medical School 
University of Warwick 
Gibbet Hill Campus, Coventry, CV4 7AL 
02476 573357 
j.yeung.4@warwick.ac.uk 
Protocol review and suggestions 
Review (internal) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Peer review (external) 

 
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LIST of CONTENTS 
GENERAL INFORMATION 
Page No. 
TITLE PAGE 
 
1 
RESEARCH REFERENCE NUMBERS 
 
1 
SIGNATURE PAGE 
2 
KEY STUDY CONTACTS 
3 
STUDY SUMMARY 
 
4 
FUNDING 
 
5 
ROLE OF SPONSOR AND FUNDER, KEY PHRASES 
6 
ROLES & RESPONSIBILITIES OF STUDY STEERING GROUPS AND INDIVIDUALS  
 
7-9 
LIST of CONTENTS 
 
10 
STUDY FLOW CHART  
11 
SECTION  
1. BACKGROUND 
 
12 
2. RATIONALE  
13 
3. THEORETICAL FRAMEWORK 
14 
4. RESEARCH QUESTION/AIM(S)  
15 
5. STUDY DESIGN/METHODS 
16-22 
6. STUDY SETTING 
23 
7. SAMPLE AND RECRUITMENT 
23-26 
8. ETHICAL AND REGULATORY COMPLIANCE 
27-32 
9. DISSEMINATION  POLICY 
33 
10. REFERENCES 
34-35 
11. APPENDICES 
36 
 
STUDY FLOW CHART 
Sampling frame: all NUH children 
receiving general anaesthesia in the 
defined study period (n=2,495) 

 
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Eligible: All children receiving an 
inhalational induction of 
anaesthesia (n=1,479) 
Ineligible: children receiving an 
intravenous induction of anaesthesia 
and/or children receiving sedation only 
(n=1,016) 
Total population sampling 
Participants (n=1,323) 
Non-Participants: children meeting 
study exclusion criteria (n=156) 
Non-randomised cohort 
allocation 
Exposed cohort (topical 
analgesia applied) (n=?) 
Exclusion from analysis: 
Lack of data / incomplete records 
(n=?) 
Insufficient topical analgesia 
application time (n=?) 
Cannula not inserted at site of 
topical analgesia application 
(n=?) 
Exclusion from analysis: 
Lack of data / incomplete records 
(n=?) 
Non-exposed cohort (topical 
analgesia not applied) (n=?) 

 
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STUDY PROTOCOL 
Topical Analgesia before Inhalational Anaesthesia: A Retrospective Observational Study 
 
 
 
 
1. BACKGROUND 
 
Many studies have identified painful procedures as one of the most feared and distressing 
components of medical care for children and their families, with fear of needle insertion remaining 
one of the most common childhood worries.1-3 
Over the last decade, however, several bodies have published guidelines for management of acute 
pain, including procedural pain. The essential question now, is no longer whether children feel pain, 
but how best to treat and prevent it.4 
Sadly, despite significant advances in pain management techniques, multiple studies and reviews 
continue to show that pain and distress remains poorly managed and that children, in particular, may 
still be suffering unnecessarily.5 
Preventing pain is not only humane, but may also reduce the risk of subsequent morbidity, with the 
International Association for the Study of Pain (IASP) statement on “Why Children’s Pain Matters” 
successfully enhancing practitioners’ appreciation that children are a vulnerable segment of the 
population who deserve special consideration.6 
One simple intervention that may be delivered prior to a needle insertion procedure, is the 
application of topical analgesia. Several topical analgesics are now available and have been found to 
be effective in several trials of non-anaesthetised children.7-11 Yet the value of topical analgesia for 
children receiving an inhalational induction of anaesthesia remains undetermined.  
 
 
 
 
 

 
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2. RATIONALE  
 
Cerebral cortical processing is a fundamental component of pain perception. 12 In non-verbal 
populations, measures of cortical activity may provide an insight into whether an individual is in pain, 
or in the case of the anaesthetised patient, whether the level of anaesthesia is sufficiently anti-
nociceptive.  
While many studies in animals,13,14 adult patients15-19 and anaesthetised children report an increase in 
electroencephalography (EEG) delta activity (with application of a topical analgesia diminishing the 
evoked increase in delta power caused by cannulation),20 a smaller number of studies also report the 
opposite finding.16,19,21,22 
Evidently, even with continuous EEG assessment, the assessment of analgesic adequacy in the 
anaesthetised patient, is problematic. In addition, EEG is rarely utilised in routine clinical anaesthetic 
practice, such that any conjecture regarding pain usually has to be inferred from limited surrogate 
markers such as spinal reflex withdrawal activity, resulting in patient movement.  
In light of the observation that topical analgesia may diminish the evoked increase in delta power 
caused by cannulation,20 any ability to reduce this more measurable surrogate marker, may further 
support the provision of topical analgesia for children receiving an inhalational induction of 
anaesthesia.  
 
 
 
 
 
 
 
 
 
 
 
 

 
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3. THEORETICAL FRAMEWORK 
 
This study will be performed as a retrospective cohort observational study (a study which looks back 
in time, identifies cohorts (groups) of 'exposed' (those who received topical analgesia (skin numbing 
cream)) and 'non-exposed' (those who did not receive topical analgesia (skin numbing cream)) 
children and follows them over a period of time to see how their exposures affect their outcomes).  
Since no studies have been conducted to date, to determine the value of topical analgesia (skin 
numbing cream) for children receiving an inhalational induction of anaesthesia (gas to go off to sleep), 
this has been designed as a non-randomised preparatory study. Being non-experimental in nature, 
this study will attempt to evaluate preliminary null hypotheses of association. Where association(s) 
and/or potential benefit(s) are observed to a statistically significant level, the value and feasibility of a 
future experimental study, in the form of a prospective randomised controlled trial, will be evaluated.  
Through acting as a first step in exploring a novel intervention, this approach is felt to offer a safe and 
cost-effective indication of the value a future large-scale experimental trial, which in an 
uninvestigated field and with only a suggestible potential for benefit, would face numerous approval 
challenges.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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4. RESEARCH QUESTION / AIM(S) 
 
The primary aim of this study is as follows: 
To determine whether topical analgesia (numbing skin cream) application prior to receiving 
inhalational induction of anaesthesia (gas to go off to sleep) may offer any beneficial effects for 
paediatric patients. 
The primary outcome measure of interest is as follows: patient movement (as a surrogate marker of 
pain) during intravenous cannulation (insertion of a drip line into a vein). 
The frequency of occurrence of the primary outcome measure will then be compared between those 
who received and did not receive topical analgesia (numbing skin cream) to test the primary 
‘preliminary null hypothesis of association’ (default statistical belief): that the application of topical 
analgesia (skin numbing cream) prior to inhalational induction of anaesthesia (gas to go off to sleep) 
does not affect the frequency of patient movement during intravenous cannula insertion (insertion of 
drip line into a vein). 
 
The secondary aim of this study is as follows: 
To determine whether topical analgesia (numbing skin cream) application prior to receiving 
inhalational induction of anaesthesia (gas to go off to sleep) may offer any other beneficial effects for 
paediatric patients.  
Secondary outcome measures will include: rate of successful initial venous cannulation (insertion of a 
drip line into a vein at first attempt), duration of the anaesthesia (as a surrogate marker of procedure 
time) and frequency of dermal (skin) reactions (itching, redness, blanching and swelling).  
The frequency of occurrence or duration of each of the secondary outcomes measures will then be 
compared between those who received and did not receive topical analgesia (numbing skin cream) to 
test the secondary ‘preliminary null hypothesis of association’ (default statistical belief): that the 
application of topical analgesia (skin numbing cream) prior to inhalational induction of anaesthesia 
(gas to go off to sleep) does not affect the initial cannulation (first drip line insertion) success rate, 
time to secure the drip line or affect the frequency of dermal (skin) side effects. 
 
Where association(s) and/or potential benefit(s) are observed, the value and feasibility of a future 
experimental study, in the form of a prospective randomised controlled trial, will be evaluated.  
 
 

 
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5. STUDY DESIGN AND METHODS OF DATA COLLECTION AND DATA ANALYSIS 
 
This study will be performed as a retrospective cohort observational study (a study which looks back 
in time, identifies cohorts (groups) of 'exposed' (those who received topical analgesia (skin numbing 
cream)) and 'non-exposed' (those who did not receive topical analgesia (skin numbing cream)) 
children and follows them over a period of time to see how their exposures affect their outcomes).  
Once HRA approval has been gained, it is planned that data collection and the subsequent analyses 
will proceed as follows: 
Stage 1: ‘Identification’ (by a member of the usual care team) 
All children from 1 month to 18 years of age undergoing elective or urgent inhalational induction of 
anaesthesia at Nottingham University Hospitals NHS Trust over a six month study period (August 2020 
to January 2021) will be identified and considered eligible for inclusion. 
Bluespier Theatre Management Systems at Nottingham University Hospitals NHS Trust (a secure pre-
populated dataset) will be used for initial patient identification (all children receiving an inhalational 
induction of anaesthesia during the study period) and entered into an password protected Microsoft 
Excel file entitled the ‘initial non-anonymised dataset’ (using the unique Nottingham University 
Hospitals NHS Trust patient identification number - the only form of personal identifiable data to be 
recorded at any stage of the study). This will be performed by a member of the usual care team (M. 
Billingham, Department of Anaesthesia, Nottingham University Hospitals NHS Trust) and the dataset 
will be stored securely on an NHS Trust server following NHS Information Governance and data 
security policies and procedures. 
 
Stage 2: Exclusion (by a member of the usual care team) 
Children meeting the study exclusion criteria will be excluded at this stage by a member of the usual 
care team (M. Billingham, Department of Anaesthesia, Nottingham University Hospitals NHS Trust). 
Exclusion criteria are as follows: children receiving an attempted awake venous cannula insertion 
and/or a failed intravenous induction of anaesthesia prior to an inhalational induction of anaesthesia, 
child or family history of malignant hyperthermia, congenital or idiopathic methaemoglobianaemia, 
glucose-6-phosphate dehydrogenase deficiency (G6PD), known sensitivity to topical analgesia and the 
use of analgesics within the preceding 24 hours. 
All children meeting these exclusion criteria will be removed from the ‘initial non-anonymised 
dataset’ to create a ‘non-anonymised participant dataset’ (a password protected Microsoft Excel 
document which will be stored securely on an NHS Trust server following NHS Information 
Governance and data security policies and procedures). 

 
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Stage 3: ‘Recruitment’ (by a member of the usual care team) 
The ‘non-anonymised participant dataset’ will contain all children who will become study participants 
(identified as being eligible and not meeting the study exclusion criteria). Using a total population 
(purposive) sampling technique, pre-existing information for all of these children (n=1,323) will be 
collected into a ‘non-anonymised research dataset’, which will be stored securely as a password 
protected Microsoft Excel document on an NHS Trust server following NHS Information Governance 
and data security policies and procedures, with subsequent data collection only completed for these 
sampled children. This will be performed by a member of the usual care team (M. Billingham, 
Department of Anaesthesia, Nottingham University Hospitals NHS Trust).  
As such, only pre-existing child data will be collected (for children essentially being ‘recruited’ as units 
of observation) and no children will be actively ‘recruited’ as participants for interventional research 
purposes.  
 
Stage 4: Data Collection (by a member of the usual care team) 
Exposure status and outcome measures will be recorded for each ‘recruited’ unit of observation at 
this stage by a member of the usual care team (M. Billingham, Department of Anaesthesia, 
Nottingham University Hospitals NHS Trust) and incorporated into the ‘non-anonymised research 
dataset’.  
The unique Nottingham University Hospitals NHS Trust patient identification number (the only form 
of non-anonymised data to be recorded at any stage of the study) will be utilised for accessing the 
appropriate records, which will involve access to the Royal College of Anaesthesia logbook records (a 
mandatory and routine anaesthetic data collection process necessary for annual revalidation), Trust 
theatre records (Bluespier Theatre Management Systems at Nottingham University Hospitals NHS 
Trust), Perioperative care records, Trust medical records, Trust anaesthetic charts and Trust 
prescription charts. 
At first, the exposure status will be established for each unit of observation (that is whether the 
individual child did or did not receive topical analgesia retrospectively). This will be an observational 
process according to events which have already occurred. Treatment allocation will not be influenced 
by this research project and a randomised interventional approach will not be implemented. The 
exposure status will be determined from the Royal College of Anaesthesia logbook ‘note’ section, 
where this information is routinely recorded. Trust prescription charts (electronically available 
through the Digital Health Record (DHR)) will always offer this information, however, should this not 
be immediately available to the usual care team member via the logbook.  
The Royal College of Anaesthesia logbook will subsequently be accessed for each of the ‘exposed’ and 
‘non-exposed’ units of observation and used to incorporate the following basic demographics into the 

 
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‘non-anonymised research dataset’: gender, age (date of birth will not be registered in order to 
maintain confidentiality), ASA grade (an identifier of patient wellbeing) and priority (elective or 
emergency procedure). 
Further non-dependent information, including the grade of anaesthetist performing cannula insertion 
(Consultant or Trainee), history of prematurity (<38 weeks gestation) and child skin colour (light 
(Fitzpatrick scale I to IV) or dark (Fitzpatrick scale ≥ V)) will also be collected from the Royal College of 
Anaesthesia logbook, Trust anaesthetic charts and Trust medical records using the DHR.  
Trust medical records and prescription charts will also be used to extract the required information to 
calculate body mass index (BMI) from data on height and weight, however, for children younger than 
2 years of age, BMI is not applicable and therefore weight-to-age will be used. BMI and weight-to-age 
will then be converted to a z-score, with the use of age- and gender-specific growth charts from the 
Centers for Disease Control (CDC), to allow for comparison of patients of different ages. 
For the recording of outcome status, all primary and a large proportion of secondary outcome 
measures are routinely recorded as an ‘incident’ or ‘note’ or in the case of procedure time as ‘start-
end’ in the Royal College of Anaesthesia logbook but also in the Trust anaesthetic charts, Trust 
theatre records and Perioperative care records for all. These measures will be defined and recorded 
into the ‘non-anonymised research dataset’, as follows: 
Occurrence of patient movement (as a surrogate marker of pain) during intravenous cannulation for 
those children receiving an inhalational induction. Movement will be defined as reflex hand and/or 
arm withdrawal and/or the initiation of excitatory movement(s) at the time of needle insertion. 
Occurrence of dermal (skin) reactions at the site of topical analgesia application was assessed 
(inspection and verbal confirmation where possible) for erythema (redness) and oedema (swelling), 
blanching (pallor) and pruritis (itching) and where present, were documented by the healthcare 
provider. 
Rate of FTSI (first time successful insertion) of cannula (with success defined as skin breached only 
once and the ability to freely instil 5 ml of normal saline intravenously (into the vein)).  
For FTSI measurement, whilst the logbook may or may not offer this information, this will be always 
recorded in the Theatre records and Perioperative care records (with an ‘X’ marking a successful 
cannulation and an ‘F’ marking a failed cannulation in the perioperative are records skin check 
section). Where an F marking is registered, FTSI will be recorded as ‘No’.  
Although the ‘duration of procedure’, being defined as the time from first application of venous stasis 
to securing the intravenous cannula, would be the ideal indicator or the effect of topical analgesia on 
the temporal nature of cannulation, this information is not available for a vast majority of the units of 
observation. Instead, a proxy marker will to be used in this study: the ‘overall anaesthetic time’, which 
will always be available via the Logbook (Start – end time) and the Bluespier Theatre record 
(‘Anaesthetic Start time to (arrival in) Theatre’). 

 
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A summary of all the predictor (independent) and outcome (dependent) variables to be collected and 
where this information may be retrieved is summarised in the following Tables: 
Predictor variable 
Measurement 
Source of 
information 
Use of topical 
analgesia 
Yes or No 
RCoA Logbook 
(Notes) 
Trust prescription 
charts 
Age 
Years 
RCoA Logbook 
Gender 
Male or Female 
RCoA Logbook 
Adiposity 
BMI or weight-to-
age z score 
Trust prescription 
charts 
Medical records 
Ethnicity / Skin 
colour 
Light (Fitzpatrick 
scale I to IV) or Dark 
(Fitzpatrick scale ≥ 
V) 
Trust medical 
records 
History of 
prematurity (<38 
weeks gestation) 
Yes or No 
Anaesthetic record 
Trust medical 
records 
Grade of 
Anaesthetist 
performing 
cannulation 
Consultant or non-
Consultant 
RCoA Logbook 
Anaesthetic record 
Theatre record 
(Bluespier) 
Perioperative care 
record 
ASA 
1, 2, 3, 4 or 5 
RCoA Logbook 
Priority 
Elective or Urgent 
RCoA Logbook 
 
Outcome variable 
Measurement 
Source of 
information 
Patient movement 
Yes or No 
RCoA Logbook 

 
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(Incidents) 
FTSI (first time 
successful insertion) 
Yes or No 
RCoA Logbook 
(Notes) 
Theatre record 
(Bluepsier) 
Perioperative care 
record (skin check 
section) 
Skin side effects: 
Oedema 
Erythema 
Blanching 
Pruritis 
 
Yes or No 
Yes or No 
Yes or No 
Yes or No 
RCoA Logbook 
(Incidents) 
Perioperative care 
record (skin check 
section) 
Proxy-procedure 
time (overall 
anaesthetic time) 
Minutes 
RCoA Logbook (Start 
– end) 
Theatre record 
(Bluespier) 
 
Evidently, a vast proportion of exposure and outcome measures may be evaluated via access to the 
mandatory Royal College of Anaesthesia logbook records, Trust anaesthetic charts, Trust theatre 
records, Trust medical records, Perioperative care records and Trust prescription charts, which will be 
available to a usual care team member (M. Billingham, Department of Anaesthesia, Nottingham 
University Hospitals NHS Trust).  
Where exposure and outcome variables are unavailable in the child’s pre-existing data, these units of 
observation will be excluded from the analyses. In addition, all units of observation who received 
venous cannula insertion beyond the area of topical analgesia application and those who received 
topical analgesia less than 60 minutes prior to their inhalational induction of anaesthesia (considered 
insufficient topical analgesia application time) will also be excluded from the ‘exposed’ cohort during 
the analyses.  
 
Stage 5: Anonymisation Process and Generation of Anonymised Research Dataset for Research 
Purposes (by a member of the usual care team)  

 
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Each unit of observation entered into the ‘non-anonymised research dataset’ will be allocated a Study 
ID (NOT0001 to NOT1323), alongside their Trust patient identification number. The Trust patient 
identification number will then be removed from the dataset at this stage, with the remaining 
information (including the Study ID) incorporated into an 'anonymised research dataset’, by a 
member of the usual care team (M. Billingham, Department of Anaesthesia, Nottingham University 
Hospitals NHS Trust).  
This 'anonymised research dataset’ will be made available for research purposes in a password 
protected Microsoft Excel format (ready for conversion into an IBM SPSS format) and stored securely 
on an NHS Trust server following NHS Information Governance and data security policies and 
procedures.  
Only one usual care team member (M. Billingham, Department of Anaesthesia, Nottingham University 
Hospitals NHS Trust) will retain access to each of the non-anonymised datasets (in addition to the 
'anonymised research dataset’) and at no point will identifiable patient details be made available to 
any non-usual care team member.  
 
Stage 6: Data Analysis 
All statistical analyses will be performed using IBM SPSS Statistics Version 27.0 (Armonk, NY, USA) on 
an NHS Trust secure server following NHS Information Governance and data security policies and 
procedures. At this stage, the 'anonymised research dataset’ (in Microsoft Excel format) will be 
converted into an IBM SPSS Version 27.0 dataset (the ‘final anonymised research dataset’). No 
personal identifiable information will ever be utilised on the IBM SPSS platform. All of the analyses 
will be performed by the Chief Investigator (M. Billingham, Department of Anaesthesia, Nottingham 
University Hospitals NHS Trust).  
The baseline characteristics of those included will be summarised in terms of frequencies and 
percentages for categorical variables, with mean and standard deviation, or median and interquartile 
range (IQR), utilised for continuous variables, where appropriate. 
With use of bivariate and multivariable analysis, the influence of all potential contributory factors for 
each outcome of interest will be examined. Where outcome information is unavailable, these units of 
observation (individual child data) will be excluded from the analyses. 
For three of the outcome variables (patient movement, dermal side effects and FTSI), the crude 
(unadjusted) risk ratio and 95% confidence intervals (CI) will be measured for each of the categorical 
predictor variables (gender, skin colour, grade of anaesthetist inserting the cannula, priority, history 
of prematurity and application of topical analgesia) and the Mann Whitney U test will be calculated 
for each of the continuous predictor variables (age, BMI or weight-to-age z score). In addition, a 
Kaplan–Meier survival analysis, to compare the difference in mean anaesthesia time between curves 
will be performed (as a proxy marker of procedure time) for each cohort.    

 
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Multivariable binomial logistic binomial regression models (using all ‘explanatory’ baseline predictor 
variables) will subsequently be used to analyse the impact of topical analgesia exposure on frequency 
of movement and cannula FTSI (first time successful insertion) rates and a multivariable Cox 
regression analysis will be performed to analyse the impact of topical analgesia exposure on overall 
anaesthesia time.  
From the models, adjusted odds ratios (AOR) or hazard ratios will be calculated, and model fit will be 
assessed by the Hosmer-Lemeshow test, c statistic, Nagelkerke’s pseudo-R2 and McFadden adjusted 
pseudo-R2. 
Within each of the multivariable analyses, statistical significance will be assessed at the 5% level 
based on a two tailed comparison.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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6. STUDY SETTING 
This is a single centre study which will be performed at Nottingham University Hospitals NHS Trust. 
The paediatric services at the Trust provide secondary and tertiary care for more than 450,000 
children from Nottinghamshire and beyond.  
 
  
7. SAMPLE AND RECRUITMENT 
 
7.1. Eligibility Criteria 
 
7.1.1. Inclusion criteria  
Inclusion criteria include: data from all children from 1 month to 18 years of age undergoing elective 
or urgent inhalational induction of anaesthesia at Nottingham University Hospitals NHS Trust over a 
six month study period (August 2020 to January 2021). 
 
7.1.2. Exclusion criteria  
Exclusion criteria include: data from children receiving an attempted awake venous cannula insertion 
and/or a failed intravenous induction of anaesthesia prior to an inhalational induction of anaesthesia, 
child or family history of malignant hyperthermia, congenital or idiopathic methaemoglobianaemia, 
glucose-6-phosphate dehydrogenase deficiency (G6PD), known sensitivity to topical analgesia and the 
use of analgesics within the preceding 24 hours. 
 
7.2. Sampling 
 
7.2.1. 
Size of sample 
Overall, all data from all children eligible for participation will be entered into the analyses. This will 
entail the recruitment of data from 1,323 children who have received an inhalational induction of 
anaesthesia and not met any of the study exclusion criteria. This sample size has been determined 
following the generation of preliminary dataset summaries, using the Bluespier Theatre Management 
System (without any requirement to access individual patient data), which has recorded 1,479 eligible 
children, with 156 children meeting the exclusion criteria, leaving 1,323 potential participants (units 
of observation) for whom further information may be collected from pre-existing data, once 
authorised.  

 
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Where formal hypothesis testing is performed, sample size calculations may be made using the 
following formulae:  
Kelsey (Methods in Observational Epidemiology 2nd Edition, Table 12-15) and Fleiss (Statistical 
Methods for Rates and Proportions, formulas 3.18 &3.19) 
Examination of previous audits suggest approximately 50% of children receive topical analgesia. 
Expecting an incidence of movement in non-exposed group of approximately 20% (Kong CF, Chew 
STH, Ip-Yam PC. Intravenous opioids reduce airway irritation during induction of anaesthesia with 
desflurane in adults. Br J Anaesth 2000;85:364-367 noted an incidence of 24%), study sample size 
calculations were performed as follows: 
Sample Size: X-Sectional, Cohort, & Randomized Clinical Trials 
Two-sided significance level (1-alpha): 95 
Power (1-beta, % chance of detecting): 80 
Ratio of sample size, Unexposed/Exposed: 1 
Percent of Unexposed with Outcome: 20 
Percent of Exposed with Outcome: 9.9 
Odds Ratio: 0.44 
Risk/Prevalence Ratio: 0.5 
Risk/Prevalence difference: -10 
____________________________________________________ 
Kelsey Fleiss Fleiss with CC 
____________________________________________________ 
Sample Size – Exposed  
197  
195  
215 
Sample Size – Non-exposed  197  
195  
215 
____________________________________________________ 
Total sample size:  
 
394  
390  
430 
____________________________________________________ 
 
As such, a study sample size of 430 children would appear to give a power of >90% to detect a risk 
ratio of 0.5 at the 5% significance level. 

 
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Yet, this preparatory study has been designed to test a number of preliminary hypotheses, with a 
plethora of co-factors (predictor variables) and it has therefore been decided to use a larger sample 
size to ensure the study is sufficiently powered, with the recruitment of the data from all suitable 
children (n=1,323) across the six month study period.     
 
7.2.2. 
Sampling technique 
All children who may become units of observation (identified using the Bluespier Theatre 
Management Systems at Nottingham University Hospitals NHS Trust as being eligible and not meeting 
the study exclusion criteria) will be included into a Microsoft Excel document (the ‘non-anonymised 
participant dataset’). Using a total population (purposive) sampling technique, pre-existing 
information for each of these units of observation (n=1,323) will be collected into a ‘non-anonymised 
research dataset’, which will be stored securely as a password protected Microsoft Excel document on 
an NHS Trust server following NHS Information Governance and data security policies and procedures, 
with subsequent information collection only completed from these sampled children’s pre-existing 
data. This will be performed by a member of the usual care team (M. Billingham, Department of 
Anaesthesia, Nottingham University Hospitals NHS Trust).   
 
7.3. Recruitment 
 
7.3.1. 
Sample identification 
Once HRA approval has been gained, it is planned that individual participants will be identified, 
screened for exclusion and ‘recruited’ as units of observation (with no active involvement of 
patients/service users as participants) into the study sample as follows: 
Stage 1: ‘Identification’ (by a member of the usual care team) 
All children from 1 month to 18 years of age undergoing elective or urgent inhalational induction of 
anaesthesia at Nottingham University Hospitals NHS Trust over a six month study period (August 2020 
to January 2021) will be identified and considered eligible for inclusion. 
Bluespier Theatre Management Systems at Nottingham University Hospitals NHS Trust (a secure pre-
populated dataset) will be used for initial patient identification (all children receiving an inhalational 
induction of anaesthesia during the study period) and entered into an password protected Microsoft 
Excel file entitled the ‘initial non-anonymised dataset’ (using the unique Nottingham University 
Hospitals NHS Trust patient identification number - the only form of personal identifiable data to be 
recorded at any stage of the study). This will be performed by a member of the usual care team (M. 
Billingham, Department of Anaesthesia, Nottingham University Hospitals NHS Trust) and the dataset 

 
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will be stored securely on an NHS Trust server following NHS Information Governance and data 
security policies and procedures. 
 
Stage 2: Exclusion (by a member of the usual care team) 
Children meeting the study exclusion criteria will be excluded at this stage by a member of the usual 
care team (M. Billingham, Department of Anaesthesia, Nottingham University Hospitals NHS Trust). 
Exclusion criteria are as follows: children receiving an attempted awake venous cannula insertion 
and/or a failed intravenous induction of anaesthesia prior to an inhalational induction of anaesthesia, 
child or family history of malignant hyperthermia, congenital or idiopathic methaemoglobianaemia, 
glucose-6-phosphate dehydrogenase deficiency (G6PD), known sensitivity to topical analgesia and the 
use of analgesics within the preceding 24 hours. 
All children meeting these exclusion criteria will be removed from the ‘initial non-anonymised 
dataset’ to create a ‘non-anonymised participant dataset’ (a password protected Microsoft Excel 
document which will be stored securely on an NHS Trust server following NHS Information 
Governance and data security policies and procedures). 
 
Stage 3: ‘Recruitment’ (by a member of the usual care team) 
The ‘non-anonymised participant dataset’ will contain all children who will become study participants 
(identified as being eligible and not meeting the study exclusion criteria). Using a total population 
(purposive) sampling technique, pre-existing information for all of these children (n=1,323) will be 
collected into an ‘non-anonymised research dataset’, which will be stored securely as a password 
protected Microsoft Excel document on an NHS Trust server following NHS Information Governance 
and data security policies and procedures, with subsequent data collection only completed for these 
sampled children. This will be performed by a member of the usual care team (M. Billingham, 
Department of Anaesthesia, Nottingham University Hospitals NHS Trust).  
As such, only pre-existing child data will be collected (for children essentially being ‘recruited’ as units 
of observation) and no children will be actively ‘recruited’ as participants for interventional research 
purposes.  
 
Of note, preliminary dataset summaries generated within the Bluespier Theatre Management System 
for each of the aforementioned three stages (without any requirement to access individual patient 
data), has recorded 1,479 eligible children, with 156 children meeting the exclusion criteria, leaving 
1,323 potential participants for whom further information collection (from pre-existing data), once 
authorised and recruited (as units of observation), may proceed.  

 
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7.3.2. 
Consent 
This study involves retrospective, observational, data collection and analysis from pre-existing clinical 
information by members of the usual care team. There is no active participation by children or their 
parents, no changes in treatment, or collection of new data. Furthermore, all data to be utilised for 
the purposes of research, will also be completely anonymised by a member of the usual care team, 
therefore we are requesting permission to waive the requirement to obtain written informed 
consent.  
 
 
 
 
8. ETHICAL AND REGULATORY CONSIDERATIONS 
 
No study related activities will begin until the study has Health Research Authority approval. The 
study will be conducted in line with the principles of International Conference on Harmonisation of 
Good Clinical Practice and the UK policy framework for health and social care research 2017. The 
study will be conducted under the supervision of the Sponsor and comply with requests for 
monitoring visits by appropriate regulatory authorities. Data collection, storage, access and retention 
will comply with GDPR 2018 and Data Protection Act 2018 requirements and all data will be 
anonymised for analysis. 
 
8.1. Assessment and management of risk 
This study is observational and considered to confer a low risk to participants. No active clinical 
interventions (with any potential to cause participant harm) will be introduced during this study. 
 
8.2. Research Ethics Committee (REC) review & reports 
This study involves retrospective, observational, data collection and analysis from pre-existing clinical 
information by members of the usual care team. There is no active participation by children or their 

 
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parents, no changes in treatment, no collection of new data and no identifiable information will be 
accessible to non-members of the usual care team, therefore we do not intend to seek REC approval. 
Substantial amendments that require review by HRA will not be implemented until the HRA grants a 
favourable opinion for the study. 
All correspondence with the HRA will be retained, with the Chief Investigator producing the annual 
report as required and notifying the HRA of the end of the study. 
If the study is ended prematurely, the Chief Investigator will notify the HRA, including the reasons for 
the premature termination. 
Within one year after the end of the study, the Chief Investigator will submit a final report with the 
results, including any publications/abstracts, to the HRA. 
 
8.3. Peer review 
The peer review process has been instigated by the Chief Investigator (M. Billingham, Department of 
Anaesthesia, Nottingham University Hospitals NHS Trust), who has obtained independent external 
peer review from the following individuals: 
Christopher Tench (Senior Medical Statistician, Faculty of Medicine and Health Sciences, University of 
Nottingham) 
Joyce Yeung (Associate Clinical Professor in Anaesthesia and Critical Care, University of Warwick) 
In addition, support for this study has also been provided by the National Institute for Health 
Research (NIHR) Research Design Service (RDS) East Midlands group (with Dr. Doyo Enki as support 
advisor) 
Furthermore, the study protocol has been internally reviewed and amended by a department / 
committee within the Chief Investigator’s institution (the Nottingham University Hospitals NHS 
Research and Innovation department) and by Associate Clinical Professor Tim Card (Honorary 
Consultant Physician and Gastroenterologist at Nottingham University Hospitals NHS Trust, Member 
of Epidemiology Expert Review Panel for CRUK and Member of the International Editorial board for 
Alimentary Pharmacology and Therapeutics). 
The peer review process for the study has been approved by the sponsor, who will continue to 
monitor conduct of the study against nationally agreed standards. 
 
8.4. Patient & Public Involvement 

 
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Although regulatory guidelines from the Health Research Authority and Research Ethics Committee 
do not mandate patient consent for the completion of this study, patient and public involvement has 
and will continue to form a central part of the project.  
This study has worked with several service users and the public by actively involving and engaging 
them in all parts of the research process as partners. This has been performed through consultation 
and collaboration with the Nottingham University Hospitals NHS Trust, Patient and Public Involvement 
and Engagement (PPI) department (Head of department: Kate Frost) and the NUH and NIHR 
GenerationR, Young Person Advisory Group (YPAG).  
Through integrating PPI into our research process, it has been possible to formulate clear questions, 
processes and adjust the protocol to clarify and prioritise topics that are important for service users 
(including a focus on consent, our reasons for not requesting consent and the acceptability of our 
planned approach to the YPAG members). 
A selection of replies from the YPAG are listed here: 
“Yes, the summary uses appropriate language.” 
“I like the 'consent' paragraph with the 3 reasons. It makes it easier to read.”  
“Explanations of how they are going to use the data is good” 
“I think it is okay to use data – I would want my data to be used to help other people” 
“Overall, the summary is really good. It's easy to read and there isn't many pages to read from. I look 
forward to working with Matt and yourself in the new year.”  
Furthermore, through collaboration with the PPI, public interest may be satisfied and appreciation of our 
outcomes enhanced, through public dissemination of our findings beyond peer-reviewed publication. 
This will involve publication of our findings on the hospital website, informing the YPAG and supplying 
information in a patient group newsletter/website that are patient - and public centric rather than solely 
researcher-led. 
 
8.5. Regulatory Compliance  
Before any data is collected for the study, the Chief Investigator/Principal Investigator or designee will 
apply for HRA approval for the study and will make contact with the R&D department. 
Prior to commencing recruitment, the local R&I team will confirm their capacity and capability to 
conduct the study, as per the HRA approval letter.  

 
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Any amendment to the protocol will be considered to potentially affect a site’s capacity to continue in 
the study, the Chief Investigator/ Principal Investigator or designee will inform the Sponsor of the 
proposed amendment. The amendment will be submitted as per Section 8.7. 
 
8.6. Protocol compliance  
Protocol deviations, non-compliances, or breaches (recognised as departures from the approved 
protocol) will be documented and reported to the Chief Investigator and Sponsor immediately.  
The research sponsor will ensure arrangements and systems are in place for the management and 
monitoring of research, taking a risk based approach. This study is observational and considered to 
confer a low risk to participants. The monitoring and auditing of the conduct of the study will reflect 
that set out in the UK Framework for Health and Social Care 2017 and Sponsor SOP RES-013 and SOP 
QMS-004.  
 
8.7. Amendments  
It will be the sponsor’s responsibility to decide whether an amendment is substantial or non-
substantial for the purposes of submission to the HRA. The sponsor will submit a valid notice of 
amendment for consideration. Site R&D departments will be provided with the information on the 
amendment. The level of review will be dictated by the category as assessed by the HRA (A, B or C).   
 
8.8. Adverse Events  
This study is retrospective and observational and so is considered to confer no risk to participants. No 
active clinical interventions are to be undertaken. The clinical safety profile of topical analgesia is now 
well established. The secondary outcomes of this study will observe the dermal side effects of topical 
analgesia use, but these are expected and will not constitute an adverse event although they will be 
documented in the study datasets and the Chief Investigator informed.  
Of note, this research will not influence any of the anaesthetic practices offered to any of the children 
entered into the study. To this extent, provision of topical analgesia will be left solely to the discretion of 
the clinical team with no influence made by the research team (this is a non-randomised, non-
interventional study design). Therefore, no active intervention is to be introduced in this study with the 
potential to result in an adverse event, however, through observation of negative clinical outcomes and 
amending practices (which will or will not have already occurred in the past) this study may promote 
patient safety (in the future). 

 
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8.9. Data protection and patient confidentiality  
All investigators and study site staff will comply with the requirements of the General Data Protection 
Regulation 2018 and Data Protection Act 2018 with regards to the collection, storage, processing and 
disclosure of personal information and will uphold the Regulation’s/Act’s core principles.  
Sample (original) sources of information, including the pre-collected datasets (the RCoA Logbook and 
Bluespier records), alongside anaesthetic and surgical records and prescription charts, will remain as 
originally intended: as permanent, indelible records, without amendment by the research activity. 
Overall 5 datasets will be generated during this study: 
The ‘initial non-anonymised dataset’ (containing all eligible children) 
The ‘non-anonymised participant dataset’ (containing children not meeting the exclusion criteria of 
the study) 
The ‘non-anonymised research dataset’ (containing data from 1,323 children ‘recruited’ (as units of 
observation) from the ‘non-anonymised participant dataset’ using a consecutive sampling technique) 
The 'anonymised research dataset’ (the Microsoft Excel dataset containing the 1,323 recruited units 
of observation following data collection and anonymisation (removal of Trust patient identification 
number)) 
The ‘final anonymised research dataset’ (the IBM SPSS version of the 'anonymised research dataset’, 
which will be used for data analysis) 
Each of these datasets will be stored securely as a password protected documents (as Microsoft Excel 
or IBM SPSS formats) on an NHS Trust server following NHS Information Governance and data security 
policies and procedures. 
Only the CI (M. Billingham, Department of Anaesthesia, Nottingham University Hospitals NHS Trust), 
who is also a member of the usual care team, will have access to patients’ personal data. The CI will 
also act as data custodian.  
In compliance with the ICH/GCP guidelines, the Chief Investigator will maintain all records and 
documents regarding the conduct of the study. These will be retained for at least 5 years or for longer 
if required. If the responsible investigator is no longer able to maintain the study records, a second 
person will be nominated to take over this responsibility. 
The Investigator Site File, Sponsor Trial Master File and study documents shall be finally archived by 
the sponsor at secure archive facilities according to Sponsor SOP RES-028. This archive shall include a 
copy of each of the study datasets and associated meta-data encryption codes. Access to the data is 
by written request to the Sponsor. 

 
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8.10. 
Indemnity 
As Nottingham University Hospitals NHS Trust is acting as sponsor for this study, NHS indemnity 
applies. NHS bodies are legally liable for the negligent acts and omissions of their employees. Non-
negligent harm is not covered by the NHS indemnity scheme. The Nottingham University Hospitals 
NHS Trust, therefore, cannot agree in advance to pay compensation in these circumstances. In 
exceptional circumstances an ex-gratia payment may be offered. 
 
8.11. 
Access to the final study dataset 
Two completely anonymised datasets generated by this study, essentially containing identical 
information, will be considered here as the ‘final study dataset’ (these being both the Microsoft Excel 
file: the ‘anonymised research dataset’ and the IBM SPSS adapted file: the ‘final anonymised research 
dataset’). 
Each of these files will be stored securely as a password protected documents on an NHS Trust server 
following NHS Information Governance and data security policies and procedures. 
Prior to the dissemination of the findings of the study, only the CI (M. Billingham, Department of 
Anaesthesia, Nottingham University Hospitals NHS Trust) and the Sponsor will have access to these 
files.  
Following the dissemination of the findings of the study, only one of the completely anonymised 
participant level datasets (the ‘anonymised research dataset’), will be made publicly available.  
 
 
 
 
 
 
 
 

 
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9. DISSEMINATION POLICY 
9.1.Dissemination policy 
This study will be registered on the ClinicalTrials.gov database. The study protocol, full study report, 
the anonymised participant level dataset (the ‘anonymised research dataset’), and statistical code(s) 
for generating the results will be made publicly available after publication of the study. 
No personal or patient identifiable data will be published and it is planned that the anonymised 
findings will be published via a peer-reviewed medical journal in the form of an original research 
paper. 
In addition, following our collaboration with the Patient and Public Involvement and Engagement (PPI) 
department, the study findings will also be published on the hospital website, the Young Person 
Advisory Group (YPAG) will be notified and information will be supplied in a patient group 
newsletter/website that are patient - and public centric rather than solely researcher-led. 
Although the supporting body will be acknowledged within the publication, none of the individuals offering 
support will have access to any of the datasets or possess publication rights. In addition, none of the data 
generated during the study will be used for secondary analyses. 
 
9.2. Authorship eligibility guidelines and any intended use of professional writers 
In line with the ICMJE (International Committee of Medical Journal Editors) recommendations, 
authorship will be based on the following 4 criteria:  
 
Substantial contributions to the conception or design of the work; or the acquisition, analysis, or 
interpretation of data for the work; AND  
 
Drafting the work or revising it critically for important intellectual content; AND  
 
Final approval of the version to be published; AND  
 
Agreement to be accountable for all aspects of the work in ensuring that questions related to the 
accuracy or integrity of any part of the work are appropriately investigated and resolved.  
Contributors who meet fewer than all 4 of the above criteria for authorship will not be listed as authors, 
but will be acknowledged. Examples of activities that alone (without other contributions) do not qualify a 
contributor for authorship are acquisition of funding; general supervision of a research group or general 
administrative support; and writing assistance, technical editing, language editing, and proofreading. 
 

 
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10. REFERENCES 
 
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4. Lee GY, Yamada J, Kyololo O, Shorkey A, Stevens B. Pediatric Clinical Practice Guidelines for 
Acute Procedural Pain: A Systematic Review. Pediatrics 2014;133:500-515.  
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transformative action in paediatric pain: a Lancet Child & Adolescent Health Commission 
(2020). Available at URL: https://doi.org/10.1016/S2352-4642(20)30277-7 
6. Finley GA, Franck LS, Grunau RE, von Baeyer CL. Why Children’s Pain Matters. Seattle, WA: 
IASP Press, 2005. 
7. Lander J, Hodgins S, Nazarali J, McTavish J, Ouellette J, Friesen E. Determinants of success and 
failure of EMLA. Pain 1996;64:89–97. 
8. Lander JA, Weltman BJ. EMLA and Amethocaine for reduction of children’s pain associated 
with needle insertion. Cochrane Database of Systematic Reviews 2006, Issue 3.  
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cannulation in children with a eutectic mixture of lidocaine and prilocaine (EMLA cream): 
comparison with placebo cream and no local premedication. Acta Anaesthesiol Scand 
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children: effect on the pain associated with venous cannulation. Br J Anaesth 1986;58:1242–5. 
11. Woolfson AD, McCafferty DF, Boston V. Clinical experiences with a novel percutaneous 
amethocaine preparation: prevention of pain due to venepuncture in children. Br J Clin 
Pharmacol 1990;30:273–9. 
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2007;55:377–91. 
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experimental surgery. Lab Anim 2008;42:45–61. 
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the surgical procedure during isoflurane–nitrous oxide anesthesia: hysterectomy versus 
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is sensitive to noxious stimuli during isoflurane or sevoflurane anesthesia. Anesthesiology 
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22. Kox WJ, Heymann von C, Heinze J, Prichep LS, John ER, Rundshagen I. Electroencephalographic 
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11. APPENDICES 
 
11.1. 
Appendix 1 – Schedule of Procedures 
Procedures 
Planned Time Schedule (2021) 
May 
May - June  
June - July 
August 
Participant sampling (identification, 
exclusion and recruitment) 
(by usual care team member) 
X 
 
 
 
Data Collection 
(by usual care team member) 
X 
X 
 
 
Creation of anonymised research 
datasets 
(by usual care team member) 
 
X 
 
 
Statistical analysis (by CI) 
 
 
X 
 
Dissemination of findings 
 
 
 
X 
 
11.2. 
Appendix 2 – Amendment History 
Amendment 
No. 
Protocol 
version no. 
Date issued 
Author(s) of 
changes 
Details of changes made 
1 
0.1 
26/10/2020 
M Billingham Amendments in line with Trust R&I 
recommendations and PPI input 
2 
0.2 
05/12/2020 
M Billingham Amendments in line with Trust R&I 
recommendations, NIHR RDS review, 
peer review