The Influence of Electroencephalographic Density Spectral Array Guidance of Sevoflurane Administration on Recovery From General Anaesthesia in Children Between 6 Months and 12 Years.
Phase: NA
Conditions: Anesthesia, Depth of Hypnosis Monitoring
Sponsor: Erasmus Medical Center

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The influence of electroencephalographic 
density spectral array guidance of sevoflurane 
administration on recovery from general 
anaesthesia in children between 6 months and 
12 years.  
A randomised controlled trial.  
 
 
 
Research group:  
 
MSc. I.J. de Heer 
 
Erasmus MC Sophia – Department of Anaesthesia  
Prof. Dr. F Weber  
Erasmus MC Sophia – Department of Anaesthesia 
MSc. G. Karaöz – Bulut 
Erasmus MC Sophia – Department of Anaesthesia 
BSc. H.A.C. Raab   
Erasmus MC – Department of Anaesthesia 

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PROTOCOL TITLE  
“The influence of electroencephalographic density spectral array guidance of sevoflurane 
administration on recovery from general anaesthesia in children between 6 months and 12 years”. 
Protocol ID 
DSA-RCT-1 
Short title 
The effect of DSA on recovery of anaesthesia in 
children 
EudraCT number  
Not applicable 
Version 
1.5 
Date 
14-07-2022 
Coordinating 
investigator/project leader 
Prof. Dr. F. Weber              Dept. of Anaesthesia 
                                            ErasmusMC Sophia 
Principal investigator(s) (in 
Dutch: hoofdonderzoeker/ 
uitvoerder) 
Prof. Dr. F. Weber              Dept. of Anaesthesia 
                                            ErasmusMC Sophia 
Sponsor (in Dutch: 
verrichter/opdrachtgever) 
Dept. of Anaesthesia, Erasmus MC 
Subsidising party 
Investigator initiated 
Independent expert (s) 
Drs. J.J. van Wijk. Dept. of Anaesthesia Erasmus 
MC Sophia. Tel: 010-7042289 
Laboratory sites <if applicable> 
Not applicable 
Pharmacy <if applicable> 
Not applicable 
 
 
PROTOCOL SIGNATURE SHEE 
Name 
Signature 
Date 
Head of Department: 
Dr. C.D. van der Marel 
 
 
Coordinating Investigator/Project 
leader/Principal Investigator: 
Prof. Dr. F. Weber 
 
 
 
 
ANNY
14107122
Fout Wt ÷:

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TABLE OF CONTENTS 
 
1. 
INTRODUCTION AND RATIONALE ................................................................................ 10 
1.1 
General introduction .................................................................................................. 10 
1.2 
Density spectral array monitoring .............................................................................. 10 
Electroencephalographic density spectral array (DSA) is a three dimensional method to 
display electroencephalogram (EEG) signals consisting of the EEG frequency (y-axis), the 
power of the EEG signal (colour-coded to be integrated into a two dimensional plot) and the 
development of the EEG power spectrum over time (x-axis) (see figure 1).7 ......................... 10 
1.3 
General anaesthesia supplemented with caudal analgesia ..................................... 11 
1.4 
Sevoflurane anaesthesia ........................................................................................... 11 
1.5 
Post-anaesthesia discharge criteria – The Steward Post-Anaesthetic Recovery 
Score 12 
1.6 
Previous research related to this topic and significance of the project .................... 12 
2. 
OBJECTIVES .................................................................................................................... 13 
3. 
STUDY DESIGN ............................................................................................................... 14 
4. 
STUDY POPULATION ..................................................................................................... 15 
4.1 
Population (base) ...................................................................................................... 15 
4.2 
Inclusion criteria ......................................................................................................... 15 
4.3 
Exclusion criteria ........................................................................................................ 15 
4.3.1 
primary exclusion criteria ................................................................................... 15 
4.3.2 
secondary exclusion criteria ............................................................................... 15 
4.4 
Sample size calculation ............................................................................................. 15 
5. 
TREATMENT OF SUBJECTS .......................................................................................... 16 
5.1 
Investigational product/treatment .............................................................................. 17 
5.2 
Use of co-intervention (if applicable) ......................................................................... 17 
5.3 
Escape medication (if applicable) ............................................................................. 18 
6. 
INVESTIGATIONAL PRODUCT ....................................................................................... 18 
6.1 
Name and description of investigational  product(s) ................................................. 18 
6.2 
Summary of findings from non-clinical studies ......................................................... 18 
6.3 
Summary of findings from clinical studies ................................................................. 18 
6.4 
Summary of known and potential risks and benefits ................................................ 18 
6.5 
Description and justification of route of administration and dosage ......................... 18 
6.6 
Dosages, dosage modifications and method of administration ................................ 18 
6.7 
Preparation and labelling of Investigational Medicinal Product ................................ 18 
6.8 
Drug accountability .................................................................................................... 18 
7. 
NON-INVESTIGATIONAL PRODUCT ............................................................................. 19 
7.1 
Name and description of non-investigational product(s) .......................................... 19 
7.2 
Summary of findings from non-clinical studies ......................................................... 19 
7.3 
Summary of findings from clinical studies ................................................................. 19 
7.4 
Summary of known and potential risks and benefits ................................................ 19 
7.5 
Description and justification of route of administration and dosage ......................... 19 
7.6 
Dosages, dosage modifications and method of administration ................................ 19 

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7.7 
Preparation and labelling of Non Investigational Medicinal Product ........................ 19 
7.8 
Drug accountability .................................................................................................... 19 
8. 
METHODS ........................................................................................................................ 20 
8.1 
Study parameters/endpoints ..................................................................................... 20 
8.1.1 
Main study parameter/endpoint ......................................................................... 20 
8.1.2 
Secondary study parameters/endpoints (if applicable) ..................................... 20 
8.1.3 
Other study parameters (if applicable) ............................................................... 20 
8.2 
Randomisation, blinding and treatment allocation .................................................... 20 
8.3 
Study procedures ...................................................................................................... 20 
8.4 
Withdrawal of individual subjects .............................................................................. 21 
8.4.1 
Specific criteria for withdrawal (if applicable) ..................................................... 21 
8.5 
Replacement of individual subjects after withdrawal ................................................ 21 
8.6 
Follow-up of subjects withdrawn from treatment ...................................................... 21 
8.7 
Premature termination of the study ........................................................................... 21 
9. 
SAFETY REPORTING ..................................................................................................... 22 
9.1 
Temporary halt for reasons of subject safety ............................................................ 22 
9.2 
AEs, SAEs and SUSARs ........................................................................................... 22 
9.2.1 
Adverse events (AEs) ........................................................................................ 22 
9.2.2 
Serious adverse events (SAEs) ......................................................................... 22 
9.2.3 
Suspected unexpected serious adverse reactions (SUSARs) .......................... 23 
9.3 
Annual safety report .................................................................................................. 23 
9.4 
Follow-up of adverse events ..................................................................................... 23 
9.5 
Data Safety Monitoring Board (DSMB) / Safety Committee ..................................... 23 
10. 
STATISTICAL ANALYSIS ............................................................................................. 24 
10.1 
Primary study parameter(s) ....................................................................................... 24 
10.2 
Secondary study parameter(s) .................................................................................. 24 
10.3 
Other study parameters ............................................................................................. 24 
10.4 
Interim analysis (if applicable) ................................................................................... 24 
11. 
ETHICAL CONSIDERATIONS ..................................................................................... 25 
11.1 
Regulation statement ................................................................................................. 25 
11.2 
Recruitment and consent .......................................................................................... 25 
11.3 
Objection by minors or incapacitated subjects (if applicable) ................................... 25 
11.4 
Benefits and risks assessment, group relatedness .................................................. 25 
11.5 
Compensation for injury............................................................................................. 25 
11.6 
Incentives (if applicable) ............................................................................................ 26 
12. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .......................... 27 
12.1 
Handling and storage of data and documents .......................................................... 27 
12.2 
Monitoring and Quality Assurance ............................................................................ 27 
12.3 
Amendments .............................................................................................................. 27 
12.4 
Annual progress report .............................................................................................. 27 
12.5 
Temporary halt and (prematurely) end of study report ............................................. 27 
12.6 
Public disclosure and publication policy .................................................................... 28 
13. 
STRUCTURED RISK ANALYSIS ................................................................................. 29 

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13.1 
Potential issues of concern ....................................................................................... 29 
13.2 
Synthesis ................................................................................................................... 29 
14. 
REFERENCES .............................................................................................................. 29 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
ABR 
General Assessment and Registration form (ABR form), the application 
form that is required for submission to the accredited Ethics Committee; 
in Dutch: Algemeen Beoordelings- en Registratieformulier (ABR-
formulier) 
AE 
Adverse Event 
AR 
Adverse Reaction 
CA 
Competent Authority 
CCMO 
Central Committee on Research Involving Human Subjects; in Dutch: 
Centrale Commissie Mensgebonden Onderzoek 
CV 
Curriculum Vitae 
DoH 
Depth of hypnosis 
DSA 
Density Spectral Array 
DSMB 
Data Safety Monitoring Board 
EEG 
Electroencephalogram 
EU 
European Union 
EudraCT European drug regulatory affairs Clinical Trials  
GA 
General anaesthesia 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation; in Dutch: Algemene Verordening 
Gegevensbescherming (AVG) 
IB 
Investigator’s Brochure 
IC 
Informed Consent 
IMP 
Investigational Medicinal Product  
IMPD 
Investigational Medicinal Product Dossier  
MAC 
Minimal Alveolar Concentration 
METC  
Medical research ethics committee (MREC); in Dutch: medisch-ethische 
toetsingscommissie (METC) 
(S)AE 
(Serious) Adverse Event  
SPC 
Summary of Product Characteristics; in Dutch: officiële 
productinformatie IB1-tekst 
Sponsor 
The sponsor is the party that commissions the organisation or 
performance of the research, for example a pharmaceutical 
company, academic hospital, scientific organisation or investigator. A 
party that provides funding for a study but does not commission it is not 
regarded as the sponsor, but referred to as a subsidising party. 

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SUSAR  
Suspected Unexpected Serious Adverse Reaction 
UAVG 
Dutch Act on Implementation of the General Data Protection Regulation; 
in Dutch: Uitvoeringswet AVG 
WMO 
Medical Research Involving Human Subjects Act; in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 
 
 

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SUMMARY 
Rationale:  
Electroencephalographic density spectral array (DSA) is a three dimensional method to 
display electroencephalogram (EEG) signals consisting of the EEG frequency (y-axis), the 
power of the EEG signal (colour-coded to be integrated into a two dimensional plot) and the 
development of the EEG power spectrum over time (x-axis). DSA is routinely used to 
measure depth of hypnosis (DoH) by a part of the staff members in our department. When 
DSA is used, dose adjustments of sevoflurane will be made based on monitoring depth of 
anaesthesia. However, most of our colleague do not use DSA. Dose adjustment is then 
based on (subjective) clinical surrogate parameters, or in general mostly based on a minimal 
alveolar concentration of the anaesthetic gas that is used.  
Electroencephalographic DSA monitoring provides continuous objective information on DoH 
and should result in a faster speed of emergence and recovery from general anaesthesia 
(GA). This will be addressed in a  randomised controlled trial. 
 
Objective:  
To evaluate the influence of DSA monitoring, provided by the NarcotrendTM monitor, on the 
speed of emergence and recovery from GA.  
 
Study design:  
Single centre, prospective  randomised, double-blind, controlled trial. 
 
Study population:  
Paediatric patients, aged ≥ 6 months and ≤ 12 years, scheduled for surgical procedure 
requiring general anaesthesia supplemented with caudal analgesia. 
 
Intervention:  
In patients randomised to the intervention group of the trial, the anaesthetic agent 
sevoflurane will be titrated according to the typical DSA pattern for GA with sevoflurane, 
provided by the NarcotrendTM.1 In patients randomised to the control group, sevoflurane will 
be titrated according to a Minimal Alveolar Concentration (MAC) of 0.9 respectively an end 
tidal sevoflurane concentration of 2.3% based on standard practice in our paediatric 
anaesthesia department. 
 
Main study parameters/endpoints:  
The speed of emergence from GA (time interval from discontinuation of hypnotic agent until 
criteria for transfer from the operation theatre to the recovery room are met) is the primary 

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objective of this trial. Secondary objectives of this trial are the time until discharge criteria 
from the recovery room are met, the incidence of postoperative delirium, the difference in 
intra-operative blood pressure between the intervention group and the control group, the 
incidence of recall of intraoperative events, adverse events and DoH during GA (as 
measured by the Narcotrend monitorTM). 
 
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness:  
In patients randomised to the intervention group, the anaesthetic agent sevoflurane will be 
administered on the basis of objective measures of anaesthetic depth, the typical DSA 
pattern for GA. We expect a significantly faster speed of emergence and recovery based on 
clinical experiences with the use of DSA. The NarcotrendTM monitor is validated for use in 
paediatric patients. There are thus no additional risk factors apart from those, which are 
inherent with general anaesthesia. Patient randomised to the control group will receive 
standard treatment, that is delivery of sevoflurane based on a MAC of 0.9 respectively an 
end tidal sevoflurane concentration of 2.3%.  
A non-invasive therapeutical intervention (DSA based conduct of GA) should result in the 
advantage of faster recovery, without any additional risk factor.  
 

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1. INTRODUCTION AND RATIONALE 
1.1 General introduction  
EEG-based depth of hypnosis (DoH) could result in a faster recovery after the procedure, 
compared to a standard anaesthesia regimen. A faster recovery could result in 
advantages for the patient, advantages for the health care providers (enhanced workflow) 
and an advantage on the environmental impact (less volatile anaesthetic exposure).2 
Earlier performed studies with a processed EEG device as the Narcotrend index monitor 
showed this effect of DoH monitoring in a faster recovery after the procedure.3  
However the use of processed EEG monitoring in infants or young children is limited, 
because of the limitations of the monitors with the variability in age related EEG 
expression and the anaesthesia specific EEG features.4  
In density spectral array, these limitations are less relevant due to age and anaesthesia 
specific EEG expression of the density spectral array pattern.1,5,6 Therefore, we think 
density spectral array would be a more reliable way of monitoring depth of hypnosis in 
children.  
To investigate the additional value of density spectral array in children we have to perform 
this randomized controlled trial that will investigate the influence of DSA monitoring during 
general anaesthesia (GA) on the speed of recovery after the procedure, compared to 
standard general anaesthesia management.   
 
 
1.2 Density spectral array monitoring 
Electroencephalographic density spectral array (DSA) is a three dimensional method to 
display electroencephalogram (EEG) signals consisting of the EEG frequency (y-axis), 
the power of the EEG signal (colour-coded to be integrated into a two dimensional plot) 
and the development of the EEG power spectrum over time (x-axis) (see figure 1).7  
 
 
 Figure 1 density spectral array (DSA) 
 
Density spectral array has been developed to facilitate the interpretation of unprocessed 
electroencephalogram signals. It has multiple advantages compared to the widely used 
electroencephalogram-based indices, or processed EEG monitors.  
 

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Electroencephalographic density spectral array shows age-dependent changes in EEG 
effects of general anaesthetics in children. These age-related changes likely reflect 
ongoing development within the brain.5,6,8  
Furthermore, we know that different anaesthetics act at different molecular targets and 
neural circuits. This results in anaesthetic drug specific EEG signatures that are readily 
visible in DSA.7 The index-based indices, or processed EEG monitors assume the same 
index value defines the same level of unconsciousness for all anaesthetics.  
Because of the limitations of processed EEG monitors, recently published articles 
emphasize the use of raw or “unprocessed” EEG monitoring as DSA in the measurement 
of depth of hypnosis.4,9  
We previously performed some observational studies to investigate the specific 
anaesthetic drug and age-dependent DSA signatures in children.1,10 A specific DSA 
pattern of general anaesthesia with sevoflurane in children aged 6 months to 12 years 
exists of the appearance of high delta and alpha power on the spectrogram.1     
 
1.3 General anaesthesia supplemented with caudal analgesia 
According to standard care, at Erasmus MC Sophia Children’s Hospital many surgical 
procedures are performed under general anaesthesia supplement with caudal analgesia. 
To exclude the impact of opioids on speed of recovery, we choose to include patients 
undergoing a surgical procedure requiring general anaesthesia supplemented with caudal 
analgesia.  
 
1.4 Sevoflurane anaesthesia 
At ErasmusMC Sophia Children’s Hospital many surgical procedures are perfomed under 
general anaesthesia with the volatile anaesthetic sevoflurane. This anaesthetic drug is 
used for induction and maintenance of general anaesthesia. The concentration 
sevoflurane is titrated according to age and clinical status of the patient. The minimum 
alveolar concentration (MAC) is a widely used tool in titrating the surgical level of 
anaesthesia when DoH monitoring is not used. The MAC value changes with age, where 
MAC decreases with increasing age. The average MAC concentration of sevoflurane used 
in the ErasmusMC Sophia Children’s Hospital is 0.9 respectively an end tidal sevoflurane 
of 2.3%.11,12 
 
 
 
 
 
 

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1.5 Post-anaesthesia discharge criteria – The Steward Post-Anaesthetic Recovery 
Score 
The ‘Simplified Post-Anaesthetic Recovery Score’, published by Steward13, is the golden 
standard for assessment of recovery from Anaesthesia:  
 
Consciousness 
Score 
Awake 
2 
Responds to stimuli 
1 
Not responding 
0 
Airway 
 
Cough on command or cry 
2 
Maintaining good airway 
1 
Requires airway assistance 
0 
Motor 
 
Moves limbs purposefully 
2 
Non-purposeful movement 
1 
Not moving 
0 
 
 
1.5.1 Discharge criteria from the operating room 
The patient is ready to be transferred from the operating room (OR) to the recovery room 
when the following criteria are met: 
x 
Responding to stimuli (domain Consciousness)  
Score ≥ 1 
x 
Maintaining good airway (domain Airway) 
 
Score ≥ 1 
x 
Non-purposeful movements (domain Movement) 
Score ≥ 1 
That corresponds with a total Steward Score of ≥ 3. 
 
 
 
1.5.2 Discharge criteria from the recovery room  
Complete recovery from general anaesthesia is the prerequisite for discharge from the 
recovery room. It is achieved when the patient meets the following criteria: 
x 
Awake (domain Consciousness)  
 
 
Score 2 
x 
Coughing on command or crying (domain Airway) 
Score 2 
x 
Moving limbs purposefully (domain Movement)  
Score 2 
That corresponds with a total Steward Score of 6.  
 
 
 
1.6 Previous research related to this topic and significance of the project  
By now only a limited number of paediatric trials have been published about DSA 
guidance during general anaesthesia. None of them focused on the speed of recovery 
after general anaesthesia with DSA.  
Based on clinical experience with DSA guided anaesthesia, we expect the use of DSA 
will result in a faster recovery after general anaesthesia. However, the speed of 
emergence has never been investigated in previous trials demonstrating the use of DSA 
in children.  
 

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2. OBJECTIVES 
 
Primary Objective: the influence of density spectral array monitoring with the NarcotrendTM 
monitor on the speed of emergence from general anaesthesia with sevoflurane. The speed 
of emergence is defined as the time interval between the end of hypnotic drug application 
and the moment when discharge criteria from the operating room are met (defined as a 
Steward score ≥ 3).  
 
Secondary Objectives:  
x 
Total time from discontinuation of anaesthetic drug delivery until discharge from the 
post anaesthesia care unit. 
x 
The incidence of postoperative delirium by the Cornell Assessment of Postoperative 
Delirium (CAPD) score.14,15 
x 
The difference in intra-operative blood pressure between the intervention group and 
the control group. 
x 
Differences of depth of hypnosis during the procedure, as measured by the 
Narcotrend monitorTM. 
x 
Incidence of recall of events during the procedure (awareness) 
x 
Adverse events 

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3. STUDY DESIGN 
Single centre, prospective, randomized, double blind trial. 
In paediatric patients, aged 6 months until 12 years, scheduled for a surgical procedure 
which requires general anaesthesia supplemented with caudal analgesia. General 
anaesthesia is either guided by density spectral array or by a minimal alveolar sevoflurane 
concentration of 0.9 respectively an end tidal sevoflurane concentration of 2.3%.   
The two study groups are compared with respect to the speed of recovery (primary 
objective). Secondary objectives of this trial are total time from discontinuation of anaesthetic 
drug delivery until discharge from the post anaesthesia care unit, the incidence of 
postoperative delirium, the difference in intra-operative blood pressure between the 
intervention group and the control group, ddifferences of depth of hypnosis during the 
procedure, as measured by the Narcotrend monitorTM, the incidence of recall of events during 
the procedure (awareness) and adverse events. 
 

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4. STUDY POPULATION 
4.1 Population (base)  
Paediatric patients, aged 6 months until 12 years, scheduled for a surgical procedure 
which requires general anaesthesia supplemented with caudal analgesia. The average 
annual caseload of 400 surgical procedure requiring general anaesthesia supplemented 
with caudal analgesia at Sophia Children’s Hospital indicates that it should be possible to 
recruit enough patients for this  study in a reasonable period of time (approximately 18 
months).  
 
4.2 Inclusion criteria 
In order to be eligible to participate in this study, a subject must meet all of the following 
criteria: 
 
x 
Written informed consent of the parents/legal representatives 
x 
Age > 6 months and < 12 years 
x 
Surgical procedure requiring GA supplemented with caudal analgesia 
x 
Ability of the parents or legal guardians to communicate in Dutch 
 
4.3 Exclusion criteria 
A potential subject who meets any of the following criteria will be excluded from 
participation in this study: 
4.3.1 
primary exclusion criteria 
x 
Withdrawal of informed consent 
x 
(Chronic) use of drugs influencing the electroencephalogram  
x 
Use of premedication 
x 
Known intolerance for sevoflurane 
x 
Parents/legal guardians unable to communicate in Dutch 
 
4.3.2 
secondary exclusion criteria 
x 
protocol violation 
x 
data registration failure  
 
4.4 Sample size calculation 
There are no previous studies about DSA and the speed of recovery after general 
anaesthesia.  
Based on clinical experience we expect a medium to large effect size so we performed a 
power analysis using G* power software package with an effect size d of 0.6. The 
Wilcoxon-Mann-Whitney test was used as statistical test. A sample size of 51 patients per 
study group is required to achieve a power of 0.9 with an alpha error probability of 0.05.16 
In order to compensate for possible dropouts due to protocol violation or data registration 
failure a total of 56 patients will have to be included in either group (+10%).  

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5. TREATMENT OF SUBJECTS 
The effect of DSA on recovery of anaesthesia in children protocol
 
Standard anaesthesia monitoring is used during the procedure, ECG, pulse-oxymetry, 
capnometry an non-invasive measurement of blood-pressure. 

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Patients randomized to the control group are also attached to the Narcotrend monitor, but 
with the screen of the monitor obscured. The electroencephalographic data will later be 
compared to the data of the intervention group in order to assess for differences of depth of 
hypnosis during the procedure.  
After complete recovery from GA, the day thereafter and two weeks later, parents or legal 
guardians will be contacted via telephone for a systematic interview with the patient if aged > 
6 years. This systematic interview is the “Modified Brice-interview”, which is the golden 
standard for the detection of recall of intraoperative events.17,18 Brice interviews will only be 
performed in patients of at least 6 years of age, because it is known that interviews taken in 
children of younger ages are likely not to provide the interviewer with reliable information.  
At the end of the procedure, sevoflurane will be stopped and washed out with 10L flow, FiO2 
0.5. The patients will be otherwise left undisturbed on the operation table. The sound level in 
the operation theatre will be reduced to a minimum.   
The speed of emergence and recovery will be assessed with the Steward Recovery Score 
from Anaesthesia.13  
The incidence of postoperative delirium will be assessed with the Cornell Assessment of 
Postoperative Delirium (CAPD).14,15 
 
5.1 Investigational product/treatment 
This trial is designed to investigate the additional value of Density Spectral Array 
monitoring, provided by the NarcotrendTM monitor in the “speed of emergence” after 
general anaesthesia. compare traditional general anaesthesia with sevoflurane using a 
MAC value and subjective clinical parameters to the objective and continuous approach to 
depth of hypnosis by DSA monitoring with the primary outcome parameter “speed of 
emergence”. The investigational product is the validated NarcotrendTM monitor, an 
electroencephalographic monitor, that is regularly used in anaesthesia practice in the 
Sophia children’s hospital and will be used according to intended purpose. The extended 
version as used in the operating room in the Sophia Children’s hospital offers a diversity 
of diagrams including Density Spectral Array.  
The electroencephalographic NarcotrendTM monitor records frontal EEG-activity. Standard 
paediatric ECG electrodes are used for EEG registration. 
5.2 Use of co-intervention (if applicable) 
Not applicable.  

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5.3 Escape medication (if applicable) 
The investigator can use every medication that is needed for good clinical practice. Each 
opioid or anaesthetic that is used outside the protocol will be considered as escape 
medication. The subject will be secondary excluded from analysis when escape 
medication is used.  
  
6. INVESTIGATIONAL PRODUCT  
 
6.1 Name and description of investigational  product(s) 
NarcotrendTM monitor or Narcotrend compact M is an electroencephalographic monitor  
recording frontal EEG-activity. Multiple diagrams to interpret the EEG are available on this 
monitor. The extended version as used in the operating room in the Sophia Children’s 
hospital offers a diversity of diagrams; the cerebrogram, the relative Band 
activities/Power, the Quantiles, the Power Spectrum, the Amplitude-Integrated EEG/Burst-
Suppression-Ratio and Density Spectral Array.   
6.2 Summary of findings from non-clinical studies 
Not applicable 
 
6.3 Summary of findings from clinical studies 
The Narcotrend has been validated for use in children undergoing both surgical 
procedures under general anaesthesia and gastrointestinal endoscopy under procedural 
sedation in the Sophia Children’s Hostpital.19-21 
 
6.4 Summary of known and potential risks and benefits 
Not applicable 
6.5 Description and justification of route of administration and dosage 
Not applicable 
6.6 Dosages, dosage modifications and method of administration 
Not applicable 
6.7 Preparation and labelling of Investigational Medicinal Product 
Not applicable 
 
 
6.8 Drug accountability 
Not applicable 
 
 

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7. NON-INVESTIGATIONAL PRODUCT 
Not applicable. 
 
7.1 Name and description of non-investigational product(s) 
 
Not applicable 
7.2 Summary of findings from non-clinical studies 
 
Not applicable 
7.3 Summary of findings from clinical studies 
 
Not applicable 
7.4 Summary of known and potential risks and benefits 
 
Not applicable 
7.5 Description and justification of route of administration and dosage 
 
Not applicable 
7.6 Dosages, dosage modifications and method of administration 
 
Not applicable 
7.7 Preparation and labelling of Non Investigational Medicinal Product 
 
Not applicable 
7.8 Drug accountability 
 
Not applicable 
 
 

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8. METHODS 
8.1 Study parameters/endpoints 
8.1.1 Main study parameter/endpoint 
The primary endpoint of the study is the time interval between the termination of 
anaesthetic drug delivery and discharge from the operating theatre according to 
predefined discharge criteria.  
8.1.2 Secondary study parameters/endpoints (if applicable) 
Secondary end points are: 
 
o Total time from discontinuation of anaesthetic drug delivery until discharge 
from the post anaesthesia care unit. 
o The incidence of post-operative delirium 
o Differences of depth of hypnosis during the procedure. 
o Incidence of recall of events during the procedure (awareness) 
o Adverse events 
8.1.3 Other study parameters (if applicable) 
Not applicable 
 
 
8.2 Randomisation, blinding and treatment allocation 
Patients will be allocated to either the intervention group or the control group by a 
computer-generated block randomisation. A paediatric anaesthetist who is not 
otherwise involved in this trial will perform the randomisation procedure, including the 
preparation of sealed envelopes with the randomisation codes per patient and the 
randomisation schedule.  
 
The investigator who determines the hypnotic state of the patient after discontinuation 
of delivery of anaesthetic drugs is not present at the operating theatre during the 
surgical procedure. He enters the theatre at the moment of discontinuation of drug 
delivery, which equals the start of the emergence period. That enables us to blind the 
investigator as to the study-group assignment of the patient.  
The member of the research team that provides general anaesthesia cannot be 
blinded with respect to group allocation. In patients allocated to the control group the 
screen of the Narcotrend monitor is obscured.   
 
8.3 Study procedures 
See flowchart under “study design (page 15).   
 

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8.4 Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without 
any consequences. The investigator can decide to withdraw a subject from the study 
for urgent medical reasons. 
8.4.1 Specific criteria for withdrawal (if applicable) 
In case of unexpected events requiring opioids or anaesthetics outside the protocol 
during the procedure, the patient will be withdrawn from the study. 
 
8.5 Replacement of individual subjects after withdrawal 
In order to compete with possible dropouts, due to withdrawal for whatever reason 
or due to protocol violation, the sample size of the  study is about 10% in excess of 
the results of the sample size calculation. In paediatric depth of anaesthesia studies 
dropout rates are usually within the range of +/- 5% and mostly due to equipment 
failure. As a consequence of secondary exclusion due to protocol violation or data 
registration failure, we choose to increase the number of subjects with 10% on 
forehand. There is no need to replace individual subject after withdrawal.  
 
8.6 Follow-up of subjects withdrawn from treatment 
 
Not applicable 
 
8.7 Premature termination of the study 
Not applicable 
 
 

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9. SAFETY REPORTING 
9.1 Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the 
study if there is sufficient ground that continuation of the study will jeopardise subject 
health or safety.  The sponsor will notify the accredited METC without undue delay of a 
temporary halt including the reason for such an action. The study will be suspended 
pending a further positive decision by the accredited METC. The investigator will take 
care that all subjects are kept informed.  
 
9.2 AEs, SAEs and SUSARs 
9.2.1 Adverse events (AEs) 
Adverse events are defined as any undesirable experience occurring to a subject 
during the study, whether or not considered related to [the investigational product / 
trial procedure/ the experimental intervention]. All adverse events reported 
spontaneously by the subject or observed by the investigator or his staff will be 
recorded. 
 
9.2.2 Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect that  
- 
results in death; 
- 
is life threatening (at the time of the event); 
- 
requires hospitalisation or prolongation of existing inpatients’ hospitalisation; 
- 
results in persistent or significant disability or incapacity; 
- 
is a congenital anomaly or birth defect; or 
- 
any other important medical event that did not result in any of the outcomes listed 
above due to medical or surgical intervention but could have been based upon 
appropriate judgement by the investigator. 
An elective hospital admission will not be considered as a serious adverse event. 
 
The investigator will report all SAEs to the sponsor without undue delay after 
obtaining knowledge of the events.  . 
 
 

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The sponsor will report the SAEs through the web portal ToetsingOnline to the 
accredited METC that approved the protocol, within 7 days of first knowledge for 
SAEs that result in death or are life threatening followed by a period of maximum of 8 
days to complete the initial preliminary report. All other SAEs will be reported within a 
period of maximum 15 days after the sponsor has first knowledge of the serious 
adverse events. 
9.2.3 Suspected unexpected serious adverse reactions (SUSARs) 
Not applicable  
9.3 Annual safety report 
 
Not applicable 
9.4 Follow-up of adverse events 
All AEs will be followed until they have abated, or until a stable situation has been 
reached. Depending on the event, follow up may require additional tests or medical 
procedures as indicated, and/or referral to the general physician or a medical specialist. 
SAEs need to be reported till end of study within the Netherlands, as defined in the 
protocol  
 
9.5 Data Safety Monitoring Board (DSMB) / Safety Committee 
Participants of this  study receive general anaesthesia and caudal analgesia for a planned 
surgical procedure. Both the intervention-group and the control-group receive the same 
anaesthetics. The only risk in this  study is the risk that is inherent with general 
anaesthesia, which will be applied regardless whether or not the patients agree to 
participate in the study. General anaesthesia with sevoflurane supplemented with caudal 
anaesthesia is considered appropriate and safe for many surgical procedures and is 
frequently used in general practice in the ErasmusMC Sophia children’s hospital.  
 
As a result of a risk assessment using the guideline “kwaliteitsborging van mensgebonden 
onderzoek”, provided by the Dutch Federation of University Medical Centres (NFU), we 
conclude that this study has a negligible risk level.  
 
 
 

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10. STATISTICAL ANALYSIS 
 
10.1 Primary study parameter(s) 
The time interval between the end of anaesthetic drug application and the moment when 
discharge criteria from the operating room are met (Steward score ≥ 3) is compared 
between the study groups. Therefore datasets will first be tested for normality by means 
of the Shapiro-Wilk normality test. As appropriate, either a Mann-Whitney-U-test or a t-
test will be performed.  
 
10.2 Secondary study parameter(s)  
Intergroup comparison of total time from discontinuation of hypnotic drug delivery until 
discharge from the post-anaesthesia care unit will be performed by means of an unpaired 
t-test or a Mann-Whitney-U-test.  
Intergroup comparison of the incidence of postoperative delirium will be performed by 
means of an chi square test.  
Posthoc intergroup comparison of hypnotic depth as measured by DSA is performed as 
follows: DSA patterns recorded during the procedure are categorised and assigned to 
three conditions of the specific DSA pattern for GA; appropriate DoH (presence of high 
power delta and alpha oscillations on the power spectrum), to deep DoH (presence of 
high power delta, alpha and theta oscillations on the power spectrum), to light DoH 
(presence of high power delta with the absence of high power alpha oscillations and the 
presence of high power beta oscillations). Intergroup comparison will be performed by a 
means of a chi-square test.   
 
10.3 Other study parameters 
Descriptive statistics will be applied to demographic variables, continuous variables such 
as discharge times, incidence of recall of events during the procedure (awareness) and 
adverse events. All datasets will be tested for normality by means of the Shapiro-Wilk 
normality test.  
 
10.4 Interim analysis (if applicable) 
We will not perform an interim analysis.  
 

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11. ETHICAL CONSIDERATIONS 
11.1 Regulation statement 
The study will be conducted according to the principles of the Declaration of Helsinki 
(seventh revision 2013) and in accordance the Medical Research Involving Subjects act 
(WMO).  
 
11.2 Recruitment and consent 
According to the procedural steps described in the 2010 version of the CONSORT flow 
diagram (http://www.consort-statement.org/consort-statement/) patients will be assessed 
for eligibility to be enrolled in the study as soon as possible after the paediatric surgeon or 
urologist has made the decision to operate the patient. Preferably patients and/or their 
legal representatives will be provided with the patient information folder (PIF) during their 
visit at the pre-anaesthetic assessment clinic. Recruitment of subjects will be done by the 
clinical investigators (I.H., F.W., G.K. and H.R.). The Dutch PIF’s and informed consent 
forms for both the parents and patients are attached as separate documents.  
 
11.3 Objection by minors or incapacitated subjects (if applicable) 
Minors cannot be forced to undergo interventions against his or her will. This study will be 
conducted according to the Code of Conduct applicable to minors as written by the 
Pediatric Association of the Netherlands (Nederlandse Vereniging voor 
Kindergeneeskunde). The parents will be informed about the possibility to withdraw their 
child at any moment in the study without consequences for the medical care in an 
information letter they will receive upon inclusion.  
 
11.4 Benefits and risks assessment, group relatedness 
Patients randomised to the intervention group might benefit from a better GA technique. 
Patients randomised to the control group, thus receiving standard treatment, can neither 
expect any benefit nor any disadvantages from participating in the study.  
 
11.5 Compensation for injury 
 
The sponsor/investigator has a liability insurance which is in accordance with article 7 of 
the WMO. 
  

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The sponsor (also) has an insurance which is in accordance with the legal requirements 
in the Netherlands (Article 7 WMO). This insurance provides cover for damage to 
research subjects through injury or death caused by the study. 
The insurance applies to the damage that becomes apparent during the study or within 4 
years after the end of the study. 
 
11.6 Incentives (if applicable) 
Not applicable 

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12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
12.1 Handling and storage of data and documents 
All personal data will be coded by serial numbers. Only the project leader (I.H.) will have 
access to the key. Statistics will be performed with the coded numbers. Published data 
from this study cannot be traced to a specific child. All coded data will be stored in a 
secure place for a minimum of 15 years. We will use Castor EDC as an electronic data 
capture. All personal data will be handled according to the EU General Data Protection 
Regulation and the Dutch Act on implementation of the General Data Protection 
Regulation.  
 
12.2 Monitoring and Quality Assurance  
The ‘Monitoringplan’ is constructed in accordance with the least ErasmusMC guidelines. 
The Clinical trial center will be contacted for the fulfilment of the ‘Monitoringplan’.  
 
12.3 Amendments  
Amendments are changes made to the research after a favourable opinion by the 
accredited METC has been given. All amendments will be notified to the METC that gave 
a favourable opinion.  
 
All substantial amendments will be notified to the METC and to the competent authority. 
 
Non-substantial amendments will not be notified to the accredited METC and the 
competent authority, but will be recorded and filed by the sponsor.  
 
12.4 Annual progress report 
The sponsor/investigator will submit a summary of the progress of the trial to the 
accredited METC once a year. Information will be provided on the date of inclusion of the 
first subject, numbers of subjects included and numbers of subjects that have completed 
the trial, serious adverse events/ serious adverse reactions, other problems, and 
amendments.  
 
12.5 Temporary halt and (prematurely) end of study report 
The investigator/sponsor will notify the accredited METC of the end of the study within a 
period of 8 weeks. The end of the study is defined as the last patient’s last visit.  

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The sponsor will notify the METC immediately of a temporary halt of the study, including 
the reason of such an action.  
    
In case the study is ended prematurely, the sponsor will notify the accredited METC 
within 15 days, including the reasons for the premature termination. 
 
Within one year after the end of the study, the investigator/sponsor will submit a final 
study report with the results of the study, including any publications/abstracts of the study, 
to the accredited METC.  
 
12.6 Public disclosure and publication policy 
The investigators are responsible for the public disclosure and publication of the research 
data. No sponsor is involved in the publication of the data.  
Parents may request an overview of the study results after completion of the study. 

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13. STRUCTURED RISK ANALYSIS  
 
13.1 Potential issues of concern 
 
Not applicable (see chapter 13.2) 
 
13.2 Synthesis 
Only paediatric patients who are scheduled for a surgical of urological procedure requiring 
general anaesthesia supplemented with caudal analgesia, aged 6 months until 12 years, 
are eligible to be included in this study. Participants of this study will not be exposed to an 
increased risk compared to the (negligible) risk of GA.  
The aim of this trial is to investigate if there is a significant benefit of DSA guided GA 
compared to GA guided by MAC and assessment of clinical signs of hypnotic depth. 
Based on our personal experience we expect that DSA guidance will result in a faster 
recovery. We do not expect any negative effects of DSA guidance of GA.  
 
 
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