The Effect of Virtual Reality on Postoperative Pain and Anxiety in Cardiac Surgery.
Phase: NA
Conditions: Post Operative Pain, Post Operative Anxiety, Heart Surgery, Coronary Artery Bypass Grafting, Virtual Reality
Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

NL79616.018.21 /  Short title: VR for pain and anxiety management after cardiac surgery 
(VRECOVERY trial) 
 
 
 
 
 
 
 
 
 
 
 
 
The effect of Virtual Reality on postoperative 
pain and anxiety in cardiac surgery. 
(VRECOVERY trial) 
June 2022 
 
 
 
 
 
 
 

NL79616.018.21 /  Short title: VR for pain and anxiety management after cardiac surgery 
(VRECOVERY trial) 
 
 
 
The effect of virtual reality on postoperative pain and anxiety in cardiac 
surgery. (VRECOVERY trial) 
Protocol ID 
NL79616.018.21 
Short title 
VR pain and anxiety management in cardiac surgery 
(VRECOVERY trial) 
Version 
3.0 
Date 
30-6-2022 
Coordinating 
investigator/project leader 
 
J. Kluin, MD PhD 
Cardiothoracic Surgeon, Department of Cardiothoracic 
Surgery 
Principal investigator 
J. Kluin, MD PhD 
Cardiothoracic Surgeon, Department of Cardiothoracic 
Surgery 
Investigators 
J. Kluin, MD PhD 
Cardiothoracic Surgeon, Department of Cardiothoracic 
Surgery 
M. Haverkamp, MD 
Cardiothoracic Surgeon, Department of Cardiothoracic 
Surgery 
S. el Mathari, MD 
PhD Candidate, Department of Cardiothoracic Surgery 
C.D. Dolman, MSc 
PhD Candidate, Department of Cardiothoracic Surgery 
Subsidising party 
AmsterdamUMC Scholarship 2020 
Independent expert 
W.J.P. van Boven, MD PhD 
Cardiothoracic surgeon, Department of Cardiothoracic 
Surgery 
  

NL79616.018.21 /  Short title: VR for pain and anxiety management after cardiac surgery 
(VRECOVERY trial) 
 
 
 
TABLE OF CONTENTS 
 
1. 
INTRODUCTION AND RATIONALE .............................................................................. 8 
2. 
OBJECTIVES ................................................................................................................. 9 
3. 
STUDY DESIGN ...........................................................................................................10 
4. 
STUDY POPULATION ..................................................................................................11 
4.1 
Population (base) ...................................................................................................11 
4.2 
Inclusion criteria .....................................................................................................11 
4.3 
Exclusion criteria ....................................................................................................11 
4.4 
Sample size calculation ..........................................................................................11 
5. 
TREATMENT OF SUBJECTS .......................................................................................13 
5.1 
Investigational product/treatment ............................................................................13 
6. 
INVESTIGATIONAL PRODUCT ....................................................................................14 
6.1 
Name and description of investigational  product ...................................................14 
6.2 
Summary of findings from non-clinical studies ........................................................14 
6.3 
Summary of known and potential risks and benefits ...............................................14 
6.4 
Description and justification of route of administration and dosage .........................15 
7. 
METHODS ....................................................................................................................16 
7.1 
Study parameters ...................................................................................................16 
7.1.1 
Main study parameters ....................................................................................16 
7.1.2 
Secondary study parameters ...........................................................................16 
7.2 
Randomisation, blinding and treatment allocation ..................................................16 
7.3 
Study procedures ...................................................................................................16 
7.4 
Withdrawal of individual subjects ............................................................................17 
7.5 
Replacement of individual subjects after withdrawal ...............................................17 
7.6 
Follow-up of subjects withdrawn from treatment .....................................................18 
7.7 
Premature termination of the study .........................................................................18 
7.8 
Potential risk analysis due to COVID-19 regulations ...............................................18 
8. 
SAFETY REPORTING ..................................................................................................19 
8.1 
Temporary halt for reasons of subject safety ..........................................................19 
8.2 
AEs and SAEs ........................................................................................................19 
8.2.1 
Adverse events (AEs) ......................................................................................19 
8.2.2 
Serious adverse events (SAEs) .......................................................................19 
8.3 
Follow-up of adverse events ...................................................................................20 
9. 
STATISTICAL ANALYSIS .............................................................................................21 
9.1 
Primary study parameters ......................................................................................21 
10. 
ETHICAL CONSIDERATIONS ...................................................................................22 
10.1 
Regulation statement .............................................................................................22 
10.2 
Recruitment and consent........................................................................................22 
10.3 
Benefits and risks assessment, group relatedness .................................................22 
10.4 
Compensation for injury .........................................................................................22 
10.5 
Incentives ...............................................................................................................22 
11. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .........................23 

NL79616.018.21 /  Short title: VR for pain and anxiety management after cardiac surgery 
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11.1 
Handling and storage of data and documents ........................................................23 
11.2 
Amendments ..........................................................................................................23 
11.3 
Annual progress report ...........................................................................................24 
11.4 
Temporary halt and (prematurely) end of study report ............................................24 
11.5 
Public disclosure and publication policy ..................................................................24 
11.6 
Monitoring and Quality Assurance ..........................................................................24 
12. 
STRUCTURED RISK ANALYSIS...............................................................................26 
12.1 
Potential issues of concern .....................................................................................26 
12.2 
Synthesis ...............................................................................................................27 
13. 
REFERENCES ..........................................................................................................27 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
3D 
Three Dimensional 
AE 
Adverse Event 
CABG Coronary Artery Bypass Grafting 
CV 
Curriculum Vitae 
IC 
Informed Consent 
METC  Medical research ethics committee (MREC); in Dutch: medisch-ethische 
toetsingscommissie (METC) 
RCT 
Randomized Control Trial 
(S)AE 
(Serious) Adverse Event  
VR 
Virtual Reality 
WMO 
Medical Research Involving Human Subjects Act; in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 
 
 

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SUMMARY 
 
Rationale: Post-operative pain and anxiety are common problems in cardiac surgery. These 
two components can lead to many adverse outcomes in patients, resulting in a longer 
recovery time and a lower overall well-being. Common treatment of these problems is by use 
of analgesics such as opioids, NSAIDS and paracetamol. However, analgesics come with 
side effects which affect the quality of life. Therefore there is a need for alternative pain and 
anxiety management. 
 
Virtual Reality (VR) modalities are currently emerging as non-pharmacological tools for post-
operative pain and anxiety management. Earlier studies in other surgical fields showed the 
potential positive effects of VR modalities on postoperative pain and anxiety. However, such 
a study is never performed in the field of cardiac surgery. Therefore we decided to perform a 
randomized control trial (RCT) in which we assess the feasibility of VR in postoperative pain 
and anxiety management in the field of cardiac surgery. 
 
Objective: The objective of this study is to investigate the effect of VR on post-operative pain 
and anxiety management in cardiac surgery patients undergoing a coronary artery bypass 
grafting (CABG) procedure. 
 
Study design: This study is a single-center randomized control trial. 
 
Study population: Patients who have undergone a CABG procedure (n=100).  
 
Intervention: The intervention group (n=50) will use the VR distraction therapy device at day 
1, 2 and 3 after surgery on the general ward. The control group (n=50) will be treated with 
conventional post-operative pain and anxiety management. 
 
Main study parameters/endpoints: The main study parameters at day 1, 2 and 3 after 
surgery. These are the Numeric Rating Scale (NRS) to assess the effect of pain on mobility, 
the Quality of Recovery-15 questionnaire, the State-Trait Anxiety Inventory-6 questionnaire 
and assessment of analgesic use. At follow-up, participants will be called to gather one-time 
QoR-15 and STAI-6 questionnaire data 6 weeks after the surgery.  
 
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness: This is a study with use of a digital VR distraction therapy device. This 
device is known to have potential adverse effects of nausea and dizziness. However, the 

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used software is optimized to minimize these adverse effects. And the potential benefits of 
reducing pain and anxiety in the post-surgical phase outweigh these potential adverse 
effects. 

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1. INTRODUCTION AND RATIONALE 
 
Post-operative pain and anxiety are common problems in all surgical fields.[1]  These pain 
and anxiety are due to the surgical tissue damage and the unpleasant psychological 
experience of undergoing a surgical procedure.[2] Those two components can lead to many 
adverse outcomes in patients, resulting in a longer recovery time and a lower overall well-
being.[3] Pain and anxiety levels after cardiac surgery are often more severe than average 
due to the relative more invasive surgical procedures. The incidence of chronic pain and/or 
anxiety after cardiac surgery is 21-55%.[4] The occurring pain syndromes know a wide 
variety (visceral, musculoskeletal or neurogenic) and are commonly treated by use of 
analgesics such as opioids, NSAIDS and paracetamol. However, due to the many side 
effects of these analgesics which affect the quality of life [5] there is a need for alternative 
pain and anxiety management. 
 
Virtually Reality (VR) modalities are currently emerging as non-pharmacological tools for 
post-operative pain and anxiety management. The effective potential of these modalities are 
due to their possibilities for distraction from reality, resulting in distraction therapy. Virtual 
reality environments are taught to divert the patients attention away from the nociceptive 
input, resulting in less attention for pain perception and therefore more comfort in the clinical 
recovery path.  
 
A recently published systematic review and meta-analysis [6] showed that the effects in 
general are still not clear as several studies yielded both positive and non-significant results 
for VR distraction therapy devices. The preliminary conclusion on this is that the application 
of VR distraction therapy can relief post-operative pain and anxiety, however this could not 
be stated firmly yet because of the heterogeneity in most studies due to different types of 
surgery and various timing of VR usage.  
 
Also, there are no studies performed yet in the field of cardiac surgery concerning post-
operative pain and anxiety management using VR distraction therapy. Therefore we decided 
to perform a randomized control trial (RCT) in which we assess the feasibility of VR in 
postoperative pain and anxiety management in the field of cardiac surgery. Also we will 
assess if there are predictive factors to select specific patients who can mostly benefit from 
this innovative intervention. The used VR distraction therapy device in this study will be the 
Healthy Mind VR device. This is a CE-mark Class I device.[7] 

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2. OBJECTIVES 
 
Primary Objective: To investigate the effect of VR distraction therapy with breathing 
exercises in post-operative pain and anxiety management in cardiac surgery patients 
undergoing coronary artery bypass grafting (CABG) procedure. 
 

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3. STUDY DESIGN 
 
This study is a single-center randomized control trial. 
 
The study will consist of 100 participants who have undergone an uncomplicated surgical 
CABG procedure. The intervention group includes 50 patients using a VR distraction therapy 
device with 3D interactive nature environments in the post-operative stage for pain and 
anxiety management and breathing exercises. The VR distraction therapy device consists of 
a head-mounted display and a configuration tablet. The control group includes 50 patients 
who will be treated with conventional post-operative pain and anxiety management. 
 
The intervention group will test-use the VR distraction therapy device on the day of clinical 
admission prior to surgery and use it therapeutic at day 1, 2 and 3 after surgery on the 
general ward. Daily usage of this tool consists of two sessions each day (morning and 
afternoon) with a duration of 20 minutes per session. The specific virtual environment for 
each session will be selected freely by the participants. 
 
Outcomes will be measured daily, at the end of each session. Outcomes will be measured by 
using the Numeric Rating Scale (NRS) to assess the effect of pain on mobility (in retrospect), 
Quality of Recovery-15 (QoR-15) questionnaire, State-Trait Anxiety Inventory-6 (STAI-6) 
questionnaire and assessment of analgesic use. 
 
At follow-up, participants will be called to gather one-time QoR-15 and STAI-6 questionnaire 
data 6 weeks after the surgery. 
P 
100 participants who have undergone an uncomplicated surgical CABG procedure 
I 
VR distraction therapy device with 3D interactive nature environments in the post-
operative stage for pain and anxiety management. 50 participants will use the VR 
distraction therapy device at day 1, 2 and 3 after surgery on the general ward. Daily 
usage of this tool consists of two sessions each day (morning and afternoon) with a 
duration of 20 minutes per session. 6 week after surgery data on pain and anxiety at 
follow-up will be gathered by phone call using two questionnaires. 
C 
Conventional post-operative pain and anxiety management in 50 participants 
O 
 
Numeric Rating Scale (NRS) to assess the effect of pain on mobility 
 
Quality of Recovery-15 (QoR-15) questionnaire 
 
State-Trait Anxiety Inventory-6 (STAI-6) questionnaire  
 
Assessment of analgesic use 
 

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4. STUDY POPULATION 
4.1 Population (base)  
The study population consists of patients who are ≥18 years of age and have undergone a 
surgical CABG procedure. 
 
4.2 Inclusion criteria 
In order to be eligible to participate in this study, a subject must meet all of the following 
criteria: 
- 
Age ≥18 years or older with written informed consent 
- 
Patients undergoing surgical CABG 
4.3 Exclusion criteria 
A potential subject who meets any of the following criteria will be excluded from 
participation in this study: 
 
- 
Major comorbidities besides coronary artery disease 
- 
Complicated surgical procedure 
- 
Hearing and/or visual impairments 
- 
Psychiatric impairments 
- 
Complaints of vomiting and nausea 
- 
History of epilepsy 
- 
Claustrophobia 
- 
Facial wounds and skin defects at site of application 
- 
Patients placed in clinical isolation 
- 
Readmission to the intensive care unit 
4.4 Sample size calculation 
In total, 100 subjects will be included in this study. 50 subjects in the patient group that will 
receive VR therapy and 50 subjects in the patient group that will not receive VR therapy. 
Since literature is limited about our primary outcomes in the field of cardiac surgery, a 
retrospective pilot was done in our clinical pool of CABG patients for the assessment of 
one of our primary outcomes (NRS-score) upon which we based our sample size 
calculation. See below for details. 
 
A retrospective assessment for NRS-score is performed in 35 patients who have 
undergone an uncomplicated CABG procedure in our department the past year (2020). 
Since the data was non-normally distributed, a two-sided Wilcoxon (Mann-Whitney) Rank-
Sum test was performed in nQuery Advisor version 8.5.1 [8] on Windows with P(X<Y) 
=0.5 and a test significance level of 0.05. Since this statistical test allows only a maximum 

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of 8 categories and none of the pilot patients scored 0, 9 or 10 for the NRS-score, only 
NRS-scores 1 - 8 were used as categories in this test. This resulted in a power of 92,7% 
for a sample size of 100 subjects (50 per group) (Table 1). 
 
 
Table 1. Sample size calculation using a two-sided Wilcoxon (Mann-Whitney) Rank-Sum test in nQuery 
Advisor version 8.5.1 on Windows with P(X<Y) =0.5. 
 

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5. TREATMENT OF SUBJECTS 
 
5.1 Investigational product/treatment 
The investigational product that will be used in this study is the Healthy Mind Virtual 
Reality device.[7] VR distraction therapy device aimed to reduce pain and anxiety in 
hospitalized patients. This is a CE mark class I medical device. The device contains 
software which puts patients in immersive virtual experiences to distract them from reality 
using advanced psychological principles like medical hypnosis. The software also 
contains breathing exercises which are essential in the postoperative setting in cardiac 
surgery.  
 
By using the brain’s cognitive and affective capacities, pain pathways are modulated 
through combined visual and auditory stimulations, attention diversion and relaxation.  
With the use of virtual reality the patient is transported into a designed 3D environment to 
journey through natural experiences of choice. This device is designed to eventually be a 
drug-free therapeutic tool that facilitates the work of caregivers, transform conventional 
clinical pathways of patients and improve their recovery. 
 

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6. INVESTIGATIONAL PRODUCT  
 
6.1 Name and description of investigational  product 
Our investigational product is the Healthy Mind Virtual Reality device. [7] This product is 
intended to be a VR distraction therapy device to reduce pain and anxiety by usage of 
software which gives patients an immersive experience in a calming VR environment with 
integrated breathing exercises.  
 
6.2 Summary of findings from non-clinical studies 
This device is developed with evidence based efficiency of VR treatment modalities in 
reducing pain and anxiety throughout different medical fields. See the literature review of 
the Healthy Mind VR device for an extensive description of these previous studies.[9]  
 
At the current moment there are no completed studies in which the Healthy Mind VR 
device is used as investigational product. However, there are several ongoing clinical 
trials in France and Switzerland. 
 
6.3 Summary of known and potential risks and benefits 
Potential risks: 
Some patients may present a non-adherence to the VR relaxation technique, resulting in 
discomfort and/or nausea and dizziness. The limitations of VR can be related to lacking 
physical adaptation which can potentially result in cyber-sickness.  
 
The brain uses three sources of data to inform the body about its position and 
movements: the inner ear, muscles, and eyes. Once the head mounted display is on your 
head, the eyes indicate that you are in a different environment, but the inner ear and 
muscles say that this is not the case: this inconsistency of sensory information usually 
translates into temporary symptoms such eye fatigue, disorientation (dizziness, 
imbalance) and nausea. However, the Healthy Mind software was created specifically for 
patients with reduced mobility (lying or sitting) and optimized to minimize adverse effects 
such as nausea. For example, the user is not in constant movement in the virtual 
environment. Users remain static and are being teleported to new areas of the 
environment. This way, the gap between the inner ear and the virtual world is minimalized. 
Furthermore, participants in this study will be excluded from further participation as soon 
as the above mentioned symptoms are noticed. 
 

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Potential benefits: 
The VR technique of Healthy Mind uses the brain’s cognitive and affective capacities to 
modulate pain pathways through combined visual and auditory stimulations, attention 
diversion and relaxation. The software on this device puts patients in immersive 
experiences in VR to distract them from reality. The software also integrates breathing 
exercises which are essential in the postoperative setting in cardiac surgery for lung 
recovery.  
 
Altogether, the potential benefits of these elements would be pain reduction, anxiety 
reduction, improved lung recovery and faster general post-operative recovery. 
 
6.4 Description and justification of route of administration and dosage 
Since this a non-pharmaceutical investigational product, there is no evidence based 
description of dosage. However, usage for 2-3 sessions each day is maintained as the 
standard use in various clinics with similar VR therapeutic devices. Administration in this 
case is usage of a head-mounted device with earphones bringing the participants in a 
virtual reality environment for a session of 20 minutes. 
 
 
  

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7. METHODS 
7.1 Study parameters 
7.1.1 Main study parameters 
The main study parameters are: 
- 
Numeric Rating Scale (NRS) to assess the effect of pain on mobility 
- 
Quality of Recovery-15 (QoR-15) questionnaire 
- 
State-Trait Anxiety Inventory-6 (STAI-6) questionnaire  
- 
Assessment of analgesic use 
7.1.2 Secondary study parameters 
The secondary study parameters are: 
- 
Functional Ambulation Categories Score 
 
 
7.2 Randomisation, blinding and treatment allocation 
For randomisation, we use a simple random allocation approach. This randomization 
sequence will be prepared in SPSS 26.0 (SPSS Inc, Chicago, IL) for Windows. This 
randomization will be performed postoperatively by the research team, in case of an 
uncomplicated procedure, directly after the patient returns to the clinical ward after 
surgery. Blinding however, is not possible in this study as usage of the medical device is 
clear. 
 
7.3 Study procedures 
The study will consist of 100 participants who have undergone an uncomplicated surgical 
CABG procedure.  
 
The intervention group includes 50 patients using a VR distraction therapy device with 3D 
interactive nature environments in the post-operative stage for pain and anxiety 
management. The control group includes 50 patients who will be treated with conventional 
post-operative pain and anxiety management. 
 
The intervention group will test-use the VR distraction therapy device on the day of clinical 
admission prior to surgery and use it therapeutic at day 1, 2 and 3 after surgery on the 
general ward.  
 

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Daily usage of the VR distraction therapy device consists of two sessions each day 
(morning and afternoon) with a duration of 20 minutes per session. The specific virtual 
environment for each session will be selected freely by the participants. 
 
Outcomes will be measured daily, at the end of each session, which is done 1) after the 
doctor’s ward visit in the morning and 2) after the shift change of the nurse team. 
Outcomes will be measured at the same aforementioned moments in the control group. 
Outcomes will be measured by using the Numeric Rating Scale (NRS) to assess the effect 
of pain on mobility, Quality of Recovery-15 questionnaire, State-Trait Anxiety Inventory-6 
questionnaire and assessment of analgesic use. 
 
At follow-up, participants will be called to gather one-time QoR-15 and STAI-6 
questionnaire data 6 weeks after the surgery. 
 
Numeric Rating Scale (NRS) score 
The NRS score is a numeric scale in which individuals rate pain from 0 (no pain) tot 10 
(worst pain). This is a subjective score which is assessed verbally and used frequently in 
standard clinical care in multiple medical specialties. 
 
Quality of Recovery-15 (QoR-15) questionnaire 
The QoR-15 questionnaire is a clinical validated instrument to measure post-operative 
quality of recovery. 
 
State-Trait Anxiety Inventory-6 questionnaire 
The STAI-6 questionnaire is a validated psychological inventory designed to measure 
worry, tension and anxiety in an individual. 
 
7.4 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. 
 
7.5 Replacement of individual subjects after withdrawal 
Upon withdrawal of a subject, the data collected will not be used for the study and 
will be deleted. 
 

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7.6 Follow-up of subjects withdrawn from treatment 
Not applicable. 
 
7.7 Premature termination of the study 
Study participants can withdraw their consent at any time during the study. Patients 
that experience eye fatigue, nausea or disorientation will not be included in this study. 
In addition, since all the elements of this study are harmless and carry no significant 
risks, it is unlikely that premature termination will occur during the study.  
7.8 Potential risk analysis due to COVID-19 regulations  
The main risk for our study due to unexpected upscaling of COVID-19 regulations 
would be the delay of elective CABG surgery. This would be due to a (temporary) 
reduced intensive care unit capacity. However, this would not impact the study 
feasibility, as a consequence the study will take longer to include the target number of 
inclusions. 

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8. SAFETY REPORTING 
8.1 Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the investigating group will 
suspend the study if there is sufficient ground that continuation of the study will jeopardise 
subject health or safety. The investigating group 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.  
 
8.2 AEs and SAEs 
8.2.1 Adverse events (AEs) 
Adverse events are defined as any undesirable experience occurring to a subject 
during the study considered caused by the study. All adverse events caused by the 
study will be reported and recorded by the investigator or his staff. 
 
8.2.2 Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect caused by the 
study 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 direct investigator will report all SAEs which are caused by the study to the 
principal investigator without undue delay after obtaining knowledge of the events. 
 
The investigator will report these SAEs through the web portal ToetsingOnline to the 
accredited METC that approved the protocol, within 7 days of first knowledge for 

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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 investigator has first knowledge of the serious 
adverse events. 
 
8.3 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  

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9. STATISTICAL ANALYSIS 
9.1 Primary study parameters 
The included data  (NRS score, STAI-6 score, QoR-15 score) will be presented as mean 
± standard deviation. Ratios will be given for statistical assessment of non-continuous 
variables (assessment of analgesic use). Because the data is expected to be non-
normally distributed, Wilcoxon (Mann-Whitney) Rank-Sum testing will be performed to 
analyze differences between groups. Differences between groups will be assessed for 
each measurement at each point in the study (day 1, 2 and 3) and cumulative as mean 
values. SPSS 26.0 (SPSS Inc, Chicago, IL) for Windows is used to assess statistical 
analyses. 
 
 
 

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10. ETHICAL CONSIDERATIONS 
10.1 Regulation statement 
This study will be conducted according to the principles of the Declaration of Helsinki 
(version 2013, Fortaleza, Brazil) and in accordance with the Medical Research Involving 
Human Subjects Act (WMO).  
 
10.2 Recruitment and consent 
 
Eligible patients will be recruited from a surgery waiting-list of the Heartcenter. Since only 
healthcare providers with  a treatment-relationship with the patient have access the patient 
record file, the treating physician will be asked to contact the patient for his/her willingness 
to participate in this study. After the patient gives permission to be contacted by the 
investigator (S. el Mathari), the investigator will contact the patient by phone with additional 
information about the study to inquire if the patient is interested in study participation. And 
if so, patient information will be sent to their home address. Patients will be then given 7 
days to read the patient information and to consider the study participation. After this 7-day 
period, the patients will be contacted again by the aforementioned investigator. If they are 
willing to participate, an informed consent form will be handed out at clinical admission for 
signing. 
 
10.3 Benefits and risks assessment, group relatedness 
The used VR device has a risk for inducing, eye fatigue, nausea or disorientation. 
However, the potential benefits of reducing post-operative pain and anxiety and 
shortening post-surgical recovery time, outweigh these risks. 
 
10.4 Compensation for injury 
The investigator (AmsterdamUMC) has a liability insurance which is in accordance with the 
legal requirements in the Netherlands (Article 7 WMO). The Medical Ethical Commission 
granted exemption for a damage/injury insurance in accordance with the WMO. 
10.5 Incentives 
The subjects will receive no financial compensation or other incentives.  

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11. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
11.1 Handling and storage of data and documents 
The participant’s identity will remain confidential. His or her name will not be published 
and will not be disclosed to anyone outside the research group. All personal details and 
other identifiable data provided or collected during this study will be kept in the strictest 
confidence. Participants will be assigned a code number following their first contact with 
the researcher. This number will be used throughout the project and will be the only 
identifier on all data. No identifiable (e.g. name etc.) of participants will be revealed at 
scientific meetings, conferences, presentations, publications or any other vehicles of 
public communication. In any such publication arising from this research the individual 
results will not be identifiable. Only the research team will have access to the collected 
data. 
 
- 
Each researcher will store documents bearing identifiable and personal information in 
a locked cabinet with access strictly restricted to members of the research group. 
- 
All computerised data/information will be stored on pass-word protected computers, to 
which only a member of the research team has access. 
- 
Code numbers will be used for all computerised data/information collected. These 
data are therefore stored in a coded fashion. 
- 
All gathered data/information will be stored for the duration of the study. It will then be 
kept in a locked cabinet for up to 15 years 
 
11.2 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.  
 
A ‘substantial amendment’ is defined as an amendment to the terms of the METC 
application, or to the protocol or any other supporting documentation, that is likely to 
affect to a significant degree: 
- the safety or physical or mental integrity of the subjects of the trial; 
- the scientific value of the trial; 
- the conduct or management of the trial; or 
- the quality or safety of any intervention used in the trial. 
 
All substantial amendments will be notified to the METC and to the competent authority. 

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Non-substantial amendments will not be notified to the accredited METC and the 
competent authority, but will be recorded and filed by the investigators.  
 
11.3 Annual progress report 
The 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.  
 
11.4 Temporary halt and (prematurely) end of study report 
The investigator will notify the accredited METC and the competent authority of the end of 
the study within a period of 90 days. The end of the study is defined as the last patient’s 
last visit.  
 
The investigator 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 investigator will notify the accredited METC 
and the competent authority within 15 days, including the reasons for the premature 
termination. 
 
Within one year after the end of the study, the investigator will submit a final study report 
with the results of the study, including any publications/abstracts of the study, to the 
accredited METC and the Competent Authority.  
 
11.5 Public disclosure and publication policy 
This project is sponsored by Healthy Mind VR providing the needed VR devices for this 
study. Healthy Mind VR will be mentioned in the acknowledgements at publication and the 
Healthy Mind device will be mentioned in the study materials. Further, no special 
arrangements are made regarding the disclosure of publication material and will be 
disclosed unreservedly.  
11.6 Monitoring and Quality Assurance 
Monitoring of the conduct of the study will be done by the Clinical Monitoring Center 
(CMC) of the AmsterdamUMC. The CMC performs quality control measurements to 
ensure protection of the rights, safety and well-being of the research subjects and 

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scientific quality of the research data. After approval of the protocol by the METC the 
investigators will have an intake appointment with the CMC to prepare a monitoring plan. 
The monitoring visits will be planned and the frequency of these visits will be conform the 
NFU-standards depending on the risk-stratification and duration of the study. 

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12. STRUCTURED RISK ANALYSIS  
12.1 Potential issues of concern 
 
a. Level of knowledge about mechanism of action 
The software on the Healthy Mind VR device puts patients in immersive experiences in 
VR to distract them from reality using advanced psychological principles like medical 
hypnosis. By using the brain’s cognitive and affective capacities, pain pathways are 
modulated through combined visual and auditory stimulations, attention diversion and 
relaxation.  
 
b. Previous exposure of human beings with the test product 
Similar studies in which subjects were exposed to a similar product were mainly 
performed in pediatric patient populations. In all these studies, the used VR devices 
seemed to be an effective tool in pain and anxiety reduction in these patients.[10]  
 
Regarding the specific Healthy Mind VR device, there are no published studies yet. 
However, there are several ongoing clinical trials in France and Switzerland with the 
Healthy Mind VR device and similar VR distraction therapy devices. [11-13] 
 
c. Can the primary or secondary mechanism be induced in animals and/or in ex-vivo 
human cell material? 
Not applicable. 
 
d. Selectivity of the mechanism to target tissue in animals and/or human beings 
Not applicable. 
 
e. Analysis of potential effect 
Potential adverse effects of the Healthy Mind VR device are nausea and dizziness due to 
non-adherence to the virtual relaxation technique. This could be related to lacking physical 
adaptation which can potentially result in cyber-sickness. However, the Healthy Mind 
software is optimized to minimize these adverse effects by avoiding constant movement 
and using static teleportation when moving to other digital environments. Furthermore, 
participants in this study will be excluded from further participation as soon as the above 
mentioned symptoms are noticed. Additionally we would like to address that these 
potential symptom are very unlikely to result in significant (lasting) damaging effect. 
 
 

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f. Pharmacokinetic considerations 
Not applicable. 
 
g. Study population 
The study population consists of patients which are 18 years or older of age and have 
undergone an uncomplicated surgical CABG procedure. All included subjects are on the 
general clinical ward and are in stable condition.  
 
h. Interaction with other products 
Not applicable. 
 
i. Predictability of effect 
Not applicable. 
 
j. Can effects be managed? 
As mentioned above, the potential adverse effects in this study are nausea and dizziness.  
These effects can be effectively managed when observed. The device will be tuned off 
immediately and common management for these adverse effects will be applied.  This will 
be either expectant policy or supplementation of commonly used anti-emetics. 
 
12.2 Synthesis 
Altogether, there are no significant risks to this study. The software of the device is 
optimized to reduce the potential adverse effects being nausea and dizziness. Also 
adequate management strategies are available for these potential effects. Since these 
potential effects are highly unlikely to result in significant (remaining) damage, the 
potential benefits of reducing pain and anxiety in the post-surgical phase outweigh these. 
 
 
13. REFERENCES 
 
1. 
Cabedo, N., et al., Prevalence and characterization of postoperative pain in the 
Postanaesthesia Care Unit. Rev Esp Anestesiol Reanim, 2017. 64(7): p. 375-383. 
2. 
Meissner, W. and R. Zaslansky, A survey of postoperative pain treatments and 
unmet needs. Best Pract Res Clin Anaesthesiol, 2019. 33(3): p. 269-286. 
3. 
Joshi, G.P. and B.O. Ogunnaike, Consequences of inadequate postoperative pain 
relief and chronic persistent postoperative pain. Anesthesiol Clin North Am, 2005. 
23(1): p. 21-36. 
4. 
Cogan, J., Pain management after cardiac surgery. Semin Cardiothorac Vasc 
Anesth, 2010. 14(3): p. 201-4. 

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5. 
Sloot, S., et al., Side effects of analgesia may significantly reduce quality of life in 
symptomatic multiple myeloma: a cross-sectional prevalence study. Supportive 
Care in Cancer, 2015. 23(3): p. 671-678. 
6. 
Ding, L.Y., et al., Effects of virtual reality on relieving postoperative pain in surgical 
patients: A systematic review and meta-analysis. International Journal of Surgery, 
2020. 82: p. 87-94. 
7. 
VR, H.M., Healthy Mind Therapeutic Virtual Reality. 2021: 
https://healthymind.fr/en/. p. https://healthymind.fr/en/. 
8. 
Ludbrook, J., nQuery Advisor 6.0. Clinical and Experimental Pharmacology and 
Physiology, 2006. 33(1-2): p. 167-167. 
9. 
VR, H.M. Literature Review Healthy Mind VR. 2021; Available from: 
https://healthymind.fr/Comm/ENG%20Synthesis%20Pain%20&%20Anxiety%2022
_10_2020.pdf. 
10. 
Eijlers, R., et al., Systematic Review and Meta-analysis of Virtual Reality in 
Pediatrics: Effects on Pain and Anxiety. Anesthesia and Analgesia, 2019. 129(5): 
p. 1344-1353. 
11. 
Harry van Goor, M., PhD, FRCS. The Effect of Virtual Reality on Post-surgical 
Pain and Recovery. (VIRTUAL). 2020; Available from: 
https://clinicaltrials.gov/ct2/show/NCT03933124. 
12. 
Arnaud Bosteels, M., Virtual Reality for Post Operative Pain Management After 
Total Knee Arthroplasty (VR4POPKA). 2018. 
13. 
Ryan Li, M., Virtual Reality for Postoperative Pain Management. 2021.