This study is a prospective, randomized controlled trial with two parallel groups. After randomization, participants will receive either (1) standard care after surgery (control group) or (2) VR based intervention along with standard care treatment.
The study protocol follows the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) (38) instructions and received the ethical approval from the Babes-Bolyai University committee as from the committee of Municipal Hospital of Cluj-Napoca and was retrospectively registered on ClinicalTrials.gov (NCT03776344).
Study sample size
Using G*Power 22.214.171.124 (39), we had estimated a minimum of 50 participants (25 in each group) needed to detect an effect size of 0.49, with α = 0.05 and power =0.80. The expected effect size of 0.49 was chosen in the light of the results found by the most recent meta-analyses (25,26), being a conservative effect size given that in their analysis Chan and colleagues (25) found a medium effect size (SMD= -0.49, 95% CI -0.83 to -0.14) and the analysis of Georgescu and colleagues (26) a large effect size was found (Hedges'g =1.08, 95% CI 0.46 to 1.70) for studies with parallel design aiming to decrease pain at hospitalized patients. Moreover, as we expected some dropouts (based on other studies using VR systems for treating anxiety(40)) and some incomplete or unusable data, especially on the physiological measure, we aimed to recruit 30 participants in each group.
All the participants were recruited from one community hospital from Romania. Starting October 2018, each patient admitted to the hospital for surgery was screened for eligibility criteria to this trial.
The below criteria had to be cumulative met in order that a participant to be included in the trial.
- Adults aged 18-65 years, after surgery of varicose veins, hernia repair or gallbladder surgery.
- Patient in the acute care units, 1-3 days following surgery.
- Willing and able to provide informed consent and participate in the study visit and study follow-up questionnaire.
Presence of any criteria listed below will conduct at the exclusion of the participant from the trial.
- Patients with neoplastic pathologies.
- Patients with a history of motion sickness.
- Patients with severe visual impairment (i.e. not able to clearly see without glasses; patients with contact lenses will not be excluded).
- Patients with severe/profound cognitive impairments measured with Six-item Cognitive Impairment Test (6CIT).
- Use of strong opioids (i.e. morphine)
- Other reasons for exclusion (Non-Romanian speaking patients, patients with severe psychological problems, etc.)
Some of the exclusion criteria were dependent on the VR device or were designed as a precautionary measure for not harming participants after using VR technology. Particularly, we excluded the participants with profound visual impairments (i.e those which cannot clearly saw without glasses or without contact lenses) due to the incompatibility with the VR headset which was not equipped with the eyes glasses spencer. Similarly, patients with a history of motion sickness were excluded for preventing any severe dizziness or injury.
Randomization and blinding
Randomization was conducted within the type of surgery using a random number generator, with an equal number of participants in the control and experimental group. An independent researcher had conducted the randomization sequence and the allocation sequence was stored on a secured computer until the participants were assigned to one of the interventions. The medical personnel and trial assessors were blind to the group allocation, but the study participants and research assistant knew the allocations. Precaution strategies to prevent the blind from breaking up included a limited number of persons interacting with the patients (i.e. only the research assistant) and a reminder to the patients not to talk about research allocations and study procedure. In addition, the treatment room was a different room of the patient hospital room. If an allocation was revealed by any circumstances, this was reported to the trial coordinator, and re-blinding occured using another assessor (i.e. research assistant).
Recruitment procedure and interventions
The process of recruitment and data collection is presented in Figure 1. The day following the surgical procedure, all patients from the acute care unit who met the primary criteria for inclusion (i.e., age, type of surgery, type of opioids used, free of visual impairments, able to fluently speak in Romanian and without recorded psychological problems) were invited by the research assistant to participate. Information regarding duration, procedure, implications, and conditions for withdrawing are presented and explained. On the consent form, participants were asked if they agree to use of their data should they choose to participate. Participants were asked for permission for the research team to share relevant data with people from the Universities taking part in the research or from regulatory authorities, where relevant. In addition, was presented that this trial does not involve collecting biological specimens for storage. Those who were interested and signed the informed consent were invited in the treatment room where they completed the Six-item Cognitive Impairment Test for assessing the eligibility regarding executive functions. Subsequently, patients were randomly allocated to one of the two groups:
- Treatment group: VR based intervention
Patients allocated to the VR based intervention followed the standard protocol after surgery as prescribed by the current medical personnel, and exposed for 15 minutes to an interactive virtual environment (i.e., Nature Treks© VR). This application is a commercially available app from the Oculus store (available at
https://www.oculus.com/experiences/go/1723271804396968/), promoting relaxation through fifteen highly immersive environments. Each environment recreates a different natural scene (e.g., a tropical beach, savannas at sunset, snowy forests) which can be explored by the patients through a controller. Concomitant with the activities (e.g., walking on the beach, climbing the mountains) environmental effects are changing smoothly to create a vivid experience. Additionally, in some environments (i.e., deep blue and black beginning), patients can freely explore the scenes in 360 degrees for enhancing the feeling of presence and immersion.
As previous studies testing the efficacy of the analgesic effect of VR (30) showed that better immersion is associated with lower scores for pain intensity, the device used is an Oculus Rift® (available at - https://www.oculus.com/). This device is the premium device from Oculus, equipped with a highly immersive headset, one controller, and integrated headphones.
Five minutes before and during the VR exposures, the fluctuations of skin conductance were measured for all patients. Before and after the intervention, pain intensity, relaxation, and VR adverse effects were assessed. Additionally, the catastrophizing level, anxiety, and depression related to health and presence in the VR environment were quantified.
- Control group: standard of care intervention
Patients allocated to the standard of care group followed the treatment after surgery as prescribed by current medical personnel. They also followed the same protocol as the patients in the intervention group regarding psychological and physiological measures. Specifically, they were conducted in the treatment room and asked to indicate the non-dominant hand for setting up the equipment to SC measures. After that, the SC was measured continuously for 20 minutes without exposure to the VR environments. At the end, they completed psychological measures and were conducted in their hospital room.
Data collection procedure
Figure 2 offers an overview of the process of the data collection and measures. All psychological and physiological measures were collected by a previously trained researcher in a single session. In the case that a participant explicitly requested to end the study procedure for any reasons, the procedure was stopped and counted as a dropout. Those patients who asked to end the procedure earlier, were asked to respond at a short interview to quantify the reasons. No strategies for improving adherence were considered as the study protocol is designed as a single session only. However, the research assistant was careful at difficulties arises from the interaction with the VR headset or skin conductance apparatus, which could result from insufficient or inadequate instructions for use or any malfunction of the software. Moreover, we recorded any event resulting from user error or intentional misuse.
The level of pain intensity and relaxation were collected before and after the exposure to VR environments in the experimental group, respectively before and after physiological measures in the control group. The SC was measured during the exposure to VR content in the experimental group and for a period of 15 minutes in the control group. For ensuring an accurate baseline for the physiological measure and for controlling the individual differences in SC, the signal of SC for each participant was taken before the study procedure start for five minutes. During this time, participants had no other instructions, and the communication was maintained at the minimum level. The amount of analgesic consumption for each participant will be extracted from the medical records. Excepting for the fluctuations of skin conductance, all measures were collected through an online platform.
The present study assesses the efficacy of a Nature Track© VR to decrease pain intensity in surgical patients. The primary outcome is pain intensity measured right before the exposure to the VR content and after. The secondary outcomes measure the effects of the application on relaxation and the amount of time spent by each patient thinking about pain. Also, to allow for an in-depth investigation on the effect of VR environments, the primary outcome will be complemented with measures of the adverse effects, level of immersion and level of presence in the VR.
The pain intensity was measured using the Numerical Rating Scale (NRS) (41) by asking participants to report their intensity before and after the intervention on a scale from 0 (“no pain”) to 10 (“extremely painful”). To help patients to discriminate between different pain levels, we asked them to report the mean level of pain intensity in the last 24 hours, the peak of intensity in the same period and the intensity right before the intervention. We chose NRS for this study rather than other measures more extensively used, such as Visual Analog Scales (VAS), due to the consensus of the better psychometrics properties (42–45). The value of pain right before the intervention will be used in the analysis of VR effectiveness.
Concomitantly, fluctuations of the SC were measured as a physiological indicator of postoperative pain (46–48). The SC were measured using the BIOPAC MP150 system (49). The two finger electrodes were attached to the first phalange of the index and medius fingers from the non-dominant hand with Velcro straps. The electrodes were connected to the computer using the USB connection input. To ensure good contact with the skin, isotonic gel was added to the electrodes prior to attaching to the fingers. At the beginning, participants had few minutes to relax, get ready and comfortable with the experimental structure. After that, patients were instructed not to move for the duration of the recording.
As the level of relaxation could affect the perception of the pain intensity, the state of relaxation was measured using the NRS from 0 (“extremely stressed” to 10 (“relaxed”) before and after the intervention. We chose to measure it by using NRS rather than other scale designed to measure relaxation due to his factual effect and similarities with the pain intensity measures.
Time spent thinking about pain
Another factor which can contribute to an increased perception of pain intensity is the amount of thinking time spent by a patient at pain (50). Consequently, we asked patients to report after the interventions, on NRS from 0 (“not at all”) to 10 (“all the time”), the amount of time they spent thinking about their pain during the exposure to the VR content in the experimental group and during the measuring of SC conductance in the control group.
Potential adverse effects were evaluated using the Simulator Sickness Questionnaire (SSQ) (51). As some of the unintended effects of VR could also be effects of the opioid’s consumptions (e.g., headaches, nausea), we asked participants to complete the scale twice, before and after the exposure of VR. The SSQ was previously validated and proved robust psychometrics properties (51,52) being the most widely used measure of cyber-sickness. The patients were instructed to answer on a 4-point Likert scale, corresponding to not at all, slight, moderate and strong sensations regarding the occurrence of possible side effects such as general discomfort, fatigue, headache, and dizziness.
Treatment satisfaction and presence
The presence in VR was assessed using Igroup presence questionnaire (IPQ). This is a 14 items questionnaire assessing different aspects of presence and immersion into VR world through items such as: “In the computer generated world I had a sense of "being there" or “How aware were you of the real world surrounding while navigating in the virtual world? (i.e. sounds, room temperature, other people, etc.)?”. In the end, once the IPQ was completed, the patients were instructed to answer an additional question (i.e., Are you willing to use VR systems in the future?) with dichotomous response developed by the authors for assessing the willingness for further sessions with VR system.
The amount of analgesic used will be extracted from the medical records. The usage of opioids will be coded as present and absent. The mean drug metabolism time will be calculated in order to determine if an opioid agent is active, coding 1 if the opioid agent is active and 0 if is out of his action range.
Level of catastrophizing was measured through the Pain Catastrophizing Scale (PCS) (53). This scale is a self-report measure with 13 items structured in three subscales, namely rumination, magnification, and helplessness, and proved good psychometrics properties. Patients were instructed to answer on a scale from 0 (“not at all”) to 4 (“all the time”).
Assessment of mood
Anxiety and depression levels were assessed through the Hospital Anxiety and Depression Scale (HADS)(54). This scale is a self-report measure with 14 items, with half of the items measuring anxiety symptoms (e.g., items targeting tension, panic attacks) and the other half measuring depression symptoms (e.g., items targeting anhedonia or inability to enjoy things or experiences). Responses are recorded on a scale from 0 to 3, and each item has a different response in accordance with the item content.
Cognitive abilities were measured though the Six-item Cognitive Impairment Test (6CIT) (55), a screening tool for measuring the global cognitive status. The items of the 6CIT cover six questions; one assessing the memory (remembering a 5-item name and address), two items including calculation (reciting numbers backward from 20 to 1 and months of the year backward) and three items assessing orientation (year, month, and time of day). The cutoff of seven from the total score was used for excluding patients with low cognitive abilities (56).
Preliminary analyses and preprocessing data of skin conductance
Demographic characteristics and psychological measures will be explored for missing data, and distribution abnormalities. Means and standard deviations will be used to characterize the sample. Preprocessing of skin conductance measure will be performed using AcqKnowledge 4.1 first though the visual inspection of the raw signal and then applying the Smoothing function with a smoothing factor of three samples. This function has the same effect as the low pass filter by replacing the high-frequency signal with the mean values across three milliseconds to subtract the artifacts, without changing the waves form.
Behavioral data will be analyzed using STATA SE, version 16.1 in accordance with the intent to treat principal (57). Descriptive statistics (i.e. age, gender, assessment of mood, pain catastrophizing, opioid consumption, level of pain intensity, level of relaxation) for the baseline values will be presented within each randomized group. These will include counts and percentages for binary variables and mean and standard deviations, or medians with lower and upper quartiles, for continuous variables, along with minimum and maximum values and missing values. There will be no tests of statistical significance or confidence intervals for differences between randomised groups on any baseline variable. The effectiveness of the intervention on pain intensity (primary outcome) will be assessed by employing random coefficient analysis. We will include the time of assessment, groups assignment (VR intervention and standard of care) and the interaction between time of assessment and group in the multi-level regression model. Similar, for the secondary outcome’s measures (relaxation, time spent by patients thinking about pain, and treatment satisfaction and presence) random coefficient analysis will be performed. Although the intervention is minimal invasive the adverse effects of the VR intervention will be measured with SSQ scale and pre-post differences will be assessed by t-test statistic or the non-parametric equivalent. Physiological data will be processed using the AcqKnowledge 4.1 software, and for each patient, a difference score in the area under the curve between the last five minutes of measurement and baseline level of SC will be extracted. Pearson correlation will be employed to examine the relationship between the level of SC and pain intensity (as a difference score between pre-post intervention). A P-value will be used to estimate statistical significance for all analyses.