Discomfort Improvement for Critically-ill Patients using Electronical Relaxation Devices: results of the Cross Over Randomized Controlled Trial E-CHOISIR (Electronical-CHOIce of a System for Intensive care Relaxation)

doi:10.21203/rs.3.rs-1768651/v1

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Discomfort Improvement for Critically-ill Patients using Electronical Relaxation Devices: results of the Cross Over Randomized Controlled Trial E-CHOISIR (Electronical-CHOIce of a System for Intensive care Relaxation)

https://doi.org/10.21203/rs.3.rs-1768651/v1

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Purpose: To assess the impact of different electronical-relaxation devices on common patients’ stressful symptoms experienced in Intensive-Care-Unit (ICU).

Methods: Sixty critically-ill patients were enrolled in four relaxation-sessions using a randomized cross-over design: standard-relaxation (TV/radio), music-therapy (MUSIC-CARE©), and two virtual-reality systems using either real-motion pictures (DEEPSEN©) or synthetic-motion pictures (HEALTHY-MIND©). The goal was to determine which device was the best to improve overall patient discomfort’s intensity (0-10 Numeric-Rating-Scale (NRS); primary endpoint). Secondary endpoints were specific stressful symptoms (pain, anxiety, dyspnea, thirst, and lack-of-rest-feeling), and stress-response measured by Analgesia/Nociception-Index (ANI). Multivariate mixed-effect analysis was used taking into account patient’s characteristics and multiple measurements.

Results: Fifty patients followed the full research-protocol, and ten patients did at least one research-planned session of relaxation. HEALTHY-MIND© was associated with a significant decrease of overall discomfort, the primary endpoint (median NRS=4[2-6] vs. 2[0-5]; p=0.01, mixed-effect model), confirmed by a significant decrease of stress-response (increase of ANI, secondary endpoint; p<0.01). Regarding other secondary endpoints, each of the two virtual-reality systems was associated with a decrease of anxiety (p<0,01), while HEALTHY-MIND© was associated also with a decrease of pain (p=0.001) and DEEPSEN© with a decrease of lack-of-rest (p=0.01). Three incidents (claustrophobia/dyspnea/agitation) were reported among 109 virtual-reality sessions. Cybersickness was rare (NRS=0[0-0]).

Conclusion: Electronical relaxation therapy is a promising, safe and effective non-pharmacological solution that can be used to improve overall discomfort in ICU patients. Its effectiveness depends on technical characteristics (real or synthetic imagined world, association or not with music-therapy), as well as the type of symptoms.

Virtual-reality

Music-therapy

Non-pharmacological therapies

Palliative care

Intensive Care

Admission in an Intensive-Care-Unit (ICU) is associated with many causes of suffering, related to the illness or intensive therapies and environment [1, 2]. The consequences can be serious, from the development of an adrenergic stress-response interfering with critical illness (tachycardia, polypnea, patient/ventilator asynchrony, agitation, immunosuppression…) [3, 4], to the development of a Post-Intensive-Care-Syndrome (PICS), including neuro-psychological disorders (anxiety, depression, post-traumatic-stress-syndrome) and chronic pain that delay the return to a social and professional normal life [5, 6]. The link between suffering in ICU and the development of PICS has been highlighted for a long time [7], leading to conceptualize modern intensive care as the most humane possible [8, 9]. For all these reasons, palliative care has become part of intensive care, along with the treatment of organ dysfunctions. In order to prevent drug-related side effects that can be serious in critically-ill patients [10], current guidelines for the management of pain, agitation, delirium, immobility and sleep disruption (PADIS) suggest to develop non pharmacological therapies [1, 11].

Electronical technology has been developed in medical settings, such as music-therapy using programmable shape and length of music score [12, 13], and immersive virtual reality (VR), to offer a non-pharmacological treatment of pain and anxiety [14]. Literature regarding the use of VR in medical care is beginning to be abundant, but its use to relieve overall discomfort and baseline stressful symptoms in ICU has never been the object of a randomized comparating study.

In this context, we propose to assess the impact of different electronical relaxation devices to improve ICU patients’ stressful symptoms, through a cross-over randomized study. The primary goal was to determine the best technique to improve overall patient’s discomfort (primary endpoint), among 3 different relaxation devices (VR system with real motion pictures, VR system with computer generated pictures, music-therapy scored in U-shape provided through a computer and an headset), compared to a standard relaxation session (TV, radio available at bedside). Secondary goals were to measure the impact on 5 of the main stressful symptoms experienced by ICU patients (pain, anxiety, dyspnea, thirst and lack-of-rest), and on electrophysiological measurement of stress-response using the Analgesia/Nociception-Index (ANI) and usual physiological variables (secondary endpoints).

Ethics approval

This randomized controled trial (RCT) was approved by an ethics committee [Comité de Protection des Personnes Sud-Méditerranée-1 (ID-RCB:2016-A00748-43)] according to French law [15], and registered on Clinical Trials NCT04017299, 12 July 2019. The research was funded by the French healthcare ministry (Direction Générale de l’Offre de Soins (DGOS)/General Healthcare Supply Direction).

Patient population

The trial took place in the medical-surgical ICU of the University Hospital of Saint Eloi, Montpellier, France, from July 2019 to December 2019.

All consecutive patients over 18-yo admitted to the ICU were eligible if they were alert and non delirious, following the French validated versions of the Confusion-Assessment-Method for the ICU (CAM-ICU) [16, 17] and the Richmond-Agitation-Sedation-Scale (RASS) that had to be ≥ 0 [18], and with current organ dysfunctions defined by a Sequential-Organ-Failure-Assessment (SOFA) score ≥ 3 [19].

The exclusion criteria were: patient transferred from another ICU, dying patients, patients needing hygiene precautions limiting the access to the headsets, patients undergoing psychotic treatment or with previous known cognitive impairment, patients hospitalized for brain injury, and according to French law [15]: pregnant or breastfeeding women, patients under tutelage or curatorship, patients not registered with the national social security system, or who refused to participate.

Conduct of the study and description of the electronical relaxation tools

Patients were screened daily for eligibility by investigators, and included in the study after written consent. Patients underwent four relaxation sessions consecutively, after randomization of the session order, using a cross-over design. The randomization was made by the statistic department, and provided via envelopes available for the ICU investigators. The four relaxation sessions are described as follows:

STANDARD SESSION: a relaxation and distraction period of 15 minutes during which usual distraction was chosen by the patient (e.g. television, radio). The bedroom’s door was kept closed, and any nursing or medical procedures of care were prevented during the session.
MUSIC-CARE© (Paris, France): a 15 minutes relaxation session of psychomusical intervention (music-therapy) using the MUSIC-CARE© device [12], U-shaped music score provided through a high-quality audio headset, the style of music being chosen by the patient from the range offered by the software available at each bed-side computer.
HEALTHY-MIND© VR system (Paris, France): a 15 minutes relaxation session of VR immersing the patient into an artificial world created from computer-generated pictures using a software linked to the Occulus Rift© helmet and a headset. The patient is able to choose four kinds of environments (beach, mountain, snow and Japan) using synthetic motion pictures, breathing exercises and hypnotic speech.
DEEPSEN© VR system (Saint-Didier-au-Mont-d’Or, France): a 15 minutes relaxation session of VR, immersing the patient into a series of filmed sequences, using an “all-in-one” headset created by the company. The patient was able to choose the film among four kinds of videos (Norway, mountain countryside, India and Camargue, a quiet seaside in South of France, near Montpellier) using real motion pictures, breathing exercises and hypnotic speech.

Figure 1 shows an example of virtual reality’s world and headsets. Headsets and headphones were cleaned with sporicidal wipes before and after sessions, and protective caps were disposed between the device and the patient on each session.

Data handling

After enrollment in the study, a relaxation technique was proposed to the patient at the time of the day she or he preferred, from morning to afternoon, in the order of randomization. At baseline, before starting the session, the following vital variables were recorded from the patient’s bedside monitoring: heart rate, blood pressure, respiratory rate and Analgesia/Nociception-Index (ANI). Only instant-ANI (PhysioDoloris© monitor, MDoloris Medical Systems, Lille, France) was recorded because it had previously been reported to be more accurate that mean-ANI in ICU patients [20, 21]. Then, the patient was asked to report her or his symptoms’ intensity using a large visual Numerical-Rating-Scale (NRS) ranging from 0 to 10 (0 = no symptom at all; 10 = the worst possible symptom) [2, 22]. Overall discomfort (physical and psychological discomfort) and five current stressful symptoms were assessed: pain, anxiety, thirst, dyspnea and lack-of-rest. All parameters were recorded again after the end of each relaxation session.

Statistical analysis

1. Primary endpoint

Variation of the intensity of patient’s overall discomfort before and after each relaxation session to determine which technique was the most effective to reduce discomfort.

2. Exploratory secondary endpoints

2.1. Secondary endpoint related to patient’s suffering

Variation of the intensity of five stressful symptoms: pain, anxiety, dyspnea, thirst, lack-of-rest [2]

2.2. Secondary endpoints: physiological stress-response

Variation of physiological variables (heart rate, arterial blood pressure, respiratory rate), and ANI, as an electrophysiological parameter related to the stress-response. ANI measures heart-rate-variability from the bed-side electrocardiographic monitoring of the patient, providing a number from 0 to 100 through spectral analysis. This number is an estimation of the balance between parasympathetic and sympathetic outflows: 100 means a high parasympathetic modulation (low stress level = low risk of suffering), 0 means extremely low parasympathetic modulation (high stress level = high risk of suffering) [20].

3. Safety and feasibility

The intensity of cybersickness (defined as a visuospatial vertigo associated or not with nausea and vomiting) was self-reported by the patient after the relaxation session. The feasibility of the relaxation technique was assessed by the investigation team using the 0–10 NRS, who collected also any incident that could occurred during the relaxation sessions.

4. Number of patients needed to be enrolled

The sample size was calculated based on the number of possible orders of relaxation sessions that was calculated as follows: 4 types of sessions x 3 x 2 = 24 possible orders of sessions. Two different patients were expected to be enrolled at least for each kind of sequence (i.e 48 patients). To take into account lost to follow-up patients and missing data, 60 patients were expected to be enrolled in the study.

5. Presentation of data and analysis

Description of the data was made using usual descriptive statistics for quantitative variable (mean (standard-deviation) or median [25th -75th percentiles] depending on the distribution of the data) and for qualitative data (n, number of data available (frequency in percentage)). All relaxation-sessions were included in intent-to-treat analysis. Univariate analysis was carried out to compared data « before » versus « after » each relaxation sessions for NRS, ANI and physiological variables, using the Student’s t test or the Wilcoxon-Mann-Whitney’s U test according to the distribution of data.

The comparison of electronical techniques between them and the standard relaxation session was carried out by a mixed-effects multivariate analysis, adjusted on session’s order and significant patient’s characteristics, to take into account potential biases and repeated measurements. A backward selection was made manually by removing at each step the variable with the highest p-value to ultimately keep only the significant variables (p < 0.05) in the model. The type of relaxation technique and the session order were always maintained in the model during the selection.

For all statistical tests, a p value of 0.05 was considered statistically significant. Data were analyzed by an independent statistician using the SAS Enterprise Guide version 9.4 (SAS Institute, Cary, NC).

Patient baseline characteristics

Among the 277 patients admitted to the ICU during the study period, 190 were eligible and 60 were enrolled. Figure 2 shows the study flow chart. Fifty patients (83%) did the full protocol (four relaxation sessions), and ten patients did one to three sessions. Reasons to not perform all sessions were mainly sight problems, claustrophobia, patients who became too tired or delirious (CAM-ICU +), or who left the ICU before the end of the protocol. Patients’ demographic and medical characteristics were summarized in Table 1. During the first session, 18 patients were assisted with High-Flow-Oxygen-Therapy, two with Non-Invasive-Ventilation (facemask), and one was intubated; two patients were on continuous extra-renal replacement therapy, and seven required vasopressors.

Table 1

Demographic and medicals characteristics
Medical characteristics upon admission to ICU
Age (yr)	62 [51–69]
Sex (F/M)	20/40
BMI (kg.m^− 2)	27 [22–30]
SAPS II score	36 [28–44]
SOFA score	6 [4–8]
Reason for admission to the ICU
Liver transplant, n (%)	18 (30%)
Post-operative, n (%)	17 (28%)
ARDS, n (%)	6 (10%)
Hemorrhagic shock, n (%)	5 (8%)
Septic shock, n (%)	4 (7%)
Others, n (%)	10 (17%)
Characteristics upon enrolment into the study
RASS level	0 [0–0]
CAM-ICU negative, n (%)	60 (100%)
Length of stay in ICU before enrollment (days)	2,7 [1, 1–3, 6]
Invasive mechanical ventilation before enrollment, n (%)	36 (60%)
Time between extubation and enrollment (hours)	25 [14–42]
Sedation before enrollment, n (%)	36 (60%)
Number of tubes or catheters at inclusion	4 [2–5]
Medical characteristics of patients on the first relaxation session
Mechanical ventilation, n (%)	1 (2%)
Non-invasive ventilation, n (%)	2 (3%)
High flow nasal oxygen therapy, n (%)	18 (30%)
Dialysis, n (%)	2 (3%)
Vasopressors, n (%)	7 (12%)
Sedation at enrollment, n (%)	0 (0%)
Analgesic administration at enrollment, n (%)	45 (75%)
Acetaminophen, n (%)	19 (32%)
Nefopam, n (%)	38 (63%)
Tramadol, n (%)	32 (53%)
Major opioid, n (%)	2 (3%)
Epidural analgesia, n (%)	3 (5%)
Anxiolytic administration at enrollment, n (%)	16 (27%)
Continuous data are expressed in median [25th-75th percentiles]. BMI: Body Mass Index; SAPS II: Simplified Acute Physiology Score II; SOFA: Sequential Organ Failure Assessment score; RASS: Richmond Agitation-Sedation Scale; CAM-ICU: Confusion Assessment Method for the ICU; ARDS: Acute Respiratory Distress Syndrome

Impact of relaxation sessions on overall discomfort (primary endpoint)

In univariate analysis, HEALTHY-MIND© VR system was associated with significant decrease in overall discomfort (median NRS = 4 [2–6]) before the session vs. 2 [0–5] after the session, p = 0.02). The two other specific relaxation techniques and the standard-relaxation were not associated with significant changes (Table 2). These results were confirmed by mixed-effects multivariate analysis, showing that HEALTHY MIND© VR system was the only relaxation technique associated with a significant decrease in overall discomfort (reduction by 0.8 point; p = 0.01, mixed-effect model) (Table 3).

Table 2

Symptoms, Analgesia-Nociception-Index and physiological variables recorded before and after each of the four relaxation sessions
	Type of relaxative techniques
	STANDARD		MUSIC CARE®		VR DEEPSEN®		VR HEALTY MIND®
Symptoms
NRS Overall Discomfort
BEFORE	4	[2;6]	4	[2;6]	5	[2;6]	4	[2;6]
AFTER	4	[2;5]	2,5	[1;5]	4	[1,5;5]	2	[0;5]
p	0,27		0,06		0,21		0,02
NRS Pain
BEFORE	2	[0;5]	2	[0;5]	3	[0;5]	2,5	[0;5]
AFTER	2	[0;5]	1	[0;5]	2	[0;4]	1	[0;4]
p	0,7		0,45		0,3		0,12
NRS Anxiety
BEFORE	2,5	[0;5]	3	[0;5]	3	[0;5]	3	[0;5]
AFTER	2	[0;4]	2	[0;5]	1	[0;4]	1,7	[0;4]
p	0,52		0,32		0,03		0,05
NRS Thirst
BEFORE	6	[1;9]	6	[1;8]	5	[1;8]	4	[0;7]
AFTER	6	[0;8]	5	[1;8]	4	[0;8]	4	[0;6]
p	0,68		0,53		0,38		0,93
NRS Dyspnea
BEFORE	1,5	[0;5]	2	[0;5,5]	2	[0;5]	2	[0;4]
AFTER	1	[0;4]	1	[0;4]	2	[0;5]	0,5	[0;4]
p	0,89		0,13		0,44		0,5
NRS Lack of Rest
BEFORE	4	[2;6]	5	[2;7]	5	[3;8]	5	[3;8]
AFTER	4	[1;6]	4	[0;5]	2	[1;5]	3,5	[2;5]
p	0,49		0,05		< 0,01		0,02
ANI and physiological variables
ANI
BEFORE	62	[48;85]	66	[56;82]	72	[53;80]	67	[51;80]
AFTER	69	[51;82]	82	[65;93]	80	[70;98]	91	[70;98]
p	0,45		< 0,01		< 0,01		< 0,01
Heart Rate (/min)
BEFORE	89	[81;102]	88	[80;102]	87	[78;99]	88	[77;100]
AFTER	92	[79;102]	85	[81;101]	84	[74;98]	92	[80;97]
p	0,88		0,68		0,51		0,69
Respiratory Rate (/min)
BEFORE	21	[18;24]	20	[17;26]	20	[17;25]	21	[16;27]
AFTER	22	[18;27]	19	[15;24]	21	[17;26]	20	[16;24]
p	0,74		0,34		0,81		0,14
Systolic Blood Pressure (mmHg)
BEFORE	134	[120;144]	128	[117;154]	136	[121;151]	134	[118;146]
AFTER	133	[119;146]	127	[113;143]	137	[120;151]	131	[115;148]
p	0,99		0,51		0,86		0,82
Diastolic Blood Pressure (mmHg)
BEFORE	72	[65;82]	71	[62;82]	70	[62;81]	73	[65;82]
AFTER	72	[64;79]	66	[61;77]	75	[61;84]	71	[62;81]
p	0,52		0,18		0,38		0,65
The data correspond to a rating from 0 to 10 on a numerical rating scale, were 0 is the best and 10 the worst intensity, and are expressed in median [25th-75th percentiles]. The p value was calculated via Mann-Whitney-Wilcoxon test for non parametric data and via Student's t test for parametric data.

Table 3

Multivariate mixed effect model - Benefits of specific electronical relaxation techniques compared to standard relaxation
		Gain estimate	p			Gain estimate	p
Overall discomfort	MUSIC CARE®	-0,4	0,25	ANI	MUSICARE®	0,7	0,87
	VR DEEPSEN®	-0,1	0,85		VR DEEPSEN®	8,5	0,07
	VR HEALTY MIND®	-0,8	0,01		VR HEALTY MIND®	13	0,006
	STANDARD	0	.		STANDARD	0	.
Pain	MUSIC CARE®	-0,3	0,23	Heart rate	MUSICARE®	0.1	0,39
	VR DEEPSEN®	-0,3	0,19		VR DEEPSEN®	-0.5	0,75
	VR HEALTY MIND®	-0,8	0,001		VR HEALTY MIND®	1.0	0,47
	STANDARD	0	.		STANDARD	0	.
Anxiety	MUSIC CARE®	-0,1	0,7	Systolic blood pressure	MUSICARE®	2,2	0,7
	VR DEEPSEN®	-0,9	0,001		VR DEEPSEN®	2.1	0,5
	VR HEALTY MIND®	-0,8	0,004		VR HEALTY MIND®	2,2	0,8
	STANDARD	0	.		STANDARD	.	.
Thirst	MUSIC CARE®	0,0	0,88	Diastolic blood pressure	MUSICARE®	-2	0,2
	VR DEEPSEN®	0,0	0,93		VR DEEPSEN®	1,8	0,2
	VR HEALTY MIND®	-0,3	0,45		VR HEALTY MIND®	-0,3	0,8
	STANDARD	0	.		STANDARD	0	.
Dyspnea	MUSIC CARE®	-0,6	0,06	Respiratory rate	MUSICARE®	-1	0,4
	VR DEEPSEN®	-0,3	0,42		VR DEEPSEN®	0,5	0,65
	VR HEALTY MIND®	-0,3	0,39		VR HEALTY MIND®	-2	0,12
	STANDARD	0	.		STANDARD	0	.
Lack of rest feeling	MUSIC CARE®	-0,7	0,26
	VR DEEPSEN®	-1,6	0,01
	VR HEALTY MIND®	-1,2	0,07
	STANDARD	0	.
This multivariable mixed model was adjusted to the number of session and significant patient characteristics, reporting the estimate of the improvement of the self-reported assessment of symptoms’ intensity, Analgesia/Nociception Index (ANI) and physiological variables, for each relaxation device, compared to the standard relaxation session.

Impact of relaxation sessions on five common ICU stressful symptoms (exploratory secondary endpoints related to patient’s suffering)

Variation of symptoms’ intensities are shown in Table 2 (univariate analysis) and Table 3 (multivariate analysis). HEALTHY-MIND© VR system was associated with a reduction of pain and anxiety’s intensities by 0.8 point compared to the standard relaxation (p = 0.001 and 0.004 respectively, mixed-effects model). DEEPSEN© VR system was associated with a reduction of anxiety by 0.9 point (p = 0.004) and a reduction of lack of rest by 1.6 point (p = 0.01).

Impact of relaxation sessions on Analgesia/Nociception Index (ANI) and physiological variables (exploratory secondary endpoints)

ANI increased significantly after each relaxation session except for the standard relaxation (univariate analysis, Table 2). The multivariate analysis showed a significant change for HEALTHY-MIND© VR system only (estimate gain + 13, p < 0.01) (Table 3). Other physiological variables did not change significantly.

Safety

Incidents were reported in three patients during the 109 VR sessions: self-withdrawal related to claustrophobia (n = 1) or agitation (n = 1), displacement of the headset to the nose and mouth associated with tachypnea and dyspnea (n = 1). In all, prematured interruptions of relaxation sessions before the end of the 15-minutes planned session occurred in 12/218(6%) sessions (3/54(6%), 4/53(8%), 3/56(5%), 2/55(4%), for the standard-relaxation, HEALTHY-MIND© and DEEPSEN© VR systems, and MUSIC-CARE©, respectively). Main reasons were eyesight problems, annoying, interruptions related to visit of patient’s relatives or urgent care. Cyber-sickness was rarely observed after the use of music-therapy or VR headsets, with a median NRS of dizziness of 0 [0–0]. Five on 56 patients (11%) reported a NRS ≥ 4 for dizziness after a session with DEEPSEN© VR system, 2/53 (4%) after a session with HEALTHY-MIND© VR system, 1/55 (2%) after standard session, and none after MUSIC-CARE© relaxation. No other serious side-effects were observed. Ten patients (17%) did not complete the four sessions: three because of discharge from ICU, three because of fatigue or anxiety, two because of eyesight problems, one because of the appearance of delirium, and one who developed claustrophobia.

Feasibility

The placement and use of devices were easy according to the investigators (feasibility-NRS of 10 [10;10] for standard; 10 [9;10] for MUSIC-CARE©; 10 [8;10] for DEEPSEN©; 10 [8;10] for HEALTHY-MIND©). Investigators were present for the placement and configuration of headset. Some patients learned their use very quickly and used it with autonomy after the end of the research protocol.

The main findings of this randomized comparative trial are that using electronical relaxation devices is feasible, safe and well tolerated in more than 90% of alert and non-delirious critically-ill patients. Some devices are more effective than others to relieve ICU patients from stressful symptoms. VR with synthetic motion pictures (imagined world) is the most effective to decrease overall discomfort, compared to real world or music-therapy only (primary endpoint). This result is reinforced by a significantly greater increase of ANI with this kind of VR compared to other devices. Exploratory secondary-endpoints may explain this result because this relaxation-device was also associated with a significant decrease of both pain and anxiety, while the other kind of VR (real world) was associated with a significant decrease of anxiety and lack of rest, but not pain (multivariate analysis). These findings should be discussed and nuanced by the fact that some symptoms (pain, anxiety, dyspnea) had a light intensity (< 4/10) in the included population. These devices could have demonstrated different properties in other populations of ICU patients, and these results should not discourage further research in patients with moderate to severe pain, anxiety or dyspnea. Such research is mandatory because similar relaxation devices may have different impacts depending on the type of symptoms, as reported by the present study.

The study highlights also that pain is not always today the top of stressful symptoms in ICU patients, contrary to other symptoms like thirst. Pain management has been improved in ICU for many years [23], including the elaboration of new pain scales [22, 24], the measurement and recognition of pain and related outcomes [25, 26], and the development of practice guidelines promoting multimodal analgesia as the top priority [1]. Pain could be considered as the cornerstone for improvement of patients’ suffering in ICU. However other symptoms should be considered [2, 27] and have arisen more and more interest like anxiety [28], dyspnea [29, 30], thirst [31, 32] and sleep disruption [1]. It should be noted that for the latter symptom, the intensity of “lack of rest” was measured in the present study instead of “sleep disruption” because the relaxation sessions were organized during the day and not at night.

There has been an increased interest to use non-pharmacological strategies to relieve stressful symptoms in ICU. Listening music was proved to be effective on anxiety [28] while optimizing the ventilator setting was effective on both anxiety and dyspnea [33], and should even be encouraged first before escalating analgesia-sedation in mechanically-ventilated patients [34, 35]. Sleep and thirst should be facilitated using a bundle of non-pharmacological techniques (e.g. earplugs, eyemask, reduction of noise, light and care to promote sleep [1]; oral swab wipes, ice-cold water sprays, lip moisturizer, mini mint ice cubs to minimize thirst [31, 32]).

The present study reports promising results regarding the use of VR to improve anxiety (both devices), pain (imagined world) or lack of rest (real world). Previous studies reported that music-therapy could improve anxiety [28] and pain in ICU [12, 36]. In the present study, MUSIC-CARE© was the only device associated with a possible effect on dyspnea, with a trend toward significance (decrease of 0.6 additional point, p = 0.057, multivariate analysis, Table 3). In a larger population or in patients with higher dyspnea intensity, this technique could have demonstrated significant improvement. This is consistent with a previous report by our group that observed significant improvement of ventilatory parameters with MUSIC-CARE© in intubated patients during the weaning of mechanical ventilation [12].

The present study reports that devices using both music and VR could be more effective than music-therapy alone on overall discomfort and specific symptoms. Strong scientific arguments supporting the beneficial effect of VR have recently spread in medical sphere, especially for the management of mental health disorders including anxiety [37]. Results are promising to manage pain after surgery, severe burns [38, 39] or before nociceptive procedures [40]. Hypothesis is that VR, by providing multisensory inputs, deflects attention into the virtual world and lowers the pain intensity [41]. Thus, the kind of virtual world may play a role as suggested by our results. However, patients’ characteristics that were not investigated in this study (preference for real or computed generated pictures for example) should be taken into account as potential bias when interpreting the results.

The present study is the first randomized study about VR evaluating the improvement of baseline patient’s overall comfort in a mixed medical-surgical ICU, compared to music-therapy and standard-relaxation. A recent review on VR in ICU reported 21 studies, mostly of them being observational, non-comparative, feasibility studies [42], whose reports are consistent with the present study with a completion rate of 74%, (95%CI: 51%-96.0%). In two proof-of-concept studies designed by the same group, heart-rate and blood-pressure decreased in 37 patients [43], while respiratory rate and discomfort decreased in 33 patients [44]. Physiological variables did not change in the present study. This may be explained by differences in the severity of critical-illness among studied populations. Usually, physiological variables may change only a little in critically-ill patients compared to behavioural-pain-scales [45, 46] or hear-rate-variability devices [20]. Among RCTs, one assessed the type of computer-generated video (urban versus mountain world versus a video displayed on the bedroom-TV screen) on 45 patients, reporting a better restoration feeling with the mountain world [47], consistently with findings of the present study that highlights a different impact of VR related to devices’ characteristics. Three RCTs included 48(24/group) [48], 100(25/group) [49] and 200(100/group) [50] post-cardiac surgery patients. Among them, one reported a significant higher subjective sleep quality and objective sleep efficiency after VR compared to usual sleep protocol (eyemask and earplug if desired) [48]; one was negative on pain, anxiety, fatigue (but positive on relaxation) after VR, hypnosis alone or associated with VR, compared to standard daily care [49]; one failed to prove non-inferiority of VR compared to nitrous-oxyde for the management of pain and anxiety during chest-drain removal, that is the care-procedure known as the most painful in the ICU [51], deserving the most effective analgesia. Another negative RCT investigated the impact of VR on PICS in 89 patients with COVID-19 [52].

The present study presents some strengths and limitations. Strengths include the prospective recording of parameters by a research team who assure for non disturbance of care during the relaxation time, the cross-over randomized design, the multivariate analysis that took into account multiple assessments, and the measurement of the most common stressful symptoms [2] using validated complementary subjective and objective tools [20, 22]. Regarding the study limits, as previously discussed, a lack of power related to only moderate symptoms intensities could explain the lack of significance for some results. This study should be reproduced in patients with clinically significant symptoms (i.e. pain, anxiety, dyspnea), and calibrated on each of these stressful symptoms. However, although the absolute values of symptoms’ improvement were rather small, it is important to note that all the results pointed in the same direction: a specific relaxation device, such as music-therapy or VR, can improve self-reported patient’s symptoms and patient’s stress response. Finally, these results may be biased by the fact that a lot of attention was paid to enrolled patients during the study: multi-daily visit, dialogue, taking into account diverse symptoms and pain, with multiple assessments by nurses and physicians, followed by frequent multidisciplinary management as basically performed for pain according to the guidelines. Thus, further studies are needed to measure the impact of electronical devices in ICU at a large scale, in multiple centers with diverse ICU populations and cultures, and to explore all different characteristics of the devices and their impact on short and long-term outcomes.

This first RCT investigating different VR devices compared to standard relaxation and to music-therapy shows that VR with computer-generated pictures is the most effective to improve overall discomfort and to reduce the physiological stress-response in ICU patients. Moreover, the type of virtual world and music-therapy may impact the symptoms differently: beneficial effects of these new therapies depend on the device characteristics and the targeted symptoms.

Electronical relaxation therapies are effective palliative care tools for improving stressful symptoms in ICU patients.
Effectiveness depends on the type of symptom and the characteristics of the devices.
Overall discomfort and adrenergic stress response are significantly more improved by virtual-reality using a synthetic imagined world than using a real world or music-therapy alone.

Virtual-reality using a synthetic imagined world is a more effective palliative care tool for improving overall discomfort and adrenergic stress response in critically-ill patients than using a real world or music-therapy alone.

ANI Analgesia Nociception Index

CAM-ICU Confusion Assessment Method for the ICU

ICU Intensive Care Unit

NRS Numeric Rating Scale

RASS Richmond Agitation Sedation Scale

SAPS Simplified Acute Physiological Score

SOFA Sequential Organ Failure Assessment Score

VR Virtual Reality

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

Human Ethics Statement

The study was approved by an ethics committee [Comité de Protection des Personnes Sud-Méditerranée-1 (ID-RCB:2016-A00748-43)] according to French law, and registered on Clinical Trials NCT04017299.

Adult Consent to Participate

Adult patients over 18-yo admitted to the ICU were eligible if they were alert and non delirious, following the French validated versions of the Confusion-Assessment-Method for the ICU (CAM-ICU) [16, 17] and the Richmond-Agitation-Sedation-Scale (RASS) that had to be ³ 0 [18]. Patients were screened daily for eligibility by investigators, and included in the study after written consent.

Human Accordance Statement

The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Data Availability Statement

Data are protected by the Clinical Research Direction of the Montpellier University Hospitals, and will be available for research upon request after approval by a French ethics committee according to the law.

Funding

The research was funded by the French healthcare ministry (Direction Générale de l’Offre de Soins (DGOS)/General Healthcare Supply Direction).

COMPETING INTERESTS

Samir Jaber reports consulting fees from Drager, Xenios, Medtronic and Fisher and Paykel. Other authors declare no conflicts of interest.

AUTHORS’ CONTRIBUTIONS

LMG and CR contributed equally to the study. GC, OG, JC, ADJ, NM and SJ designed the trial and obtain the research funding. LMG, CR and OG enrolled the patients, performed the research and collected the data. NM performed an independent statistical analysis. LMG, CR and GC drafted the manuscript. All authors reread and approved the manuscript.

ACKOWLEDGMENTS

First of all, the authors would like to thank all the patients who participated in the study, and are very grateful for the participation of nurses, assistant nurses, physicians and physiotherapists of the medical-surgical ICU at the Saint-Eloi University Hospital, Montpellier. The authors are also grateful to the Medical Information Department (DIM) of Montpellier University Hospitals for the statistical analysis, and to the Direction of Clinical Research and Innovation for their help and guidance with administrative and regulatory concerns, as well as research quality control.

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Competing interest reported. Samir Jaber reports consulting fees from Drager, Xenios, Medtronic and Fisher and Paykel. Other authors declare no conflicts of interest.

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Discomfort Improvement for Critically-ill Patients using Electronical Relaxation Devices: results of the Cross Over Randomized Controlled Trial E-CHOISIR (Electronical-CHOIce of a System for Intensive care Relaxation)

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Abstract

Figures

Introduction

Material And Methods

Ethics approval

Patient population

Conduct of the study and description of the electronical relaxation tools

Data handling

Statistical analysis

1. Primary endpoint

2. Exploratory secondary endpoints

2.1. Secondary endpoint related to patient’s suffering

2.2. Secondary endpoints: physiological stress-response

3. Safety and feasibility

4. Number of patients needed to be enrolled

5. Presentation of data and analysis

Results

Patient baseline characteristics

Impact of relaxation sessions on overall discomfort (primary endpoint)

Impact of relaxation sessions on Analgesia/Nociception Index (ANI) and physiological variables (exploratory secondary endpoints)

Safety

Feasibility

Discussion

Conclusion

KEY MESSAGES

SUMMARY

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1