# A Bundle of Interventions to Prevent Pressure Ulcers During Prone Position in Adult Patients With Acute Respiratory Distress Syndrome: Results of a French Stepped-Wedge Randomized Controlled Trial

Lucile Gay, Laure Huot, Hodane Yonis, Sabine Valera, Sami Hraeich, Dominique Matthieu, Arnaud Gacouin, Carole Ouisse, Jean Reignier, Audrey Massard, et al.

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Lucile Gay, Laure Huot, Hodane Yonis, Sabine Valera, Sami Hraeich, et al. A Bundle of Interventions to Prevent Pressure Ulcers During Prone Position in Adult Patients With Acute Respiratory Distress Syndrome: Results of a French Stepped-Wedge Randomized Controlled Trial. Nursing in Critical Care, 2025, 30 (4), pp.e70084. 10.1111/nicc.70084. hal-05142638

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RESEARCH ARTICLE

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# A Bundle of Interventions to Prevent Pressure Ulcers During Prone Position in Adult Patients With Acute Respiratory Distress Syndrome: Results of a French Stepped-Wedge Randomized Controlled Trial

Lucile Gay<fnref n="1" /> | Laure Huot² | Hodane Yonis³ | Sabine Valera⁴ | Sami Hraeich⁴ | Dominique Matthieu⁵ | Arnaud Gacouin⁵ |
Carole Ouisse⁶ | Jean Reignier⁶ | Audrey Massard⁷ | Jean-Pierre Quenot⁷ | Caroline Revol⁸ | Adrien Robine⁸ |
Olivier Guillemault⁹ | Gaël Bourdin⁹ | Angélina Robert¹⁰ | Jean-Claude Lacherade¹⁰ | Céline Perarder¹¹ | Michel Badet¹¹ |
Loredana Baboi³,¹² | Muriel Rabilloud¹³ | Evelyne Decullier¹⁴ | Eloïse Montagne¹⁴ | Raphaële Girard¹⁵ | Christine Arcuset¹⁶ |
Julie Mevel¹⁷ | Aurélie Méry de Montigny¹³ | Claude Guérin¹⁸

**Correspondence:** Lucile Gay (lucile.gay@chu-lyon.fr)

**Received:** 2 September 2024 | **Revised:** 9 May 2025 | **Accepted:** 20 May 2025

**Funding:** This work was supported by Programme Hospitalier de Recherche Infirmière et Paramédicale # PHRIP-16-16-0223, 2017-A01449-44.

**Keywords:** eye complication | eye protection | pressure ulcers | prone position | skin protection

## ABSTRACT

**Background:** In patients with moderate-to-severe acute respiratory distress syndrome, the frequency of pressure ulcers is higher in the prone position than in the supine position.

**Aim:** To assess the effect of a bundle of interventions to prevent pressure ulcers in patients with acute respiratory distress syndrome prone.

**Study Design:** ESCARD is a stepped-wedge prospective multicentre trial conducted in France that included patients with moderate-to-severe acute respiratory distress syndrome, intubated and with an indication for pronation. In the control period, patients received the routine means of each centre. In the experimental period, the bundle of specific standardized means included: eye protection with methylcellulose; strapped lower eyelids; 15° body inclination; specific cushions inserted between the mattress and head/thorax and knees/feet; head rotation every 4 h. The primary end-point was the occurrence of a new pressure

**Abbreviations:** AE, adverse event; ARDS, acute respiratory distress syndrome; COVID-19, Coronavirus Disease 2019; CRF, case report form; F₁O₂, inspiratory fraction of oxygen in air; ICC, intra-class correlation; ICU, intensive care unit; IQR, inter-quartile range; ITT, intention-to-treat; NPUAP, National Pressure Ulcer Advisory Panel Pressure Injury; OR, odds ratio; PaO₂, oxygen partial arterial pressure; PEEP, positive end-expiratory pressure; SAPS, simplified acute physiology score; SOFA, sequential organ failure assessment.

This is an open access article under the terms of the [Creative Commons Attribution-NonCommercial-NoDerivs License](https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

© 2025 The Author(s). *Nursing in Critical Care* published by John Wiley & Sons Ltd on behalf of British Association of Critical Care Nurses.

<footnote n="1">¹Hôpital de la Croix-Rousse, Lyon, France | ²Pôle de Santé Publique, Service d'Evaluation Economique en Santé, Lyon, France | ³Médecine Intensive Réanimation, Hôpital de la Croix-Rousse, Lyon, France | ⁴Médecine Intensive Réanimation, Hôpital Nord, Marseille, France | ⁵Médecine Intensive Réanimation, Hôpital Pontchaillou, Rennes, France | ⁶Médecine Intensive Réanimation, Nantes, France | ⁷Médecine Intensive Réanimation, CHU François Mitterrand, Dijon, France | ⁸Réanimation Polyvalente, Bourg-en-Bresse, France | ⁹Réanimation Polyvalente, Hopital Saint Joseph Saint Luc, Lyon, France | ¹⁰Réanimation Polyvalente, Centre Hospitalier Départemental Vendée, Bd Stéphane Moreau, La Roche-sur-Yon, France | ¹¹Réanimation Polyvalente, Centre Hospitalier Métropole Savoie, Chambéry, France | ¹²Médecine Intensive Réanimation, Hospices Civils de Lyon, Hôpital de la Croix-Rousse, Lyon, France | ¹³Hospices Civils de Lyon, Pôle Santé Publique, Service de Biostatistique et Bioinformatique, Lyon, France | ¹⁴Hospices Civils de Lyon, Pôle de Santé Publique, Service de Recherche et épidémiologie Clinique, Lyon, France | ¹⁵Hospices Civils de Lyon, Lyon, France | ¹⁶Hospices Civils de Lyon, Service des maladies infectieuses, Hôpital de la Croix-Rousse, Lyon, France | ¹⁷Hospices Civils de Lyon, Service de Stomathérapie, Hôpital de la Croix-Rousse, Lyon, France | ¹⁸Université de Lyon, Faculté de Médecine Lyon-Est, Lyon, France</footnote>
ulcer at any location and stage in the anterior part of the body 7 days after inclusion. It was assessed from pictures taken in the supine position and independently analysed by two experts blinded to the allocated period.

**Results:** From 16 April 2018 to 3 December 2020 (with an interruption between 12 March and 15 July 2020 because of COVID pandemic), a total of 160 patients were included in 9 centres; 156 were analysed. At the first proning session, all 6 specific pre-ventive means were implemented in 1.2% of the patients in the control period and 91.8% in the experimental period. At Day 7, 53 patients (63.9%) in the control versus 40 (54.8%) in the experimental period had a new pressure ulcer at any location and of any stage (odds ratio = 0.92; 95% confidence interval [0.39; 2.18]). There was a 42.8% discrepancy between the two experts.

**Conclusions:** In this prospective multicentre stepped-wedge trial, the bundle of interventions did not lead to a significant reduction in the frequency of new pressure ulcers in moderate-to-severe acute respiratory distress syndrome patients treated by prone position.

**Relevance to Clinical Practice:** The critical care nurses were able to manage patients enrolled in a complex trial up to its planned end. Even though negative, the study should encourage intensive care unit (ICU) nurses to better define the bundle of interventions including introducing other methods not used in the present study. ICU nurses should also assess the stage of pressure ulcers consistently over time. ICU nurses should consider further studies because pressure ulcer is a relevant issue of concern during the pronation in acute respiratory distress syndrome patients. If so, the new trial should include a larger number of ICUs.

**Trial Registration:** The protocol was approved by an ethics committee (number 2017-A01449-44 on 7 October 2017) and was recorded in [clinicaltrials.gov](https://clinicaltrials.gov) (NCT03125421)

# 1 | Introduction

The PROSEVA trial found that the prone positioning of patients with moderate-to-severe acute respiratory distress syndrome (ARDS) under invasive mechanical ventilation in intensive care units (ICU), for more than 16 consecutive hours per session, reduces mortality as compared with the supine position [1]. Prone positioning in this setting therefore received a strong recommendation from experts in 2023 [2].

# 2 | Background

Pressure ulcers are more frequent in the prone (43%–57.1%) than in the supine (34%–42.5%) position [3, 4]. These complications are a source of concern as they may be a source of superinfection and pain [5], whether they are located on the patient's face [6] or elsewhere [7–10]. Furthermore, since the longer the pronation, the more likely the risk of pressure ulcers occurrence, and long proning sessions are recommended, there is a need for preventive methods. However, as published data essentially concern the supine position and are largely inconclusive [11–15], trials aiming at testing preventive methods are highly desired [12].

# 3 | Aims and Objectives of Study

We designed a trial to investigate the effect of a bundle of interventions to prevent pressure ulcers in prone ARDS patients under invasive mechanical ventilation. We also investigated the impact of prone positioning on the eyes because the data on both the ocular complications and their prevention, in either supine or prone position, are extremely limited in ICU patients [16]. We tested the hypothesis that a bundle of interventions, including eye protection, skin protection, body inclination, specific cushion and head rotation, reduces the occurrence of new pressure ulcers during the first week after inclusion, as compared with routine interventions, in moderate-to-severe ARDS patients who are intubated and prone.

# 4 | Design and Methods

ESCARD is a prospective, multicentre, controlled, stepped-wedge cluster randomized trial [17] conducted in France in nine centres. The study was sponsored by the Hospices Civils de Lyon and funded by a grant from the French Ministry of Health (Programme Hospitalier de Recherche Infirmière et Paramédicale # PHRIP-16-16-0223). The report is presented according to the CONSORT guidelines [18] (Supporting Information 1).

To be included, patients had to meet all the following criteria: (1) age ≥ 18 years; (2) admitted to the ICU; (3) intubated; (4) mechanically ventilated; (5) having ARDS, as defined by the Berlin criteria [19] and oxygen arterial partial pressure to inspired air fraction ratio (PaO₂/FiO₂) < 150 mmHg on Positive End-Expiratory Pressure (PEEP) ≥ 5 cmH₂O and oxygen fraction in air (FiO₂) ≥ 0.6; (6) indication of prone position from the clinician in charge; (7) measured body weight ≤ 140 kg; (8) written informed assent given by the next of kin; (9) affiliation to the national social security system. Exclusion criteria were (1) contraindication to prone positioning according to clinician's decision; (2) prone position before inclusion; (3) under legal protection or guardianship (e.g., cognitive impairment); (4) pregnancy; (5) tra cheostomy; (6) extracorporeal membrane oxygenation; and (7) participation to another interventional study that may interfere with the primary end-point according to the clinician's opinion (e.g., a study on devices to support the abdomen in the prone position).

We hypothesized that 57% of patients would experience a new pressure ulcer at Day 7 in the control group, according to an ancillary study of the PROSEVA trial [1]. This hypothesis was reasonable because the inclusion and exclusion criteria of patients and the pronation protocol in the present study were similar to those used in the PROSEVA trial [1]. We expected a 50% reduction in the proportion of patients with a new pressure ulcer at Day 7, according to unpublished personal data, and therefore that this would occur in 28.5% of the experimental group. For a bilateral alpha risk of 5% and a coefficient of variation between clusters of 0.1, the inclusion of two patients per cluster and per
## Summary

* What is known about this topic

* Prone position improves survival in patients intubated and mechanically ventilated for moderate-to-severe acute respiratory distress syndrome as compared with the supine position.

* However, it is still associated with a high rate of pressure ulcers in the anterior part of the body.

* Preventive means of pressure ulcers are therefore highly desirable. There are many preventive strategies, and these are different across centres, which requires an attempt at standardization.

* What this paper adds

* In the present study, we defined a bundle of five preventive means we tested against a control group.

* We adopted a stepped-wedge design in this multi-centre prospective trial performed in France.

* We did not find any difference regarding the occurrence of new pressure ulcers between the two groups.

* The study showed, however, that nursing means to prevent pressure ulcers in the prone position are feasible and should encourage further studies.

period would result in a power of at least 80%. Therefore, a total of 180 patients was required for the study.

## 4.1 | Data Collection Tools and Methods

The participating centres were selected based on the willingness to participate and the extensive experience in the prone position. Each centre involved a nurse and a physician dedicated to the study. In February 2016, a survey regarding the use of the methods known to be used for pressure ulcer prevention was sent out to each centre to collect their usual nursing care practice during pronation (Supporting Information 2); these constituted the practices of the control period. The results of this survey were also used to determine the preventive practice to be implemented during the experimental period. Specific methods identified from the survey and the literature for the experimental period were: (1) eye protection with methylcellulose eye drops [16], (2) strapped lower eyelid [16], (3) body inclination at 15° above the horizontal plane, (4) a cushion (Repose; Hospidex, La Ciotat, France) inserted between the mattress and head/thorax, (5) a cushion (Repose; Hospidex) inserted between the mattress and knees/feet and (6) alternate left/right side lateral rotation of the head every 4 h. Non-specific means routinely applied in each centre could also be used in the experimental period, except for the support of the abdomen and skin protection as the Repose (Hospidex) cushion was used (Supporting Information 3).

The nine centres, that is, clusters, were randomized centrally and independently before the start of the study. All centres started the study with a period of 3 months using their usual practices (control strategy). Then, every 3 months, a new centre implemented the standardized experimental strategy, according to the randomization list previously defined. At the end of the 10 3-month periods, all centres were using the experimental strategy (Table 1).

The primary end-point was the occurrence of a new pressure ulcer of any stage (according to the National Pressure Ulcer Advisory Panel Pressure Injury [NPUAP] 4-stage classification [20]) and at any location on the anterior side of the body, at Day 7 after inclusion and relative to the baseline assessment. The secondary end-points are detailed in the Supporting Information 4.

The primary end-point was assessed from pictures taken by the nurses dedicated to the study in each centre under standardized conditions and validated by an external expert committee (Supporting Information 5). The same model of camera (Lumix TZ70 digital camera; Panasonic, Kadoma, Japan) was used in each centre. For each patient, three pictures were taken to cover: firstly, head, neck and shoulders; secondly, shoulders to pelvis; and lastly, pelvis to feet. A 10-cm long ruler and a colour scale (red indicating budding, black indicating necrosis and yellow indicating fibrin) were placed on the skin near the pressure ulcer to facilitate pressure ulcer grading. The pictures were to be taken immediately after the patient was installed in the supine position (at inclusion, at Day 7 and at ICU discharge for survivors); for non-survivors, no picture was taken at the time of death. The pictures were stored and coded anonymously. After the end of the study, all pictures were sent out to two experts blinded to the period for an independent and unbiased assessment. The pictures were examined using Photoshop (Adobe, San Jose, CA, USA) software to determine the stage of pressure ulcers according to the NPUAP classification. The following body locations were analysed: forehead, nose, eyes, chin, cheeks, lips, anterior part of the thorax, breasts in females, knees, iliac crests, dorsal face of the feet, external genitals in males. Any disagreement between the two experts was resolved by a third expert, whose assessment was ultimately retained. In addition, the nurse in charge of the patient visually assessed pressure ulcers according to the NPUAP classification and reported this in the case report form (CRF) on a daily basis from inclusion to Day 7 and at ICU discharge in survivors, under the same conditions as for the picture. The latter assessment was to be used in case of missing pictures at any time point. There were no important changes to methods, including outcomes, after trial commencement.

Survivors at ICU discharge were checked for eye pain, oedema or redness, and visual acuity was assessed using the Monoyer chart, which gives a result that ranges from 1 to 10, with patients seated 5 m from the chart.

The patients were followed until hospital discharge, and their vital status at discharge from the ICU and hospital was collected from the medical chart. The safety was assessed from adverse events (AEs) and serious AE collected during the study period. The lengths of ICU and hospital stay were computed from the corresponding dates of admission and discharge. The ventilator-associated pneumonia and bacteraemia occurring during the ICU were assessed using standard definitions [21].

An electronic CRF was created for the purpose of the study (Ennov Clinical, V8.2.30; Ennov, Paris, France).

After inclusion, each patient was allocated to the control or experimental intervention corresponding to his/her centre and to
<table><caption>TABLE 1 | Inclusion of patients in each centre and period—Intention-to-treat population (N = 156).</caption><thead><tr><th rowspan="3">Centre</th><th colspan="10">Time (periods)</th><th rowspan="3">Total</th></tr><tr><th>1</th><th>2</th><th>3</th><th>4</th><th>5</th><th>6</th><th>7</th><th>8</th><th>9</th><th>10</th></tr><tr><th>16/04/2018<br>15/07/2018</th><th>16/07/2018<br>15/10/2018</th><th>16/10/2018<br>15/01/2019</th><th>16/01/2019<br>15/04/2019</th><th>16/04/2019<br>15/07/2019</th><th>16/07/2019<br>15/10/2019</th><th>16/10/2019<br>15/01/2020</th><th>16/01/2020<br>15/06/2020</th><th>16/06/2020<br>15/09/2020</th><th>16/09/2020<br>15/12/2020</th></tr></thead><tbody><tr><td>1</td><td>2</td><td>2</td><td>3</td><td>2</td><td>1</td><td>2</td><td>3</td><td>2</td><td>2</td><td>0</td><td>19</td></tr><tr><td>2</td><td>3</td><td>2</td><td>2</td><td>2</td><td>2</td><td>2</td><td>2</td><td>2</td><td>2</td><td>1</td><td>20</td></tr><tr><td>3</td><td>1</td><td>2</td><td>2</td><td>1</td><td>2</td><td>0</td><td>0</td><td>3</td><td>2</td><td>1</td><td>14</td></tr><tr><td>4</td><td>2</td><td>2</td><td>2</td><td>2</td><td>2</td><td>2</td><td>3</td><td>2</td><td>1</td><td>2</td><td>20</td></tr><tr><td>5</td><td>1</td><td>2</td><td>2</td><td>2</td><td>2</td><td>0</td><td>1</td><td>0</td><td>1</td><td>1</td><td>12</td></tr><tr><td>6</td><td>2</td><td>2</td><td>2</td><td>1</td><td>2</td><td>3</td><td>3</td><td>3</td><td>1</td><td>3</td><td>22</td></tr><tr><td>7</td><td>3</td><td>2</td><td>2</td><td>2</td><td>0</td><td>3</td><td>2</td><td>2</td><td>0</td><td>1</td><td>17</td></tr><tr><td>8</td><td>2</td><td>2</td><td>1</td><td>5</td><td>0</td><td>3</td><td>1</td><td>2</td><td>2</td><td>2</td><td>20</td></tr><tr><td>9</td><td>2</td><td>1</td><td>4</td><td>2</td><td>0</td><td>1</td><td>1</td><td>1</td><td>0</td><td>0</td><td>12</td></tr><tr><td>Total</td><td>18</td><td>17</td><td>20</td><td>19</td><td>11</td><td>16</td><td>16</td><td>17</td><td>11</td><td>11</td><td>156</td></tr></tbody></table>

Note: Grey cells indicate the control period and unfilled cells the experimental period.
the period (Table 1). The preventive means were started in the hour following inclusion, as defined above. In both periods, the proning session lasted 16 consecutive hours.

## 4.2 | Data Analysis

Normality of the data was assessed by using visual inspection of histograms and Q-Q plots, and the Shapiro-Wilk test. Quantitative and qualitative variables were described in the whole population, experimental and control groups as median [inter-quartile range, IQR] and count and percentage point (the missing values were not used in the denominator for this computation), respectively.

Missing data for the primary end-point (lack of picture for early ICU discharge before Day 7 or technical reason) were replaced by the last available data recorded in the CRF. Missing data for any other variable were not replaced. All analyses were performed on the Intention-To-Treat (ITT) population, namely all included patients with complete data for the primary end-point at inclusion and ≥ 1 post-inclusion visit. The statistical strategy planned to perform inferential tests on the primary end-point only. This, namely the occurrence of a new pressure ulcer at Day 7 at any location and of any stage, was assessed using a logistic mixed model with time (coded from 1 to 10 for the 10 periods) and period (experimental vs. control) as fixed effects and a cluster random effect on the intercept. The interaction between time and period was tested. The effect of the intervention was estimated by an odds ratio and its 95% confidence intervals, with the corresponding *p*-value. A post hoc analysis on eye complication was performed by using Fisher exact test. No additional analysis was performed. No interim analysis was planned. The full trial protocol can be found in the Supporting Information 6.

The analysis (Supporting Information 3) was conducted using the SAS Enterprise Guide 7.1 software (SAS Institute Inc., Cary, NC, USA).

## 5 | Ethics Statement

Written informed assent for participation of the patient was obtained from the next of kin for each participant. As soon as the patient's condition allowed it, confirmation of his/her written consent was requested. Further information on methods can be found in Supporting Information 4.

## 6 | Results

The study was conducted from 16 April 2018 to 3 December 2020. The study was stopped in the nine centres from 12 March to 15 July 2020 because of the COVID-19 pandemic as a result of an injunction of the ministry of health in France who asked for the interruption and who later authorized the restart. This did not affect the planned end date (December 2020). A total of 160 patients were included in the nine centres. Four patients were excluded from the analysis (1 patient refused the use his/her data; two deaths the day of inclusion; 1 patient not placed

in prone position), leading to 156 for ITT population (83 and 73 in the control and experimental periods, respectively; Table 1). Seventy-one patients (85.5%) in the control period and 55 (75.3%) in the experimental period completed the study.

## 6.1 | Patient Characteristics and Management at Inclusion

A pressure ulcer was observed in 34 patients (41%) in the control period and 34 (46.6%) in the experimental period, according to the independent expert committee (Table 2), but 8 (9.6%) and 8 (11%), respectively, when clinically assessed by the nurses from the participating centres. Patient management at the time of inclusion is presented in Supporting Information 7.

## 6.2 | Implementation of Specific and Non-Specific Skin Preventive Means

The median [IQR] number of proning sessions was 2 [1–3] in the control period and 2 [1–4] in the experimental period; and the median [IQR] cumulative time spent in the prone position was 32 [18–57] and 31 [16–53] hours, respectively.

At the time of the first proning session, all 6 specific preventive means were implemented in 1.2% of the patients in the control period and 91.8% of the patients in the experimental period. The difference for body inclination (15°; 28.9% and 95.9% respectively) and head rotation every 4 h (46.3% and 94.4% respectively) was less marked (Table 3). In the control and experimental periods, the median [IQR] number of specific means was, respectively, 2 [0–6] and 6 [2–6] at the time of the first proning session, 2 [0–5] and 6 [5, 6] at Day 1, 2 [0–4] and 6 [6] at Day 2, 2 [0–4] and 6 [5, 6] at Day 3, 1.5 [0–4] and 6 [5, 6] at Day 4, 2 [0–4] and 6 [5, 6] at Day 5, 2 [0–4] and 6 [5, 6] at Day 6 and 2 [0–3] and 6 [6] at Day 7.

## 6.3 | Primary End-Point: New Pressure Ulcer At Any Location and of Any Stage

At Day 7, 93 patients (59.6%) had a new pressure ulcer at any location and of any stage in the total cohort; 53 (63.9%) in the control versus 40 (54.8%) in the experimental period (odds ratio = 0.92; 95% confidence interval [0.39; 2.18]; *p* = 0.85; Table 4). The time (*p* = 0.30), the period (*p* = 0.85) and their interaction were not statistically significant. The ICC was close to zero, indicating no heterogeneity between centres. However, there was marked uncertainty regarding the accuracy of the new pressure ulcer, with 42.8% of discrepancy between the two experts.

## 6.4 | Secondary End-Points Related to Pressure Ulcers

At ICU discharge, 46 (55.4%) patients in the control period and 27 (37.0%) in the experimental period had a new pressure ulcer; the median [IQR] total number of new pressure ulcers was, respectively, 1 [0–3] and 1 [0–2] at Day 7, and 1 [0–2] and 0 [0–1] at ICU discharge. At Day 7, fewer patients in the
<table><caption>**TABLE 2** | Characteristics of patients at time of inclusion in each intervention period and in the whole cohort—Intention-to-treat population (N=156).</caption><thead><tr><th rowspan="2">Variable</th><th>Control</th><th>Experimental</th><th>Total</th></tr><tr><th>(n=83)</th><th>(n=73)</th><th>(N=156)</th></tr></thead><tbody><tr><td>Male sex</td><td>61 (73.5)</td><td>55 (75.3)</td><td>116 (74.4)</td></tr><tr><td>Age, years</td><td>62 [52-69]</td><td>63 [52-72]</td><td>62 [52-71]</td></tr><tr><td>Origin of ICU admission</td><td></td><td></td><td></td></tr><tr><td>Emergency room</td><td>33 (39.8)</td><td>30 (41.1)</td><td>63 (40.4)</td></tr><tr><td>Acute care ward</td><td>32 (38.6)</td><td>25 (34.2)</td><td>57 (36.5)</td></tr><tr><td>Prehospital emergency</td><td>15 (18.1)</td><td>9 (12.3)</td><td>24 (15.4)</td></tr><tr><td>Operating room</td><td>3 (3.6)</td><td>7 (9.6)</td><td>10 (6.4)</td></tr><tr><td>Long term care or rehabilitation ward</td><td>0</td><td>2 (2.7)</td><td>2 (1.3)</td></tr><tr><td>Context</td><td></td><td></td><td></td></tr><tr><td>Medical</td><td>78 (94.0)</td><td>66 (90.4)</td><td>144 (92.3)</td></tr><tr><td>Emergency surgery</td><td>3 (3.6)</td><td>4 (5.5)</td><td>7 (4.5)</td></tr><tr><td>Scheduled surgery</td><td>2 (2.4)</td><td>3 (4.1)</td><td>5 (3.2)</td></tr><tr><td>BMI, kg/m<sup>2</sup></td><td>29 [25-33]</td><td>28 [24-31]</td><td>28 [24-32]</td></tr><tr><td>SAPS II at ICU admission (range 0-163) (n=155)</td><td>48 [38-62]</td><td>47 [39-55]</td><td>48 [38-59]</td></tr><tr><td>SOFA score (range 0-24) (n=154)</td><td>10 [8-12]</td><td>9 [7-12]</td><td>9 [7-12]</td></tr><tr><td>Waterlow scale (range 1-64)</td><td>21 [18-25]</td><td>19 [16-22]</td><td>21 [18-24]</td></tr><tr><td>Charlson comorbidity score<sup>a</sup></td><td>3 [2-6]</td><td>3 [1-5]</td><td>3 [1-5]</td></tr><tr><td>Patients with pressure ulcer at inclusion<sup>b</sup></td><td>34 (41.0)</td><td>34 (46.6)</td><td>68 (43.6)</td></tr><tr><td>Patients with at least one pressure ulcer by location</td><td></td><td></td><td></td></tr><tr><td>Knees</td><td>16 (19.3)</td><td>19 (26.0)</td><td>35 (45.3)</td></tr><tr><td>Dorsal side of feet</td><td>7 (8.4)</td><td>11 (15.1)</td><td>18 (23.5)</td></tr><tr><td>Lips</td><td>9 (10.8)</td><td>7 (9.6)</td><td>16 (20.4)</td></tr><tr><td>Thorax</td><td>4 (4.8)</td><td>5 (6.8)</td><td>9 (11.6)</td></tr><tr><td>Nose</td><td>5 (6.0)</td><td>5 (3.2)</td><td>10 (9.2)</td></tr><tr><td>Cheeks</td><td>1 (1.2)</td><td>4 (5.5)</td><td>5 (6.7)</td></tr><tr><td>Chin</td><td>1 (1.2)</td><td>3 (4.1)</td><td>4 (5.3)</td></tr><tr><td>Forehead</td><td>1 (1.2)</td><td>1 (1.4)</td><td>2 (2.6)</td></tr><tr><td>Genitals in men</td><td>2 (2.4)</td><td>0</td><td>2 (2.4)</td></tr><tr><td>Breasts</td><td>1 (1.2)</td><td>0</td><td>1 (1.2)</td></tr><tr><td>Iliac crests</td><td>0</td><td>1 (1.4)</td><td>1 (1.4)</td></tr><tr><td>Eyelids</td><td>0</td><td>0</td><td>0</td></tr></tbody></table>

Note: Values are median [1st-3rd quartiles] and counts (percentage-point in group).

Abbreviations: BMI, body mass index; ICU, intensive care unit; SAPS, simplified acute physiology score; SOFA, sepsis-associated organ failure assessment.

experimental period exhibited ≥ 1 pressure ulcer on the forehead, chin, lips, thorax or breasts than in the control period; the converse was found for the nose and dorsal side of the feet (Table 4).

## 6.5 | Other Secondary End-Points

The distribution of any ocular complication at that time was not significantly different between periods (p = 0.15; Table 4).

<footnote>a1-2: mild score; 3-4 moderate score; and ≥ 5 severe score.</footnote>

<footnote>bAs assessed by the independent experts committee.</footnote>
<table><caption>**TABLE 3** | Specific and non-specific preventive means in the control and experimental periods at the time of inclusion—Intention-to-treat population (N=156).</caption><thead><tr><th colspan="3">Specific preventive means</th><th colspan="3">Non-specific preventive means</th></tr><tr><th>Preventive measures</th><th>Control (n=83)</th><th>Experimental (n=73)</th><th>Preventive measures</th><th>Control (n=83)</th><th>Experimental (n=73)</th></tr></thead><tbody><tr><td>Lower eyelid protection</td><td>12 (14.5)</td><td>73 (100.0)</td><td>Mattress</td><td></td><td></td></tr><tr><td>Eye protection with methylcellulose (N=153)</td><td>22 (27.5)</td><td>72 (98.6)</td><td>Air dynamic</td><td>74 (89.2)</td><td>50 (68.5)</td></tr><tr><td>Body inclination from horizontal</td><td></td><td></td><td>Air static</td><td>7 (8.4)</td><td>8 (11)</td></tr><tr><td>0°</td><td>16 (19.3)</td><td>0</td><td>Form memory</td><td>0</td><td>1 (1.4)</td></tr><tr><td>10°</td><td>35 (42.2)</td><td>2 (2.7)</td><td>Foam</td><td>2 (2.4)</td><td>14 (19.2)</td></tr><tr><td>15°</td><td>24 (28.9)</td><td>70 (95.9)</td><td>Upper eyelid protection</td><td>36 (43.4)</td><td>67 (91.8)</td></tr><tr><td>20°</td><td>5 (6.0)</td><td>1 (1.4)</td><td>Endotracheal tube secured</td><td>12 (14.5)</td><td>37 (50.7)</td></tr><tr><td>25°</td><td>3 (3.6)</td><td>0</td><td>Gastric tube secured</td><td>9 (10.8)</td><td>32 (43.8)</td></tr><tr><td>Specific cushion for head and thorax (N=155)</td><td>3 (3.7)</td><td>73 (100)</td><td>Vascular lines secured</td><td>4 (4.8)</td><td>20 (27.4)</td></tr><tr><td>Specific cushion for knees/ feet (N=155)</td><td>4 (4.9)</td><td>73 (100.0)</td><td>Arms installation</td><td>72 (86.7)</td><td>69 (94.5)</td></tr><tr><td>Head turned every 4 h (N=154)</td><td>38 (46.3)</td><td>68 (94.4)</td><td>Abdomen supported</td><td>21 (25.3)</td><td>3 (4.1)</td></tr><tr><td>Head not turned every 4 h— reason (N=48)</td><td></td><td></td><td>Mouth care</td><td>76 (91.6)</td><td>71 (97.3)</td></tr><tr><td>Missing</td><td>4</td><td>0</td><td>Enteral nutrition during pronation (N=129)</td><td>41 (61.2)</td><td>44 (71)</td></tr><tr><td>Different rate</td><td>16 (40.0)</td><td>0</td><td>Skin massage every 4 h</td><td>59 (71.1)</td><td>68 (93.2)</td></tr><tr><td>Not in the routine care</td><td>16 (40.0)</td><td>0</td><td>Skin protection (N=155)</td><td>43 (51.8)</td><td>6 (8.3)</td></tr><tr><td>Physically or technically impossible</td><td>8 (20.0)</td><td>4 (100.0)</td><td></td><td></td><td></td></tr><tr><td>Total number of specific preventive measures</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>0</td><td>5 (6.0)</td><td>0</td><td></td><td></td><td></td></tr><tr><td>1</td><td>30 (36.1)</td><td>0</td><td></td><td></td><td></td></tr><tr><td>2</td><td>35 (42.2)</td><td>0</td><td></td><td></td><td></td></tr><tr><td>3</td><td>8 (9.6)</td><td>0</td><td></td><td></td><td></td></tr><tr><td>4</td><td>4 (4.8)</td><td>0</td><td></td><td></td><td></td></tr><tr><td>5</td><td>0</td><td>6 (8.2)</td><td></td><td></td><td></td></tr><tr><td>6</td><td>1 (1.2)</td><td>67 (91.8)</td><td></td><td></td><td></td></tr></tbody></table>

Note: Values are counts (percent).

At the time of ICU discharge, 97 patients (62.2%) were alive among the total population; 56 (67.5%) in the control and 41 (56.2%) in the experimental group. At the time of hospital

discharge, 88 (56.4%) were alive among the total population; 48 (57.8%) in the control and 40 (54.8%) in the experimental group.
<table><caption>TABLE 4 | Primary and secondary end-points in each intervention period—Intention-to-treat population (N=156).</caption><thead><tr><th></th><th>Control (N=83)</th><th>Experimental (N=73)</th><th></th></tr></thead><tbody><tr><td>Primary end-point</td><td></td><td></td><td></td></tr><tr><td>Occurrence of a new pressure ulcer of any stage and at any location at Day 7 relative to baseline</td><td>53 (63.9)</td><td>40 (54.8)</td><td>Odds ratio (95% CI)<br>0.92 [0.39; 2.18]<br>p-value = 0.85</td></tr><tr><td>Secondary end-points</td><td></td><td></td><td></td></tr><tr><td>Pressure ulcers</td><td></td><td></td><td></td></tr><tr><td>Occurrence of a new pressure ulcer of any stage and at any location at ICU discharge relative to baseline</td><td>46 (55.4)</td><td>27 (37.0)</td><td></td></tr><tr><td>Total number of new pressure ulcers of any stage and at any location at Day 7 at ICU discharge</td><td>1 [0-3]<br>1 [0-2]</td><td>1 [0-2]<br>0 [0-1]</td><td></td></tr><tr><td>Mean (SD)</td><td>2.04 (2.34)<br>1.69 (2.44)</td><td>1.59 (2.31)<br>0.96 (1.87)</td><td></td></tr><tr><td>Occurrence of at least one new pressure ulcer of any stage by location at Day 7 at ICU discharge</td><td></td><td></td><td></td></tr><tr><td>Forehead</td><td>6 (7.2)<br>8 (9.6)</td><td>1 (1.4)<br>0</td><td></td></tr><tr><td>Nose</td><td>9 (10.8)<br>6 (7.2)</td><td>14 (19.2)<br>8 (11.0)</td><td></td></tr><tr><td>Eyelids</td><td>1 (1.2)<br>0</td><td>0<br>0</td><td></td></tr><tr><td>Chin</td><td>23 (27.7)<br>17 (20.5)</td><td>12 (16.4)<br>5 (6.8)</td><td></td></tr><tr><td>Cheeks</td><td>9 (10.8)<br>10 (12.0)</td><td>9 (12.3)<br>3 (4.1)</td><td></td></tr><tr><td>Lips</td><td>18 (21.7)<br>15 (18.1)</td><td>12 (16.4)<br>9 (12.3)</td><td></td></tr><tr><td>Thorax</td><td>21 (25.3)<br>16 (19.3)</td><td>7 (9.6)<br>7 (9.6)</td><td></td></tr><tr><td>Breasts</td><td>5 (6.0)<br>3 (3.6)</td><td>1 (1.4)<br>1 (1.4)</td><td></td></tr><tr><td>Knees</td><td>11 (13.3)<br>9 (10.8)</td><td>11 (15.1)<br>6 (8.2)</td><td></td></tr><tr><td>Iliac crests</td><td>2 (2.4)<br>2 (2.4)</td><td>1 (1.4)<br>2 (2.7)</td><td></td></tr><tr><td>Dorsal side of feet</td><td>2 (2.4)<br>2 (2.4)</td><td>7 (9.6)<br>6 (8.2)</td><td></td></tr><tr><td>Genitals (men)</td><td>2 (2.4)<br>0</td><td>1 (1.4)<br>1 (1.4)</td><td></td></tr><tr><td>Eye exam and visual acuity at ICU discharge</td><td></td><td></td><td></td></tr><tr><td>At least one ocular complication at ICU discharge (n=94)</td><td>10 (18.5)</td><td>3 (7.5)</td><td>p-value = 0.15<br>(Fisher exact test)</td></tr><tr><td>Visual acuity at ICU discharge (n=48)</td><td>8 [7-9]</td><td>10 [7-10]</td><td></td></tr><tr><td>Mean (SD)</td><td>7.76 (1.98)</td><td>8.09 (2.92)</td><td></td></tr></tbody></table>

(Continues)
<table><caption>TABLE 4 | (Continued)</caption><thead><tr><th></th><th>Control (N=83)</th><th>Experimental (N=73)</th></tr></thead><tbody><tr><td>Survival and lengths of stay</td><td></td><td></td></tr><tr><td>Survival at ICU discharge</td><td>56 (67.5)</td><td>41 (56.2)</td></tr><tr><td>Survival at hospital discharge</td><td>48 (57.8)</td><td>40 (54.8)</td></tr><tr><td>Length of ICU stay (days) in survivors (n=97)</td><td>18 [10.5-28.0]</td><td>19 [15.0-30.0]</td></tr><tr><td>Mean (SD)</td><td>20.3 (12.02)</td><td>23.2 (12.15)</td></tr><tr><td>Length of hospital stay (days) in survivors (n=88)</td><td>31 [17.5-53.5]</td><td>31 [20.5-50.0]</td></tr><tr><td>Mean (SD)</td><td>38.04 (24.64)</td><td>36.58 (21.82)</td></tr><tr><td>Ventilation-associated pneumonia and bacteraemia</td><td></td><td></td></tr><tr><td>Occurrence of at least one episode of ventilation-associated pneumonia during the ICU stay</td><td>25 (30.1)</td><td>24 (33.3)</td></tr><tr><td>Occurrence of at least one episode of bacteraemia during the ICU stay</td><td>18 (21.7)</td><td>17 (23.6)</td></tr></tbody></table>

Note: Values are median [inter-quartile range] and counts (percentage).

During ICU stay, 25 patients (30.1%) in the control period and 24 (33.3%) in the experimental period had ≥1 episode of ventilator-associated pneumonia; 18 (21.7%) and 17 (23.6%), respectively, had ≥1 episode of bacteraemia (Table 4 and Supporting Information 8).

## 6.6 | Safety

A total of 74 AE in the control period and 35 in the experimental period were recorded. Twenty-six (31%) patients had ≥1 AE in the control period and 20 (27%) in the experimental period, respectively, 22 (26%) and 14 (19%) had ≥1 serious AE. Five AE were considered to be related to the study: 1 in the experimental period (emesis) and 4 in the control period (keratitis, reintubation, epistaxis and intolerance of prone positioning).

## 7 | Discussion

The present study found a significant reduction in the frequency of new pressure ulcers in the experimental period compared with the control period 7 days after inclusion. Various reasons for this negative result can be put forward. The most important reason, and rather unexpected, may be related to issues with picture analysis. We had reasoned that taking standardized pictures would allow us to objectively measure the presence (and therefore the frequency) and the stage of pressure ulcers. The independent analysis by experts at the end of the study was intended to guarantee an unbiased assessment; however, despite standardization (i.e., purchase of a dedicated camera of the same model for all participating centres, photo-taking procedure), it was surprising to observe that the discrepancy between experts was greater than 40%, precluding assessment of stage. This could be related, at least in part, to the quality of the images that resulted, for instance, from a lack of standardized lighting in the room. A pilot study, which we did not perform, may have

identified such issues; this may have also allowed the training of experts in the analysis of these images. Moreover, there were many missing data for skin injury as a result of the dramatic difference between the frequency of pressure ulcers as assessed by nurses or experts.

Another aspect that could have also contributed to the negative result is that patients exhibited a higher frequency of pressure ulcer at baseline than expected. In the PROSEVA trial [1], 7.2% of the patients enrolled in the prone position group had a pressure ulcer on the ventral part of their body at the time of randomization versus threefold this frequency herein. The reasons for this discrepancy are unclear. However, the high rate of pressure ulcers in the present study might have resulted from an overestimation of stage 1; for instance, it is not easy to distinguish between a stage 1 pressure ulcer and an allergic reaction to a skin electrode, which is further compounded by the difficulties related to image analysis discussed above.

In addition, there was a certain degree of overlap of preventive strategies between the two periods. Ideally, each specific component of management in the experimental period should have been applied to all the patients during that period and to none of the patients in the control period. This was not the case because some of these components were already part of the routine practice of the centres (Supporting Information 2; Table 1); the final version of the protocol used in the present study was the minimum common design defined after discussion with the centres. However, it is of note that the stepped-wedge design used herein is appropriate for the introduction of a new diagnosis procedure or a new intervention. Unlike a conventional two-group parallel design, the two arms of the protocol (control and experimental) are not conducted concomitantly in each centre, avoiding some contamination bias in management and issues with patients' relatives by using the same technique for all patients at a given centre during a given time period.
The present study may have lacked power as only 156 patients of the 180 expected were included. Although the trial was stopped at the planned date and the expected rate of inclusion was not achieved in some centres, notably, centre 9 did not resume including patients once the COVID-19 pandemic was over. In addition, the study enrolled nine centres among the approximately 500 ICUs in France, limiting the generalizability of the results. Also, because the study was conducted in a single country, the results in other countries might have been different for cultural and organizational reasons. However, the results strongly suggest that the difference between periods would not reach significance with the expected number of patients. The frequency of new pressure ulcers during the first week after inclusion was presumed to be 57%, in line with our previous finding in the same setting of patients with ARDS [5]. The observed frequency of 63.9% in the control period in the present study could theoretically make the expected 50% reduction reasonable, a hurdle that was, however, too high to overcome. In addition, the assessment of ocular complications was limited by the lack of pre-intervention baseline measurement. Another limitation was the interruption of the trial because of the COVID-19 pandemic, making it so that enrolled patients were not consecutive as the trial resumed while the pandemic was still active; the practice of pronation after the study resumed may have changed within the centres and differently from one centre to another. However, 86% of patients were included before the interruption because of the COVID-19 pandemic.

## 9 | Implications and Recommendations for Practice

The study reveals that performing a complex trial like this was feasible by ICU nurses. Furthermore, ICU nurses offered a safe environment to the patients enrolled in the trial. Nevertheless, the numerous weaknesses suggest that ICU nurses may require additional skills and training in this specific area. A consensus across ICU nurses for the preventive means of pressure ulcers in the prone position should be set out. ICU nurses should better define the bundle of interventions that may prevent pressure ulcers in the prone position and propose new means requiring implementation. A consensus should also be found for a better assessment of the stage of pressure ulcers. It is only after this process that a new trial led by ICU nurses and involving a large number of ICU nurses should be done.

## 10 | Conclusions

This prospective multicentre stepped-wedge trial found that the bundle of interventions did not lead to a significant reduction in the frequency of new pressure ulcers in moderate-to-severe ARDS patients treated by prone position. The study found that ICU nurses were able to run a trial on preventive means of pressure ulcers. It also highlighted areas that need improvement in the perspective of a new trial, which is required given the frequency of pressure ulcers in the prone position and the frequency of use of prone position in moderate-to-severe ARDS patients.

## Acknowledgements

The authors would like to thank Blandine Sauzaret for her help in the pressure ulcer assessment, Lorraine Bernard and Aurélie Belleville for contributing to the data analysis and their help in the administrative tasks, and Philip Robinson for this help in the submission of the revised version.

## Ethics Statement

The protocol was approved by an ethics committee (Comité de Protection des Personnes CPP Nord-Ouest III number 2017-A01449-44 on 7/10/2017).

## Consent

Written informed consent for participation of the patient in the trial was obtained from the next of kin for each participant. As soon as the patient's condition allowed, confirmation of his/her written consent was sought.

## Conflicts of Interest

The authors declare no conflicts of interest.

## Data Availability Statement

The data that supports the findings of this study are available in the supplementary material of this article.

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## Supporting Information

Additional supporting information can be found online in the Supporting Information section.