Morales-Quinteros et al. Trials (2022) 23:30 https://doi.org/10.1186/s13063-021-05991-2 STUDY PROTOCOL Open Access Awake prone positioning in nonintubated spontaneous breathing ICU patients with acute hypoxemic respiratory failure (PRONELIFE)—protocol for a randomized clinical trial L. Morales-Quinteros1,2* , M. J. Schultz3,4,5, A. Serpa-Neto3,6,7, M. Antonelli8, D. L. Grieco8, O. Roca9,10, N. P. Juffermans3,11, C. de Haro2,12, D. de Mendoza13, Ll. Blanch2,10,12, M. Camprubí-Rimblas2,10, Gemma Gomà12, A. Artigas-Raventós2,10,12 and for the PRONELIFE collaborative group Abstract Background: It is uncertain whether awake prone positioning can prevent intubation for invasive ventilation in spontaneous breathing critically ill patients with acute hypoxemic respiratory failure. Awake prone positioning could benefit these patients for various reasons, including a reduction in direct harm to lung tissue, and prevention of tracheal intubation-related complications. Design and methods: The PRONELIFE study is an investigator-initiated, international, multicenter, randomized clinical trial in patients who may need invasive ventilation because of acute hypoxemic respiratory failure. Consecutive patients admitted to participating ICUs are randomly assigned to standard care with awake prone positioning, versus standard care without awake prone positioning. The primary endpoint is a composite of tracheal intubation and all-cause mortality in the first 14 days after enrolment. Secondary endpoints include time to tracheal intubation and effects of awake prone positioning on oxygenation parameters, dyspnea sensation, and complications. Other endpoints are the number of days free from ventilation and alive at 28 days, total duration of use of noninvasive respiratory support, total duration of invasive ventilation, length of stay in ICU and hospital, and mortality in ICU and hospital, and at 28, 60, and 90 days. We will also collect data regarding the tolerance of prone positioning. * Correspondence: lfmoralesq@tauli.cat 1 Department of Intensive Care Medicine, Hospital Universitari Sant Pau, Barcelona, Spain 2 Translational Research Laboratory, Institut d’Investigació i Innovació Parc Taulí I3PT Universitat Autònoma de Barcelona Sabadell, Parc del Tauli- 08208 Sabadell, Barcelona, Spain Full list of author information is available at the end of the article © The Author(s). 2022 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Morales-Quinteros et al. Trials (2022) 23:30 Page 2 of 11 Discussion: The PRONELIFE study is among the first randomized clinical trials investigating the effect of awake prone positioning on intubation rate in ICU patients with acute hypoxemic failure from any cause. The PRONELIFE study is sufficiently sized to determine the effect of awake prone positioning on intubation for invasive ventilation—patients are eligible in case of acute hypoxemic respiratory failure without restrictions regarding etiology. The PRONELIFE study is a pragmatic trial in which blinding is impossible—however, as around 35 ICUs worldwide will participate in this study, its findings will be highly generalizable. The findings of the PRONELIFE study have the potential to change clinical management of patients who may need invasive ventilation because of acute hypoxemic respiratory failure. Trial registration: ISRCTN ISRCTN11536318. Registered on 17 September 2021. The PRONELIFE study is registered at clinicaltrials.gov with reference number NCT04142736 (October, 2019). Keywords: ICU, Acute respiratory failure, Hypoxemia, Prone position, Awake prone positioning, Invasive ventilation, Intubation, Invasive ventilation, Randomized controlled trial Background pragmatic study that compares standard care with awake Acute hypoxic respiratory failure represents one of the prone positioning versus standard care without awake most common reasons for intensive care unit (ICU) ad- prone positioning in patients with acute hypoxemic re- mission [1]. Initial management of hypoxemic patients spiratory failure from any cause. We hypothesize that should involve immediate administration of simple sup- awake prone positioning reduces the need for plemental oxygen via a nasal prong or a non-rebreather intubation. mask, or more complex forms of respiratory support like high-flow nasal oxygen (HFNO) oxygen or noninvasive ventilation (NIV), depending on severity of hypoxic re- Methods spiratory failure and the underlying cause, but also pa- Design tient characteristics and the availability of oxygen The “PRone positioN in patients with spontanEous venti- interfaces. Unfortunately, patients with acute hypoxemic Lation and acute hypoxemic respIratory FailurE” (PRO- respiratory failure often need to proceed with invasive NELIFE) study is a pragmatic, investigator-initiated, ventilation. While life-saving, this intervention comes international and multicenter, two-arm, superiority ran- with disadvantages, including ventilator-induced lung in- domized clinical trial in patients with acute hypoxemic re- jury and respiratory muscle waist, but also intubation- spiratory failure from any cause. The study will be related side-effects. In addition, intubated patients often conducted according to the Declaration of Helsinki princi- need sedation, which has side-effects of its own. ples as stated in the current version of Fortaleza, Brazil, In intubated invasively ventilated ICU patients, prone 2013 [11]. The Institutional Review Board of the Sagrat positioning can be used to improve oxygenation, and Cor University Hospital, Barcelona, Spain, approved the this intervention has been shown to improve outcome in study protocol (reference number 2019/68-UCI-HUSC). patients with severe ARDS. This survival benefit could The study is registered at www.clinicaltrials.gov be mediated, at least in part through a reduction in dir- (NCT04142736, October 2019). The PRONELIFE ect harm to lung tissue, as regional differences in lung study is planned to be performed in the 35 ICUs aeration, compliance, and shear strain are minimized by worldwide. Patients will be provisionally included this intervention [2, 3]. In theory, nonintubated patients under a strategy of deferred consent, for reasons as could also benefit from prone positioning [4, 5], a strat- explained below. egy named “awake prone positioning” [6, 7]. Some evi- dence for benefit of awake prone positioning comes from a handful of studies, mostly case reports and Consort diagram single-center observation case series [5, 8, 9]. The find- The Consolidated Standards of Reporting Trials ings thus far show that awake prone positioning can in- (CONSORT) [12] diagram of the PRONELIFE study is deed improve oxygenation and also reduce dyspnea presented in Fig. 1. Consecutive patients admitted to the sensation. Besides that, awake prone positioning seems participating ICUs are screened for eligibility. Demo- to be well-accepted and easy to perform, and to have graphic data are registered regardless of meeting enroll- relatively few side-effects [10]. ment criteria. If excluded from participation, the In the absence of sufficient randomized clinical trial reason(s) for exclusion will be reported. The study over- evidence, we designed the PRONELIFE study, a view is presented in Fig. 2. Morales-Quinteros et al. Trials (2022) 23:30 Page 3 of 11 Fig. 1 Consolidated Standards of Reporting Trials (CONSORT) diagram Inclusion and exclusion criteria provisionally included under a strategy of deferred con- Patients admitted to the ICU with acute hypoxemic re- sent, there is no need for written informed consent at spiratory failure from any cause will be eligible for par- start of the study—however, if consent is not obtained ticipation, unless prompt intubation is irrepressible within 48 h, a patient drops out of the study and will be (Table 1). Acute respiratory failure is defined as the need replaced. for supplementary oxygen with an FiO2 of at least 40% by Venturi facemask, HFNO, NIV, or CPAP needed to Study endpoints achieve and maintain an SpO2 of between 88 and 92%. The primary endpoint is the composite of tracheal in- The PRONELIFE study has the following exclusion tubation and all-cause mortality within 14 days after criteria: age < 18 years, having any contraindication for enrollment. prone positioning (Table 2), previous participation in Secondary endpoints are the effects of awake proning this trial, and participation in other interventional trials on the following clinical outcome variables: with the same primary endpoint. We also exclude preg- nant patients, patients who refuse intubation, and those  Time to tracheal intubation (only in patients who only receiving comfort care. As patients will be need invasive ventilation); Morales-Quinteros et al. Trials (2022) 23:30 Page 4 of 11 Fig. 2 Study overview  Oxygenation parameters; center. Central randomization with the use of a  Dyspnea sensation (while awake in prone versus permutated-block randomization list (with block sizes of supine position); 4 to 8) will be used. Participants will be allocated to the  The number of days free from invasive ventilation prone positioning or standard care on a 1:1 ratio. By the and alive at day 28; nature of the intervention, it will not be possible to blind  Duration of use of noninvasive ventilatory support, clinicians to whether a participant has been randomized including the use of a non-rebreather mask, CPAP, to awake proning or standard care. Interventions will be high-flow nasal oxygen (HFNO) oxygen, or noninva- blinded to data analysts and outcome assessors. sive ventilation (NIV);  Duration of invasive ventilation; Prone positioning  Ventilation-free days (VFD) at 28 days from ICU The study intervention will last for at least 48 h and is admission, defined as the number of days alive and divided in 4 blocks of 6 h each: patients will be placed in free from IMV during the first 28 days from start of the prone position for up to 2 h, which can be prolonged IMV; if the patient feels comfortable, but could also be inter-  Length of stay in ICU and hospital; rupted if a patient meets any of the discontinuation cri-  Mortality in ICU and hospital, and at 28, 60, and 90 teria which are any of the following: days; and  Tolerance of prone positioning (only in patients in  Developing a contraindication (Table 1); the prone positioning group).  Worsening of dyspnea (at any time, according to predefined criteria, as described in Table 2); Randomization and blinding Randomization will be performed using a dedicated Table 2 Borg dyspnea scale password-protected website and will be balanced per 0 Nothing at all 0.5 Very, very slight (just noticeable) Table 1 Contraindication for awake prone position 1 Very slight • Suspected increased intracranial pressure (e.g., severe brain injury) 2 Slight breathlessness • Hemoptysis • Vomiting 3 Moderate • Recent abdominal wound (less than 15 days) • Tracheal surgery or sternotomy during the previous 15 days 4 Somewhat severe • Facial trauma or facial surgery during the previous 15 days 5 Severe breathlessness • Deep venous thrombosis treated for less than 2 days • Cardiac pacemaker inserted in the last 2 days 6 • Unstable spine, femur, or pelvic fractures 7 Very severe breathlessness • Hemodynamic instability (defined by a systolic blood pressure below 90 mmHg, mean blood pressure below 65 mmHg, or requirement for 8 vasopressor) 9 Very, very severe (almost maximal) • Pregnant women • Presence of chest tube 10 Maximal Morales-Quinteros et al. Trials (2022) 23:30 Page 5 of 11 Table 3 Hemodynamic instability definition Witnesses), oxygenation target ranges can be higher, 94 Defined as any of the following not responding to fluid to 96% for SpO2 and 9 to 11.5 kPa for PaO2 [13–15]. resuscitation: Opiates and benzodiazepines are allowed at low dosages • Systolic arterial pressure < 90 mmHg, or to improve comfort. • Mean arterial pressure < 65 mmHg, or • Increased needs of vasopressor agents, or • ECG evidence of ischemia or significant uncontrolled ventricular Intubation criteria arrhythmia The decision to continue with invasive mechanical venti- lation is based on clinical judgment rather than isolated  A further and sustained drop in SpO2 refractory to gasometrical criteria. Any of the following criteria should an increase in FiO2; nausea or vomiting; and be considered for proceeding to endotracheal intubation:  Increasing hemodynamic instability that is unrelated to sedatives (if given) and cannot be corrected by  Respiratory or cardiac arrest; vasopressor or inotrope infusion (as described in  Respiratory pauses; Table 3)  Altered level of consciousness such as uncontrolled agitation not responding to medical treatment, or a During the change in position, from supine to prone drop in the Glasgow Coma Score; or from prone to supine, FiO2 will be increased by 25%  Evidence of exhaustion such as an unacceptable above baseline. Each change in position is guided by two increase in use of accessory muscles or healthcare workers and an attending physician, but more thoracoabdominal paradox; healthcare workers could be needed. While the patient  Inability to clear secretions from the airway in remains in a prone position, skin protection will be used patients with abundant sputum production, or to avoid pressure sores. Also, the application of cushions evidence of aspiration; or will enhance patient tolerance. Arms can be at the side,  Hemodynamic instability as defined in Table 3 in a swimmer’s position, and can be moved to increase comfort. In addition, the presence of 2 of the following criteria Food and comfort breaks are planned while patients within 1 h of start noninvasive ventilatory support: are in supine. If the patient is receiving enteral or oral feeding, this is interrupted from 1 h before prone until a  Respiratory rate > 35 breaths/min, or increased patient is in a supine position. respiratory rate from the baseline; The best-fitting and most-tolerated oxygen interface  Not improving or increased dyspnea; will be used in the prone position—this could be differ-  pH < 7.30 or less from its baseline, or PaCO2 > 20% ent from patient to patient, and different from what is from the baseline value; or used in the supine position, and could differ between pa-  SpO2 < 88% tients but also institutions (i.e., depending on the avail- ability of masks with or without a reservoir bag and with Weaning from the noninvasive oxygen delivery system or without the Venturi system, HFNO, CPAP or NIV). Weaning from the oxygen therapy delivery system will be done according to local protocols and preferences. Table 4 provides guidance for oxygen requirements Standard of care coupled with the reduction in gas flow rates of the In all patients, whether receiving prone positioning or HFNO. not, the best standard of care is provided, according to the standard care by the local teams. Invasive ventilation When in a supine position, the patient will be placed If patient continues with invasive ventilation, settings are in 30–45° semi-recumbent position but this can be chan- chosen in line with the local guidelines for invasive ven- ged for the comfort of the patient to supine, semi- tilation. The use of lung-protective ventilation with a sitting, sitting, or a lateral decubitus position. low tidal volume and low pressures is advocated. Also, Vitals parameters, including SpO2 and the SpO2/FiO2, sufficient levels of PEEP should be used, and prone are continuously monitored. The oxygenation target ranges for SpO2 are 88 to 92%; this is 7 to 8 kPa for Table 4 High-flow nasal cannula scheme for oxygen PaO2. For patients in whom the risk of potentially dan- requirements coupled with gas flow rates gerous hypoxemia could become unacceptable during FiO2 21–30% 30–40% 40–60% 60–100% the study (e.g., in patients who develop cardiac ischemia Flow 30 L/min 30–40 L/min 40–50 L/min 50–70 L/min due to cardiac infarction or failed revascularization, or In case the patient is using NIV, sessions could be interrupted when the severe untreatable anemia such as with Jehovah’s respiratory rate is < 25 breaths/min and the FiO2 < 40% (for a SpO2 88%) Morales-Quinteros et al. Trials (2022) 23:30 Page 6 of 11 positioning is to be applied if a patient develops severe Acute Physiology and Chronic Health Evaluation II hypoxemia, defined as PaO2/FiO2 < 150 mmHg at a (APACHE II) score, and the Simplified Acute Physiology minimum FiO2 of 60% and 5 cmH2O. Score II (SAPS II). Data on the standard of care (described below) will be Fluid regimens collected daily for the first 48 h and every 6 h, up to day We advise to use a restricted fluid strategy, i.e., targeting 28. The total number of hours spent in prone position a neutral cumulative fluid balance as soon as a patient in a day (cumulative), the number of prone sessions, and can be weaned of vasopressors. Crystalloid infusions are their duration is recorded. After the protocol, every day preferred over colloid infusions. until day 14, clinical outcome variables are discharge of the ICU or death, whichever comes first. Data on dur- Sedation ation of noninvasive respiratory support, length of stay In patients under invasive ventilation, the local guideline in ICU and hospital, location of the patient (in ICU, hos- for sedation is to be followed, and preferably consists of pital, another facility, or home), and life status (alive or combinations of use of analgo-sedation over hypno- deceased) will be assessed on 28 and 90 days (Fig. 3). sedation, use of bolus over continuous infusion of sedat- One hour before each position change (supine to ing agents, and the use of sedation scores (e.g., 3 times prone and prone to supine), the following variables will per day, and using a Richmond Agitation Sedation Scale) be collected for the duration of the protocol: respiratory [16, 17]. Also, the level of pain is to be determined, e.g., variables (respiratory rate SpO2, SpO2/FiO2, ROX index; by using the Numeric Rating Scale, the Visual Analog SpO2/FiO2: RR, dyspnea defined according to the Borg Scale (VAS), the Critical Care Pain Observation Tool dyspnea scale); noninvasive mean arterial pressure; heart (CCPOT) or Behavioral Pain Scale (BPS). rate; noninvasive support device parameters: Venturi facemask, HFNO, CPAP, NIV; adverse effects possibly Weaning from invasive ventilation related to prone position (hypotension, bradycardia hyp- Weaning from invasive ventilation follows local proto- oxemia, pressure ulcers, vomiting, displacements of the cols and preferences. In all patients, it should be tested respiratory support device, peripheral or venous central whether the patient accepts assist ventilation at least two line, orogastric or nasogastric tube, or urinary catheter), times a day; this should also be tried when the patient if any are recorded in the eCRF. shows respiratory muscle activity during assist ventila- In case prone positioning is not tolerated, all reasons tion. The attending physician decides when to extubate for a premature change in body position are reported. a patient, based on general extubation criteria (i.e., re- The following parameters of the respiratory support sponsive and cooperative, adequate cough reflex, ad- devices will be collected within 1 h before and 1 h after equate oxygenation with FiO2 ≤ 0.4, hemodynamically randomization, and every day at a fixed time point until stable, no uncontrolled arrhythmia and a rectal cessation of the respiratory support: Venturi facemask: temperature > 36 °C, and after successfully passing a flow (liters/min), FiO2; HFNO: flow (liters/min), FiO2; spontaneous breathing trial (SBT) with a T-piece or CPAP: PEEP, flow (liters/min), tidal volume, FiO2; NIV: ventilation with minimal support (pressure support level PEEP, pressure support over PEEP, flow (liters/min), < 10 cmH2O) and FiO2 ≤ 0.4). In case SBTs are used, an tidal volume, FiO2. SBT is judged as successful when the following criteria If the patient meets the criteria for intubation, the are met for at least 30 min, and the attending physician reasons for intubation are documented in the eCRF. takes the final decision for extubation: Data on the administration on the administration of steroids, Remdesivir, Tocilizumab, Heparin/low molecu-  Respiratory rate < 35 breath/min; lar weight heparin, and antihypertensive medications are  Peripheral oxygen saturation > 90%; recorded. Fluid balance is collected from the nursing  Increase < 20% of heart rate and blood pressure; and chart.  No signs of anxiety and diaphoresis. Power calculation Data collection We will include a total of 650 patients. The required Data will be entered via an electronic case report from sample size is calculated using data from two multicen- (eCRF). On ICU admission and within 48 h, demo- ter randomized controlled trials reporting intubation graphic and baseline data and data on disease severity rates in patients with acute hypoxemic respiratory failure will be collected. Data collection includes gender, age, [18, 19]. It was conservatively assumed that the rate of height, weight, date of hospital admission, date of ICU tracheal intubation will be 45% in the standard treat- admission, cause of respiratory failure, chest X-ray, the ment group. Accordingly, 650 patients (n = 325 per Sequential Organ Failure Assessment (SOFA) score, the group) would provide 80% power to detect a relative risk Morales-Quinteros et al. Trials (2022) 23:30 Page 7 of 11 Fig. 3 Schedule of events of 0.75 for the primary endpoint at a 2-sided α level of consent will be requested as soon as possible thereafter 0.05, assuming a dropout rate of 10%. After enrollment and never later than 48 h after randomization. If in- of 70% of the patients, an unblinded sample size reesti- formed consent is not obtained within those 48 h, or if a mation will be performed, and sample size could be legal representative denies participation within this time increased to a maximum of 1000 patients if needed. frame, the patient is excluded, and data will no longer be used, nor will this patient be counted for the sample size Deferred informed consent of 325 inclusions in each group (that is the provisionally For this study, we will include patients using a strategy included patient for whom informed consent is not using deferred informed consent because we explicitly obtained within the time frame of 48 h is “replaced” by a want to randomize and start ventilation according to new patient until the total number of 325 patients in randomization within 1 h after ICU admission. Never- each arm is definitively included). On the consent form, theless, the legal representative’s written informed participants will be asked if they agree to use their data Morales-Quinteros et al. Trials (2022) 23:30 Page 8 of 11 should they choose to withdraw from the trial. Partici- They guarantee the integrity of data collection and en- pants will also be asked for permission for the research sure timely completion of the case report forms. team to share relevant data with people from the Hospi- An independent monitor will be installed. Remote tals taking part in the research or from regulatory monitoring utilizing queries on the database will be done authorities. This trial does involve collecting biological by a statistician and analyzed by the monitor to signalize specimens. early aberrant patterns, trends, issues with consistency or credibility, and other anomalies. On-site monitoring will comprise controlling the presence and completeness Statistical analysis of the research dossier and the informed consent forms, Statistical analysis will be based on the intention-to-treat and source data checks will be performed in the files of principle. We will also perform a per-protocol analysis, 25% of the patients. comparing patients who received awake prone position- An independent Data and Safety Monitoring Board ing and patients who received standard of care. (DSMB) watches over the ethics of conducting the study Continuous normally distributed variables will be under the Declaration of Helsinki and monitors safety expressed by their mean and standard deviation or when parameters and the overall conduct of the research. The not normally distributed as medians and their interquar- DSMB is composed of three independent individuals tile ranges. Categorical variables will be expressed as n (Prof. Arthur Slutsky, Prof. Claude Guerin, and Dr. Tài (%). Where appropriate, statistical uncertainty will be Pham). The DSMB will meet by conference calls. The expressed by the 95% confidence levels. first meeting is scheduled after the first 100 patients. The primary outcome, the number of days free of ven- After this meeting, the DSMB will meet every 6 months. tilation at day 14, will be analyzed using Cox’s regres- All unexpected adverse events will be reported to the sion. The possible imbalance between groups will be DSMB. Any report or advice of the DSMB will be sent modeled in the Cox model. To further compare groups, to the sponsor of the study, the Institut d'Investigació i Student’s t test will be used. If continuous data is not Innovació Parc Taulí (I3PT), Sabadell, Spain. Should the normally distributed, the Mann-Whitney U test will be sponsor decide not to implement the advice of the used. Categorical variables will be compared with the DSMB fully, the sponsor will send the recommendation chi-square test or Fisher’s exact tests. Time-dependent to the reviewing Institutional Review Board, including a data will be analyzed using a proportional hazard model note to substantiate why (part of) the advice of the adjusted for possible imbalances of patients’ baseline DSMB will not be followed. All substantial amendments characteristics. No interim analysis will be conducted. will be notified to the Sponsor Ethical Review Board first The level and pattern of missing data in the baseline and the Funder. Then the PI will notify the centers, and variables and outcomes will be established by forming a copy of a revised protocol will be sent back to the PI appropriate tables and the likely causes of any missing to add to the Investigator Site File. Any deviations in the data will be investigated. If necessary, multiple imput- protocol will be fully documented using a breach report ation or Bayesian methods for missing data will be used. form. Non-substantial amendments (typing errors and A P value < 0.05 is considered statistical significance. administrative changes) will not be notified to the Spon- The analysis will be performed with R statistics version sor Ethical Review Board. The protocol will be updated 3.0.2 (R Foundation, Vienna, Austria). in the clinical trial registry. Study organization Discussion The steering committee comprises the principal investi- PRONELIFE is among the first clinical trials of awake gator, the coordinating investigators, and eight inter- prone positioning in patients with acute hypoxemic re- national experts in ventilatory support in critically ill spiratory failure that will recruit a sufficient number of patients. patients to test the hypothesis that this intervention pre- The coordinating investigator is responsible for ad- vents tracheal intubation. PRONELIFE will also collect ministrative management and communication with the data regarding other patient-centered outcomes, includ- local investigators and assists at the participating clinical ing duration of ventilation if needed, length of stay in sites in trial management, record keeping, and data ICU and hospital, and mortality. We will also study the management. The coordinating investigators help set up tolerability of awake prone positioning and its effects on local training in the participating ICUs to ensure the oxygenation. study is conducted according to the ICH-GCP guide- Invasive ventilation is a life-support strategy associated lines, guarantee data collection integrity, and ensure with serious complications that may result in significant timely completion of the case report forms. The local in- morbidity and mortality. In addition, endotracheal intub- vestigators provide structural and scientific leadership. ation is a high-risk procedure in critically ill patients, Morales-Quinteros et al. Trials (2022) 23:30 Page 9 of 11 with major complications like severe hypoxemia, cardio- positioning relatively well [24, 36, 37]. Awake prone po- vascular instability, and even cardiac arrest [20–22]. The sitioning is also associated with few complications. Data primary endpoint of this study is a composite of the are limited, but thus far, no severe adverse events have need for invasive ventilation and death within the first been described in the literature. Pressure sores, fre- 14 days. We decide to use this composite endpoint, hy- quently developing in intubated ICU patients [38] and pothesizing that the intervention under study will impact with higher morbidity [39], have only been rarely de- two outcomes that are invariable related. Using a com- scribed in patients who received awake prone position- posite outcome will also increase the event rate, improve ing [9, 31]. Intolerance to awake prone positioning could the statistical efficiency for sample size calculation, and be related to musculoskeletal discomfort [24, 26, 37, 40], improve the study’s precision. We chose the need for in- nausea and vomiting [26], cough [37], and anxiety [40]. vasive ventilation and death within the first 14 days be- Our study will focus on these aspects. cause we hypothesize that the impact of awake prone PRONELIFE will also collect other important and positioning will not last beyond the first 2 weeks. Of patient-centered endpoints such as dyspnea sensation, note, we will report the two components of the compo- duration of use of noninvasive ventilatory support, and site as two secondary endpoints. duration of invasive ventilation and the classical ICU Evidence for the benefit of awake prone positioning in endpoints like the length of ICU and hospital stay, and nonintubated ICU patients is scarce. Its first use was de- various mortality rates. scribed in a case series of patients with hypoxemic re- We anticipate the PRONELIFE study to be highly feas- spiratory failure, showing improvements in oxygenation ible and easy to conduct as the study procedures are [8]. Improvements in oxygenation were also reported in straightforward, without difficult or complex interven- two studies in patients with severe hypoxemia after lung tions making the treatment of patients clear and easy. transplantation [5, 23]. A rapidly growing number of Furthermore, the PRONELIFE study uses a deferred mainly small observational studies describe the use of consent strategy to include patients rapidly in the study awake prone positioning in patients with spontaneous and those admitted during evenings or nights when re- breathing with acute respiratory failure in whom hypo- searchers and family members are often not around to xemia is refractory to supplementary oxygen. It has been ask for informed consent. This will create a study popu- shown that awake prone positioning can improve oxy- lation representative of the average ICU population. genation within minutes [24–28], and the effects are Also, PRONELIFE will be performed in the ICUs of maintained for up to 1 h after turning back to supine different hospitals worldwide, increasing the generalizability and disappear mostly after 6 to 12 h [29]. A total of 15 of its findings. Furthermore, we include patients with any studies, representing 449 patients, were recently used in cause of respiratory failure. one meta-analysis [30], assessing the change in oxygen- One important limitation of PRONELIFE is that blind- ation (i.e., PaO2/FiO2 ratio, PaO2, and SpO2) induced by ing is not possible due to the nature of the intervention awake prone positioning. Two recent studies failed to tested, which could induce bias. However, the indication show benefit of awake prone positioning in patients with for invasive ventilation, which directly influences the pri- acute respiratory failure [31, 32]. Of note, one of these mary outcome, is clearly stated, and all analyses will be studies had an observational design, and it remained un- performed in a blinded fashion. Second, we foresee that certain whether the intervention was used as a routine another limitation could derive from the time under or life-saving therapy [32]. The other study was a ran- prone position a patient with spontaneous breathing domized clinical trial that was underpowered for sample could tolerate continuously. Knowing from studies that size estimation [31]. In both studies, patients were only the benefit of prone position in ARDS could depend on included patients with COVID-19 infection. Evidence its duration [41], the protocol design will count the total suggests that direct versus indirect causes of lung injury time of prone positioning for each patient. Although pa- possess different pathophysiologic characteristics that tients randomized to the intervention will have 2 h might impact both the progression and outcome of under prone position, this strategy could be further pro- ARDS [33–35]. Therefore, the prone position could longed if the patient feels comfortable. affect mortality, and its impact may vary according to The results of PRONELIFE have the potential to the etiology of lung injury. Also, in both studies, the in- change clinical practice in terms of how we manage tubation criteria were not clearly defined. Our study will patients with acute hypoxemic respiratory failure. include different etiologies of acute respiratory failure, In conclusion, the PRONELIFE study is an inter- and we have clearly described intubation criteria. national, investigator-initiated randomized clinical trial Awake prone positioning is an attractive intervention that is adequately powered to test the hypothesis that for several reasons. First, many patients with hypoxemic awake prone positioning benefits ICU patients with acute respiratory failure seem to tolerate awake prone acute hypoxemic respiratory failure. Morales-Quinteros et al. Trials (2022) 23:30 Page 10 of 11 Trial status del Tauli- 08208 Sabadell, Barcelona, Spain. 3Department of Intensive & Pending to start recruiting. Laboratory of Experimental Intensive Care and Anesthesiology, Amsterdam UMC, location “AMC”, Amsterdam, The Netherlands. 4Mahidol Oxford Tropical Date recruitment will begin in 1 February 2022. Medicine Research Unit (MORU), Mahidol University, Bangkok, Thailand. Recruitment will be completed in February 2024. 5 Nuffield Department of Medicine, University of Oxford, Oxford, UK. 6 Protocol Version 5.4, 16 July 2021. Department of Critical Care Medicine, Hospital Israelita Albert Einstein, Sao Paulo, Brazil. 7Department of Intensive Care Medicine, Austin Hospital and Abbreviations University of Melbourne, Melbourne, VIC, Australia. 8Department of APACHE II: Acute physiology and chronic health evaluation II; ARDS: Acute Anesthesiology and Intensive Care Medicine, Catholic University of the respiratory distress syndrome; BPS: Behavioral pain scale; CCPOT: Critical care Sacred Heart, “A. Gemelli” University Hospital, Rome, Italy. 9Department of pain observation tool; CONSORT: Consolidated standards of reporting trials; Intensive Care Medicine & Vall d’Hebron Research Institute, Vall d’Hebron CPAP: Continuous positive airway pressure; DSMB: Data and safety University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain. 10 monitoring board; eCRF: Electronic case report form; FiO2: Fraction of Centro de Investigación Biomédica en Red en Enfermedades Respiratorias, inspired oxygen; HFNO: High-flow nasal oxygen; ICH-GCP: International Instituto de Salud Carlos III, Madrid, Spain. 11Department of Intensive Care conference on harmonization-good clinical practice; IMV: Invasive mechanical Medicine, Onze Lieve Vrouwe Gasthuis (OLVG) Hospital, Amsterdam, The ventilation; ICU: Intensive care unit; NIV: Noninvasive ventilation; Netherlands. 12Department of Intensive Care Medicine, Corporación Sanitaria PaCO2: Partial pressure of arterial carbon dioxide; PaO2: Partial pressure of Universitaria Parc Tauli, Barcelona, Spain. 13Department of Intensive Care arterial oxygen; PEEP: Positive end-expiratory pressure; ROX: Respiratory Medicine, Sagrat Cor University Hospital, Grupo Quironsalud, Barcelona, OXygenation; SAPS II: Simplified acute physiology score II; SBT: Spontaneous Spain. breathing trial; SOFA: Sequential organ failure assessment; SpO2: Peripheral capillary oxygen saturation; VAS: Visual analog scale; VFD: Ventilator-free days Received: 29 October 2021 Accepted: 29 December 2021 Acknowledgements Funding source: this study is an investigator-initiated trial, funded by the References Institut d'Investigació i Innovació Parc Taulí (I3PT). This study is partially 1. Stefan MS, Shieh MS, Pekow PS, Rothberg MB, Steingrub JS, Lagu T, et al. funded and Sponsored by the European Society of Intensive Care Medicine Epidemiology and outcomes of acute respiratory failure in the United (ESICM) and the Spanish Respiratory Society (SEPAR). States, 2001 to 2009: a national survey. J Hosp Med. 2013;8(2):76–82. https:// doi.org/10.1002/jhm.2004. Authors’ contributions 2. Gattinoni L, Taccone P, Carlesso E, Marini JJ. Prone position in acute LMQ, MJS, and AA designed the study. LMQ, MJS, ASN, MA, DLG, OR, NJ, LlB, respiratory distress syndrome. Rationale, indications, and limits. Am J Respir CH, DM, MCR, and AA approved the design of PRONELIFE. ASN performed Crit Care Med. 2013;188(11):1286–93. https://doi.org/10.1164/rccm.201308-1 the power calculations and designed the statistical analysis plan. LMQ 532CI. prepared the initial draft of this manuscript. LMQ, MJS, ASN, MA, DLG, OR, NJ, 3. Scholten EL, Beitler JR, Prisk GK, Malhotra A. Treatment of ARDS with prone LlB, CH, DM, MCR, and AA approved the initially submitted version of this positioning. Chest. 2017;151(1):215–24. https://doi.org/10.1016/j.chest.2016. manuscript. The authors read and approved the final manuscript. 06.032. 4. Ding L, Wang L, Ma W, Hangyon H. Efficacy and safety of early prone Funding positioning combined with HFNC or NIV in moderate to severe ARDS: a This article has partial funding from the Institut d'Investigació i Innovació multi-center prospective cohort study. Crit Care. 2020;24(1):28. https://doi. Parc Taulí (I3PT). org/10.1186/s13054-020-2738-5. 5. Feltracco P, Serra E, Barbieri S, Persona P, Rea F, Loy M, et al. Non-invasive Availability of data and materials ventilation in prone position for refractory hypoxemia after bilateral lung Morales-Quinteros, Serpa Neto, Artigas, and Schultz had full access to all data transplantation. Clin Transpl. 2009;23(5):748–50. https://doi.org/10.1111/j.13 in the study and take responsibility for the integrity of the data and the 99-0012.2009.01050.x. accuracy of the data analysis; the members of the Steering Committee for 6. Stilma W, Åkerman E, Artigas A, Bentley A, Bos LD, Bosman TJC, et al. Awake PRONELIFE Collaborative Group vouch for the accuracy and completeness of proning as an adjunctive therapy for refractory hypoxemia in non-intubated the data and for the fidelity of the study to the protocol. All data needed to patients with COVID-19 acute respiratory failure: guidance from an evaluate the conclusions of the trial will be present and tabulated in the final international group of healthcare workers. Am J Trop Med Hyg. 2021;104(5): manuscript. Individual de-identified raw data will be available from the corre- 1676–86. https://doi.org/10.4269/ajtmh.20-1445. sponding author on reasonable request during the first year after publication 7. Koeckerling D, Barker J, Mudalige NL, Oyefeso O, Pan D, Pareek M, et al. of the primary manuscript arising from this study. Awake prone positioning in COVID-19. Thorax. 2020;75(10):833–4. https:// doi.org/10.1136/thoraxjnl-2020-215133. Declarations 8. Valter C, Christensen AM, Tollund C, Schønemann NK. Response to the prone position in spontaneously breathing patients with hypoxemic Ethics approval and consent to participate respiratory failure. Acta Anaesthesiol Scand. 2003;47(4):416–8. https://doi. The study was approved by the referral ethics committee Sagrat Cor org/10.1034/j.1399-6576.2003.00088.x. University Hospital, Barcelona, Spain (reference number 2019/68-UCI-HUSC) 9. Scaravilli V, Grasselli G, Castagna L, Zanella A, Isgrò S, Lucchini A, et al. Prone (Additional file 1). For inclusion into the study, and due to national positioning improves oxygenation in spontaneously breathing emergency regulations, verbal informed consent from the patient’s relatives nonintubated patients with hypoxemic acute respiratory failure: A or legal representative will be provided (Additional file 2). See Additional file retrospective study. J Crit Care. 2015;30(6):1390–4. https://doi.org/10.1016/j. 3 for the SPIRIT checklist of the study protocol. jcrc.2015.07.008. 10. Jayakumar D, Ramachandran Dnb P, Rabindrarajan Dnb E, Vijayaraghavan Consent for publication Md B, et al. Standard care versus awake prone position in adult Not applicable. nonintubated patients with acute hypoxemic respiratory failure secondary to COVID-19 infection-a multicenter feasibility randomized controlled trial. J Competing interests Intensive Care Med. 2021;36(8):918–24. https://doi.org/10.1177/08850666211 The authors declare that they have no competing interests. 014480. 11. 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