Awake Prone Positioning in Nonintubated Spontaneous Breathing ICU Patients with Acute Hypoxemic Respiratory Failure (PRONELIFE) – Protocol for a Randomized Clinical Trial

Awake Prone Positioning in Nonintubated Spontaneous Breathing ICU Patients with Acute Hypoxemic Respiratory Failure (PRONELIFE) – Protocol for a Randomized Clinical Trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Awake Prone Positioning in Nonintubated Spontaneous Breathing ICU Patients with Acute Hypoxemic Respiratory Failure (PRONELIFE) – Protocol for a Randomized Clinical Trial Luis Morales-Quinteros, Marcus J Schultz, Ary Serpa Neto, Massimo Antonelli, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-924132/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 10 Jan, 2022 Read the published version in Trials → Version 1 posted 4 You are reading this latest preprint version 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. Discussion The PRONELIFE study is amongst 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 has the potential to change clinical management of patients who may need invasive ventilation because of acute hypoxemic respiratory failure. Trial registration ISRCTN, ISRCTN11536318. Registered 17 September 2021, https://www.isrctn.com/ISRCTN11536318 The PRONELIFE study is registered at clinicaltrials.gov with reference number NCT04142736 (October, 2019). Translational Medicine Internal Medicine Integrative & Complementary Medicine ICU acute respiratory failure hypoxemia prone position awake prone positioning invasive ventilation intubation invasive ventilation Figures Figure 1 Figure 2 Figure 3 Background Acute hypoxic respiratory failure represents one of the most common reasons for intensive care unit (ICU) admission 1 . Initial management of hypoxemic patients should involve immediate administration of simple supplemental oxygen via a nasal prong or a non–rebreather mask, or more complex forms of respiratory support like high–flow nasal oxygen (HFNO) oxygen or non–invasive ventilation (NIV), depending on severity of hypoxic respiratory failure and the underlying cause, but also patient characteristics and the availability of oxygen interfaces. Unfortunately, patients with acute hypoxemic respiratory failure often need proceed with invasive ventilation. While life–saving, this intervention comes with disadvantages, including ventilator–induced lung injury and respiratory muscle waist, but also intubation–related side–effects. In addition, intubated patients often need sedation, which has side–effects of its own. In intubated invasively ventilated ICU patients, prone positioning can be used to improve oxygenation, and this intervention has been shown to improve outcome in patients with severe ARDS. This survival benefit could be mediated, at least in part through a reduction in direct harm to lung tissue, as regional differences in lung aeration, compliance, and shear strain are minimized by this intervention 2,3 . In theory, nonintubated patients could also benefit from prone positioning 4,5 , a strategy named 'awake prone positioning' 6,7 . Some evidence for benefit of awake prone positioning comes from a handful of studies, mostly case reports and single–center observation case series 5,8,9 . The findings thus far show that awake prone positioning can indeed improve oxygenation and also reduce dyspnea sensation. Besides that, awake prone positioning seems to be well–accepted and easy to perform, and to have relatively few side–effects 10 . In the absence of sufficient randomized clinical trial evidence, we designed the PRONELIFE study, a pragmatic study that compares standard care with awake prone positioning versus standard care without awake prone positioning in patients with acute hypoxemic respiratory failure from any cause. We hypothesize that awake prone positioning reduces the need for intubation. Methods DESIGN The 'PRone positioN in patients with spontanEous ventiLation and acute hypoxemic respIratory FailurE' (PRONELIFE) study is a pragmatic, investigator–initiated, international and multicenter, two–arm, randomized clinical trial in patients with acute hypoxemic respiratory failure from any cause. The study will be conducted according to the Declaration of Helsinki principles as stated in the current version of Fortaleza, Brazil, 2013 11 . The Institutional Review Board of the Sagrat Cor University Hospital, Barcelona, Spain, approved the study protocol (reference number 2019/68-UCI-HUSC). The study is registered at www.clinicaltrials.gov (NCT04142736, October 2019). The PRONELIFE study is planned to be performed in the 35 ICUs worldwide. Patients will be provisionally included under a strategy of deferred consent, for reasons as explained below. CONSORT DIAGRAM The Consolidated Standards of Reporting Trials (CONSORT) 12 diagram of the PRONELIFE study is presented in Figure 1 . Consecutive patients admitted to the participating ICUs are screened for eligibility. Demographic data are registered regardless of meeting enrollment criteria. If excluded from participation, the reason(s) for exclusion will be reported. INCLUSION AND EXCLUSION CRITERIA Patients admitted to the ICU with acute hypoxemic respiratory failure from any cause will be eligible for participation, unless prompt intubation is irrepressible ( Table 1 ). Acute respiratory failure is defined as the need for supplementary oxygen with an FiO 2 of at least 40% by Venturi facemask, HFNO, NIV or CPAP needed to achieve and maintain an SpO 2 of between 88 to 92%. The PRONELIFE study has the following exclusion criteria: age < 18 years, having any contraindication for prone positioning ( Table 2 ), previously participation in this trial, and participation in other interventional trials with the same primary endpoint. We also exclude pregnant patients, patients who refuse intubation, and those only receiving comfort care. As patients will be provisionally included under a strategy of deferred consent, there is no need for written informed consent at start of the study––however, if consent is not obtained within 48 hours, a patient drops out of the study and will be replaced. STUDY ENDPOINTS The primary endpoint is the composite of tracheal intubation and all–cause mortality within 14 days after enrollment. Secondary endpoints are the effects of awake proning on the following clinical outcomes variables: time to tracheal intubation (only in patients who need invasive ventilation); oxygenation parameters; dyspnea sensation (while awake in prone versus supine position); the number of days free from invasive ventilation and alive at day 28; duration of use of non–invasive ventilatory support, including the use of a non–rebreather mask, CPAP, high–flow nasal oxygen (HFNO) oxygen or noninvasive ventilation (NIV); duration of invasive ventilation; ventilation-free days (VFD) at 28 days from ICU admission, defined as the number of days alive and free from IMV during the first 28 days from start of IMV length of stay in ICU and hospital; mortality in ICU and hospital, and at 28, 60, and 90 days; and tolerance of prone positioning (only in patients in the prone positioning group). RANDOMIZATION AND BLINDING Randomization will be performed using a dedicated password–protected website and will be balanced per center. Central randomization with the use of a permutated–block randomization list (with block sizes of 4 to 8) will be used. Participants will be allocated to the prone positioning or standard care on a 1:1 ratio. By the nature of the intervention it will not be possible to blind clinicians to whether a participant has been randomized to awake proning or standard care. PRONE POSITIONING The study intervention will last for at least 48 hours and is divided in 4 blocks of 6 hours each: patients will be placed in the prone position for up to 2 hours, which can be prolonged if the patient feels comfortable, but could also be interrupted if a patient meets any of the discontinuation criteria which are any of the following: developing a contraindication ( Table 1 ); worsening of dyspnea (at any time, according to predefined criteria, as described in Table 2 ); a further and sustained drop in SpO 2 refractory to an increase in FiO 2 ; nausea or vomiting; and increasing hemodynamic instability that is unrelated to sedatives (if given) and cannot be corrected by vasopressor or inotrope infusion (as described in Table 3 ) During the change in position, from supine to prone or from prone to supine, FiO 2 will be increased by 25% above baseline. Each change in position is guided by two healthcare workers and an attending physician, but more healthcare workers could be needed. While the patient remains in a prone position, skin protection will be used to avoid pressure sores. Also, the application of cushions will enhance patient tolerance. Arms can be at the side, in a swimmer's position, and can be moved to increase comfort. Food and comfort breaks are planned while patients are in supine. If the patient is receiving enteral or oral feeding, this is interrupted from 1 hour before prone until a patient is in a supine position. The best–fitting and most–tolerated oxygen interface will be used in the prone position––this could be different from patient to patient, and different from what is used in the supine position, and could differ between patients but also institutions (i.e., depending on the availability of masks with or without a reservoir bag and with or without the Venturi system, HFNO, CPAP or NIV). STANDARD OF CARE In all patients, whether receiving prone positioning or not, the best standard of care is provided, according to the standard care by the local teams. When in a supine position, the patient will be placed in 30–45° semi–recumbent position but this can be changed for the comfort of the patient to supine, semi–sitting, sitting or a lateral decubitus position). Vitals parameters, including SpO 2 and the SpO 2 /FiO 2 are continuously monitored. The oxygenation target ranges for SpO 2 is 88% to 92%; this is 7 kPa to 8 kPa for PaO 2 . For patients in whom the risk of potentially dangerous hypoxemia could be become unacceptable during the study (e.g., in patients who develop cardiac ischemia due to cardiac infarction or failed revascularization, or severe untreatable anemia such as with Jehovah's Witnesses), oxygenation target ranges can be higher, 94% to 96% for SpO 2 and 9 kPa to 11.5 kPa for PaO 2 13–15 . Opiates and benzodiazepines are allowed at low dosages to improve comfort. INTUBATION CRITERIA The decision to continue with invasive mechanical ventilation is based on clinical judgment rather than isolated gasometrical criteria. Any of the following criteria should be considered for proceeding to endotracheal intubation: Respiratory or cardiac arrest; Respiratory pauses; Altered level of consciousness such as uncontrolled agitation not responding to medical treatment, or a drop in the Glasgow Coma Score; Evidence of exhaustion such as an unacceptable increase in use of accessory muscles or thoracoabdominal paradox; Inability to clear secretions from the airway in patients with abundant sputum production, or evidence of aspiration; or Hemodynamic instability as defined in Table 3 In addition, the presence of 2 of the following criteria within 1 hour of start non–invasive ventilatory support: Respiratory rate > 35 breaths/min, or increased respiratory rate from the baseline; Not improving or increased dyspnea; pH 20% from the baseline value; or SpO2 < 88% WEANING FROM THE NON–INVASIVE OXYGEN DELIVERY SYSTEM Weaning from the oxygen therapy delivery system will be done according to local protocols and preferences. Table 4 provides guidance for oxygen requirements coupled with the reduction in gas flow rates of the HFNO. INVASIVE VENTILATION If patient continues with invasive ventilation, settings are chosen in line with the local guidelines for invasive ventilation. The use of lung–protective ventilation with a low tidal volume and low pressures is advocated. Also, sufficient levels of PEEP should be used, and prone positioning is to be applied if a patient meets develops severe hypoxemia, defined as PaO 2 /FiO 2 < 150 mmHg at a minimum FiO 2 of 60% and 5 cm H 2 O). FLUID REGIMENS We advise to use a restricted fluid strategy, i.e., targeting a neutral cumulative fluid balance as soon as a patient can be weaned of vasopressors. Crystalloid infusions are preferred over colloid infusions. SEDATION In patients under invasive ventilation, the local guideline for sedation is to be followed, and preferably consists of combinations of use of analgo–sedation over hypno–sedation, use of bolus over continuous infusion of sedating agents, and the use of sedation scores (e.g., 3 times per day, and using a Richmond Agitation Sedation Scale 16,17 . Also, the level of pain is to be determined, e.g. by using the Numeric Rating Scale, the Visual Analogue Scale (VAS), the Critical Care Pain Observation Tool (CCPOT) or Behavioral Pain Scale (BPS). WEANING FROM INVASIVE VENTILATION Weaning from invasive ventilation follows local protocols and preferences. In all patients, should be tested whether the patient accepts assist ventilation at least two times a day; this should also be tried when the patient shows respiratory muscle activity during assist ventilation. The attending physician decides when to extubate a patient, based on general extubation criteria (i.e., responsive and cooperative, adequate cough reflex, adequate oxygenation with FiO2 ≤ 0.4, hemodynamically stable, no uncontrolled arrhythmia and a rectal temperature > 36° Celsius and after successfully passing a spontaneous breathing trial (SBT) with a T–piece or ventilation with minimal support (pressure support level < 10 cm H2O) and FiO2 ≤ 0.4. In case SBTs are used, an SBT is judged as successful when the following criteria are met for at least 30 minutes, the attending physician takes the final decision for extubation: Respiratory rate 90%; Increase < 20% of heart rate and blood pressure; and No signs of anxiety and diaphoresis. DATA COLLECTION On ICU admission and within 48 hours, demographic and baseline data and data on disease severity will be collected. Data collection includes gender, age, height, weight, date of hospital admission, date of ICU admission, cause of respiratory failure, chest X-ray, the Sequential Organ Failure Assessment (SOFA) score, the Acute Physiology and Chronic Health Evaluation II (APACHE II) score and the Simplified Acute Physiology Score II (SAPS II). Data on the standard of care (described below) will be collected daily for the first 48 hours and every 6 hours, up to day 28. The total number of hours spent in prone position in a day (cumulative), the number of prone sessions and their duration is recorded. After the protocol, every day until day 14, clinical outcome variables discharge of the ICU or death, whichever comes first. Data on duration of non–invasive respiratory support, length of stay in ICU and hospital, location of the patient (in ICU, hospital, another facility, or home), and life status (alive or deceased) will be assessed on 28 and 90 days ( Figure 3 ). One hour before each position change (supine to prone and prone to supine), the following variables will be collected for the duration of the protocol: respiratory variables (respiratory rate SpO 2 , SpO 2 /FiO 2 , ROX index; SpO 2 /FiO 2 : RR, dyspnea defined according to the Borg dyspnea scale); noninvasive mean arterial pressure; heart rate; noninvasive support device parameters: Venturi facemask, HFNO, CPAP, NIV; adverse effects possibly related to prone position (hypotension, bradycardia hypoxemia, pressure ulcers, vomiting, displacements of the respiratory support device, peripheral or venous central line, orogastric or nasogastric tube, or urinary catheter), if any are recorded. In case prone positioning is not tolerated, all reasons for a premature change in body position are reported. The following parameters of the respiratory support devices will be collected within 1 hour before and 1 hour after randomization, and every day at a fixed time point until cessation of the respiratory support: Venturi facemask: flow (liters/min), FiO 2 ; HFNO: flow (liters/min), FiO 2 ; CPAP: PEEP, flow (liters/min), tidal volume, FiO 2 ; NIV: PEEP, pressure support over PEEP, flow (liters/min), tidal volume, FiO 2 . If the patient meets the criteria for intubation, the reasons for intubation are documented in the eCRF. Data on the administration on the administration of steroids, Remdesivir, Tocilizumab, Heparin/low molecular weight heparin, antihypertensive medications are recorded. Fluid balance is collected form the nursing chart. POWER CALCULATION We will include a total of 650 patients. The required sample size is calculated using data from two multicenter randomized controlled trials reporting intubation rates in patients with acute hypoxemic respiratory failure 18,19 . It was conservatively assumed that the rate of tracheal intubation will be 45% in the standard treatment group. Accordingly, 650 patients (n= 325 per group) would provide 80% power to detect a relative risk of 0.75 for the primary endpoint at a 2-sided α level of 0.05, assuming a dropout rate of 10%. After enrollment of 70% of the patients, an unblinded sample size reestimation will be performed, and sample size could be increased to a maximum of 1000 patients if needed. DEFERRED INFORMED CONSENT For this study, we will include patients using a strategy using deferred informed consent because we explicitly want to randomize and start ventilation according to randomization within 1 hour after ICU admission. Nevertheless, the legal representative's written informed consent will be requested as soon as possible thereafter and never later than 48 hours after randomization. If informed consent is not obtained within those 48 hours, or if a legal representative denies participation within this time frame, the patient is excluded, and data will no longer be used, nor will this patient be counted for the sample size of 325 inclusions in each group (that is the provisionally included patient for whom informed consent is not obtained within the time frame of 48 hours is 'replaced' by a new patient until the total number of 325 patients in each arm is definitively included). STATISTICAL ANALYSIS Statistical analysis will be based on the intention–to–treat principle. We will also perform a per–protocol analysis, comparing patients who received awake prone positioning and patients who received standard of care. Continuous normally distributed variables will be expressed by their mean and standard deviation or when not normally distributed as medians and their interquartile ranges. Categorical variables will be expressed as n (%). Where appropriate, statistical uncertainty will be expressed by the 95%–confidence levels. The primary outcome, the number of days free of ventilation at day 14, will be analyzed using Cox's regression. The possible imbalance between groups will be modeled in the Cox model. To further compare groups, Student's t-test will be used. If continuous data is not normally distributed, the Mann-Whitney U-test will be used. Categorical variables will be compared with the Chi-square test or Fisher's exact tests. Time–dependent data will be analyzed using a proportional hazard model adjusted for possible imbalances of patients' baseline characteristics. No interim analysis will be conducted. A P–value < 0.05 is considered statistical significance. The analysis will be performed with R statistics version 3.0.2 (R Foundation, Vienna, Austria). STUDY ORGANIZATION The steering committee comprises the principal investigator, the coordinating investigators, and eight (inter–) national experts in ventilatory support in critically ill patients. The coordinating investigator is responsible for administrative management and communication with the local investigators and assists at the participating clinical sites in trial management, record keeping, and data management. The coordinating investigators help set up local training in the participating ICUs to ensure the study is conducted according to the ICH–GCP guidelines, guarantee data collection integrity, and ensure timely completion of the case report forms. The local investigators provide structural and scientific leadership. They guarantee the integrity of data collection and ensure timely completion of the case report forms. An independent monitor will be installed. Remote monitoring utilizing queries on the database will be done by a statistician and analyzed by the monitor to signalize early aberrant patterns, trends, issues with consistency or credibility, and other anomalies. On-site monitoring will comprise controlling the presence and completeness of the research dossier and the informed consent forms, and source data checks will be performed in the files of 25 % of the patients. An independent Data and Safety Monitoring Board (DSMB) watches over the ethics of conducting the study under the Declaration of Helsinki, monitors safety parameters and the overall conduct of the research. The DSMB is composed of three independent individuals (Prof. Arthur Slutsky, Prof. Claude Guerin, and Dr. Tài Pham). The DSMB will meet by conference calls. The first meeting is scheduled after the first 100 patients. After this meeting, the DSMB will meet every six months. All unexpected adverse events will be reported to the DSMB. Any report or advice of the DSMB will be sent to the sponsor of the study, the Institut d'Investigació i Innovació Parc Taulí (I3PT), Sabadell, Spain. Should the sponsor decide not to implement the advice of the DSMB fully, the sponsor will send the recommendation to the reviewing Institutional Review Board, including a note to substantiate why (part of) the advice of the DSMB will not be followed. Discussion PRONELIFE is amongst the first clinical trials of awake prone positioning in patients with acute hypoxemic respiratory failure that will recruit a sufficient number of patients to test the hypothesis that this intervention prevents tracheal intubation. PRONELIFE will also collect data regarding other patients–centered outcomes, including duration of ventilation if needed, length of stay in ICU and hospital, and mortality. We will also study the tolerability of awake prone positioning and its effects on oxygenation. Invasive ventilation is a life–support strategy associated with serious complications that may result in significant morbidity and mortality. In addition, endotracheal intubation is a high–risk procedure in critically ill patients, with major complications like severe hypoxemia, cardiovascular instability, and even cardiac arrest 20–22 . The primary endpoint of this study is a composite of the need for invasive ventilation and death within the first 14 days. We decide to use this composite endpoint, hypothesizing that the intervention under study will impact two outcomes that are invariable related. Using a composite outcome will also increase the event rate, improve the statistical efficiency for sample size calculation, and improve the study's precision. We chose the need for invasive ventilation and death within the first 14 days because we hypothesize that the impact of awake prone positioning will not last beyond the first two weeks. Of note, we will report the two components of the composite as two secondary endpoints. Evidence for the benefit of awake prone positioning in nonintubated ICU patients is scarce. Its first use was described in a case series of patients with hypoxemic respiratory failure, showing improvements in oxygenation 8 . Improvements in oxygenation were also reported in two studies in patients with severe hypoxemia after lung transplantation 5,23 . A rapidly growing number of mainly small observational studies describe the use of awake prone positioning in patients with spontaneous breathing with acute respiratory failure in whom hypoxemia is refractory to supplementary oxygen. It has been shown that awake prone positioning can improve oxygenation within minutes 24–28 , and the effects are maintained for up to one hour after turning back to supine and disappear mostly after 6 to 12 hours 24,29 . A total of 15 studies, representing 449 patients, were recently used in one meta–analysis 30 , assessing the change in oxygenation (i.e., PaO 2 /FiO 2 ratio, PaO 2 , and SpO 2 ) induced by awake prone positioning. Two recent studies failed to show benefit of awake prone positioning in patients with acute respiratory failure 31,32 . Of note, one of these studies had an observational design, and it remained uncertain whether the intervention was used as a routine or life–saving therapy 32 . The other study was a randomized clinical trial that was underpowered for sample size estimation 31 . In both studies, patients were only included patients with COVID-19 infection. Evidence suggests that direct versus indirect causes of lung injury possess different pathophysiologic characteristics that might impact both the progression and outcome of ARDS 33–35 . Therefore, the prone position could affect mortality, and its impact may vary according to the etiology of lung injury. Also, in both studies, the intubation criteria were not clearly defined. Our study will include different etiologies of acute respiratory failure, and we have clearly described intubation criteria. Awake prone positioning is an attractive intervention for several reasons. First, many patients with hypoxemic acute respiratory failure seem to tolerate awake prone positioning relatively well 24,36,37 . Awake prone positioning is also associated with few complications. Data are limited, but thus far, no severe adverse events have been described in the literature. Pressure sores, frequently developing in intubated ICU patients 38 and with higher morbidity 39 , have only been rarely described in patients who received awake prone positioning 9,31 . Intolerance to awake prone positioning could be related to musculoskeletal discomfort 24,26,37,40 , nausea and vomiting 26 , cough 37 , and anxiety 40 . Our study will focus on these aspects. PRONELIFE will also collect other important and patient–centered endpoints such as dyspnea sensation, duration of use of noninvasive ventilatory support and duration of invasive ventilation, and the classical ICU endpoints like the length of ICU and hospital stay, and various mortality rates. We anticipate the PRONELIFE study to be highly feasible and easy to conduct as the study procedures are straightforward, without difficult or complex interventions making the treatment of patients clear and easy. Furthermore, the PRONELIFE study uses a deferred consent strategy to include patients rapidly in the study and those admitted during evenings or nights when researchers and family members are often not around to ask for informed consent. This will create a study population representative of the average ICU population. Also, PRONELIFE will be performed in the ICUs of different hospitals worldwide, increasing the generalizability of its findings. Furthermore, we include patients with any cause of respiratory failure. One important limitation of PRONELIFE is that blinding is not possible due to the nature of the intervention tested, which could induce bias. However, the indication for invasive ventilation, which directly influences the primary outcome, is clearly stated, and all analyses will be performed in a blinded fashion. Second, we foresee that another limitation could derive from the time under prone position a patient with spontaneous breathing could tolerate continuously. Knowing from studies that the benefit of prone position in ARDS could depend on its duration 41 , the protocol design will count the total time of prone positioning for each patient. Although patients randomized to the intervention will have 2 hours under prone position, this strategy could be further prolonged if the patient feels comfortable. The results of PRONELIFE have the potential to change clinical practice in terms of how we manage patients with acute hypoxemic respiratory failure. In conclusion, the PRONELIFE study is an international, investigator–initiated randomized clinical trial that is adequately powered to test the hypothesis that awake prone positioning benefits ICU patients with acute hypoxemic respiratory failure. Trial status Pending to start recruiting. Abbreviations APACHE II: Acute Physiology and Chronic Health Evaluation II ARDS: Acute Respiratory Distress Syndrome BPS: Behavioral Pain Scale CCPOT: Critical Care Pain Observation Tool cmH2O: centimeters of water CONSORT: Consolidated Standards of Reporting Trials CPAP: Continuous Positive Airway Pressure DSMB: Data and Safety Monitoring Board eCRF: Electronic Case Report Form FiO2: Fraction of Inspired Oxygen HFNO: High Flow Nasal Oxygen ICH-GCP: International Conference on Harmonization-Good Clinical Practice IMV: Invasive Mechanical Ventilation ICU: Intensive Care Unit kPa: kilopascal Min: minute NIV: Non-Invasive Ventilation PaCO2: Partial Pressure of Arterial Carbon Dioxide PaO2: Partial Pressure of Arterial Oxygen PEEP: Positive End-Expiratory Pressure ROX: Respiratory OXygenation SAPS II: Simplified Acute Physiology Score II SBT: Spontaneous Breathing Trial SOFA: Sequential Organ Failure Assessment SpO2: Peripheral capillary Oxygen Saturation VAS: Visual Analogue Scale VFD: Ventilator Free Days Declarations Competing interests The authors declare that they have no competing interests. Authors’ contributions LMQ, MJS, AA designed the study. LMQ, MJS, ASN, MA, DLG, OR, NJ, LlB, CH, DM, MCR, AA approved the design of PRONELIFE. ASN performed the power calculations and designed the statistical analysis plan. LMQ prepared the initial draft of this manuscript. LMQ, MJS, ASN, MA, DLG, OR, NJ, LlB, CH, DM, MCR, AA approved the initially submitted version of this manuscript. All authors read and approved the final manuscript. Acknowledgement Funding source: this study is an investigator-initiated trial, funded by the Institut d'Investigació i Innovació Parc Taulí (I3PT). This study is partially funded and Sponsored by the European Society of Intensive Care Medicine and the Spanish Respiratory Society (SEPAR). Author details 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, Spain. 3 Department of Intensive & Laboratory of Experimental Intensive Care and Anesthesiology, Amsterdam UMC, location 'AMC', The Netherlands. 4 Mahidol Oxford Tropical Medicine Research Unit (MORU), Mahidol University, Bangkok, Thailand. 5 Nuffield Department of Medicine University of Oxford, Oxford, UK. 6 Department of Anesthesiology and Intensive Care Medicine, Catholic University of the Sacred Heart, 'A. Gemelli' University Hospital, Rome, Italy. 7 Department of Intensive Care Medicine, Sagrat Cor University Hospital, Grupo Quironsalud, Barcelona, Spain. 8 Department of Intensive Care Medicine & Vall d’Hebron Research Institute, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain. 9 Department of Intensive Care Medicine, Corporación Sanitaria Universitaria Parc Tauli. 10 Centro de Investigación Biomédica en Red en Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain. 11 Department of Critical Care Medicine, Hospital Israelita Albert Einstein, Sao Paulo, Brazil. 12 Department of Intensive Care Medicine, Austin Hospital and University of Melbourne, Melbourne, VIC, Australia References 1. Stefan MS, Shieh MS, Pekow PS, et al. Epidemiology and outcomes of acute respiratory failure in the United States, 2001 to 2009: a national survey. J Hosp Med . 2013;8:76-82. 2. Gattinoni L, Taccone P, Carlesso E MJ. Prone position in acute respiratory distress syndrome. Rationale, indications, and limits. Am J Respir Crit Care Med . 2013;188:1286-1293. 3. Scholten EL, Beitler JR, Prisk GK MA. Treatment of ARDS With Prone Positioning. Chest . 2017;151:215-224. 4. Ding L, Wang L, Ma W HH. Efficacy and safety of early prone positioning combined with HFNC or NIV in moderate to severe ARDS: a multi-center prospective cohort study. Crit Care . 2020;24:28. 5. Feltracco P, Serra E, Barbieri S, Persona P, Rea F, Loy M OC. Non-invasive ventilation in prone position for refractory hypoxemia after bilateral lung transplantation. Clin Transpl . 2009;23:748-750. 6. Stilma W, Åkerman E, Artigas A, Bentley A BL. Awake Proning as an Adjunctive Therapy for Refractory Hypoxemia in Non-Intubated Patients with COVID-19 Acute Respiratory Failure: Guidance from an International Group of Healthcare Workers. Am J Trop Med Hyg . 2021;Mar 11:tpm. 7. Koeckerling D, Barker J, Mudalige NL, Oyefeso O, Pan D, Pareek M, Thompson JP NG. Awake prone positioning in COVID-19. Thorax . 2020;75:833-834. 8. Valter C, Christensen AM, Tollund C SN. Response to the prone position in spontaneously breathing patients with hypoxemic respiratory failure. Acta Anaesthesiol Scand . 2003;47:416-418. 9. Scaravilli V, Grasselli G, Castagna L, et al. Prone positioning improves oxygenation in spontaneously breathing nonintubated patients with hypoxemic acute respiratory failure: A retrospective study. J Crit Care . 2015;30(6):1390-1394. doi:10.1016/j.jcrc.2015.07.008 10. Jayakumar D, Ramachandran Dnb P, Rabindrarajan Dnb E, Vijayaraghavan Md BKT, Ramakrishnan Ab N VAR. Standard Care Versus Awake Prone Position in Adult Nonintubated Patients With Acute Hypoxemic Respiratory Failure Secondary to COVID-19 Infection-A Multicenter Feasibility Randomized Controlled Trial. J Intensive Care Med . 2021;May 5:8850. 11. WMA Declaration of Helsinki - Ethical principles for medical research involving human subjects. October 2013. In: http://www.wma.net/en/30publications/ 10policies/b3/. http://www.ncbi.nlm.nih.gov/pubmed/24141714. 12. Moher D, Schulz KF AD. The CONSORT statement: revised Parallel-group, recommendations for improving the quality of reports of randomized trials. JAMA . 2001;285:1987-1991. 13. Schjørring OL, Klitgaard TL, Perner A, Wetterslev J, Lange T, Siegemund M, Bäcklund M, Keus F, Laake JH, Morgan M, Thormar KM, Rosborg SA, Bisgaard J, Erntgaard AES, Lynnerup AH, Pedersen RL, Crescioli E, Gielstrup TC, Behzadi MT, Poulsen LM, Estrup S, La AC. Lower or Higher Oxygenation Targets for Acute Hypoxemic Respiratory Failure. N Engl J Med . 2021;384:1301-1311. 14. Mackle D, Bellomo R, Bailey M, Beasley R, Deane A, Eastwood G, Finfer S, Freebairn R, King V, Linke N, Litton E, McArthur C, McGuinness S, Panwar R YP. Conservative Oxygen Therapy during Mechanical Ventilation in the ICU. N Engl J Med . 2020;382:989-998. 15. Barrot L, Asfar P, Mauny F, Winiszewski H, Montini F, Badie J, Quenot JP, Pili-Floury S, Bouhemad B, Louis G, Souweine B, Collange O, Pottecher J, Levy B, Puyraveau M, Vettoretti L, Constantin JM CG. Liberal or Conservative Oxygen Therapy for Acute Respiratory Distress Syndrome. N Engl J Med . 2020;382:999-1008. 16. Ely EW, Truman B, Shintani A et al. Monitoring sedation status over time in ICU patients: reliability and validity of the Richmond Agitation-Sedation Scale (RASS). JAMA . 2003;289:2983-2991. 17. Sessler CN, Gosnell MS, Grap MJ et al. The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med . 2002;166:1338-1344. 18. Frat J-P, Thille AW, Mercat A, et al. High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure. N Engl J Med . 2015;372(23):2185-2196. doi:10.1056/NEJMoa1503326 19. Grieco DL, Menga LS, Cesarano M, Rosà T, Spadaro S, Bitondo MM, Montomoli J, Falò G, Tonetti T, Cutuli SL, Pintaudi G, Tanzarella ES, Piervincenzi E, Bongiovanni F, Dell’Anna AM, Delle Cese L, Berardi C, Carelli S, Bocci MG, Montini L, Bello G, Natalini D AM. Effect of Helmet Noninvasive Ventilation vs High-Flow Nasal Oxygen on Days Free of Respiratory Support in Patients With COVID-19 and Moderate to Severe Hypoxemic Respiratory Failure: The HENIVOT Randomized Clinical Trial. JAMA . 2021;325:1731-1743. 20. Jaber S, Amraoui J, Lefrant J, Arich C, Cohendy R, Landreau L et al. Clinical practice and risk factors for immediate complications of endotracheal intubation in the intensive care unit: a prospective multicenter study. Crit Care Med . 2006;34:2355-2361. 21. Simpson GD, Ross MJ, McKeown DW RD. Tracheal intubation in the critically ill: a multi-centre national study of practice and complications. Br J Anaesth . 2012;108:792-799. 22. Russotto V, Myatra SN, Laffey JG, Tassistro E, Antolini L, Bauer P, Lascarrou JB, Szuldrzynski K, Camporota L, Pelosi P, Sorbello M, Higgs A, Greif R, Putensen C, Agvald-Öhman C, Chalkias A, Bokums K, Brewster D, Rossi E, Fumagalli R, Pesenti A, Foti G BG. Intubation Practices and Adverse Peri-intubation Events in Critically Ill Patients From 29 Countries. JAMA . 2021;325:11164-11172. 23. Feltracco P, Serra E, Barbieri S et al. Noninvasive high-frequency percussive ventilation in the prone position after lung transplantation. Transpl Proc . 2012;44:2016–2021. 24. Elharrar X, Trigui Y, Dols AM, Touchon F, Martinez S, Prud’homme E et al. Use of Prone Positioning in Nonintubated Patients With COVID-19 and Hypoxemic Acute Respiratory Failure. JAMA . 2020;323:2336-2338. 25. Despres C, Brunin Y, Berthier F, Pili-Floury S BG. Prone positioning combined with high-flow nasal or conventional oxygen therapy in severe Covid-19 patients. Crit Care . 2020;24:256. 26. Ng Z, Tay WC HC. Awake Prone Positioning for Non-intubated Oxygen Dependent COVID-19 Pneumonia Patients. Eur Respir J . 2020;56:2001198. 27. Caputo ND, Strayer RJ LR. Early Self-Proning in Awake, Non-intubated Patients in the Emergency Department: A Single ED’s Experience During the COVID-19 Pandemic. Acad Emerg Med . 2020;27:375-378. 28. Damarla M, Zaeh S, Niedermeyer S et al. Prone positioning of nonintubated patients with COVID-19. Am J Respir Crit Care Med . 2020;202:604-606. 29. Hallifax RJ, Porter BM, Elder PJ, Evans SB, Turnbull CD, Hynes G, Lardner R, Archer K, Bettinson HV, Nickol AH, Flight WG, Chapman SJ, Hardinge M, Hoyles RK, Saunders P, Sykes A, Wrightson JM, Moore A, Ho LP, Fraser E, Pavord ID, Talbot NP, Bafadhel M, Pe RN. Successful awake proning is associated with improved clinical outcomes in patients with COVID-19: single-centre high-dependency unit experience. BMJ Open Respir Res . 2020;7:e000678. 30. Reddy MP, Subramaniam A, Lim ZJ et al. Prone positioning of non-intubated patients with COVID-19 - A Systematic Review and Meta-analysis. medRxiv . 2020;preprint [. 31. Rosén J, von Oelreich E, Fors D, Jonsson Fagerlund M, Taxbro K, Skorup P, Eby L, Campoccia Jalde F, Johansson N, Bergström G FP. Awake prone positioning in patients with hypoxemic respiratory failure due to COVID‑19: the PROFLO multicenter randomized clinical trial. Crit Care . 2021;25:209. 32. Ferrando C, Mellado-Artigas R, Gea A, Arruti E, Aldecoa C, Adalia R et al. Awake prone positioning does not reduce the risk of intubation in COVID-19 treated with high-flow nasal oxygen therapy: a multicenter, adjusted cohort study. Crit Care . 2020;24:597. 33. Dicker RA, Morabito DJ, Pittet JF, Campbell AR MR. Acute respiratory distress syndrome criteria in trauma patients: why the definitions do not work. J Trauma . 2004;57:522-526. 34. Calfee CS, Janz DR, Bernard GR, May AK, Kangelaris KN M, MA et al. Distinct molecular phenotypes of direct vs indirect ARDS in single-center and multicenter studies. Chest . 2015;147:1539-1548. 35. Luo L, Shaver CM, Zhao Z, Koyama T, Calfee CS BJ, Between WL. Clinical predictors of hospital mortality differ direct and indirect acute respiratory distress syndrome. Chest . 2017;151:755-763. 36. Sartini C, Tresoldi M, Scarpellini P, Tettamanti A, Carcò F, Landoni G et al. Respiratory Parameters in Patients With COVID-19 After Using Noninvasive Ventilation in the Prone Position Outside the Intensive Care Unit. JAMA . 2020;323:2338-2340. 37. Coppo A, Bellani G, Winterton D, Di Pierro M, Soria A, Faverio P et al. Feasibility and physiological effects of prone positioning in non-intubated patients with acute respiratory failure due to COVID-19 (PRON-COVID): a prospective cohort study. Lancet Respir Med . 2020;8:765-774. 38. Girard R, Baboi L, Ayzac L, Richard J-C GC. The impact of patient positioning on pressure ulcers in patients with severe ARDS: results from a multicentre randomised controlled trial on prone positioning. Intensive Care Med . 2014;40:397-403. 39. Labeau SO, Afonso E, Benbenishty J, Blackwood B, Boulanger C BS, Al. E. Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study. Intensive Care Med . 2021;47:160-169. 40. Xu Q, Wang T, Qin X, Jie Y, Zha L LW. Early awake prone position combined with high-flow nasal oxygen therapy in severe COVID-19: a case series. Crit Care . 2020;24:250. 41. Guérin C, Reignier J, Richard JC, Beuret P, Gacouin A, Boulain T, Mercier E, Badet M, Mercat A, Baudin O, Clavel M, Chatellier D, Jaber S, Rosselli S, Mancebo J, Sirodot M, Hilbert G, Bengler C, Richecoeur J, Gainnier M, Bayle F, Bourdin G, Leray V, Girar AL. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med . 2013;368:2159-2168. Tables TABLE 1. CONTRAINDICATION FOR AWAKE PRONE POSITION Suspected increased intracranial pressure (e.g., severe brain injury) Hemoptysis Vomiting Recent abdominal wound (less than 15 days) Tracheal surgery or sternotomy during the previous 15 days Facial trauma or facial surgery during the previous 15 days Deep venous thrombosis treated for less than 2 days Cardiac pacemaker inserted in the last 2 days Unstable spine, femur, or pelvic fractures Hemodynamic instability (defined by a systolic blood pressure below 90 mmHg, mean blood pressure below 65 mmHg, or requirement for vasopressor) Pregnant women Presence of chest tube TABLE 2. BORG DYSPNEA SCALE 0 Nothing at all 0.5 Very, very slight (just noticeable) 1 Very slight 2 Slight breathlessness 3 Moderate 4 Somewhat severe 5 Severe breathlessness 6 7 Very severe breathlessness 8 9 Very, very severe (almost maximal) 10 Maximal TABLE 3. HEMODYNAMIC INSTABILITY DEFINITION Defined as any of the following not responding to fluid resuscitation: Systolic arterial pressure < 90 mmHg, or Mean arterial pressure < 65 mmHg, or Increased needs of vasopressor agents, or ECG evidence of ischemia or significant uncontrolled ventricular arrhythmia TABLE 4. HIGH FLOW NASAL CANNULA SCHEME FOR OXYGEN REQUIREMENTS COUPLED WITH GAS FLOW RATES* FiO 2 21-30% 30-40% 40-60% 60-100% Flow 30 L/min 30-40 L/min 40-50 L/min 50-70 L/min * In case the patient is using NIV, sessions could be interrupted when the respiratory rate is < 25 breaths/min and the FiO2 <40% (for a SpO2 88%) Cite Share Download PDF Status: Published Journal Publication published 10 Jan, 2022 Read the published version in Trials → Version 1 posted Reviews received at journal 14 Dec, 2021 Reviewers invited by journal 14 Dec, 2021 Editor assigned by journal 25 Nov, 2021 First submitted to journal 20 Sep, 2021 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-924132","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":70117270,"identity":"2e4e8fa7-7d56-43c7-bee7-b360a606d7cb","order_by":0,"name":"Luis 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11:05:57","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-924132/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-924132/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13063-021-05991-2","type":"published","date":"2022-01-10T14:49:05+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":16522490,"identity":"9017f623-5388-46cc-8a7e-a799df9ddbcc","added_by":"auto","created_at":"2021-12-16 16:29:06","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":102063,"visible":true,"origin":"","legend":"\u003cp\u003eConsolidated Standards of Reporting Trials (CONSORT) diagram\u003c/p\u003e","description":"","filename":"FIGURE1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-924132/v1/c87365a37606b0b9e89078bd.jpg"},{"id":16522491,"identity":"3ee344f7-d86a-44cf-9afb-3257b79115b4","added_by":"auto","created_at":"2021-12-16 16:29:06","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":154585,"visible":true,"origin":"","legend":"\u003cp\u003eProtocol Summary\u003c/p\u003e","description":"","filename":"FIGURE2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-924132/v1/3f38151f0a345647d4b3cb30.jpg"},{"id":16522492,"identity":"9ccfc903-235c-48eb-892a-85f0ac56d271","added_by":"auto","created_at":"2021-12-16 16:29:06","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":170142,"visible":true,"origin":"","legend":"\u003cp\u003eSchedule of events\u003c/p\u003e","description":"","filename":"FIGURE3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-924132/v1/8c5eb64e7aae903c82718f3a.jpg"},{"id":17162418,"identity":"bacb3a39-bb26-41cf-b2ff-f18e95f03ca4","added_by":"auto","created_at":"2022-01-10 14:49:08","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":537940,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-924132/v1/6fc9867d-7bbb-4b14-a00f-8bedfce0e70f.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eAwake Prone Positioning in Nonintubated Spontaneous Breathing ICU Patients with Acute Hypoxemic Respiratory Failure (PRONELIFE) – Protocol for a Randomized Clinical Trial\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003eAcute hypoxic respiratory failure represents one of the most common reasons for intensive care unit (ICU) admission\u003csup\u003e1\u003c/sup\u003e. Initial management of hypoxemic patients should involve immediate administration of simple supplemental oxygen via a nasal prong or a non\u0026ndash;rebreather mask, or more complex forms of respiratory support like high\u0026ndash;flow nasal oxygen (HFNO) oxygen or non\u0026ndash;invasive ventilation (NIV), depending on severity of hypoxic respiratory failure and the underlying cause, but also patient characteristics and the availability of oxygen interfaces. Unfortunately, patients with acute hypoxemic respiratory failure often need proceed with invasive ventilation. While life\u0026ndash;saving, this intervention comes with disadvantages, including ventilator\u0026ndash;induced lung injury and respiratory muscle waist, but also intubation\u0026ndash;related side\u0026ndash;effects. In addition, intubated patients often need sedation, which has side\u0026ndash;effects of its own.\u003c/p\u003e\n\u003cp\u003eIn intubated invasively ventilated ICU patients, prone positioning can be used to improve oxygenation, and this intervention has been shown to improve outcome in patients with severe ARDS. This survival benefit could be mediated, at least in part through a reduction in direct harm to lung tissue, as regional differences in lung aeration, compliance, and shear strain are minimized by this intervention\u003csup\u003e2,3\u003c/sup\u003e. In theory, nonintubated patients could also benefit from prone positioning\u003csup\u003e4,5\u003c/sup\u003e, a strategy named \u0026apos;awake prone positioning\u0026apos;\u003csup\u003e6,7\u003c/sup\u003e. Some evidence for benefit of awake prone positioning comes from a handful of studies, mostly case reports and single\u0026ndash;center observation case series\u003csup\u003e5,8,9\u003c/sup\u003e. The findings thus far show that awake prone positioning can indeed improve oxygenation and also reduce dyspnea sensation. Besides that, awake prone positioning seems to be well\u0026ndash;accepted and easy to perform, and to have relatively few side\u0026ndash;effects\u003csup\u003e10\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eIn the absence of sufficient randomized clinical trial evidence, we designed the PRONELIFE study, a pragmatic study that compares standard care with awake prone positioning versus standard care without awake prone positioning in patients with acute hypoxemic respiratory failure from any cause. We hypothesize that awake prone positioning reduces the need for intubation.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cem\u003eDESIGN\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe \u0026apos;PRone positioN in patients with spontanEous ventiLation and acute hypoxemic respIratory FailurE\u0026apos; (PRONELIFE) study is a pragmatic, investigator\u0026ndash;initiated, international and multicenter, two\u0026ndash;arm, randomized clinical trial in patients with acute hypoxemic respiratory failure from any cause. The study will be conducted according to the Declaration of Helsinki principles as stated in the current version of Fortaleza, Brazil, 2013\u003csup\u003e11\u003c/sup\u003e. The Institutional Review Board of the Sagrat Cor University Hospital, Barcelona, Spain, approved the study protocol (reference number 2019/68-UCI-HUSC). The study is registered at www.clinicaltrials.gov (NCT04142736, October 2019). The PRONELIFE study is planned to be performed in the 35 ICUs worldwide. Patients will be provisionally included under a strategy of deferred consent, for reasons as explained below.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCONSORT DIAGRAM\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe Consolidated Standards of Reporting Trials (CONSORT)\u003csup\u003e12\u003c/sup\u003e diagram of the PRONELIFE study is presented in \u003cstrong\u003eFigure 1\u003c/strong\u003e. Consecutive patients admitted to the participating ICUs are screened for eligibility. Demographic data are registered regardless of meeting enrollment criteria. If excluded from participation, the reason(s) for exclusion will be reported.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eINCLUSION AND EXCLUSION CRITERIA\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003ePatients admitted to the ICU with acute hypoxemic respiratory failure from any cause will be eligible for participation, unless prompt intubation is irrepressible (\u003cstrong\u003eTable 1\u003c/strong\u003e). Acute respiratory failure is defined as the need for supplementary oxygen with an FiO\u003csub\u003e2\u003c/sub\u003e of at least 40% by Venturi facemask, HFNO, NIV or CPAP needed to achieve and maintain an SpO\u003csub\u003e2\u003c/sub\u003e of between 88 to 92%.\u003c/p\u003e\n\u003cp\u003eThe PRONELIFE study has the following exclusion criteria: age \u0026lt; 18 years, having any contraindication for prone positioning (\u003cstrong\u003eTable 2\u003c/strong\u003e), previously participation in this trial, and participation in other interventional trials with the same primary endpoint. We also exclude pregnant patients, patients who refuse intubation, and those only receiving comfort care. As patients will be provisionally included under a strategy of deferred consent, there is no need for written informed consent at start of the study\u0026ndash;\u0026ndash;however, if consent is not obtained within 48 hours, a patient drops out of the study and will be replaced.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSTUDY ENDPOINTS\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe primary endpoint is the composite of tracheal intubation and all\u0026ndash;cause mortality within 14 days after enrollment.\u003c/p\u003e\n\u003cp\u003eSecondary endpoints are the effects of awake proning on the following clinical outcomes variables:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003etime to tracheal intubation (only in patients who need invasive ventilation);\u003c/li\u003e\n \u003cli\u003eoxygenation parameters;\u003c/li\u003e\n \u003cli\u003edyspnea sensation (while awake in prone versus supine position);\u003c/li\u003e\n \u003cli\u003ethe number of days free from invasive ventilation and alive at day 28;\u003c/li\u003e\n \u003cli\u003eduration of use of non\u0026ndash;invasive ventilatory support, including the use of a non\u0026ndash;rebreather mask, CPAP, high\u0026ndash;flow nasal oxygen (HFNO) oxygen or noninvasive ventilation (NIV);\u003c/li\u003e\n \u003cli\u003eduration of invasive ventilation;\u003c/li\u003e\n \u003cli\u003eventilation-free days (VFD) at 28 days from ICU admission, defined as the number of days alive and free from IMV during the first 28 days from start of IMV\u003c/li\u003e\n \u003cli\u003elength of stay in ICU and hospital;\u003c/li\u003e\n \u003cli\u003emortality in ICU and hospital, and at 28, 60, and 90 days; and\u003c/li\u003e\n \u003cli\u003etolerance of prone positioning (only in patients in the prone positioning group).\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cem\u003eRANDOMIZATION AND BLINDING\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eRandomization will be performed using a dedicated\u0026nbsp;password\u0026ndash;protected website and will be balanced per center. Central randomization with the use of a permutated\u0026ndash;block randomization list (with block sizes of 4 to 8) will be used. Participants will be allocated to the prone positioning or standard care on a 1:1 ratio. By the nature of the intervention it will not be possible to blind clinicians to whether a participant has been randomized to awake proning or standard care.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePRONE POSITIONING\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe study intervention will last for at least 48 hours and is divided in 4 blocks of 6 hours each: patients will be placed in the prone position for up to 2 hours, which can be prolonged if the patient feels comfortable, but could also be interrupted if a patient meets any of the discontinuation criteria which are any of the following:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003edeveloping a contraindication (\u003cstrong\u003eTable 1\u003c/strong\u003e);\u003c/li\u003e\n \u003cli\u003eworsening of dyspnea (at any time, according to predefined criteria, as described in \u003cstrong\u003eTable 2\u003c/strong\u003e);\u003c/li\u003e\n \u003cli\u003ea further and sustained drop in SpO\u003csub\u003e2\u003c/sub\u003e refractory to an increase in FiO\u003csub\u003e2\u003c/sub\u003e;\u003c/li\u003e\n \u003cli\u003enausea or vomiting; and\u003c/li\u003e\n \u003cli\u003eincreasing hemodynamic instability that is unrelated to sedatives (if given) and cannot be corrected by vasopressor or inotrope infusion (as described in \u003cstrong\u003eTable 3\u003c/strong\u003e)\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eDuring the change in position, from supine to prone or from prone to supine, FiO\u003csub\u003e2\u003c/sub\u003e will be increased by 25% above baseline. Each change in position is guided by two healthcare workers and an attending physician, but more healthcare workers could be needed. While the patient remains in a prone position, skin protection will be used to avoid pressure sores. Also, the application of cushions will enhance patient tolerance. Arms can be at the side, in a swimmer\u0026apos;s position, and can be moved to increase comfort.\u003c/p\u003e\n\u003cp\u003eFood and comfort breaks are planned while patients are in supine. If the patient is receiving enteral or oral feeding, this is interrupted from 1 hour before prone until a patient is in a supine position.\u003c/p\u003e\n\u003cp\u003eThe best\u0026ndash;fitting and most\u0026ndash;tolerated oxygen interface will be used in the prone position\u0026ndash;\u0026ndash;this could be different from patient to patient, and different from what is used in the supine position, and could differ between patients but also institutions (i.e., depending on the availability of masks with or without a reservoir bag and with or without the Venturi system, HFNO, CPAP or NIV).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSTANDARD OF CARE\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eIn all patients, whether receiving prone positioning or not, the best standard of care is provided, according to the standard care by the local teams.\u003c/p\u003e\n\u003cp\u003eWhen in a supine position, the patient will be placed in 30\u0026ndash;45\u0026deg; semi\u0026ndash;recumbent position but this can be changed for the comfort of the patient to supine, semi\u0026ndash;sitting, sitting or a lateral decubitus position).\u003c/p\u003e\n\u003cp\u003eVitals parameters, including SpO\u003csub\u003e2\u003c/sub\u003e and the SpO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e are continuously monitored. The oxygenation target ranges for SpO\u003csub\u003e2\u003c/sub\u003e is 88% to 92%; this is 7 kPa to 8 kPa for PaO\u003csub\u003e2\u003c/sub\u003e. For patients in whom the risk of potentially dangerous hypoxemia could be become unacceptable during the study (e.g., in patients who develop cardiac ischemia due to cardiac infarction or failed revascularization, or severe untreatable anemia such as with Jehovah\u0026apos;s Witnesses), oxygenation target ranges can be higher, 94% to 96% for SpO\u003csub\u003e2\u003c/sub\u003e and 9 kPa to 11.5 kPa for PaO\u003csub\u003e2\u003c/sub\u003e\u003csup\u003e13\u0026ndash;15\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eOpiates and benzodiazepines are allowed at low dosages to improve comfort.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eINTUBATION CRITERIA\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe decision to continue with invasive mechanical ventilation is based on clinical judgment rather than isolated gasometrical criteria. Any of the following criteria should be considered for proceeding to endotracheal intubation:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eRespiratory or cardiac arrest;\u003c/li\u003e\n \u003cli\u003eRespiratory pauses;\u003c/li\u003e\n \u003cli\u003eAltered level of consciousness such as uncontrolled agitation not responding to medical treatment, or a drop in the Glasgow Coma Score;\u003c/li\u003e\n \u003cli\u003eEvidence of exhaustion such as an unacceptable increase in use of accessory muscles or thoracoabdominal paradox;\u003c/li\u003e\n \u003cli\u003eInability to clear secretions from the airway in patients with abundant sputum production, or evidence of aspiration; or\u003c/li\u003e\n \u003cli\u003eHemodynamic instability as defined in \u003cstrong\u003eTable 3\u003c/strong\u003e\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eIn addition, the presence of 2 of the following criteria within 1 hour of start non\u0026ndash;invasive ventilatory support:\u003c/p\u003e\n\u003cul class=\"decimal_type\"\u003e\n \u003cli\u003eRespiratory rate \u0026gt; 35 breaths/min, or increased respiratory rate from the baseline;\u003c/li\u003e\n \u003cli\u003eNot improving or increased dyspnea;\u003c/li\u003e\n \u003cli\u003epH \u0026lt; 7.30 or less from its baseline, or PaCO\u003csub\u003e2\u003c/sub\u003e \u0026gt; 20% from the baseline value; or\u003c/li\u003e\n \u003cli\u003eSpO2 \u0026lt; 88%\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cem\u003eWEANING FROM THE NON\u0026ndash;INVASIVE OXYGEN DELIVERY SYSTEM\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWeaning from the oxygen therapy delivery system will be done according to local protocols and preferences. \u003cstrong\u003eTable 4\u003c/strong\u003e provides guidance for oxygen requirements coupled with the reduction in gas flow rates of the HFNO.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eINVASIVE VENTILATION\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eIf patient continues with invasive ventilation, settings are chosen in line with the local guidelines for invasive ventilation. The use of lung\u0026ndash;protective ventilation with a low tidal volume and low pressures is advocated. Also, sufficient levels of PEEP should be used, and prone positioning is to be applied if a patient meets develops severe hypoxemia, defined as PaO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e \u0026lt; 150 mmHg at a minimum FiO\u003csub\u003e2\u003c/sub\u003e of 60% and 5 cm H\u003csub\u003e2\u003c/sub\u003eO).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFLUID REGIMENS\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWe advise to use a restricted fluid strategy, i.e., targeting a neutral cumulative fluid balance as soon as a patient can be weaned of vasopressors. Crystalloid infusions are preferred over colloid infusions.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSEDATION\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eIn patients under invasive ventilation, the local guideline for sedation is to be followed, and preferably consists of combinations of use of analgo\u0026ndash;sedation over hypno\u0026ndash;sedation, use of bolus over continuous infusion of sedating agents, and the use of sedation scores (e.g., 3 times per day, and using a Richmond Agitation Sedation Scale\u003csup\u003e16,17\u003c/sup\u003e. Also, the level of pain is to be determined, e.g. by using the Numeric Rating Scale, the Visual Analogue Scale (VAS), the Critical Care Pain Observation Tool (CCPOT) or Behavioral Pain Scale (BPS).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eWEANING FROM INVASIVE VENTILATION\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWeaning from invasive ventilation follows local protocols and preferences. In all patients, should be tested whether the patient accepts assist ventilation at least two times a day; this should also be tried when the patient shows respiratory muscle activity during assist ventilation. The attending physician decides when to extubate a patient, based on general extubation criteria (i.e., responsive and cooperative, adequate cough reflex, adequate oxygenation with FiO2 \u0026le; 0.4, hemodynamically stable, no uncontrolled arrhythmia and a rectal temperature \u0026gt; 36\u0026deg; Celsius and after successfully passing a spontaneous breathing trial (SBT) with a T\u0026ndash;piece or ventilation with minimal support (pressure support level \u0026lt; 10 cm H2O) and FiO2 \u0026le; 0.4. In case SBTs are used, an SBT is judged as successful when the following criteria are met for at least 30 minutes, the attending physician takes the final decision for extubation:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eRespiratory rate \u0026lt; 35 breath/min;\u003c/li\u003e\n \u003cli\u003ePeripheral oxygen saturation \u0026gt; 90%;\u003c/li\u003e\n \u003cli\u003eIncrease \u0026lt; 20% of heart rate and blood pressure; and\u003c/li\u003e\n \u003cli\u003eNo signs of anxiety and diaphoresis.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cem\u003eDATA COLLECTION\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eOn ICU admission and within 48 hours, demographic and baseline data and data on disease severity will be collected. Data collection includes gender, age, height, weight, date of hospital admission, date of ICU admission, cause of respiratory failure, chest X-ray, the Sequential Organ Failure Assessment (SOFA) score, the Acute Physiology and Chronic Health Evaluation II (APACHE II) score and the Simplified Acute Physiology Score II (SAPS II).\u003c/p\u003e\n\u003cp\u003eData on the standard of care (described below) will be collected daily for the first 48 hours and every 6 hours, up to day 28. The total number of hours spent in prone position in a day (cumulative), the number of prone sessions and their duration is recorded. After the protocol, every day until day 14, clinical outcome variables discharge of the ICU or death, whichever comes first. Data on duration of non\u0026ndash;invasive respiratory support, length of stay in ICU and hospital, location of the patient (in ICU, hospital, another facility, or home), and life status (alive or deceased) will be assessed on 28 and 90 days (\u003cstrong\u003eFigure 3\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eOne hour before each position change (supine to prone and prone to supine), the following variables will be collected for the duration of the protocol: respiratory variables (respiratory rate SpO\u003csub\u003e2\u003c/sub\u003e, SpO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e, ROX index; SpO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e: RR, dyspnea defined according to the Borg dyspnea scale); noninvasive mean arterial pressure; heart rate; noninvasive support device parameters: Venturi facemask, HFNO, CPAP, NIV; adverse effects possibly related to prone position (hypotension, bradycardia hypoxemia, pressure ulcers, vomiting, displacements of the respiratory support device, peripheral or venous central line, orogastric or nasogastric tube, or urinary catheter), if any are recorded.\u003c/p\u003e\n\u003cp\u003eIn case prone positioning is not tolerated, all reasons for a premature change in body position are reported.\u003c/p\u003e\n\u003cp\u003eThe following parameters of the respiratory support devices will be collected within 1 hour before and 1 hour after randomization, and every day at a fixed time point until cessation of the respiratory support: Venturi facemask: flow (liters/min), FiO\u003csub\u003e2\u003c/sub\u003e; HFNO: flow (liters/min), FiO\u003csub\u003e2\u003c/sub\u003e; CPAP: PEEP, flow (liters/min), tidal volume, FiO\u003csub\u003e2\u003c/sub\u003e; NIV: PEEP, pressure support over PEEP, flow (liters/min), tidal volume, FiO\u003csub\u003e2\u003c/sub\u003e.\u003c/p\u003e\n\u003cp\u003eIf the patient meets the criteria for intubation, the reasons for intubation are documented in the eCRF.\u003c/p\u003e\n\u003cp\u003eData on the administration on the administration of steroids, Remdesivir, Tocilizumab, Heparin/low molecular weight heparin, antihypertensive medications are recorded. Fluid balance is collected form the nursing chart.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePOWER CALCULATION\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWe will include a total of 650 patients. The required sample size is calculated using data from two multicenter randomized controlled trials reporting intubation rates in patients with acute hypoxemic respiratory failure\u003csup\u003e18,19\u003c/sup\u003e. It was conservatively assumed that the rate of tracheal intubation will be 45% in the standard treatment group. Accordingly, 650 patients (n= 325 per group) would provide 80% power to detect a relative risk of 0.75 for the primary endpoint at a 2-sided \u0026alpha; level of 0.05, assuming a dropout rate of 10%. After enrollment of 70% of the patients, an unblinded sample size reestimation will be performed, and sample size could be increased to a maximum of 1000 patients if needed.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eDEFERRED INFORMED CONSENT\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eFor this study, we will include patients using a strategy using deferred informed consent because we explicitly want to randomize and start ventilation according to randomization within 1 hour after ICU admission. Nevertheless, the legal representative\u0026apos;s written informed consent will be requested as soon as possible thereafter and never later than 48 hours after randomization. If informed consent is not obtained within those 48 hours, or if a legal representative denies participation within this time frame, the patient is excluded, and data will no longer be used, nor will this patient be counted for the sample size of 325 inclusions in each group (that is the provisionally included patient for whom informed consent is not obtained within the time frame of 48 hours is \u0026apos;replaced\u0026apos; by a new patient until the total number of 325 patients in each arm is definitively included).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSTATISTICAL ANALYSIS\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eStatistical analysis will be based on the intention\u0026ndash;to\u0026ndash;treat principle. We will also perform a per\u0026ndash;protocol analysis, comparing patients who received awake prone positioning and patients who received standard of care.\u003c/p\u003e\n\u003cp\u003eContinuous normally distributed variables will be expressed by their mean and standard deviation or when not normally distributed as medians and their interquartile ranges. Categorical variables will be expressed as n (%). Where appropriate, statistical uncertainty will be expressed by the 95%\u0026ndash;confidence levels.\u003c/p\u003e\n\u003cp\u003eThe primary outcome, the number of days free of ventilation at day 14, will be analyzed using Cox\u0026apos;s regression. The possible imbalance between groups will be modeled in the Cox model. To further compare groups, Student\u0026apos;s t-test will be used. If continuous data is not normally distributed, the Mann-Whitney U-test will be used. Categorical variables will be compared with the Chi-square test or Fisher\u0026apos;s exact tests. Time\u0026ndash;dependent data will be analyzed using a proportional hazard model adjusted for possible imbalances of patients\u0026apos; baseline characteristics. No interim analysis will be conducted.\u003c/p\u003e\n\u003cp\u003eA P\u0026ndash;value \u0026lt; 0.05 is considered statistical significance. The analysis will be performed with R statistics version 3.0.2 (R Foundation, Vienna, Austria).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSTUDY ORGANIZATION\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe steering committee comprises the principal investigator, the coordinating investigators, and eight (inter\u0026ndash;) national experts in ventilatory support in critically ill patients.\u003c/p\u003e\n\u003cp\u003eThe coordinating investigator is responsible for administrative management and communication with the local investigators and assists at the participating clinical sites in trial management, record keeping, and data management. The coordinating investigators help set up local training in the participating ICUs to ensure the study is conducted according to the ICH\u0026ndash;GCP guidelines, guarantee data collection integrity, and ensure timely completion of the case report forms. The local investigators provide structural and scientific leadership. They guarantee the integrity of data collection and ensure timely completion of the case report forms.\u003c/p\u003e\n\u003cp\u003eAn independent monitor will be installed. Remote monitoring utilizing queries on the database will be done by a statistician and analyzed by the monitor to signalize early aberrant patterns, trends, issues with consistency or credibility, and other anomalies. On-site monitoring will comprise controlling the presence and completeness of the research dossier and the informed consent forms, and source data checks will be performed in the files of 25 % of the patients.\u003c/p\u003e\n\u003cp\u003eAn independent Data and Safety Monitoring Board (DSMB) watches over the ethics of conducting the study under the Declaration of Helsinki, monitors safety parameters and the overall conduct of the research. The DSMB is composed of three independent individuals (Prof. Arthur Slutsky, Prof. Claude Guerin, and Dr. T\u0026agrave;i Pham). The DSMB will meet by conference calls. The first meeting is scheduled after the first 100 patients. After this meeting, the DSMB will meet every six months.\u003c/p\u003e\n\u003cp\u003eAll unexpected adverse events will be reported to the DSMB. Any report or advice of the DSMB will be sent to the sponsor of the study, the Institut d\u0026apos;Investigaci\u0026oacute; i Innovaci\u0026oacute; Parc Taul\u0026iacute; (I3PT), Sabadell, Spain. Should the sponsor decide not to implement the advice of the DSMB fully, the sponsor will send the recommendation to the reviewing Institutional Review Board, including a note to substantiate why (part of) the advice of the DSMB will not be followed.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003ePRONELIFE is amongst the first clinical trials of awake prone positioning in patients with acute hypoxemic respiratory failure that will recruit a sufficient number of patients to test the hypothesis that this intervention prevents tracheal intubation. PRONELIFE will also collect data regarding other patients\u0026ndash;centered outcomes, including duration of ventilation if needed, length of stay in ICU and hospital, and mortality. We will also study the tolerability of awake prone positioning and its effects on oxygenation.\u003c/p\u003e\n\u003cp\u003eInvasive ventilation is a life\u0026ndash;support strategy associated with serious complications that may result in significant morbidity and mortality. In addition, endotracheal intubation is a high\u0026ndash;risk procedure in critically ill patients, with major complications like severe hypoxemia, cardiovascular instability, and even cardiac arrest\u003csup\u003e20\u0026ndash;22\u003c/sup\u003e. The primary endpoint of this study is a composite of the need for invasive ventilation and death within the first 14 days. We decide to use this composite endpoint, hypothesizing that the intervention under study will impact two outcomes that are invariable related. Using a composite outcome will also increase the event rate, improve the statistical efficiency for sample size calculation, and improve the study\u0026apos;s precision. We chose the need for invasive ventilation and death within the first 14 days because we hypothesize that the impact of awake prone positioning will not last beyond the first two weeks. Of note, we will report the two components of the composite as two secondary endpoints.\u003c/p\u003e\n\u003cp\u003eEvidence for the benefit of awake prone positioning in nonintubated ICU patients is scarce. Its first use was described in a case series of patients with hypoxemic respiratory failure, showing improvements in oxygenation\u003csup\u003e8\u003c/sup\u003e. Improvements in oxygenation were also reported in two studies in patients with severe hypoxemia after lung transplantation\u003csup\u003e5,23\u003c/sup\u003e. A rapidly growing number of mainly small observational studies describe the use of awake prone positioning in patients with spontaneous breathing with acute respiratory failure in whom hypoxemia is refractory to supplementary oxygen. It has been shown that awake prone positioning can improve oxygenation within minutes\u003csup\u003e24\u0026ndash;28\u003c/sup\u003e, and the effects are maintained for up to one hour after turning back to supine and disappear mostly after 6 to 12 hours\u003csup\u003e24,29\u003c/sup\u003e. A total of 15 studies, representing 449 patients, were recently used in one meta\u0026ndash;analysis\u003csup\u003e30\u003c/sup\u003e, assessing the change in oxygenation (i.e., PaO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e ratio, PaO\u003csub\u003e2\u003c/sub\u003e, and SpO\u003csub\u003e2\u003c/sub\u003e) induced by awake prone positioning. Two recent studies failed to show benefit of awake prone positioning in patients with acute respiratory failure\u003csup\u003e31,32\u003c/sup\u003e. Of note, one of these studies had an observational design, and it remained uncertain whether the intervention was used as a routine or life\u0026ndash;saving therapy\u003csup\u003e32\u003c/sup\u003e. The other study was a randomized clinical trial that was underpowered for sample size estimation\u003csup\u003e31\u003c/sup\u003e. In both studies, patients were only included patients with COVID-19 infection. Evidence suggests that direct versus indirect causes of lung injury possess different pathophysiologic characteristics that might impact both the progression and outcome of ARDS\u003csup\u003e33\u0026ndash;35\u003c/sup\u003e. Therefore, the prone position could affect mortality, and its impact may vary according to the etiology of lung injury. Also, in both studies, the intubation criteria were not clearly defined. Our study will include different etiologies of acute respiratory failure, and we have clearly described intubation criteria.\u003c/p\u003e\n\u003cp\u003eAwake prone positioning is an attractive intervention for several reasons. First, many patients with hypoxemic acute respiratory failure seem to tolerate awake prone positioning relatively well\u003csup\u003e24,36,37\u003c/sup\u003e. Awake prone positioning is also associated with few complications. Data are limited, but thus far, no severe adverse events have been described in the literature. Pressure sores, frequently developing in intubated ICU patients\u003csup\u003e38\u003c/sup\u003e and with higher morbidity\u003csup\u003e39\u003c/sup\u003e, have only been rarely described in patients who received awake prone positioning\u003csup\u003e9,31\u003c/sup\u003e. Intolerance to awake prone positioning could be related to musculoskeletal discomfort\u003csup\u003e24,26,37,40\u003c/sup\u003e, nausea and vomiting\u003csup\u003e26\u003c/sup\u003e, cough\u003csup\u003e37\u003c/sup\u003e, and anxiety\u003csup\u003e40\u003c/sup\u003e. Our study will focus on these aspects.\u003c/p\u003e\n\u003cp\u003ePRONELIFE will also collect other important and patient\u0026ndash;centered endpoints such as dyspnea sensation, duration of use of noninvasive ventilatory support and duration of invasive ventilation, and the classical ICU endpoints like the length of ICU and hospital stay, and various mortality rates.\u003c/p\u003e\n\u003cp\u003eWe anticipate the PRONELIFE study to be highly feasible and easy to conduct as the study procedures are straightforward, without difficult or complex interventions making the treatment of patients clear and easy. Furthermore, the PRONELIFE study uses a deferred consent strategy to include patients rapidly in the study and those admitted during evenings or nights when researchers and family members are often not around to ask for informed consent. This will create a study population representative of the average ICU population. Also, PRONELIFE will be performed in the ICUs of different hospitals worldwide, increasing the generalizability of its findings. Furthermore, we include patients with any cause of respiratory failure.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOne important limitation of PRONELIFE is that blinding is not possible due to the nature of the intervention tested, which could induce bias. However, the indication for invasive ventilation, which directly influences the primary outcome, is clearly stated, and all analyses will be performed in a blinded fashion. Second, we foresee that another limitation could derive from the time under prone position a patient with spontaneous breathing could tolerate continuously. Knowing from studies that the benefit of prone position in ARDS could depend on its duration\u003csup\u003e41\u003c/sup\u003e, the protocol design will count the total time of prone positioning for each patient. Although patients randomized to the intervention will have 2 hours under prone position, this strategy could be further prolonged if the patient feels comfortable.\u003c/p\u003e\n\u003cp\u003eThe results of PRONELIFE have the potential to change clinical practice in terms of how we manage patients with acute hypoxemic respiratory failure.\u003c/p\u003e\n\u003cp\u003eIn conclusion, the PRONELIFE study is an international, investigator\u0026ndash;initiated randomized clinical trial that is adequately powered to test the hypothesis that awake prone positioning benefits ICU patients with acute hypoxemic respiratory failure.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eTrial status\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePending to start recruiting.\u0026nbsp;\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAPACHE II: Acute Physiology and Chronic Health Evaluation II\u003c/p\u003e\n\u003cp\u003eARDS: Acute Respiratory Distress Syndrome\u003c/p\u003e\n\u003cp\u003eBPS: Behavioral Pain Scale\u003c/p\u003e\n\u003cp\u003eCCPOT: Critical Care Pain Observation Tool\u003c/p\u003e\n\u003cp\u003ecmH2O: centimeters of water\u003c/p\u003e\n\u003cp\u003eCONSORT: Consolidated Standards of Reporting Trials\u003c/p\u003e\n\u003cp\u003eCPAP: Continuous Positive Airway Pressure\u003c/p\u003e\n\u003cp\u003eDSMB: Data and Safety Monitoring Board\u003c/p\u003e\n\u003cp\u003eeCRF: Electronic Case Report Form\u003c/p\u003e\n\u003cp\u003eFiO2: Fraction of Inspired Oxygen\u003c/p\u003e\n\u003cp\u003eHFNO: High Flow Nasal Oxygen\u003c/p\u003e\n\u003cp\u003eICH-GCP: International Conference on Harmonization-Good Clinical Practice\u003c/p\u003e\n\u003cp\u003eIMV: Invasive Mechanical Ventilation\u003c/p\u003e\n\u003cp\u003eICU: Intensive Care Unit\u003c/p\u003e\n\u003cp\u003ekPa: kilopascal\u003c/p\u003e\n\u003cp\u003eMin: minute\u003c/p\u003e\n\u003cp\u003eNIV: Non-Invasive Ventilation\u003c/p\u003e\n\u003cp\u003ePaCO2: Partial Pressure of Arterial Carbon Dioxide\u003c/p\u003e\n\u003cp\u003ePaO2: Partial Pressure of Arterial Oxygen\u003c/p\u003e\n\u003cp\u003ePEEP: Positive End-Expiratory Pressure\u003c/p\u003e\n\u003cp\u003eROX: Respiratory OXygenation\u003c/p\u003e\n\u003cp\u003eSAPS II: Simplified Acute Physiology Score II\u003c/p\u003e\n\u003cp\u003eSBT: Spontaneous Breathing Trial\u003c/p\u003e\n\u003cp\u003eSOFA: Sequential Organ Failure Assessment\u003c/p\u003e\n\u003cp\u003eSpO2: Peripheral capillary Oxygen Saturation\u003c/p\u003e\n\u003cp\u003eVAS: Visual Analogue Scale\u003c/p\u003e\n\u003cp\u003eVFD: Ventilator Free Days\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLMQ, MJS, AA designed the study. LMQ, MJS, ASN, MA, DLG, OR, NJ, LlB, CH, DM, MCR, AA approved the design of PRONELIFE. ASN performed the power calculations and designed the statistical analysis plan. LMQ prepared the initial draft of this manuscript. LMQ, MJS, ASN, MA, DLG, OR, NJ, LlB, CH, DM, MCR, AA approved the initially submitted version of this manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFunding source: this study is an investigator-initiated trial, funded by the Institut d\u0026apos;Investigaci\u0026oacute; i Innovaci\u0026oacute; Parc Taul\u0026iacute; (I3PT). This study is partially funded and Sponsored by the European Society of Intensive Care Medicine and the Spanish Respiratory Society (SEPAR).\u003c/p\u003e\n\n\n\n\u003cp\u003e\u003cstrong\u003eAuthor details\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003eDepartment of Intensive Care Medicine Hospital Universitari Sant Pau, Barcelona, Spain. \u003csup\u003e2\u003c/sup\u003eTranslational Research Laboratory Institut d\u0026rsquo;Investigaci\u0026oacute; i Innovaci\u0026oacute; Parc Taul\u0026iacute; I3PT Universitat Aut\u0026ograve;noma de Barcelona Sabadell, Spain. \u003csup\u003e3\u003c/sup\u003eDepartment of Intensive \u0026amp; Laboratory of Experimental Intensive Care and Anesthesiology, Amsterdam UMC, location \u0026apos;AMC\u0026apos;, The Netherlands. \u003csup\u003e4\u003c/sup\u003eMahidol Oxford Tropical Medicine Research Unit (MORU), Mahidol University, Bangkok, Thailand. \u003csup\u003e5\u003c/sup\u003eNuffield Department of Medicine University of Oxford, Oxford, UK. \u003csup\u003e6\u003c/sup\u003eDepartment of Anesthesiology and Intensive Care Medicine, Catholic University of the Sacred Heart, \u0026apos;A. Gemelli\u0026apos; University Hospital, Rome, Italy. \u003csup\u003e7\u003c/sup\u003eDepartment of Intensive Care Medicine, Sagrat Cor University Hospital, Grupo Quironsalud, Barcelona, Spain. \u003csup\u003e8\u003c/sup\u003eDepartment of Intensive Care Medicine \u0026amp; Vall d\u0026rsquo;Hebron Research Institute, Vall d\u0026apos;Hebron University Hospital, Universitat Aut\u0026ograve;noma de Barcelona, Barcelona, Spain. \u003csup\u003e9\u003c/sup\u003eDepartment of Intensive Care Medicine, Corporaci\u0026oacute;n Sanitaria Universitaria Parc Tauli.\u0026nbsp;\u003csup\u003e10\u003c/sup\u003eCentro de Investigaci\u0026oacute;n Biom\u0026eacute;dica en Red en Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain.\u0026nbsp;\u003csup\u003e11\u003c/sup\u003eDepartment of Critical Care Medicine, Hospital Israelita Albert Einstein, Sao Paulo, Brazil. \u003csup\u003e12\u003c/sup\u003eDepartment of Intensive Care Medicine, Austin Hospital and University of Melbourne, Melbourne, VIC, Australia\u003c/p\u003e"},{"header":"References","content":"\u003cp\u003e1. \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Stefan MS, Shieh MS, Pekow PS, et al.\u0026nbsp;Epidemiology and outcomes of acute respiratory failure in the United States, 2001 to 2009: a national survey.\u0026nbsp;\u003cem\u003eJ Hosp Med\u003c/em\u003e. 2013;8:76-82.\u003c/p\u003e\n\u003cp\u003e2. \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Gattinoni L, Taccone P, Carlesso E MJ.\u0026nbsp;Prone position in acute respiratory distress syndrome. 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Clinical predictors of hospital mortality differ direct and indirect acute respiratory distress syndrome.\u0026nbsp;\u003cem\u003eChest\u003c/em\u003e. 2017;151:755-763.\u003c/p\u003e\n\u003cp\u003e36. \u0026nbsp; \u0026nbsp;\u0026nbsp;Sartini C, Tresoldi M, Scarpellini P, Tettamanti A, Carc\u0026ograve; F, Landoni G \u0026nbsp;et al.\u0026nbsp;Respiratory Parameters in Patients With COVID-19 After Using Noninvasive Ventilation in the Prone Position Outside the Intensive Care Unit.\u0026nbsp;\u003cem\u003eJAMA\u003c/em\u003e. 2020;323:2338-2340.\u003c/p\u003e\n\u003cp\u003e37. \u0026nbsp; \u0026nbsp;\u0026nbsp;Coppo A, Bellani G, Winterton D, Di Pierro M, Soria A, Faverio P \u0026nbsp;et al.\u0026nbsp;Feasibility and physiological effects of prone positioning in non-intubated patients with acute respiratory failure due to COVID-19 (PRON-COVID): a prospective cohort study. \u003cem\u003eLancet Respir Med\u003c/em\u003e. 2020;8:765-774.\u003c/p\u003e\n\u003cp\u003e38. \u0026nbsp; \u0026nbsp;\u0026nbsp;Girard R, Baboi L, Ayzac L, Richard J-C GC. The impact of patient positioning on pressure ulcers in patients with severe ARDS: results from a multicentre randomised controlled trial on prone positioning. \u003cem\u003eIntensive Care Med\u003c/em\u003e. 2014;40:397-403.\u003c/p\u003e\n\u003cp\u003e39. \u0026nbsp; \u0026nbsp;\u0026nbsp;Labeau SO, Afonso E, Benbenishty J, Blackwood B, Boulanger C BS, Al. E. Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study. \u003cem\u003eIntensive Care Med\u003c/em\u003e. 2021;47:160-169.\u003c/p\u003e\n\u003cp\u003e40. \u0026nbsp; \u0026nbsp;\u0026nbsp;Xu Q, Wang T, Qin X, Jie Y, Zha L LW. Early awake prone position combined with high-flow nasal oxygen therapy in severe COVID-19: a case series. \u003cem\u003eCrit Care\u003c/em\u003e. 2020;24:250.\u003c/p\u003e\n\u003cp\u003e41. \u0026nbsp; \u0026nbsp;\u0026nbsp;Gu\u0026eacute;rin C, Reignier J, Richard JC, Beuret P, Gacouin A, Boulain T, Mercier E, Badet M, Mercat A, Baudin O, Clavel M, Chatellier D, Jaber S, Rosselli S, Mancebo J, Sirodot M, Hilbert G, Bengler C, Richecoeur J, Gainnier M, Bayle F, Bourdin G, Leray V, Girar AL. Prone positioning in severe acute respiratory distress syndrome. \u003cem\u003eN Engl J Med\u003c/em\u003e. 2013;368:2159-2168.\u003c/p\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTABLE 1. CONTRAINDICATION FOR AWAKE PRONE POSITION\u003c/strong\u003e\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eSuspected increased intracranial pressure (e.g., severe brain injury)\u003c/li\u003e\n \u003cli\u003eHemoptysis\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eVomiting\u003c/li\u003e\n \u003cli\u003eRecent abdominal wound (less than 15 days)\u003c/li\u003e\n \u003cli\u003eTracheal surgery or sternotomy during the previous 15 days\u003c/li\u003e\n \u003cli\u003eFacial trauma or facial surgery during the previous 15 days\u003c/li\u003e\n \u003cli\u003eDeep venous thrombosis treated for less than 2 days\u003c/li\u003e\n \u003cli\u003eCardiac pacemaker inserted in the last 2 days\u003c/li\u003e\n \u003cli\u003eUnstable spine, femur, or pelvic fractures\u003c/li\u003e\n \u003cli\u003eHemodynamic instability (defined by a systolic blood pressure below 90 mmHg, mean blood pressure below 65 mmHg, or requirement for vasopressor)\u003c/li\u003e\n \u003cli\u003ePregnant women\u003c/li\u003e\n \u003cli\u003ePresence of chest tube\u0026nbsp;\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp id=\"isPasted\"\u003e\u003cstrong\u003eTABLE 2. BORG DYSPNEA SCALE\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eNothing at all\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003e0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eVery, very slight (just noticeable)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eVery slight\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eSlight breathlessness\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eModerate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eSomewhat severe\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eSevere breathlessness\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eVery severe breathlessness\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eVery, very severe (almost maximal)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eMaximal\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp id=\"isPasted\"\u003e\u003cstrong\u003eTABLE 3. HEMODYNAMIC INSTABILITY DEFINITION\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDefined as any of the following not responding to fluid resuscitation:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eSystolic arterial pressure \u0026lt; 90 mmHg, or\u003c/li\u003e\n \u003cli\u003eMean arterial pressure \u0026lt; 65 mmHg, or\u003c/li\u003e\n \u003cli\u003eIncreased needs of vasopressor agents, or\u003c/li\u003e\n \u003cli\u003eECG evidence of ischemia or significant uncontrolled ventricular arrhythmia\u0026nbsp;\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp id=\"isPasted\"\u003e\u003cstrong\u003eTABLE 4. HIGH FLOW NASAL CANNULA SCHEME FOR OXYGEN REQUIREMENTS COUPLED WITH GAS FLOW RATES*\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eFiO\u003csub\u003e2\u003c/sub\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e21-30%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e30-40%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e40-60%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e60-100%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eFlow\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e30 L/min\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e30-40 L/min\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e40-50 L/min\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e50-70 L/min\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e* In case the patient is using NIV, sessions could be interrupted when the respiratory rate is \u0026lt; 25 breaths/min and the FiO2 \u0026lt;40% (for a SpO2 88%)\u003c/p\u003e\n"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"ICU, acute respiratory failure, hypoxemia, prone position, awake prone positioning, invasive ventilation, intubation, invasive ventilation","lastPublishedDoi":"10.21203/rs.3.rs-924132/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-924132/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground\u003c/p\u003e\u003cp\u003eIt 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.\u003c/p\u003e\u003cp\u003eDesign and Methods\u003c/p\u003e\u003cp\u003eThe 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.\u003c/p\u003e\u003cp\u003eDiscussion\u003c/p\u003e\u003cp\u003eThe PRONELIFE study is amongst 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 has the potential to change clinical management of patients who may need invasive ventilation because of acute hypoxemic respiratory failure.\u003c/p\u003e\u003cp\u003eTrial registration\u003c/p\u003e\u003cp\u003eISRCTN, ISRCTN11536318. Registered 17 September 2021,\u0026nbsp;https://www.isrctn.com/ISRCTN11536318\u003c/p\u003e\u003cp\u003eThe PRONELIFE study is registered at clinicaltrials.gov with reference number NCT04142736 (October, 2019).\u003c/p\u003e","manuscriptTitle":"Awake Prone Positioning in Nonintubated Spontaneous Breathing ICU Patients with Acute Hypoxemic Respiratory Failure (PRONELIFE) – Protocol for a Randomized Clinical Trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-12-16 16:29:04","doi":"10.21203/rs.3.rs-924132/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2021-12-14T22:12:08+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2021-12-14T15:21:24+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2021-11-25T14:28:36+00:00","index":"","fulltext":""},{"type":"submitted","content":"Trials","date":"2021-09-21T03:45:46+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c6185752-777e-459e-a05b-e81503953132","owner":[],"postedDate":"December 16th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":9189301,"name":"Translational Medicine"},{"id":9189302,"name":"Internal Medicine"},{"id":9189303,"name":"Integrative \u0026 Complementary Medicine"}],"tags":[],"updatedAt":"2022-01-10T14:49:05+00:00","versionOfRecord":{"articleIdentity":"rs-924132","link":"https://doi.org/10.1186/s13063-021-05991-2","journal":{"identity":"trials","isVorOnly":false,"title":"Trials"},"publishedOn":"2022-01-10 14:49:05","publishedOnDateReadable":"January 10th, 2022"},"versionCreatedAt":"2021-12-16 16:29:04","video":"","vorDoi":"10.1186/s13063-021-05991-2","vorDoiUrl":"https://doi.org/10.1186/s13063-021-05991-2","workflowStages":[]},"version":"v1","identity":"rs-924132","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-924132","identity":"rs-924132","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}