Awake prone positioning in patients with hypoxemic respiratory failure due to COVID-19: the PROFLO multicenter randomized clinical trial

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Abstract

Background

The effect of awake prone positioning on intubation rates is not established. The aim of this trial was to investigate if a protocol for awake prone positioning reduces the rate of endotracheal intubation compared with standard care among patients with moderate to severe hypoxemic respiratory failure due to COVID-19.

Methods

We conducted a multicenter randomized clinical trial. Adult patients with confirmed COVID-19, high-flow nasal oxygen or noninvasive ventilation for respiratory support and a PaO ₂/FiO ₂ ratio ≤ 20 kPa were randomly assigned to a protocol targeting 16 h prone positioning per day or standard care. The primary endpoint was intubation within 30 days. Secondary endpoints included duration of awake prone positioning, 30-day mortality, ventilator-free days, hospital and intensive care unit length of stay, use of noninvasive ventilation, organ support and adverse events. The trial was terminated early due to futility.

Results

Of 141 patients assessed for eligibility, 75 were randomized of whom 39 were allocated to the control group and 36 to the prone group. Within 30 days after enrollment, 13 patients (33%) were intubated in the control group versus 12 patients (33%) in the prone group (HR 1.01 (95% CI 0.46–2.21), P = 0.99). Median prone duration was 3.4 h [IQR 1.8–8.4] in the control group compared with 9.0 h per day [IQR 4.4–10.6] in the prone group ( P = 0.014). Nine patients (23%) in the control group had pressure sores compared with two patients (6%) in the prone group (difference − 18% (95% CI − 2 to − 33%); P = 0.032). There were no other differences in secondary outcomes between groups.

Conclusions

The implemented protocol for awake prone positioning increased duration of prone positioning, but did not reduce the rate of intubation in patients with hypoxemic respiratory failure due to COVID-19 compared to standard care.

Trial registration

ISRCTN54917435. Registered 15 June 2020 ( https://doi.org/10.1186/ISRCTN54917435).

Supplementary Information

The online version contains supplementary material available at 10.1186/s13054-021-03602-9.

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Most cited references 34

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Acute respiratory distress syndrome: the Berlin Definition.

V Ranieri, Gordon D Rubenfeld, B Taylor Thompson … (2013)

The acute respiratory distress syndrome (ARDS) was defined in 1994 by the American-European Consensus Conference (AECC); since then, issues regarding the reliability and validity of this definition have emerged. Using a consensus process, a panel of experts convened in 2011 (an initiative of the European Society of Intensive Care Medicine endorsed by the American Thoracic Society and the Society of Critical Care Medicine) developed the Berlin Definition, focusing on feasibility, reliability, validity, and objective evaluation of its performance. A draft definition proposed 3 mutually exclusive categories of ARDS based on degree of hypoxemia: mild (200 mm Hg < PaO2/FIO2 ≤ 300 mm Hg), moderate (100 mm Hg < PaO2/FIO2 ≤ 200 mm Hg), and severe (PaO2/FIO2 ≤ 100 mm Hg) and 4 ancillary variables for severe ARDS: radiographic severity, respiratory system compliance (≤40 mL/cm H2O), positive end-expiratory pressure (≥10 cm H2O), and corrected expired volume per minute (≥10 L/min). The draft Berlin Definition was empirically evaluated using patient-level meta-analysis of 4188 patients with ARDS from 4 multicenter clinical data sets and 269 patients with ARDS from 3 single-center data sets containing physiologic information. The 4 ancillary variables did not contribute to the predictive validity of severe ARDS for mortality and were removed from the definition. Using the Berlin Definition, stages of mild, moderate, and severe ARDS were associated with increased mortality (27%; 95% CI, 24%-30%; 32%; 95% CI, 29%-34%; and 45%; 95% CI, 42%-48%, respectively; P < .001) and increased median duration of mechanical ventilation in survivors (5 days; interquartile [IQR], 2-11; 7 days; IQR, 4-14; and 9 days; IQR, 5-17, respectively; P < .001). Compared with the AECC definition, the final Berlin Definition had better predictive validity for mortality, with an area under the receiver operating curve of 0.577 (95% CI, 0.561-0.593) vs 0.536 (95% CI, 0.520-0.553; P < .001). This updated and revised Berlin Definition for ARDS addresses a number of the limitations of the AECC definition. The approach of combining consensus discussions with empirical evaluation may serve as a model to create more accurate, evidence-based, critical illness syndrome definitions and to better inform clinical care, research, and health services planning.

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Prone positioning in severe acute respiratory distress syndrome.

Claude Guerin, Jean Reignier, Jean-Christophe Richard … (2013)

Previous trials involving patients with the acute respiratory distress syndrome (ARDS) have failed to show a beneficial effect of prone positioning during mechanical ventilatory support on outcomes. We evaluated the effect of early application of prone positioning on outcomes in patients with severe ARDS. In this multicenter, prospective, randomized, controlled trial, we randomly assigned 466 patients with severe ARDS to undergo prone-positioning sessions of at least 16 hours or to be left in the supine position. Severe ARDS was defined as a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (FiO2) of less than 150 mm Hg, with an FiO2 of at least 0.6, a positive end-expiratory pressure of at least 5 cm of water, and a tidal volume close to 6 ml per kilogram of predicted body weight. The primary outcome was the proportion of patients who died from any cause within 28 days after inclusion. A total of 237 patients were assigned to the prone group, and 229 patients were assigned to the supine group. The 28-day mortality was 16.0% in the prone group and 32.8% in the supine group (P<0.001). The hazard ratio for death with prone positioning was 0.39 (95% confidence interval [CI], 0.25 to 0.63). Unadjusted 90-day mortality was 23.6% in the prone group versus 41.0% in the supine group (P<0.001), with a hazard ratio of 0.44 (95% CI, 0.29 to 0.67). The incidence of complications did not differ significantly between the groups, except for the incidence of cardiac arrests, which was higher in the supine group. In patients with severe ARDS, early application of prolonged prone-positioning sessions significantly decreased 28-day and 90-day mortality. (Funded by the Programme Hospitalier de Recherche Clinique National 2006 and 2010 of the French Ministry of Health; PROSEVA ClinicalTrials.gov number, NCT00527813.).

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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

Anna Coppo, Giacomo Bellani, Dario Winterton … (2020)

Summary Background The COVID-19 pandemic is challenging advanced health systems, which are dealing with an overwhelming number of patients in need of intensive care for respiratory failure, often requiring intubation. Prone positioning in intubated patients is known to reduce mortality in moderate-to-severe acute respiratory distress syndrome. We aimed to investigate feasibility and effect on gas exchange of prone positioning in awake, non-intubated patients with COVID-19-related pneumonia. Methods In this prospective, feasibility, cohort study, patients aged 18–75 years with a confirmed diagnosis of COVID-19-related pneumonia receiving supplemental oxygen or non-invasive continuous positive airway pressure were recruited from San Gerardo Hospital, Monza, Italy. We collected baseline data on demographics, anthropometrics, arterial blood gas, and ventilation parameters. After baseline data collection, patients were helped into the prone position, which was maintained for a minimum duration of 3 h. Clinical data were re-collected 10 min after prone positioning and 1 h after returning to the supine position. The main study outcome was the variation in oxygenation (partial pressure of oxygen [PaO2]/fractional concentration of oxygen in inspired air [FiO2]) between baseline and resupination, as an index of pulmonary recruitment. This study is registered on ClinicalTrials.gov, NCT04365959, and is now complete. Findings Between March 20 and April 9, 2020, we enrolled 56 patients, of whom 44 (79%) were male; the mean age was 57·4 years (SD 7·4) and the mean BMI was 27·5 kg/m2 (3·7). Prone positioning was feasible (ie, maintained for at least 3 h) in 47 patients (83·9% [95% CI 71·7 to 92·4]). Oxygenation substantially improved from supine to prone positioning (PaO2/FiO2 ratio 180·5 mm Hg [SD 76·6] in supine position vs 285·5 mm Hg [112·9] in prone position; p<0·0001). After resupination, improved oxygenation was maintained in 23 patients (50·0% [95% CI 34·9–65·1]; ie, responders); however, this improvement was on average not significant compared with before prone positioning (PaO2/FiO2 ratio 192·9 mm Hg [100·9] 1 h after resupination; p=0·29). Patients who maintained increased oxygenation had increased levels of inflammatory markers (C-reactive protein: 12·7 mg/L [SD 6·9] in responders vs 8·4 mg/L [6·2] in non-responders; and platelets: 241·1 × 103/μL [101·9] vs 319·8 × 103/μL [120·6]) and shorter time between admission to hospital and prone positioning (2·7 days [SD 2·1] in responders vs 4·6 days [3·7] in non-responders) than did those for whom improved oxygenation was not maintained. 13 (28%) of 46 patients were eventually intubated, seven (30%) of 23 responders and six (26%) of 23 non-responders (p=0·74). Five patients died during follow-up due to underlying disease, unrelated to study procedure. Interpretation Prone positioning was feasible and effective in rapidly ameliorating blood oxygenation in awake patients with COVID-19-related pneumonia requiring oxygen supplementation. The effect was maintained after resupination in half of the patients. Further studies are warranted to ascertain the potential benefit of this technique in improving final respiratory and global outcomes. Funding University of Milan-Bicocca.

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Author and article information

Contributors

Jacob Rosén:

ORCID: http://orcid.org/0000-0001-9518-5834

jacob.rosen@surgsci.uu.se

Journal

Journal ID (nlm-ta): Crit Care

Title: Critical Care

Publisher: BioMed Central (London )

ISSN (Print): 1364-8535

ISSN (Electronic): 1466-609X

Publication date (Electronic): 14 June 2021

Publication date PMC-release: 14 June 2021

Publication date Collection: 2021

Volume: 25

Electronic Location Identifier: 209

Affiliations

[1 ]GRID grid.8993.b, ISNI 0000 0004 1936 9457, Department of Surgical Sciences, Section of Anaesthesiology and Intensive Care Medicine, , Uppsala University, ; Entrance 78, 1 floor, 751 85 Uppsala, Sweden

[2 ]GRID grid.24381.3c, ISNI 0000 0000 9241 5705, Perioperative Medicine and Intensive Care, , Karolinska University Hospital, ; Solna, Sweden

[3 ]GRID grid.465198.7, Department of Physiology and Pharmacology, Section of Anesthesiology and Intensive Care Medicine, , Karolinska Institutet, ; Solna, Sweden

[4 ]GRID grid.413253.2, Department of Anaesthesiology and Intensive Care Medicine, , Ryhov County Hospital, ; Jönköping, Sweden

[5 ]GRID grid.8993.b, ISNI 0000 0004 1936 9457, Department of Medical Sciences, Section of Infectious Diseases, , Uppsala University, ; Uppsala, Sweden

[6 ]GRID grid.24381.3c, ISNI 0000 0000 9241 5705, Acute and Reparative Medicine, , Karolinska University Hospital, ; Solna, Sweden

[7 ]GRID grid.465198.7, Department of Molecular Medicine and Surgery, Section of Thoracic Anesthesiology and Intensive Care, , Karolinska Institutet, ; Solna, Sweden

[8 ]GRID grid.24381.3c, ISNI 0000 0000 9241 5705, Department of Infectious Diseases, , Karolinska University Hospital, ; Solna, Sweden

[9 ]GRID grid.465198.7, Infectious Diseases Unit, Department of Medicine, , Karolinska Institutet, ; Solna, Sweden

Author information

Jacob Rosén http://orcid.org/0000-0001-9518-5834

Article

Publisher ID: 3602

DOI: 10.1186/s13054-021-03602-9

PMC ID: 8200797

PubMed ID: 34127046

SO-VID: c63921a9-da40-4514-81ce-2b9032cec801

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 12 April 2021

Date accepted : 11 May 2021

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100009230, Landstinget i Uppsala län;

Funded by: FundRef http://dx.doi.org/10.13039/501100004348, Stockholms Läns Landsting;

Funded by: FundRef http://dx.doi.org/10.13039/501100009753, Region Jönköpings läns;

Funded by: FundRef http://dx.doi.org/10.13039/501100003793, Hjärt-Lungfonden;

Award ID: 20210061

Award Recipient : Peter Frykholm

Funded by: Uppsala University

Open Access :

Open access funding provided by Uppsala University.

Custom metadata

ScienceOpen disciplines: Emergency medicine & Trauma

Keywords: covid-19,awake prone positioning,intensive care,critical care,respiratory failure,high-flow nasal oxygen,noninvasive ventilation,intubation rates,mechanical ventilation

Data availability:

ScienceOpen disciplines: Emergency medicine & Trauma

Keywords: covid-19, awake prone positioning, intensive care, critical care, respiratory failure, high-flow nasal oxygen, noninvasive ventilation, intubation rates, mechanical ventilation

Awake prone positioning in patients with hypoxemic respiratory failure due to COVID-19: the PROFLO multicenter randomized clinical trial

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Abstract

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Trial registration

Supplementary Information

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Novel Coronavirus Disease COVID-19

Most cited references 34

Acute respiratory distress syndrome: the Berlin Definition.

Prone positioning in severe acute respiratory distress syndrome.

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

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