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Prone positioning in awake COVID-19 patients: a systematic review and meta-analysis
1Department of Anesthesia and Intensive Care, Azienda Ospedale-Università di Padova, 35128 Padova, Italy
2Unit of Immunology, Rheumatology, Allergy, and Rare Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
3Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
4Hospital General Universitario de Valencia, 46014 Valencia, Spain
5I.M. Sechenov First Moscow State Medical University, Ministry of Public Health of Russia, 119991 Moscow, Russia
6Faculty of Medicine, Vita-Salute San Raffaele University, 20132 Milan, Italy
*Corresponding Author(s):laurapasin1704@gmail.com (Laura Pasin)
| History | Submitted: 15 June 2022 | Accepted: 03 August 2022 | Published: 08 July 2023 |
| Copyright: | ©2023 The Author(s). Published by MRE Press. |
Prone positioning is a well-established treatment in mechanically ventilated patients with acute respiratory distress syndrome. Although recommended by guidelines, limited evidence exists on the benefits of prone positioning in awake Corona Virus Disease 2019 (COVID-19) patients. Aim of our systematic review was to provide an overview of all published evidence on this intervention in the setting of COVID-19. Moreover, we aimed to investigate feasibility, efficacy and safety of awake prone positioning in COVID-19 patients with acute respiratory failure. Inclusion criteria were: adult hospitalized, awake, COVID-19 patients, lying in the prone position for respiratory failure. All kind of studies were included without language restriction. Eighty manuscripts involving 3226 patients were included. Need for mechanical ventilation was reported in 26.8% of patients. No periprocedural death or severe adverse events were reported. During prone positioning, a significant improvement in peripheral capillary oxygen saturation (SpO2) and ratio of arterial oxygen partial pressure (PaO2) to fractional inspired oxygen (FiO2) was obtained, together with a reduction in respiratory rate. These improvements persisted after resupination. Awake prone positioning in non-intubated COVID-19 patients is safe and improves oxygenation both during and after the end of proning cycles. Large, high-quality, randomized clinical trials are warranted to determine the impact of prone positioning on survival.
Cite this article
Laura Pasin, Lorenzo Dagna, Michela Consonni, Sabrina Boraso, Marina Munari, Carolina Soledad Romero García, Ekaterina Bulanjva, Giovanni Landoni. Prone positioning in awake COVID-19 patients: a systematic review and meta-analysis. Signa Vitae. 2023; 19(4): 31-36. doi: 10.22514/sv.2023.041
1. Introduction
Prone positioning is a well-established, evidence-based treatment in mechanically ventilated patients with acute respiratory distress syndrome (ARDS) [1]. Studies performed in mechanically ventilated patients with ARDS from different causes showed that early application of prone positioning was associated with improvement in gas exchanges and clinically relevant outcomes [2, 3]. From a physiological point of view, prone positioning reduces regional differences in alveolar inflation, ventilation distribution and pleural pressure gradient, thus improving respiratory mechanics and oxygenation [4].
Scarce evidence exists in awake patients undergoing prone non-invasive mechanical ventilations or conventional oxygen therapy. Although recommended in recent guidelines by the UK Intensive Care Society and international health care professionals [5, 6], little evidence exists on the benefits of prone positioning in awake coronavirus disease of 2019 (COVID-19) patients. COVID-19 patients are a large and not uniform population and might particularly benefit from this inexpensive intervention which might reduce the need for mechanical ventilation. This is especially true in limited resources settings or during pandemic outbreaks.
In spite of the limited available evidence-based medicine, since a high number of COVID-19 patients with respiratory failure required to be treated outside the intensive care unit (ICU), the use of prone position in awake, spontaneously breathing patients spread around the world with promising result [7, 8].
We decided to perform a systematic review and meta-analysis of all published studies on awake proning in COVID-19 patients in order to give the reader an overview of all the published evidence on this intervention in the setting of COVID-19. Moreover, we investigated feasibility, efficacy and safety of awake proning in COVID-19 patients with ARDS.
2. Methods
2.1 Search strategy
Electronic searches in Medline, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL) and ClinicalTrials.gov used different keywords and vocabulary terms (i.e., medical sub-heading (MeSH) terms, EMTREE terms). Keywords included both patient-related terms (acute respiratory distress syndrome, COVID-19, SARS-Cov-2), and treatment-related terms (pronation; prone positioning) (Supplementary Material). In addition, hand searches of the reference lists of suitable studies and review articles were conducted. No restrictions on language were applied.
2.2 Study selection and inclusion criteria
All references derived from database and literature searches were individually examined at title and abstract level by two investigators and different opinions were managed by consensus or by adjudication of a third author. If suitable, full text papers were studied. The following inclusion criteria were used: hospitalized awake COVID-19 patients; ≥18 years old; with or without sedation; lying in the prone position for respiratory failure. Exclusion criteria were: duplicate publications (in this case we included the paper reporting the longest follow-up or the largest cohort); pediatric patients; studies with overlapping cohorts; no COVID-19 patients; patients intubated before pronation; out-of-hospital setting; case reports; studies not reporting outcomes of interest.
2.3 Data abstraction
Study details, baseline patients’ clinical characteristics, and outcomes were collected by three investigators. If important data were missing, at least two attempts were conducted to contact the corresponding authors (e.g., by email). The primary endpoint of our study was intubation rate. Differences in peripheral arterial oxygen saturation (SpO2), the ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) and respiratory rate before/during and before/after pronation were also analyzed together with the occurrence of side effects.
2.4 Data analysis and synthesis
Categorical data were presented as absolute numbers and percentage. Continuous measurements were presented as means and standard deviations. When required, medians (interquartile ranges) were converted in means using the Wan’s method [9].
Before/during and before/after pronation variations in gas exchange, respiratory rate and oxygen saturation were analysed with Review Manager (RevMan) (Computer program), version 5.4, The Cochrane Collaboration, 2020 using the generic inverse variance method. Mean differences (MD) and 95% confidence interval (CI) were calculated. The Cochrane Q test was used to measure statistical heterogeneity and the level of statistical significance was set at 0.10 (for a two-tailed test). I2 was used to calculate statistical consistency, considering the formula: I2 = 100% × (Cochran’s Q, heterogeneity statistic—degrees of freedom). If statistical inconsistency was low (I2 < 25%) a fixed effect model was used. Otherwise, we chose a random-effect model. Moreover, in case of high heterogeneity, subgroup analyses according to the type of study design were performed.
Unadjusted p values were reported and p < 0.05 were considered statistically significant. Funnel plots were used to visually assess the presence of publication bias.
The study was registered on PROSPERO (registration ID: CRD42020199858) and performed in compliance with the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines and the Cochrane Collaboration and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [10, 11].
3. Results
3.1 Study characteristics
Searches in different databases and snowballing identified 1309 articles. Excluding 1198 non-suitable titles or abstracts, we collected and assessed 111 papers in complete form, according to the inclusion criteria (Fig. 1). Thirty-one studies were later excluded because of the presence of exclusion criteria (Fig. 1). Therefore, 80 manuscripts involving 3226 patients were finally included. References of all included manuscripts are presented in the Supplementary Material. Median (range) age of studies population was 58 (21–75) years and 73.5% of patients were male.
Characteristics of included manuscripts are presented in Supplementary Table 1. Clinical heterogeneity was mainly ascribable to inclusion criteria and respiratory support during proning (Supplementary Table 1).
Fig. 1.Flow-chart for manuscript selection. COVID: Corona Virus Disease 2019.
3.2 Qualitative and quantitative data synthesis
Need for mechanical ventilation was reported in 725/2704 (27%) patients. No death or severe adverse events were reported during pronation. Few authors reported mild adverse events related to prone positioning, in particular back pain, emesis, discomfort and anxiety (Supplementary Table 1). Mortality was reported in 550/3078 (18%).
During prone positioning, a statistically significant improvement in SpO2 (MD 3.07; 95% CI 4.05; 2.09; P for effect <0.001; I2 90%) and PaO2/FiO2 (MD 66.11; 95% CI 90.39; 41.83; P for effect <0.001; I2 96%) was obtained, while reducing respiratory rate (MD 2.88; 95% CI 2.11; 3.64; P for effect <0.001; I2 59%) (Table 1, Fig. 2). Beneficial effects persisted after resupination (Table 1, Fig. 3). Visual inspection of funnel plots suggests the presence of small publication biases (Supplementary material).
Subgroup analyses including only randomized clinical trials (RCTs) were not possible because of missing data on the outcomes of interest. When performing subgroup analyses including only retrospective studies or prospective studies the high heterogeneity was confirmed.
| Outcome | Number of included studies | Number of included patients | MD | 95% CI | P for effect | I2 (%) | |
| ΔSpO2 | |||||||
| during pronation | 15 | 1192 | 3.07 | 4.05, 2.09 | <0.001 | 90 | |
| after pronation | 11 | 636 | 4.85 | 7.12, 2.58 | <0.001 | 96 | |
| ΔPaO2/FiO2 | |||||||
| during pronation | 11 | 671 | 66.11 | 90.39, 41.83 | <0.001 | 96 | |
| after pronation | 16 | 948 | 37.10 | 51.40, 22.80 | 0.010 | 82 | |
| ΔRespiratory rate | |||||||
| during pronation | 13 | 760 | 2.88 | 2.11, 3.64 | <0.001 | 59 | |
| after pronation | 11 | 994 | 2.11 | 0.58, 3.64 | 0.007 | 79 | |
| MD: mean difference; CI: confidence interval; P: p-value; SpO2: peripheral arterial oxygen saturation; PaO2/FiO2: the ratio of arterial oxygen partial pressure to fractional inspired oxygen. |
Fig. 2. Forest plots for difference in peripheral capillary oxygen saturation (SpO2) and ratio of arterial oxygen partial pressure (PaO2) to fractional inspired oxygen (FiO2) and respiratory rate before and during pronation. CI: confidence interval; SD: standard deviation.
Fig. 3.Forest plots for difference in peripheral capillary oxygen saturation (SpO2) and ratio of arterial oxygen partial pressure (PaO2) to fractional inspired oxygen (FiO2) and respiratory rate before and after pronation. CI: confidence interval; SD: standard deviation.
4. Discussion
This systematic review and meta-analysis which included 80 manuscripts and 3226 COVID-19 patients who were managed with awake prone positioning showed that failure rate (need for endotracheal intubation) was 27%. Moreover, it showed that awake prone positioning was safe since no severe adverse events were recorded. When analyzing oxygenation variables (SpO2, PaO2/FiO2 and respiratory rate) of included patients, we found that they all significantly improved during prone positioning and that this effect persisted thereafter.
In accordance with our results, previous studies showed positive effects on patients’ oxygenation during proning. Ponnapa Reddy et al. [7], in a meta-analysis including 25 studies, showed that prone positioning, in non-intubated hypoxemic patients with COVID-19, significantly improved oxygenation. Touchon et al. [8] confirmed the positive effects of proning on gas exchanges during prone positioning, but the persistence after resupination remained undetermined. More recently, Fazzini et al. [9], in a meta-analysis including only studies with at least 20 patients, showed that prone positioning can improve oxygenation amongst non-intubated patients with ARDS when applied for at least 4 h over multiple daily cycles.
To the best of our knowledge, our meta-analysis, thanks to the high number of included studies (n = 80), is the first meta-analysis to demonstrate that improvement in oxygenation variables observed in COVID-19 patients undergoing awake prone positioning persisted after resupination. This finding is of great importance since it suggests that prone positioning does not just guarantee a transient improvement in oxygenation variables, but could be associated with clinical benefits, preventing the upgrading of required respiratory support and therefore improving patients’ outcome. Nonetheless, despite the increasingly published evidence, the role of awake prone positioning in reducing the need for endotracheal intubation in COVID-19 patients remains undetermined [9].
This study presents several limitations. First of all, most of the included studies were small, retrospective studies. Therefore, patient’s selection biases cannot be excluded and a high heterogeneity was observed. In addition, considerably heterogeneity was confirmed in subgroup analysis performed according to the type of study design, probably because of the presence of high clinical variability of included patients. Nonetheless, the aim of our review was to give the reader a complete overview of published evidence on this intervention in the setting of COVID-19. Therefore, all kind of studies were included. Our findings on improved oxygenation are promising, but evidence on major clinical outcome, such as a reduction in the need for intubation or in mortality, is still lacking. Hopefully, ongoing trials will help to better clarify the role of prone positioning on clinically relevant outcomes.
In conclusion, awake prone positioning in non-intubated COVID-19 patients is safe and improves oxygenation both during and after the end of the proning cycles. Large, high-quality, randomized clinical trials with standardized intubation criteria and prone positioning practice are warranted to determine the impact of prone positioning on mortality of COVID-19 patients.
Availability of data and materials
The data are contained within this article (and supplementary material).
Author contributions
LP and GL—designed the research study, performed statistical analysis. LD, MC, SB, MM, CSRG and EB—searched for articles and collect data. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Acknowledgment
Not applicable.
Funding
This research received no external funding.
Conflict of interest
The authors declare no conflict of interest. Giovanni Landoni, Laura Pasin and Carolina Soledad Romero García are serving as the Editorial Board members of this journal. We declare that Giovanni Landoni, Laura Pasin and Carolina Soledad Romero García had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to ZZ.
Supplementary material
Supplementary material associated with this article can be found, in the online version, at https://oss.signavitae.com/mre-signavitae/article/1670686619036729344/attachment/Supplementary%20material.docx.
