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Effect of prone versus supine position in COVID-19 patients: A systematic review and meta-analysis

Study objective To review the effects of prone position and supine position on oxygenation parameters in patients with Coronavirus Disease 2019 (COVID-19). Design Systematic review and meta-analysis of non-randomized trials. Patients Databases of EMBASE, MEDLINE and CENTRAL were systematically searched from its inception until March 2021. Interventions COVID-19 patients being positioned in the prone position either whilst awake or mechanically ventilated. Measurements Primary outcomes were oxygenation parameters (PaO₂/FiO₂ ratio, PaCO₂, SpO₂). Secondary outcomes included the rate of intubation and mortality rate. Results Thirty-five studies (n = 1712 patients) were included in this review. In comparison to the supine group, prone position significantly improved the PaO₂/FiO₂ ratio (study = 13, patients = 1002, Mean difference, MD 52.15, 95% CI 37.08 to 67.22; p < 0.00001) and SpO₂ (study = 11, patients = 998, MD 4.17, 95% CI 2.53 to 5.81; p ≤0.00001). Patients received prone position were associated with lower incidence of mortality (study = 5, patients = 688, Odd ratio, OR 0.44, 95% CI 0.24 to 0.80; p = 0.007). No significant difference was noted in the incidence of intubation rate (study = 5, patients = 626, OR 1.20, 95% CI 0.77 to 1.86; p = 0.42) between the supine and prone groups. Conclusion Our meta-analysis demonstrated that prone position improved PaO₂/FiO₂ ratio with better SpO₂ than supine position in COVID-19 patients. Given the limited number of studies with small sample size and substantial heterogeneity of measured outcomes, further studies are warranted to standardize the regime of prone position to improve the certainty of evidence. PROSPERO Registration: CRD42021234050


Introduction
The surge of Coronavirus Disease 2019 (COVID-19) cases has overwhelmed the healthcare services in some countries [1]. Persistent hypoxemia is a common presentation in patients with severe COVID-19. Large numbers of hospitalized COVID-19 patients fulfilled the criteria of acute respiratory distress syndrome (ARDS), which require invasive mechanical ventilation and high level of patient care [2]. The need for invasive mechanical ventilation has exceeded the capacity of healthcare systems, especially for those heavily affected countries.
Prior to this pandemic of COVID-19, the application of prone position has been studied in awake patients with acute respiratory failure to avoid endotracheal intubation and reduce the need for intensive care units (ICU) admissions [3][4][5] In view of a huge demand for mechanical ventilation among COVID-19 patients, the method of prone position has been extensively utilized to improve oxygenation, minimizese incidence of intubation rate and ICU admission. The method of awake selfpronation can be applied in spontaneously breathing patients receiving non-invasive ventilation or high-flow nasal cannula (HFNC) in the setting of outside ICU. Some studies have reported an improved oxygenation with a decrease in respiratory effort when applied early in COVID-19 patients with acute respiratory failure [6]. Prone position improves the ventilation/perfusion ratio and recruitment of the dorsal lung segments, resulting in the opening of collapsed dorsal alveoli with better gas exchange and oxygenation [7,8]. In mechanically ventilated non COVID-19 patients with severe ARDS, those who received prone ventilation had a lower mortality rate [9]. However, the clinical outcomes of prone position in COVID-19 (intubated/non-intubated) patients remain unclear from the literature. Therefore, a systematic review and meta-analysis is warranted to examine the effectiveness and safety of prone position in COVID-19 patients before any recommendation can be made.
We hypothesized that prone position improved oxygenation parameters in COVID-19 patients. Our primary aim was to investigate the effect of prone position on partial pressure of arterial oxygen/fraction of inspired oxygen (PaO 2 /FiO 2 ) ratio. Secondary aims were to examine the effect of prone position on peripheral oxygen saturation (SpO 2 ), arterial partial pressure of carbon dioxide (PaCO 2 ), incidence of intubation, mortality rate and number of patients discharged alive.

Data sources and searches
The review was conducted and reported in accordance to the Cochrane Handbook Systematic Reviews of Interventions [10] and the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA statement) 2015 [11], respectively. Our review protocol was published in a public database (PROSPERO CRD42021234050) prior to the literature search. The Population (COVID-19 patients), Intervention (prone position), Comparison (supine position) and Outcomes approach was used to formulate our review questions (Online Supplement eTable 1). Databases  Case series, case reports and editorials were excluded. There was no restriction applied to the publication language and publication date. The reference lists of all the included studies were manually searched for any new or additional papers. The authors of relevant studies were contacted at least twice for any missing or unclear data.

Study selection, data items, data collection, and assessment of validity
Titles and abstracts were independently screened by two authors (EC and SMI) based on the pre-defined inclusion and exclusion criteria. Studies coded with "no" were excluded. Any studies coded with "yes" were retrieved for full text screening and screened independently by two authors (EC and SMI). Studies coded with "maybe" at any stage of study selection were resolved by third author (KN) via a discussion to achieve consensus. The selection of final included studies was discussed and agreed by all the authors.
Data of all included studies were extracted independently by two authors (EC and SMI) using a standardized online data extraction form, which was piloted prior to the data extraction. Any disagreements were resolved by a third author (KN). In addition to the measured outcome, the following data, namely author, year of publication, country, study design, total sample size, mean age, gender, body mass index, citation, severity of APACHE II, duration of prone position and types of oxygen delivered were extracted.

Outcomes
Primary outcome of this review was PaO 2 /FiO 2 ratio after prone and supine position. Secondary outcomes included SpO₂, PaCO₂, mortality rate, incidence of intubation rate and number of patients discharged alive.

Risk of bias in individual studies, summary of findings and GRADE assessment
The risk of bias for all included observational studies was independently assessed by two authors (EC and SMI) using the Newcastle-Ottawa Scale [12]. Study which scored ≥7 was considered as low risk of bias. Any disagreements were discussed and resolved by a third author (KN). The certainty of evidence (GRADE) was conducted by two authors (EC and SMI) independently. Several domains, namely the risk of bias, inconsistency, imprecision, indirectness and publication bias were assessed for all the measured outcomes. Any conflicts were discussed with a third author (KN).

Summary measures and synthesis of results
Review Manager version 5.3 (The Cochrane Collaboration, Copenhagen, Denmark) was used for all statistical analyses. A two-sided pvalue of <0.05 was denoted as statistically significant. Findings were reported as odds ratio (OR) for dichotomous outcomes and mean difference (MD) for continuous outcomes, along with 95% confidence interval (CI). When the data were presented as median and range/ interquartile range, these data were converted to mean and standard deviation [13]. I-square (I 2 ) test was used to assess heterogeneity of studies. I 2 of less than 40%, 40-60% and more than 60% were categorized as low, moderate and substantial heterogeneity, respectively [10]. In view of the limited number of studies with high heterogeneity, the random-effect model (DerSimonian-Laird method) was used to pool data for all the measured outcomes. Subgroup analysis based on intubated and non-intubated COVID-19 studies was performed on the measured outcomes to explore the substantial degree of heterogeneity. Funnel plots were used to assess for publication bias.

Study selection
The study selection process is summarized in the PRISMA flow diagram (Fig. 1). The search strategy yielded 1012 articles for titles and abstracts screening, of which 47 articles were retrieved for full text screening. After applying inclusion and exclusion criteria, thirty-five studies with a total of 1712 patients were included in this review. The list of excluded studies is showed in the Online Supplement eTable 3. Searching of trial registries found 9 ongoing studies (Online Supplement eTable 4).

Clinical characteristics of eligible studies
The clinical characteristics of included studies are demonstrated in Table 1. All the included studies were cohort studies. There were no randomized clinical studies investigating the effect of supine and prone position in COVID-19 patients. Of all, seven studies [14][15][16][17][18][19][20] had two separate cohorts for intervention and a control group whilst the rest of them  only had one cohort with pre-intervention (supine position) and post-intervention (prone position). The majority of included studies were of single centered, except two which were multi-centered [14,29]. The total sample size varied across all the included studies, ranging from 9 patients to 261 patients. Most of the recruited COVID-19 patients were from general wards, emergency departments and ICUs. The mean age of all the included studies ranged between 53 and 68 years old.
In the subgroup analysis of secondary outcomes, the effect size and direction of findings remained unchanged in both intubated and nonintubated groups for the outcomes of SpO₂, PaCO₂, incidence of intubation and number of patients discharged alive, except the incidence of mortality. The incidence of mortality became non-significant in the subgroup analysis of intubated group (studies = 1, n = 215, OR 0.66, 95% CI 0.32 to 1.33; p = 0.24, Fig. 3). Funnel plots were suggestive of publication bias for all the secondary outcomes, except for the number of patients discharged alive.

Discussion
Our meta-analysis demonstrated that COVID-19 patients with prone position were associated with higher PaO 2 /FiO 2 ratio and SpO 2 than those with supine position. However, no significant differences were observed in the PaCO 2 level, incidence of intubation and number of patients discharged alive. The certainty of evidence for our measured outcomes was very low due to observational studies in nature, inconsistency, indirectness and suggestive of publication bias. It is believed that prone position expands the collapsed dorsal lung region, resulting in a better ventilation/perfusion ratio and more homogenous distribution of lung ventilation [49][50][51]. The changes of regional ventilation in the prone and supine position can be observed in both normal and ARDS lung, indicating an even distribution of distending forces throughout the lung tissues [52]. The distribution of pulmonary blood flow in the normal or diseased lung is mainly directed dorsally whether one is in supine or prone position. With this relatively constant regional perfusion in the prone position along with a significant improvement in lung homogeneity, the effect of shunt fraction is expected to reduce and lead to a marked improvement in oxygenation. This has been demonstrated in animal and human studies that the relative shunt fraction of prone position was reduced by 30% than the supine group with injured lungs [53,54]. However, Gattinoni and colleagues reported that the improvement in oxygenation during prone position did not persist after returning to supine position and the PaO 2 /FiO 2 ratio returned to baseline at 6 h following re-supination [55]. This may be explained by the recollapsed of the previously opened dorsal lung units during prone position, resulting in ventilation/perfusion mismatch and rebound hypoxemia.
Our finding did not show an improvement in PaCO 2 after the application of prone position in COVID-19 patients. This finding has to be interpreted with caveat as our review included both spontaneously breathing and mechanically ventilated patients. The outcome of PaCO 2 may not be accurate in awake spontaneously breathing patients due to the variation in respiratory rate, tidal volume and minute ventilation. However, in the mechanically ventilated patients, controlled ventilation in prone position decreased the shunt fraction and promoted elimination of carbon dioxide [56]. Prone position is believed to reduce areas of over-distension in lung, resulting in a reduction in physiological deadspace and possibly PaCO 2. Gattinoni et al. stated that the effect of PaCO 2 in the prone and supine position is also affected by the alveolar ventilation and its relationship with the total ventilated lung volume [56]. In this review, we demonstrated no significant differences in the rate of intubation and number of patients discharged alive between the prone and supine groups. Ferrando et al. emphasized that it may be due to nonstandardized or non-protocolized intubation criteria, which may limit the generalizability of the results [14]. Among all the three included studies, there was only one paper reporting their intubation criteria [16]. The duration of prone position varied at the discretion of treating physicians across all the included studies, which introduced significant bias to our findings. Pavlov and colleagues reported that COVID-19 patients with longer duration of awake prone position were associated with lower incidence of intubation [57]. The absence of standardized intubation criteria can limit the interpretation of our findings [58].
Our meta-analysis reported that the mortality rate was lower in those who received prone ventilation. The level of evidence for mortality rate was low due to limited number of studies with small sample size. Among the five included studies, four studies included awake spontaneously breathing patients and only one study examined mechanically ventilated patients. The benefit of prone position was not significant in the  subgroup analysis of intubated group. However, a cohort study by Mathews and team showed that prone ventilation reduced mortality rate in mechanically ventilated COVID-19 patients with ARDS [59]. Prone position is a cornerstone treatment for intubated classical ARDS patients. The evidence of prone position on mortality rate in intubated or non-intubated COVID-19 patients remains uncertain as the pathophysiology of classical ARDS and COVID-induced ARDS were different.
In view of the absence of randomized controlled trials in the literature, our review included observational studies only to summarize the evidence of prone and supine position on oxygenation parameters in COVID-19 patients. In this meta-analysis, a set of strict criteria were applied to assess the included observational studies, which utilized complete full prone position as an intervention group with a control group of supine ventilation. Studies with prone position sessions that were not conducted in full prone position, namely lateral position were excluded [60,61]. There are currently two randomized controlled trials (NCT04350723-350 patients; NCT04395144-346 patients) assessing the effect of awake prone position in COVID-19 patients. The safety on prone position remains uncertain, especially in the hospital setting where back-up for invasive ventilation is not readily available. Most of our included studies did not report adverse events of both prone and supine position. In a recently published article evaluating the safety of prolonged prone position in mechanically ventilated COVID-19 patients, there were nearly 72% (38/61) developed ventral pressure wounds and 95% (58/61) had limb weakness with 8% (5/61) suffered from brachial plexus injury [47]. In another case-control study by Ibarra and team, patient's nutritional status and duration of more than 24 h in prone position were found to be the risk factors for the development of pressure sores in mechanically ventilated COVID-19 patients [62]. It is believed that awake prone position may be associated with lesser adverse events as the duration of prone position would be determined by patients as tolerated. Hyman et al. showed that COVID-19 patients who were intubated and mechanically ventilated earlier in the course of hospital admission were associated with an improved survival rate [63]. Hence, one should consider early invasive ventilation in a select group of awake prone position patients, especially when there is an excessive respiratory drive which may lead to further lung damage through patient self-inflicted lung injury [64].
The recommendations on prone position in mechanically ventilated ARDS patients are clear, but it remains uncertain for awake prone position in COVID-19 patients. The updated 'Surviving Sepsis Campaign Guidelines on the Management of Adults with Coronavirus Disease 2019  in the ICU' stated that there is insufficient evidence to issue a recommendation on the use of awake prone position in non-intubated adults with severe COVID-19 [65]. There were several confounding factors, namely indication, timing, duration, frequency of prone position and type of oxygen supplementation techniques were not standardized across all the included studies. However, the World Health Organisation COVID-19 Clinical Management Living Guidance (25 Jan 2021) suggested a conditional recommendation for awake prone position of severely ill Covid-19 patients requiring supplemental oxygen (including high-flow nasal oxygen) [66]. The recently updated "British Thoracic Society/ Intensive Care Society Guidance: Respiratory care in patients with Acute Hypoxaemic Respiratory Failure associated with COVID-19" also suggested prone position or side repositioning for COVID-19 patients in the respiratory support pathway [67]. A recent expert consensus for the management of COVID-19 related acute respiratory failure (16 Mar 2021) concluded that awake self-prone position may be considered to improve oxygenation and it should be used when supplemental oxygenation is required to maintain SpO₂ > 90% [68]. At present, awake prone position may be used to delay the respiratory deterioration in selected patients who require oxygen supplementation. This will decrease the demand for invasive mechanical ventilation and further offload the pressure placed on intensive care services worldwide, especially in the resource-limited countries. In the meantime, we await the findings of ongoing high-quality clinical trials to address the uncertainties surrounding this intervention.
Our review had several limitations, which included observational studies in nature, high degree of heterogeneity, high risk of publication bias, low level of evidence, non-standardized regime of prone position and different mode of ventilation across all the included studies. Previous studies have shown that awake prone position may be most effective when started early during the exudative phase, as opposed to the intermediate phase of ARDS [49,69]. An optimum duration of prone ventilation needs to be studied further to ensure no delay in intubation if hypoxemia condition deteriorates. The clinical criteria for endotracheal intubation should be defined to minimize heterogeneity of our measured outcomes. Different adjuvant of respiratory assist devices, namely high flow nasal cannula, continuous positive airway pressure or bi-level positive airway pressure were used across included studies, which may introduce variances to our findings.

Conclusion
In this meta-analysis, prone position improved PaO₂/FiO₂ ratio with better SpO₂ than supine position in COVID-19 patients. Given the limited number of studies with small sample size and substantial heterogeneity of measured outcomes, further studies are warranted to standardize the regime of prone position to improve the certainty of evidence.

Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Source of funding
No funding was received in support of this project.

Declaration of Competing Interest
All authors have declared that they do not have any conflicts of interest in this review.