Effect of prone positioning on oxygenation and static respiratory system compliance in COVID-19 ARDS versus non-COVID ARDS

Background: Prone positioning is recommended for patients with moderate-to-severe acute respiratory distress syndrome (ARDS) receiving mechanical ventilation. While the debate continues as to whether COVID-19 ARDS is clinically different from non-COVID ARDS, there is little data on whether the physiological effects of prone positioning differ between the two conditions. We aimed to compare the physiological effect of prone positioning between patients with COVID-19 ARDS and those with non-COVID ARDS. Methods: We retrospectively compared 23 patients with COVID-19 ARDS and 145 patients with non-COVID ARDS treated using prone positioning while on mechanical ventilation. Changes in PaO 2 /FiO 2 ratio and static respiratory system compliance (Crs) after the �rst session of prone positioning were compared between the two groups: �rst, using all patients with non-COVID ARDS, and second, using subgroups of patients with non-COVID ARDS matched 1:1 with patients with COVID-19 ARDS for baseline PaO 2 /FiO 2 ratio and static Crs. We also evaluated whether the response to the �rst prone positioning session was associated with the clinical outcome. Results: When compared with the entire group of patients with non-COVID ARDS, patients with COVID-19 ARDS showed more pronounced improvement in the PaO 2 /FiO 2 ratio (adjusted difference 39.3 [95% CI 5.2–73.5] mmHg) and static Crs (adjusted difference 3.4 [95% CI 1.1–5.6] mL/cmH 2 O). However, these between-group differences were not signi�cant when the matched samples (either PaO 2 /FiO 2 -matched or compliance-matched) were analyzed. The improvements in PaO 2 /FiO 2 ratio (subdistribution hazard ratio 1.19, 95% CI 1.08–1.30) and static Crs (subdistribution hazard ratio 1.57, 95% CI 1.29–1.91) after the �rst prone positioning session were associated with successful discontinuation of mechanical ventilation in patients with COVID-19 ARDS. Conclusions: In patients with COVID-19 ARDS, prone positioning was as effective in improving respiratory physiology as in patients with


Background
After its rst outbreak in Wuhan, China in December 2019, coronavirus disease 2019 (COVID- 19) spread rapidly around the world and continues to be a global threat (1).Although most patients with COVID-19 have mild manifestations, the condition deteriorates in approximately 10%-20% of patients, requiring admission to an intensive care unit and invasive mechanical ventilation for acute respiratory distress syndrome (ARDS) (2)(3)(4).Whether ARDS due to COVID-19 (COVID-19 ARDS) is clinically distinct from ARDS due to other causes (non-COVID ARDS) has been a controversial issue (5,6).
Prone positioning is currently implemented for patients with moderate-to-severe ARDS with the potential to reduce mortality (7).The bene cial effect of prone positioning on oxygenation has been known for decades, but whether the improvement in oxygenation is directly associated with patients' survival gain has been questionable (8).We have recently shown that the extent of improvement in the ratio of partial pressure of arterial oxygen (PaO 2 ) to the fraction of inspired oxygen (FiO 2 ) after prone positioning could be a predictor of survival of patients with ARDS (9).
In this study, we aimed to investigate whether physiological responses to prone positioning differ between patients with COVID-19 ARDS and those with non-COVID ARDS, focusing not only on oxygenation, but also on static respiratory system compliance (Crs), considering recent studies that reported a prognostic value of static Crs for COVID-19 ARDS (10,11).We also evaluated whether the response to the rst session of prone positioning was associated with patients' clinical outcome.

Patients with COVID-19 ARDS
This study was a retrospective cohort study using the patients' medical records conducted at the Seoul National University Hospital, a tertiary referral hospital in South Korea, which has served as a nationally designated hospital for patients with severe and critical COVID-19.This study was approved by the institutional review board of the Seoul National University Hospital (IRB No. 2012-036-1179).We reviewed the records of all patients older than 18 years who were admitted to our center between January and December 2020 after being diagnosed as having COVID-19 using reverse transcription-polymerase chain reaction assay.Among such patients, those for whom mechanical ventilation was initiated and prone positioning was implemented were included in this study.

Treatment and prone positioning
Patients with COVID-19 ARDS were treated based on the most updated evidence at the time of their hospitalization (12,13).In patients with worsening respiratory failure, we usually used a high ow nasal cannula at rst, but mechanical ventilation with endotracheal intubation was initiated in refractory cases (14).If PaO 2 /FiO 2 ratio after initiation of mechanical ventilation was less than 200 mmHg, we actively considered prone positioning with neuromuscular blockade (7,15).Prone position was maintained for at least 16 hours per day (7).Discontinuation of prone positioning was considered if reduction in ventilator assistance was possible allowing for spontaneous or assisted ventilation.

Comparison with non-COVID ARDS
We reviewed every patient with non-COVID ARDS treated using prone positioning while on mechanical ventilation since January 2014 until December 2020, and the cohort of these patients was used for a comparison between COVID-19 ARDS and non-COVID ARDS.Some of these patients were included in our previous study (9).First, we used the entire group of patients with non-COVID ARDS while adjusting for the between-group differences.Second, for a more accurate comparison, patients with COVID-19 ARDS were matched with subgroup populations among the non-COVID ARDS group: one matched 1:1 for PaO 2 /FiO 2 ratio and one matched 1:1 for static Crs.

Study outcome and data collection
The primary outcome of this study was the extent of changes in PaO 2 /FiO 2 ratio and static Crs after the rst prone positioning session.In each patient, the changes in PaO 2 /FiO 2 ratio and static Crs were tracked during the rst prone positioning session.Using the results of arterial blood gas analysis and the ventilator setting at the time of blood sampling, PaO 2 /FiO 2 ratio and static Crs were evaluated at four timepoints for each patient: baseline (before initiation of prone positioning), P1 (approximately 10 hours after initiation of prone positioning), P2 (approximately 16 hours after initiation of prone positioning, which is the last timepoint before cessation of prone positioning), and S1 (approximately 2 hours after changing to supine position).For the main outcome of this study, each patient's response to the rst session of prone positioning was calculated as the difference in PaO 2 /FiO 2 ratio and static Crs between the baseline and P2 timepoints.

Statistical analysis
We assessed the differences between patients with COVID-19 ARDS and those with non-COVID ARDS and P values of < 0.05 for two-tailed tests were considered statistically signi cant.First, all patients with non-COVID ARDS were compared with patients with COVID-19 ARDS.Then, two subgroup populations of patients with non-COVID ARDS were used for 1:1 matched comparison with patients with COVID-19 ARDS (PaO 2 /FiO 2 -matched subgroup and compliance-matched subgroup).The matching was performed using an optimal algorithm without replacement (16).
The extent of changes in PaO 2 /FiO 2 and static Crs between baseline and P2 timepoints were compared between the COVID-19 ARDS and non-COVID ARDS groups using multivariable linear regression analysis.Comparisons between the matched samples were performed similarly (17).Because there are no de nite well-known predictors for response to prone positioning, we adjusted for age, sex, body mass index, duration of mechanical ventilation before the initiation of prone positioning, sequential organ failure assessment (SOFA) score, Charlson comorbidity index (CCI), and baseline setting of mechanical ventilator (positive end-expiratory pressure [PEEP] and tidal volume) as well as baseline PaO 2 /FiO 2 ratio, static Crs, and ventilatory ratio.Ventilatory ratio was selected as a parameter to assess the e cacy of ventilation because we did not routinely monitor the expired CO 2 level (18).
For patients with COVID-19 ARDS treated using prone positioning, we assessed whether the response of PaO 2 /FiO 2 and static Crs could predict patients' probability of successful discontinuation of mechanical ventilation within 90 days using a receiver operating characteristic (ROC) analysis.In addition, the Fine and Gray competing risk regression analysis was performed to calculate the subdistribution hazard ratio (SHR) and 95% con dence interval (CI) with adjustment for age, sex, SOFA score, CCI, and baseline PaO 2 /FiO 2 ratio and static Crs (19,20).Death occurring during mechanical ventilation was considered as the competing event.Patients who were still dependent on mechanical ventilation were censored at 90 days after the rst prone positioning session.All statistical analyses were performed using STATA software (version 14.0; StataCorp LP, College Station, TX, USA).

Clinical characteristics of patients
Until December 2020, 46 patients with COVID-19 ARDS were treated at our center using mechanical ventilation.Among them, 23 patients (50%) did not start prone positioning because their oxygenation status rapidly improved after initiation of mechanical ventilation.The remaining 23 patients (50%) were treated using prone positioning for persistent moderate-to-severe ARDS.The median interval between the diagnosis of COVID-19 and initiation of prone positioning was 9 (interquartile range [IQR] 4-12) days.To compare with patients with COVID-19 ARDS, 145 patients with non-COVID ARDS treated using prone positioning were reviewed and among them, two subgroups of 23 patients (1:1 matched for PaO 2 /FiO 2 ratio and static Crs, respectively) were selected.
Comparison of baseline characteristics and respiratory mechanics between these groups are described in Tables 1 and 2. The patients with non-COVID ARDS had more comorbidities and they were more severely ill with more organ dysfunctions and higher SOFA scores than the patients with COVID-19 ARDS.They also showed worse oxygenation (median PaO 2 /FiO 2 ratio 96 vs. 107 mmHg, P = 0.037) and lower static Crs (median 21.9 vs. 27.2mL/cmH 2 O, P = 0.005).All patients in both groups received ventilation with low tidal volume, but patients with non-COVID ARDS had higher ventilatory ratio (median 2.2 vs. 1.7,P < 0.001), requiring higher minute ventilation (median 177 vs. 140 mL/kg/min, P < 0.001).Among the patients with non-COVID ARDS, 1:1 matching was well performed, showing no between-group differences in the median values of PaO 2 /FiO 2 ratio and static Crs in PaO 2 /FiO 2 -matched and compliance-matched samples, respectively.

Oxygenation and static compliance responses
The changes in PaO 2 /FiO 2 ratio and static Crs after the rst session of prone positioning are depicted in Figure 1.Baseline measurements were performed at a median of 1.3 (IQR 0.7-2.8)hours before initiation of prone positioning.Measurements for P1 and P2 timepoints were performed at a median of 9.7 (IQR 7.6-11.2) hours and 16.0 (IQR 13.5-17.8)hours after initiation of prone positioning, respectively.Most patients with COVID-19 ARDS showed improvement in both PaO 2 /FiO 2 ratio and static Crs after prone positioning.The increase in PaO 2 /FiO 2 ratio was the most prominent at the P1 timepoint and it slightly decreased when patients were moved to a supine position (Figure 1A).The static Crs showed a continuous gradual increase during the rst prone positioning session (Figure 1B).A detailed comparison between patients with COVID-19 ARDS and those with non-COVID ARDS is presented in Table 3.
The absolute change in static Crs between baseline and P2 timepoints was also higher in patients with COVID-19 ARDS (median 3.7 [IQR -1.0-7.3]mL/cmH 2 O) than in patients with non-COVID ARDS (median -0.3 [IQR -4.0-1.9]mL/cmH 2 O).However, similar to the case of PaO 2 /FiO 2 ratio, after adjusting for other variables, this difference in static Crs was signi cant only when the analysis was conducted using the entire group of patients with non-COVID ARDS (adjusted difference 3.4 [95% CI 1.1-5.6]mL/cmH 2 O).The signi cance was lost in the analysis of matched samples (adjusted difference 0.

Association between clinical outcomes
In patients with COVID-19 ARDS, successful discontinuation of mechanical ventilation was achieved in 16 of 23 patients (69.6%) within 90 days after the rst session of prone positioning.We evaluated whether the changes in PaO 2 /FiO 2 ratio and static Crs after the rst prone positioning session were associated with successful discontinuation of mechanical ventilation.In ROC analysis, the areas under the curve were 0.893 (0.754-1.000) for the change in PaO 2 /FiO 2 ratio and 0.866 (0.714-1.000) for the change in static Crs (Figure 2).In competing risk regression analysis, the extent of improvement in PaO 2 /FiO 2 ratio (SHR 1.19, 95% CI 1.08-1.30per 10 mmHg increase) and static Crs (SHR 1.57, 95% CI 1.29-1.91 per 1 mL/cmH 2 O increase) after the rst prone positioning session were both associated with successful discontinuation of mechanical ventilation (Table 4).Among other variables, female sex, lower SOFA score, and higher baseline static Crs were associated with higher probability of successful discontinuation of mechanical ventilation.

Discussion
In this study, we compared the physiological response of prone positioning between patients with COVID-19 ARDS and non-COVID ARDS, focusing on changes in oxygenation and static Crs.Most patients with COVID-19 ARDS showed improvement in PaO 2 /FiO 2 ratio and static Crs after the rst session of prone positioning.The extent of improvement in these parameters appeared to be higher in patients with COVID-19 ARDS when compared crudely with the entire group of patients with non-COVID ARDS.However, when 1:1 matched samples (PaO 2 /FiO 2 -matched and compliance-matched) were analyzed, the physiological response to prone positioning was not different between patients with COVID-19 ARDS and those with non-COVID ARDS.
Whether patients with COVID-19 ARDS have a clinically different phenotype compared with those with typical non-COVID ARDS continues to be a controversial issue (5,21).One of the issues related to this controversy is regarding static Crs.Since the COVID-19 pandemic started, some patients with COVID-19 ARDS have been reported to have preserved static Crs despite impaired oxygenation, which is referred to as "type L (low elastance) phenotype" compared with "type H (high elastance) phenotype" (21,22).A multicenter study in Italy reported that patients with COVID-19 ARDS had higher median static Crs than those with non-COVID ARDS (41 vs. 32 mL/cmH 2 O), although there was a substantial overlap between the two groups (11).However, in several other studies, patients with COVID-19 ARDS presented with static Crs of approximately 30-35 mL/cmH 2 O, which is similar to that in previous reports of typical non-COVID ARDS (6, 10, 23-26).
In our study, patients in both groups showed substantially reduced static Crs (median 27.2 and 21.9 mL/cmH 2 O in COVID-19 and non-COVID group, respectively).Especially, patients with non-COVID ARDS in this study had extremely poor static Crs considering that a recent secondary analysis of the LUNG SAFE study, which included a large multinational cohort of patients, reported the median static Crs of 30 mL/cmH 2 O ( 27).This may be due to the selection bias that occurs in single-center studies.In fact, we could not identify any patient in either group (COVID-19 or non-COVID) who can be classi ed as having type L phenotype (static Crs ≥ 50 mL/cmH 2 O).Therefore, our ndings may not be applicable to patients with type L phenotype.
Almost every patient with COVID-19 ARDS in this study showed improvement in PaO 2 /FiO 2 ratio after prone positioning.Such improvement was rapid and most noticeable after 10 hours of prone positioning.This nding is consistent with that of another single-center study of intubated patients with COVID-19 treated using prone positioning, which reported that PaO 2 /FiO 2 ratio improved within 2 hours after initiation of prone positioning (28).In a prospective study of prone positioning in nonintubated patients, improvement in oxygenation was observed even 10 minutes after initiation of prone positioning (29).In contrast, a previous study on non-COVID ARDS showed that the oxygenation status was not always improved immediately after initiation of prone positioning (30).In other studies, including the PROSEVA trial, PaO 2 /FiO 2 ratio was higher at the end of the prone positioning session than at 1 hour after initiation of prone positioning, which is similar to our ndings for patients with non-COVID ARDS (7,31).Based on these ndings, it can be suggested that the speed of the oxygenation response after prone positioning may differ between patients with COVID-19 ARDS and those with non-COVID ARDS.Because PaO 2 /FiO 2 ratio cannot be monitored on real-time basis, monitoring oxygenation based on SpO 2 /FiO 2 ratio might provide more information on this issue.
The change in static Crs after prone positioning has not been studied as much as the change in oxygenation.In one study, static Crs was improved with prone positioning when it was accompanied only with application of high PEEP, but not with low PEEP (32).Crs is determined by compliance of the chest wall and lung.Because chest wall compliance usually decreases during prone positioning, the overall change in Crs after prone positioning depends on how much the compliance of the lung improves, which may be related to lung recruitability (8).In our study, the extent of improvement in static Crs after prone positioning appeared to be higher in patients with COVID-19 ARDS than in patients with non-COVID ARDS in a crude analysis.However, the difference was not signi cant when the analysis was performed using the matched samples.In addition to static Crs, it may be useful to monitor the lung recruitability while implementing prone positioning (33)(34)(35)(36).
The major nding of our study was that oxygenation and Crs responses after prone positioning were not different between patients with COVID-19 ARDS and those with non-COVID ARDS after careful matching and adjusting for baseline between-group differences.Because non-COVID ARDS comprises lung injuries from very heterogeneous causes, it is not easy to make a proper comparison between the two groups.Furthermore, although COVID-19 ARDS occurs by infection caused by a common single pathogen, results of several studies indicated that respiratory mechanics of patients with COVID-19 ARDS show a substantial interindividual variability, highlighting the importance of individualization in ventilator management (37).As in our study, it may be because of this interindividual variability that other studies also failed to identify signi cant differences between COVID-19 ARDS and non-COVID ARDS (38, 39).However, our nding suggests prone positioning in patients with COVID-19 ARDS is at least as effective in improving respiratory physiology as in patients with typical non-COVID ARDS.
We have recently reported that the extent of improvement in oxygenation after the rst session of prone positioning could be predictive of clinical outcome for patients with non-COVID ARDS (9).In this study, we con rmed this nding in patients with COVID-19 ARDS.In addition, we found that the improvement in static Crs after prone positioning was also associated with clinical outcome.Therefore, if the physiological effect of prone positioning is not substantial at the end of rst session, intensivists may have to consider another therapeutic options.
Our study has several limitations.First, our study was conducted at a single center and the number of patients studied was limited, although we enrolled every consecutive patient treated using prone positioning until December 2020.Second, despite our efforts to adjust for between-group differences including 1:1 matched analysis, we cannot exclude the possibility that uncontrolled individual factors affected our study ndings.Third, we could not evaluate the effect of prone positioning in patients with preserved static Crs (type L phenotype), because there were no such patients in our cohort.

Conclusions
In conclusion, in patients with COVID-19 ARDS, prone positioning was as effective in improving oxygenation and static Crs as in patients with non-COVID ARDS.Although interindividual variability in respiratory mechanics indicates the need for more individualized approaches in ventilator management, our study ndings suggest that prone positioning should be actively considered for patients with moderate-to-severe COVID-19 ARDS.In addition, the physiological response to the rst session of prone positioning should be monitored to predict the future clinical outcome.interpretation of data.JP and HYL performed the main statistical analysis, and JL and SML critically appraised those results.JP wrote the rst draft of this paper, and HYL, JL, and SML revised it critically for important intellectual content.JP, HYL, JL, and SML had access to nal version of this paper and approved it to be published.JP, HYL, JL, and SML reached agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Tables
CI, con dence interval; FiO 2 , fraction of inspired oxygen; IQR, interquartile range; PaO 2 , partial pressure of oxygen a For multivariable linear regression, the following variables were adjusted: age, sex, body mass index, duration of mechanical ventilation before initiation of prone positioning, sequential organ failure assessment (SOFA) score, Charlson comorbidity index (CCI), baseline setting of mechanical ventilator (positive end-expiratory pressure and tidal volume), and baseline respiratory mechanics before initiation of prone positioning (PaO 2 /FiO 2 , static compliance, and ventilatory ratio).

Figure 1 Changes
Figure 1

Table 1 .
Patient characteristics

Table 2 .
Acute Physiology and Chronic Health Evaluation; ARDS, acute respiratory distress syndrome; SAPS, Simpli ed Acute Physiology Score; SOFA, Sequential Organ Failure Assessment a P values are for comparison between patients with COVID-19 ARDS and patients with non-COVID ARDS.Baseline respiratory mechanics and clinical outcomes

Table 4 .
Predictors of successful discontinuation of mechanical ventilation for patients with FiO 2 , fraction of inspired oxygen; PaO 2 , partial pressure of oxygen; SOFA, Sequential Organ Failure Assessment a Subdistribution hazard ratios are described with their 95% con dence intervals.