Prone Position in Intubated, Mechanically Ventilated Patients with Coronavirus Disease-19.


 Background: Limited data are available on the use of prone position in intubated, invasively ventilated patients with Coronavirus disease-19 (COVID-19). Aim of this study is to investigate the use and effect of prone position in this population during the first 2020 pandemic wave.Methods: Retrospective, multicentre, national cohort study conducted between February 24 and June 14, 2020 in 24 Italian Intensive Care Units (ICU) on adult patients needing invasive mechanical ventilation for respiratory failure caused by COVID-19.Clinical data were collected on the day of ICU admission. Information regarding the use of prone position were collected daily. Follow-up for patient outcomes was performed on July 15, 2020. The respiratory effects of the first prone position were studied in a subset of 78 patients. Patients were classified as Responders if the PaO2/FiO2 ratio increased ≥ 20 mmHg during prone position. Results: Of 1057 included patients, mild, moderate and severe ARDS was present in 15, 50 and 35% of patients, respectively and had a resulting mortality of 25, 33 and 41%. Prone position was applied in 61% of the patients. Patients placed prone had a more severe disease and died significantly more (45% vs 33%, p<0.001). Overall, prone position induced a significant increase in PaO2/FiO2 ratio, while no change in respiratory system compliance was observed. Seventy-eight % of patients were Responders to prone position. Non-Responders had a more severe respiratory failure and died more often in the ICU (65% vs. 38%, p=0.047).Conclusions: During the COVID-19 pandemic, prone position has been widely adopted to treat mechanically ventilated patients with respiratory failure. The majority of patients improved their oxygenation during prone position, most likely due to a better ventilation perfusion matching.Trial registration: clinicaltrials.gov number: NCT04388670

Given the high number of COVID-19 patients with respiratory failure treated outside the ICU, there has been an increasing interest in the use of prone position in awake, spontaneously breathing patients (12)(13)(14)(15)(16). On the contrary, limited data are available on the use of prone position in intubated, invasively ventilated patients (17).
Aims of the present study are: (i) to describe the frequency of use of prone positioning and the clinical characteristics and outcomes of patients undergoing prone positioning in a large cohort of critically ill, mechanically ventilated patients with COVID-19; and (ii) to describe, in a subgroup of patients, the pathophysiological effects of prone positioning.

Study design
This Italian multicentre, retrospective study of prospectively collected data was approved by the Ethical Committees of all participating centres (Promoting Centre's Ethical Committee: Comitato Etico Milano Area 2; protocol: 0008489; date of approval: March 20, 2020) and registered at clinicaltrials.gov (NCT04388670). The need for informed consent from individual patients was waived owing to the retrospective nature of the study.
All patients admitted between February 22, 2020 and June 14, 2020, inclusive for those days, to the COVID-19 ICUs of 24 Italian hospitals (see Additional File for the complete list) were screened for eligibility. Laboratory-con rmed SARS-CoV-2 infection, (i.e. positive result of real-time reverse transcriptase-polymerase chain reaction assay of nasal and pharyngeal swabs), and ICU admission for acute respiratory failure constituted the inclusion criteria.
Exclusion criteria were: age < 18 years; patients treated exclusively with non-invasive respiratory support; missing clinical data regarding the use of prone position. Clinical management (including mechanical ventilation setting and pharmacological therapies) followed the local treatment guidelines of each center. The choice to position patients prone was at discretion of the attending physician.
The population of patients included in the analysis was subdivided in two groups according to the use of prone positioning: 1) PP group: patients who were turned prone at least once during their ICU stay; and 2) SP group: patients always treated in the supine position.

Data collection
An electronic case report form (REDCap electronic data capture tools) hosted at IRCCS Ca' Granda Ospedale Maggiore Policlinico was used for data collection. An extensive set of information regarding demographic and anthropometric data, comorbidities (18) and clinical data (severity scores (19)(20)(21), vital signs, type of respiratory support, use of prone positioning, respiratory parameters, laboratory tests including blood gas analysis) was collected on the day of admission to the ICU. Relevant clinical and laboratory data, including information regarding the use of prone positioning in the prior 24 hours, were then collected daily until ICU discharge or patient death (See Additional File).
Finally, the following patient outcomes were recorded: ICU and hospital survival, ICU and hospital length of stay (LOS), duration of invasive mechanical ventilation. The nal date of follow-up for patient outcomes was July 15,

2020.
Effect of prone positioning on respiratory mechanics and gas exchange To assess the physiologic effects of pronation, a subgroup of 78 patients who underwent prone positioning in two of the participating hospitals (Grande Ospedale Metropolitano Niguarda and Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, both in Milan) was investigated at three different time points: 1) prior to the rst pronation (Baseline); 2) during the last hour of the rst session of prone ventilation (Prone); and 3) within 4 hours after turning the patients back to supine position (Supine). At each time-point, end-inspiratory and end-expiratory airway occlusion manoeuvres were performed and arterial blood gases analyzed to obtain the following variables: compliance of the respiratory system (Crs, calculated as the ratio between tidal volume and airway driving pressure); ratio between partial pressure of oxygen (PaO 2 ) and inspired fraction of oxygen (FiO 2 ), -PaO 2 /FiO 2 ratio; corrected minute ventilation (22) and ventilatory ratio (23). Patients were de ned as Responders to prone position if they had an increase of the PaO 2 /FiO 2 ratio of ≥ 20 mmHg during prone ventilation as compared to baseline values in supine position (24,25).

Statistical Analysis
Continuous variables are presented as mean with standard deviation (SD) or median and interquartile range (IQR).
Categorical variables are expressed as frequencies (percentages).
Mann-Whitney rank sum test was used to compare nonparametric continuous variables between study groups. χ2 or Fisher exact test was used for categorical variables, as appropriate.
Differences among time-points were tested by one-way ANOVA for repeated measures. Pairwise multiple comparisons were tested using Tukey's test. All statistical tests were 2-tailed, and statistical signi cance was de ned as a P value below 0.05. Analyses were performed using SAS 9.4 (SAS Institute Inc., Cary, NC, USA), STATA computer software, version 16.0 (StataCorp LLC) and SigmaPlot 12.0 (Systat Software Inc., San Jose, CA).

Use of prone positioning and differences between Pronated and Non-Pronated patients
Six-hundred and forty-eight patients (61% of the overall population) were placed in prone position at least once during their stay in the ICU (PP Group), while 409 patients (39% of the overall population) were always treated in the supine position (SP Group). The frequency of use of prone positioning increased with ARDS severity (52/128 (44%), 243/426 (57%) and 229/298 (77%), p <0.001, in mild, moderate and severe ARDS respectively). Prone positioning was rst applied 2 [1 -4] days after ICU admission and a median of 3 [1 -4] pronation sessions per patient were performed. Table 1 outlines the principal differences between the two groups (see eTable 2 in the Additional File). No difference in comorbidities was observed (Charlson Comorbidity Index 2 [1][2][3] vs. 2 [1][2][3], p = 0.165). Patients in the PP group had signi cantly more severe respiratory disease, as suggested by a higher percentage of severe ARDS (44% vs. 21%, p <0.001) and a lower percentage of mild ARDS (10 vs. 23%, p < 0.001). Respiratory rate, positive endexpiratory pressure (PEEP), FiO 2 and Plateau pressure were signi cantly higher, while respiratory system compliance, PaO 2 /FiO 2 ratio and arterial pH at ICU admission were signi cantly lower in the PP group. In addition, biochemical markers of in ammation and disease severity, such as LDH, D-dimers and ferritin were consistently higher in patients of the PP Group. Patients of the PP group had higher severity scores: SOFA (4 [3 -5] vs. 4 [3][4], p<0.001) and APACHE II scores (10 [8-13] vs. 9 [7][8][9][10][11][12][13], p<0.001). Finally, ICU mortality and length of stay, length of mechanical ventilation and hospital mortality and length of stay were all signi cantly worse in patients in the PP group.

Physiological effects of prone position
In the subgroup of 78 patients, median duration of the rst pronation was 18.5 [16][17][18][19][20][21][22] hours. Respiratory system compliance did not change signi cantly with the change in body position (Figure 1, Panel A). Similarly, prone positioning had no signi cant effect on ventilatory ratio ( Figure 1, Panel C). Overall, prone positioning led to a signi cant increase in PaO 2 /FiO 2 ratio, which was followed by a subsequent signi cant decrease with re-supination ( Figure 1, Panel B). On average, PaO 2 /FiO 2 ratio after re-supination remained signi cantly higher as compared to baseline values. Table 2 Table 3 summarizes the differences between Responders and Non-Responders (see eTable 3, in the Additional File). Demographics, comorbidities and admission severity scores were similar between Responders and Non-Responders.

Discussion
In this national, multicentre, retrospective observational study performed in the ICUs of 24 Italian hospitals during the rst peak of the 2020 COVID-19 pandemic, we investigated the use of prone positioning in a cohort of 1057 critically ill, invasively ventilated patients with respiratory failure due to COVID-19. We also analyzed the pathophysiologic respiratory effects of this manoeuvre in a subset of 78 patients. A major nding of our study is that prone positioning was applied very frequently, signi cantly more often than previously reported in other populations of ARDS patients (8,26). Indeed, 61% of our patients underwent at least one pronation session during their ICU stay, as compared to 8% of the patients enrolled in the LUNG SAFE study. The frequency of use of prone positioning increased with increasing ARDS severity. Notably, 77% of COVID-19 patients with severe ARDS underwent prone positioning, as compared to the 16% of those with severe ARDS in the LUNG SAFE cohort.
Changing body position from supine to prone (or vice versa) requires dedicated and experienced personnel. Moreover, the manoeuvre frequently requires incremental dosages of sedatives and muscle relaxants (27) and may lead to hemodynamic instability. In addition, it is associated with an increased risk of device displacement and pressure ulcers (28). It is important to underline that in our study, the decision to turn the patients in prone position was at the discretion of the ICU team, i.e. there were no pre-speci ed criteria for the application of this rescue manoeuvre. Due the overwhelming number of critically ill patients requiring ICU admission, the ICU bed capacity of our hospitals had to be rapidly increased (29). Therefore, many physicians and nurses usually working outside the ICU environment and even doctors from other specialities were recruited to allow the surge in ICU capacity. This of course reduced the expertise of the whole ICU staff. Our data clearly show that prone positioning was applied to patients with more severe disease, mainly as a rescue therapy (Table 1). Consequently, the worse clinical outcomes of patients undergoing prone positioning can be explained by the higher disease severity. However, given the retrospective nature of the study, we cannot draw any conclusions on the e cacy of prone position in terms of outcome.
Another important nding, resulting from the physiological sub-study, is that, on average, the PaO 2 /FiO 2 ratio increased signi cantly from 98 [72 -212] to 158 [112 -220] mmHg, p <0.001 (Figure 1, Panel B)  The ndings of the physiologic sub-study ( Table 2) thus suggest that the main mechanism inducing an improvement in oxygenation during the rst pronation of COVID-19 patients with ARDS, is the improvement of the ventilation-perfusion matching due to a redistribution of ow from dorsal to ventral lung areas. Indeed, the lack of improvement of respiratory system compliance with the change in body position (Figure 1, Panel A) suggests that lung recruitment was not the major mechanism. We observed a modest, though signi cant increase in set respiratory rate and a resulting trend toward higher minute ventilations during prone positioning (Table 2). However, we did not observe a signi cant variation of the ventilatory ratio, a proxy of dead space and e ciency in CO 2 removal (Figure 1, Panel C). Taken together these results suggest that CO 2 production somehow increased during prone position, requiring an increase in minute ventilation to maintain stable PaCO 2 values.
We used an increase in PaO 2 /FiO 2 ratio during pronation of at least 20 mmHg as cut-off to de ne the response to prone position in terms of oxygenation. Using this de nition, 78% of the studied patients were considered Responders. There is no universally applied criteria to de ne the response to prone position, however, when looking at literature using the same cut-off (24,25), the percentage of patients with COVID-19-induced ARDS that responded to prone position seems similar to the percentage of the "general" ARDS population (25).
When analyzing the differences between Responders and Non-Responders, we observed that, despite similar comorbidities and baseline severity scores, respiratory failure was on average more severe in Non-Responders (Table  3). Indeed, Non-Responders had higher driving pressure and ventilatory ratio, suggesting a higher extension of lung dysfunction and a lower e ciency of gas exchange. In the ARDS literature, several studies did not nd a different mortality between Responders and Non-Responders (24,25), while a recent study performed on ARDS, non-COVID patients, suggested that improved oxygenation after prone positioning might be a predictor of survival (32). Also in our study performed in COVID-19 ARDS patients, we found that the mortality of Non-Responders was signi cantly higher as compared to Responders (65% vs. 38%, p = 0.039).
The retrospective observational nature of the study is a clear limitation of our study. As already discussed, the decision to place the patient in prone position was at discretion of the attending physicians and the general clinical patient management was not standardized among centers. The comparison between the two groups gives therefore useful information about the decision-making process of Italian doctors caring for severely ill COVID-patients during the rst wave of the 2020 COVID pandemic. On the contrary, the comparison does not provide information about the e cacy of pronation in terms of outcome. In addition, we have not collected information regarding complications related to prone positioning. A certain rate of complications usually occurs during prone position. It is conceivable that the rate might be higher in the speci c context of a pandemic surge. Regarding the physiologic sub-study, the absence of information of partitioned respiratory mechanics is certainly a limitation. Nevertheless, the fact that the respiratory system compliance did not change in the 3 time-points suggests that lung recruitment did not play a signi cant role during the rst pronation.

Conclusions
During the most intense months of the rst wave of 2020 COVID-19 pandemic in Italy, critically ill, intubated and mechanically ventilated patients with ARDS were frequently placed in prone position. The more severe the respiratory failure, the more frequent the use of this rescue therapy. Placing the patients prone is a cheap and effective manoeuvre, able to improve oxygenation in the vast majority of patients with respiratory failure due to COVID-19. The main mechanisms responsible for the improved oxygenation seems to be the improvement of the ventilation/perfusion matching. Availability of data and materials: The dataset used and/or analysed during the current study are available from corresponding author on reasonable request. Consent for publication: Not applicable.
Competing interests: The authors certify that they have no a liations with, or involvement in any organization or entity with any nancial or non-nancial interest in the subject matter discussed in this manuscript.
Funding: This study was funded by institutional funds of the Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. Ricerca Corrente 2019.