Early versus late awake prone positioning in non-intubated patients with COVID-19

Coronavirus disease (COVID-19) is a viral infectious disease caused by coronavirus (SARS-CoV-2) [1]. COVID-19 primarily affects the respiratory system causing mild to severe respiratory illness. Around 25–30% of COVID-19 patients develop signs of acute respiratory distress requiring higher respiratory support in terms of oxygen therapy, noninvasive and invasive positive pressure ventilation [2]. Prone positioning improves oxygenation by the uniform distribution of tidal volume and recruitment of the dorsal lung regions leading to improved lung compliance [3]. Before the COVID-19 pandemic, a small, prospective observational study demonstrated the benefit of using prone positioning among non-intubated patients with moderate acute respiratory distress syndrome (ARDS) to reduce the need for invasive mechanical ventilation [4]. Since the emergence of COVID-19, this technique has been extensively used to improve oxygenation in non-intubated COVID-19 patients with acute hypoxemic respiratory failure (AHRF) [5].

There is evidence demonstrating the benefits of early prone positioning to improve oxygenation and patient outcomes in intubated patients with moderate to severe ARDS [6]. A recent multicenter cohort study investigating the timing of prone positioning initiation among mechanically ventilated patients with COVID-19 found a lower hospital mortality among those who received early prone positioning (within 2 days of ICU admission) [7]. Another retrospective, multicenter observational study included 827 non-intubated patients with COVID-19 and found that awake prone positioning (APP) was significantly associated with lower mortality (20.0% vs 37.9%; p < 0.0001) and intubation rate (23.6% vs 40.4%; p < 0.0001) as compared to supine position [8]. Randomized controlled trials have been done to evaluate the feasibility of implementation and patient compliance with APP in patients with COVID-19, but no long-term outcomes were assessed [9‐13]. A recent systematic review found that APP improved oxygenation among patients with AHRF due to COVID-19, however, APP did not reduce intubation rates [14]. Finally, a collaborative meta-trial of six randomized controlled superiority trials, on which this post hoc analysis is based, enrolled a total of 1121 patients and found hazard ratios of 0.75 (95% CI, 0.62–0.91) for intubation and 0.87 (95% CI, 0.68–1.11) for 28-day mortality with APP, as compared to the standard care group [15].

Despite multiple studies showing benefit of prone positioning among non-intubated patients with COVID-19, there is no clear evidence available guiding the timing of awake prone positioning for patients with COVID-19 to achieve optimal patient outcomes [16]. Therefore, the primary objective of this study was to compare early versus late initiation of awake prone positioning (APP) on patient outcomes, including hospital mortality and the need for invasive mechanical ventilation (IMV).

From April 2nd, 2020 to January 26th, 2021, we participated in a collaborative meta-trial of six randomized controlled open-label superiority trials [17] to compare the effectiveness of APP versus standard care in patients with AHRF due to COVID-19 supported with high-flow nasal cannula (HFNC). The intent of the unique study design was to achieve results with a sufficient effect size, in a faster manner, and at a lower cost [18]. It was felt this novel approach was necessary during a global event, like the COVID-19 pandemic. Four hospitals joined in the American trial (NCT04325906) and the randomization was assigned by the leading institution (Rush University Medical Center). The study protocol was approved by the institutional review board (20032604-IRB01). This post hoc analysis was conducted using the American data set.

To our knowledge, this is the first study to explore the association between the time to initiate APP (early vs late) and mortality among non-intubated patients with COVID-19. In this post hoc analysis, we found that late APP was independently associated with an increase in hospital mortality, however, the association between exposure and outcome is weak (OR 1.02 [95% CI 1–1.04]). Patients who were proned within 24 h of initiating HFNC for AHRF (early APP) had a lower mortality than those who received APP after 24 h (late APP). Additionally, being elderly, intubated, and receiving hydrocortisone were significantly associated with mortality at 28 days.

Awake prone positioning is a noninvasive technique widely used among patients with COVID-19 and was found to reduce the need for invasive mechanical ventilation and improve patient outcomes in the recent large, meta-trial of six randomized controlled open-label superiority trials conducted across six countries [15]. The present study results suggest that initiating early prone positioning within 24 h of HFNC start further improves the 28-day mortality.

Several reasons may explain our research findings. First, COVID-19-induced lung injury is described to have two distinctive phenotypes, type L and type H [20]. Type L represents high compliance/low elastance, and low alveolar recruitability, while type H represents low compliance/high elastance and high alveolar recruitability [21]. Type H reportedly responds well to positive end expiratory pressure and prone positioning. This phenotype likely represents a time-related disease spectrum where the early use of HFNC and APP may improve ventilation-perfusion matching and reduce dyspnea related work of breathing and patient self-inflicted lung injury [22, 23]. High respiratory drive, commonly found among patients with COVID-19, is associated with increased transpulmonary pressure changes that lead to vascular leakage and self-inflicted lung injury in patients with existing lung injury [24]. Furthermore, respiratory rates exceeding 22 breaths/minutes are associated with a 1.9–3.2 fold increase in mortality risk in patients with COVID-19 [25]. In the present study, we found that early use of APP led to significant improvements in the oxygenation status and work of breathing, assessed by SpO₂/FiO₂ ratio and ROX index. Patients who received early APP had significantly higher SpO₂/FiO₂ ratios after being proned for 30 min as compared to those who received late prone positioning. Similarly, the ROX index, a predictor of outcome with the use of HFNC among patients with acute respiratory failure [19], was higher among patients that received early APP.

Based on morphology, early ARDS represents the exudative phase with diffuse alveolar damage, interstitial and alveolar damage followed by a late, fibroproliferative phase with interstitial fibrosis [26]. Among mechanically ventilated ARDS patients, Nakos et al. reported that patients with early ARDS (≤ 36 h from onset) had a superior oxygenation response after prone positioning than those with late ARDS (> 36 h from onset) [27]. Similarly, in a prospective study by Coppo et al., the investigators reported an average time between hospital admission to prone positioning of 2.7 days among those who responded to prone positioning, compared to 4.6 days among non-responders in non-intubated patients with COVID-19 [28]. However, their study did not report mortality between the groups. In our study, early APP group received proning within 0.75 days and late APP within 2.5 days of hospital admission. Thus, utilization of early APP during the exudative/inflammatory phase may have led to a better oxygenation response, as well as improvement in work of breathing, which may translate into improved hospital survival.

Second, patients in the early APP group were in the prone position for more total hours than those in the late APP group. On average, the early APP group received 5.07 h/day of prone positioning as compared to 3 h/day in the late APP group (p = 0.006). Prior studies have demonstrated the mortality benefit of using a longer duration of prone session among intubated patients [3].

Third, a significantly lower number of patients in the early APP group received steroids (69.6% vs 87.9%; p = 0.03). The use of steroids is widely reported for clinical management of severe COVID-19 [29]. In one retrospective, observational study steroid use is associated with increased mortality among patients with COVID-19 [30]. In a meta-analysis, the authors reported some beneficial effects of corticosteroids, but note that the overall mortality was higher for those patients that received corticosteroids [31]. A recent open-label randomized controlled (RECOVERY) trial demonstrated a mortality benefit when dexamethasone was used for patients with COVID-19 patients receiving oxygen or IMV [32]. However, another randomized controlled trial evaluating the effectiveness of hydrocortisone in COVID-related ARDS demonstrated no significant reduction in mortality or continued use of respiratory support [33]. In our multivariate analysis, we found that hydrocortisone use, alone or in addition to dexamethasone or prednisone/methylprednisone, was independently associated with the increased 28-day mortality. This might be explained by the likelihood that sicker patients may have received hydrocortisone. Previous studies have demonstrated the increased use of corticosteroids among COVID-19 patients with shock [7]. These study findings suggest further exploration of hydrocortisone use in the treatment of COVID-19 is needed.

This study has several limitations. First, this study is a post hoc analysis of the data collected for a previous randomized clinical trial. Even though post hoc analyses are inherently flawed (due to the lack of randomization, inflated statistical significance, etc.), they do provide exploratory information that could be used to generate hypotheses for future studies [34, 35]. Due to the post hoc nature of this study, we were unable to calculate the sample size to detect the true difference. The sample size in this study is very small which may have impacted the magnitude of an association between the study groups and outcomes [36]. This study included patients from only three hospitals in the USA that may have different clinical management strategies for COVID-19 patients as compared to other clinical settings. Additonally, the original study did not record computed tomography findings to further explore the underlying pathophysiological features associated with increased mortality in the late APP group. Finally, the original study did not collect the incidence of shock or daily disease severity scores that may have prompted the use of steroids such as hydrocortisone among the critically ill patients.

For patients with acute hypoxemic respiratory failure secondary to COVID-19 and require HFNC therapy, early awake prone positioning (< 24 h of HFNC use) is associated with lower 28-day mortality.