Our search strategy identified 173 publications on the subject of APP (Figure E1 in the online supplement), and 271 papers on the subject of non-invasive oxygenation modalities (Figure E2 in the online supplement) in severe COVID-19. Thus, a total of 444 potentially relevant publications were identified, and 440 were screened for inclusion after removal of duplicates (Figure 1). After full-text review, 46 published studies[8–10,12,14,28–68] and data from 4 unpublished datasets were included in the final review, with a combined 2994 subjects: 921 patients treated with APP, 870 patients treated without APP, and a group of 1203 patients in whom a significant proportion were treated with APP (Figure 1, Table 1, and Tables E1 and E2 in the online supplement). Clarifications and supplemental data were obtained from 18 corresponding authors.
Physiological response to awake prone positioning.
Nineteen studies(n=381) reported on the physiological responses to APP. APP resulted in improved SpO2 or PaO2 in all 13 studies (n=271) that reported on changes in oxygenation[8–10,28,30,33–35,40–43,45].
Ten studies (n=198) reported on changes in the PaO2/FiO2 ratio[10,12,14,29,37,38,42,43,45,46], of them nine (n=192) reported significant improvement in PaO2/FiO2 ratios with APP[10,12,14,37,38,42,43,45,46]. Mean improvement was greater than our predefined threshold of ≥ 20% in all seven studies in which changes of PaO2/FiO2 ratios were reported in sufficient detail[14,37,38,42,43,45,46]. In three studies (n=72), the improvement of the PaO2/FiO2 ratio was sustained even after the patients returned to the supine position[42,45,46]; one study (n=46) demonstrated sustained improvement in only 50% of patients, and in another report (n=26), improvement of PaO2/FiO2 was lost after returning to supine position.
Reduction of respiratory rate with APP was demonstrated in five studies (n=90)[10,28,36,40,41], but not in two other studies (n=34)[33,45]. Finally, significantly reduced PaCO2 was demonstrated only in a single small study (n=9), while no changes in PaCO2 were observed in a larger report (n=46).
Probability of intubation with awake prone positioning
Data on intubation rate were available for 870 patients treated with APP (23 published studies, n=717; 2 unpublished studies, n=153), and for 852 patients treated with HFNC, or CPAP, or NIV, without APP (16 published studies, n=645; 2 unpublished studies, n=207). In the APP group, 27% (95%CI, 19 to 37%) required intubation and mechanical ventilation, as compared to 30% (95%CI, 20 to 42%) in the control group (Figure 2). This difference was not statistically significant (p=0.71).
Subgroup analyses, with stratification according to the duration of APP (<4h daily vs ≥4h daily), the device (HFNC vs CPAP vs NIV), and the severity of the ARDS (PaO2/FiO2 <150 mmHg vs PaO2/FiO2 ≥150 mmHg) did not demonstrate any significant difference in intubation rate between patients who were treated with APP and those who were not (Figure 3).
There was a very high level of heterogeneity across all studies. Sensitivity analyses with the inclusion of the subgroup of patients with some exposure to APP, and with exclusion of unpublished data demonstrated a similar lack of benefit (Figures E3 through E11), as did the analyses according to country GDP (Figures E23 and E24).
Probability of death with awake prone positioning
Mortality data were available for 767 patients treated with APP (18 published studies, n=614; 2 unpublished studies, n=153) and for 761 patients treated with HFNC, or CPAP, or NIV, without APP (12 published studies, n=554 ;2 unpublished studies, n=207). The mortality rate was 11% (95%CI, 6 to 20%) in patients treated with APP, as compared to 22% (95%CI, 13 to 36%) in patients treated with usual care (Figure 4). This difference was not statistically significant (p=0.10).
Outcomes were highly heterogeneous between studies, and subgroup analyses did not demonstrate any significant differences in mortality across predetermined subgroups (Figure 5), and did not identify a subgroup in which APP was associated with statistically significant reduction of mortality. Sensitivity analyses with the inclusion of patients with partial exposure to APP, with exclusion of unpublished data, and with exclusion of patients treated with conventional oxygen therapy demonstrated a similar lack of mortality benefit (Figures E12 through E22). No statistically significant signal was seen in analyses restricted to high- or low-GDP countries (Figures E25 and E26)
Tolerability and comfort of awake prone positioning
Fifteen studies reported patients’ tolerability to APP, varying from 47% to 100%[9,10,12,14,28–30,32,33,35,36,40,43,45,46]. Eight papers reported on patient's discomfort while in prone position[9,12,14,32,36,40,43,45], including back pain, dyspnea, and general discomfort. The daily duration of APP was reported in 17 papers (n=366)[8–10,12,14,28,29,31,34,36,38,40,41,45–47]. In 9 papers (n=201), patients tolerated APP for less than 4 hours daily[8–10,14,28,31,38,40,41]. A single paper reported on a cohort of 55 patients who were able to achieve APP for more than 16 hours daily.