Background Awake prone positioning (APP) improves oxygenation in coronavirus disease (COVID-19) patients and, when successful, may decrease the risk of intubation. However, factors associated with APP success remain unknown. In this secondary analysis, we aimed to assess whether APP can reduce intubation rate in patients with COVID-19 and to focus on the factors associated with success. Methods In this multicenter randomized controlled trial, conducted in three high-acuity units, we randomly assigned patients with COVID-19-induced acute hypoxemic respiratory failure (AHRF) requiring high-flow nasal cannula (HFNC) oxygen to APP or standard care. Primary outcome was intubation rate at 28 days. Multivariate analyses were performed to identify the predictors associated to treatment success (survival without intubation). Results Among 430 patients randomized, 216 were assigned to APP and 214 to standard care. The APP group had a lower intubation rate (30% vs 43%, relative risk [RR] 0.70; CI95 0.54–0.90, P = 0.006) and shorter hospital length of stay (11 interquartile range [IQR, 9–14] vs 13 [IQR, 10–17] days, P = 0.001). A respiratory rate ≤ 25 bpm at enrollment, an increase in ROX index > 1.25 after first APP session, APP duration > 8 h/day, and a decrease in lung ultrasound score ≥ 2 within the first 3 days were significantly associated with treatment success for APP. Conclusion In patients with COVID-19-induced AHRF treated by HFNC, APP reduced intubation rate and improved treatment success. A longer APP duration is associated with APP success, while the increase in ROX index and decrease in lung ultrasound score after APP can also help identify patients most likely to benefit. Trial registration: This study was retrospectively registered in ClinicalTrials.gov at July 20, 2021. Identification number NCT04477655. https://clinicaltrials.gov/ct2/show/NCT04477655?term=PRO-CARF&draw=2&rank=1

Objectives To assess the effect of prone positioning therapy on intubation rate in awake patients with COVID-19 and acute respiratory failure. Trial design This is a two-center parallel group, superiority, randomized (1:1 allocation ratio) controlled trial. Participants All patients admitted to the Hospital Civil de Guadalajara and Hospital General de Occidente in Mexico for COVID-19 associated acute respiratory failure and in need of supplementary oxygen through high-flow nasal cannula are screened for eligibility. Inclusion criteria: all adult patients admitted to the COVID-19 unit who test positive for COVID-19 by PCR-test and in need for oxygen are eligible for inclusion. Randomization starts upon identification of requirement of a fraction of inspired oxygen ≥30% for an oxygen capillary saturation of ≥90% Exclusion criteria: less than 18 years-old, pregnancy, patients with immediate need of invasive mechanical ventilation (altered mental status, fatigue), vasopressor requirement to maintain median arterial pressure >65 mmHg, contraindications for prone positioning therapy (recent abdominal or thoracic surgery or trauma, facial, pelvic or spine fracture, untreated pneumothorax, do-not-resuscitate or do-not-intubate order, refusal or inability of the patient to enroll in the study. Intervention and comparator Patients of the intervention group will be asked to remain in a prone position throughout the day as long as possible, with breaks according to tolerance. Pillows will be offered for maximizing comfort at chest, pelvis and knees. Monitoring of vital signs will not be suspended. Inspired fraction of oxygen will be titrated to maintain a capillary saturation of 92%-95%. For patients in the control group, prone positioning will be allowed as a rescue therapy. Staff intensivists will monitor the patient’s status in both groups on a 24/7 basis. All other treatment will be unchanged and left to the attending physicians. Main outcomes Endotracheal intubation rate for mechanical ventilation at 28 days. Randomisation Patients will be randomly allocated to either prone positioning or control group at 1:1 ratio. Such randomization will be computer generated and stratified by center with permuted blocks and length of 4. Blinding (masking) Due to logistical reasons, only principal investigators and the data analyst will be blinded to group assignment. Numbers to be randomised (sample size) With an intubation rate of 60% according to recent reports from some American centers, and assuming a decrease to 40% to be clinically relevant, we calculated a total of 96 patients per group, for a beta error of 0.2, and alpha of 0.5. Therefore, we plan to recruit 200 patients, accounting for minimal losses to follow up, with 100 non-intubated patients in the prone position group and a 100 in the control group. Trial Status The local registration number is 048-20, with the protocol version number 2.0. The date of approval is 3rd May 2020. Recruitment started on 3rd May and is expected to end in December 2020. Trial registration The protocol was retrospectively registered under the title: “Prone Positioning in Non-intubated Patients With COVID-19 Associated Acute Respiratory Failure. The PRO-CARF trial” in ClinicalTrials.gov with the registration number: NCT04477655. Registered on 20 July 2020. Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

INTRODUCTION/HYPOTHESIS: Awake prone positioning (APP) has been increasingly used in patients with acute respiratory failure due to COVID-19; however, most data supporting this therapy are observational/retrospective. The aim of this trial was to compare the outcomes in COVID-19 patients managed with APP versus standard care (SC).METHODS: Randomized controlled superiority trial, which included patients with COVID-19 and requirement of oxygen through high-flow nasal cannula (HFNC). Patients were randomized to remain in APP as long as possible or SC while HFNC therapy was needed. The primary outcome was intubation rate; treatment failure, defined as intubation or death without intubation, and mortality were secondary, with a follow-up to 28 days. Baseline characteristics, physiological response to APP, factors associated to failure, and adverse events were also analyzed. RESULTS:We enrolled 216 patients to APP and 214 to SC. Baseline characteristics were similar. Intubation rate was 30% in APP and 43% in SC patients (RR 0.70; 95% CI 0.54-0.90, p=0.006); mortality was 33% and 37%, respectively (RR 0.89; 95% CI 0.69-1.15, p=0.37). At multivariate analysis, the factors associated to an increased risk of failure were respiratory rate at enrollment (p=< 0.001), SpO 2 /FiO 2 at enrollment (p=< 0.001), absence of silent hypoxemia (p=0.01), lung ultrasound score at enrollment (p=< 0.001) and D-dimer at hospital admission (p=< 0.001). Mean daily duration of APP was 9.4 h (5.6-12.9), with a median of 6 days (3.7-9.0). At ROC curve analysis, the best predictors of treatment failure were a daily duration of APP < 7.7h (AUROC 0.96, p=< 0.001), respiratory rate at enrollment ≥25 bpm (AUROC 0.93, p=< 0.001), D-dimer >1.4 mg/dL (AUROC 0.82, p=< 0.001), and a decrease in respiratory rate < 3 bpm after the first session of APP (AUROC 0.79, p=< 0.001). The most common adverse events were back pain in 16 (7.4%) patients and intravascular lines dislodgement in 14 (6.5%). CONCLUSIONS:We found APP is associated with a reduced risk of intubation, with no difference in mortality. As a safe and effective procedure, we suggest APP should be encouraged to all COVID-19 patients requiring oxygen support with HFNC, aiming for the longest daily duration as possible, with closer monitoring of patients with predictive factors of failure.