Chapter 4: Critical Respiratory Care

4.1 Awake Prone Positioning: Dosing & Boundaries

I. The Necessity of Exploring APP “Dose” and “Boundaries”

The benefits of prone positioning in moderate-to-severe ARDS are well-established, while its application in awake patients rapidly entered clinical practice during the COVID-19 pandemic. Awake prone positioning (APP), owing to its ability to improve oxygenation and ease of implementation, has been widely adopted in non-intubated respiratory support strategies [1]. Current evidence indicates APP is not merely a binary decision; its efficacy largely depends on achieving adequate exposure during early critical phases (cumulative prone time as a “dose” factor) and dynamically identifying failure risks across different populations and levels of respiratory support (“boundary” factors). Recent APP research has shifted from “whether it works” to “which populations benefit most, what is the optimal duration, and when should therapy be escalated.”

Focusing on APP duration and boundaries stems from the reproducibility issue of its clinical efficacy. Clinicians have observed significant variations in intubation rates and mortality across wards, teams, and time points. APP’s effect, beyond positional change, is closely related to whether sufficient daily cumulative prone time is achieved early, as well as the patient’s status at initiation (HFNO/NIV).

APP duration in research and practice is a major source of effect heterogeneity and systematic dilution. When only “whether APP was implemented” is used as the exposure factor without stratifying by daily cumulative duration, consecutive days, or early target achievement, the true effect is underestimated. In non-ICU or ward-level studies, inadequate compliance may explain uncertain outcomes, indicating APP requires a prescription-based approach. Based on recent RCT evidence [2,3], time-dependent analyses [4,5], and individual data integration studies [6], APP benefits concentrate in the early treatment phase, with a non-linear relationship between daily cumulative duration and endpoints.

Clinical boundaries of APP should address two core questions. First, applicability: whether APP benefits patients across etiologies, hypoxemia severity, and support levels. Second, escalation: how to judge “continue” vs. “timely escalation” based on early physiological responses and disease evolution. Recent guidelines and expert consensus [7–9] have supplemented evidence on early response indicators and safety risk identification, pushing APP toward more verifiable and reproducible clinical application.

II. Key Elements of Defining APP “Dose”

In COVID-19-related acute hypoxemic respiratory failure (AHRF) supported by HFNO/NIV, APP benefit increasingly depends on sufficient early prone time. Secondary analysis of RCTs (408 patients), with “intubation or 28-day mortality” as composite endpoint, showed each additional 1 h of daily APP was associated with reduced composite failure (HR = 0.93, 95% CI 0.89–0.98). The relationship was non-linear: <8 h/day carried significantly higher failure risk vs. 8–12 h/day, while >12 h/day showed no further benefit [5]. Luo et al. IPD meta-analysis pooling 14 RCTs (3,019 patients) confirmed APP overall improved intubation-free survival and reduced intubation rates and in-hospital mortality [6]. These studies indicate adequate prone duration is key to translating physiological improvements into clinical benefits.

III. Defining APP Applicability and Escalation Boundaries

(A) Applicability Boundary

The most robust APP evidence base comes from COVID-19-related AHRF, concentrated in HFNO/NIV patients. IPD meta-analyses suggest the intubation-reduction signal is more concentrated in patients with worse oxygenation requiring HFNO/NIV; improvements in conventional oxygen therapy or non-ICU patients are uncertain. Exploratory analysis by Luo et al. found ≥10 h/day within the first 3 days was associated with further improved intubation-free survival (OR = 1.85, 95% CI 1.37–2.49) [6]. Time-varying exposure analyses confirmed early implementation yields more obvious benefits [4,5]. Physiological studies by Olmos et al. shifted the “time window” further to the early bedside-observable phase [10,11].

(B) Escalation Boundary

“When to escalate” remains a core issue. In noninvasive strategies, risks of delayed intubation and patient-self-inflicted lung injury (P-SILI) persist. Recent research favors identifying high-risk trajectories using reproducible early response assessments rather than waiting for obvious deterioration. Physiological cohort studies in HFNO suggest that within 24 h of APP, clinicians should be vigilant for “oxygenation targets met but significantly increased work of breathing.” Specific indicators: obvious respiratory distress, sustained RR >30/min, ROX index persistently <3.85 or VOX index persistently <23.7 within 6 h of APP initiation. Even if SpO₂ is within target, this indicates high P-SILI risk driven by high respiratory drive, warranting decisive escalation to invasive ventilation. Expert consensus emphasizes APP should be implemented alongside a clear escalation pathway [9,12].

IV. Future Application Directions for APP

Current APP evidence concentrates in COVID-19-related respiratory failure. For non-COVID-19 populations, mechanism clues accumulate but outcome evidence remains insufficient. Prospective EIT studies suggest APP may improve ventilation distribution and uniformity in non-COVID-19 AHRF [13], supporting extrapolation of “positional changes bring intrapulmonary ventilation redistribution.” However, prerequisites must be defined: aspiration, pressure ulcers, peripheral nerve injury, and position-related hemodynamic fluctuations affect implementation. Mechanism studies should systematically record complications and tolerance factors.

Extrapolation must move beyond physiological improvement to clarify whether clinical outcomes benefit through RCTs. Future research should prioritize AHRF subgroups with consistent mechanisms and ongoing HFNO/NIV need, pre-specifying etiology stratification and escalation boundaries. Endpoint selection should include composite treatment failure/escalation endpoints with pre-specified early-response subgroup analyses. Safety evaluation must be integral: aspiration, pressure ulcers, nerve injury, hemodynamic fluctuations, and analgesia/sedation impacts on respiratory drive and APP tolerance should be prospectively reported to avoid systematic bias.

In summary, APP evidence has extended from “improving oxygenation” to “reducing treatment failure/intubation risk.” Efficacy is related to early adequate exposure; daily cumulative duration reaching threshold is more likely to translate into outcome benefits. Future research should address: replication of duration thresholds in non-COVID-19 AHRF; escalation timing based on early responses; and improving target achievement rates in real-world settings.

(Sun Qin, Zhongda Hospital, Southeast University)

References

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  2. Rosen J, Von Oelreich E, Fors D, et al. Awake prone positioning in patients with hypoxemic respiratory failure due to COVID-19: the PROFLO multicenter randomized clinical trial. Crit Care. 2021;25(1):209.

  3. Li J, Luo J, Pavlov I, et al. Awake prone positioning in non-intubated patients with COVID-19: a systematic review and meta-analysis. Lancet Respir Med. 2022;10(6):573-583.

  4. Liu L, Sun Q, Zhao H, et al. Prolonged vs shorter awake prone positioning for COVID-19 patients with acute respiratory failure: a multicentre randomised clinical trial. Intensive Care Med. 2024;50(8):1298-1309.

  5. Sun Q, Zhang R, Zhang J, et al. Impact of awake prone positioning duration on intubation or mortality in COVID-19 patients with acute respiratory failure: secondary analysis of a randomised clinical trial. Ann Intensive Care. 2025;15(1):84.

  6. Luo J, Pavlov I, Tavernier E, et al. Awake prone positioning in adults with COVID-19: an individual participant data meta-analysis. JAMA Intern Med. 2025;185(5):572-581.

  7. Grassi G, Calfee CS, Camporota L, et al. ESICM guidelines on acute respiratory distress syndrome: definition and management. Intensive Care Med. 2023;49(7):727-759.

  8. Fralick M, Colacci M, Munshi L, et al. Awake prone positioning for patients with COVID-19 and moderate hypoxaemia: a randomised clinical trial (COVID-PRONE). BMJ. 2022;376:e068585.

  9. Pavlov I, Li J, Kharat A, et al. Awake prone positioning in acute hypoxaemic respiratory failure: an international expert guidance. J Crit Care. 2023;78:154401.

  10. Olmos M, Esperatti M, Fuentes N, et al. Early physiologic changes after awake prone positioning in acute hypoxemic respiratory failure predict clinical outcomes. Intensive Care Med. 2024;50(12):2105-2113.

  11. Olmos M, Fuentes N, Busico M, et al. Effectiveness of bundle of care on tolerance of awake prone positioning in patients with acute respiratory failure: a multicenter observational study. Intensive Care Med. 2025;51(2):332-341.

  12. Myatra SN, Alhazzani W, Belley-Cote EP, et al. Awake prone positioning for adult patients with COVID-19-related acute hypoxaemic respiratory failure: a rapid practice guideline. Acta Anaesthesiol Scand. 2023;67(5):569-575.

  13. Wang J, Chen C, Zhao Z, et al. Awake prone positioning and ventilation distribution assessed by electrical impedance tomography in non-COVID-19 acute hypoxemic respiratory failure: a prospective physiology study. J Intensive Med. 2024;5(1):43-50.