Predicting High-Flow Nasal Oxygen Failure at 30 Minutes Using a Physiology-Informed Dual-Domain Model (EFI-HFNO)

This prospective, single-center, two-stage translational study develops and validates a physiology-informed dual-domain model for ultra-early (30-minute) prediction of high-flow nasal oxygen (HFNO) failure in patients with acute hypoxemic respiratory failure. The study includes a physiological validation cohort (n=24) to anchor the EIT-derived Flow Index (EFI) as a marker of inspiratory effort, followed by a temporally separated clinical derivation cohort (n=57) and independent validation cohort (n=58). Candidate predictors are screened from 1,328 clinical features. The final dual-domain model integrates persistent physiological burden (baseline PaCO₂ and 30-minute EFI) with short-term dynamic adaptation (ΔRR and ΔSpO₂ over 30 minutes). The model's discrimination is tested prospectively without refitting.

Study Overview

• Status: Completed
• Conditions: Acute Respiratory Failure; Electrical Impedance Tomography (EIT); High-Flow Nasal Oxygen Therapy
• Intervention / Treatment: Device: Mechanical Ventilation Support; Device: Electrical Impedance Tomography Monitoring; Other: High-Flow Nasal Oxygen Therapy; Device: High-Flow Nasal Oxygen Therapy With EIT Monitoring

Detailed Description

Detailed Description

This was a single-center, prospective, two-stage translational study conducted at Ruijin Hospital, Shanghai Jiao Tong University School of Medicine. The study comprised three integrated components:

1. Physiological validation cohort (n = 24) Mechanically ventilated patients with acute respiratory distress syndrome (ARDS) receiving pressure support ventilation underwent simultaneous electrical impedance tomography (EIT) and esophageal pressure monitoring. Measurements were performed at three sequentially adjusted pressure support levels: baseline clinical setting (PSbase), maximal tolerated level (PSmax), and minimal level (PSmin). The EIT-derived Flow Index (EFI) was calculated from the global impedance-time signal. Relationships between EFI and esophageal pressure swing (ΔPes) as well as pressure-time product per minute (PTP/min) were assessed using regression analysis. Changes in EFI across pressure support levels were evaluated by repeated within-subject comparisons.

2. Clinical derivation cohort (n = 57) High-risk adult patients with acute hypoxemic respiratory failure (AHRF) initiated on high-flow nasal oxygen (HFNO) were prospectively enrolled between May 2025 and September 2025. Inclusion required at least one of the following high-risk criteria: PaO₂/FiO₂ ≤ 200 mmHg or FiO₂ ≥ 0.40 to maintain SpO₂ ≥ 92%; respiratory rate ≥ 25 breaths/min; APACHE II score ≥ 12; or bilateral infiltrates on chest imaging. EIT and bedside variables (heart rate, respiratory rate, arterial blood gases, ROX index) were recorded at baseline (HFNO initiation) and at 30 minutes. HFNO failure was defined a priori as clinically meaningful escalation to noninvasive ventilation (NIV) or endotracheal intubation due to sustained hypoxemia, progressive respiratory acidosis, respiratory muscle fatigue, or hemodynamic instability. Within-tier adjustments (increasing flow or FiO₂ without changing support modality) were not considered failure.

   Patient-level analyses were performed to identify two prespecified domains of early HFNO failure:

   Persistent abnormality (physiological burden that remained abnormal after accounting for baseline): evaluated by analysis of covariance (ANCOVA) for 30-minute variables adjusted for baseline values.

   Divergent short-term response trajectory (different evolution between success and failure groups): evaluated by generalized estimating equations (GEE) with time-by-group interactions across baseline and 30 minutes.

   A multivariable logistic regression model was constructed in the derivation cohort incorporating baseline PaCO₂, 30-minute EFI, ΔRR (change in respiratory rate), and ΔSpO₂ (change in peripheral oxygen saturation). An exploratory reference model using ΔPaO₂ instead of ΔSpO₂ was also evaluated.

3. Prospective validation cohort (n = 58) An independent, temporally separate cohort of patients meeting the same inclusion/exclusion criteria was enrolled between October 2025 and March 2026 (after completion of the derivation cohort). The identical 30-minute reassessment protocol was applied. The prespecified logistic regression equation from the derivation cohort was applied directly without coefficient refitting. Discriminatory performance of the dual-domain model (baseline PaCO₂ + 30-min EFI + ΔRR + ΔSpO₂) was evaluated using area under the receiver operating characteristic curve (AUROC), sensitivity, and specificity.

Total enrollment: 164 participants (24 physiological validation + 115 clinical HFNO participants [derivation 57 + validation 58] + 25 screened but excluded as detailed in the study flow diagram).

The study was approved by the Ruijin Hospital Ethics Committee (Reference Nos. [2025]30 and [2025]232). All participants provided written informed consent.

• Study Type: Observational
• Enrollment (Actual): 164

Contacts and Locations

Study Locations

• China
  • Shanghai Municipality
    • Shanghai, Shanghai Municipality, China, 200025
      • Department of Critical Care Medicine，Ruijin Hospital，Shanghai Jiao Tong University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Adult patients with acute respiratory failure receiving HFNO

Description

Inclusion Criteria (must meet all):

• Age ≥18 years
• Acute hypoxemic respiratory failure (AHRF) requiring HFNO initiation
• At least one of the following high-risk criteria: a) PaO₂/FiO₂ ≤200 mmHg or FiO₂ ≥0.40 to maintain SpO₂ ≥92%; b) Respiratory rate ≥25/min; c) APACHE II score ≥12; d) Bilateral infiltrates on chest imaging

Exclusion Criteria:

• Neuromuscular disease affecting spontaneous breathing
• Pregnancy
• Contraindication to EIT (e.g., chest wall wounds, pacemaker)
• Do-not-intubate order
• Hypercapnic respiratory failure as primary diagnosis (PaCO₂ >50 mmHg with pH <7.30 at baseline, unless mixed mechanism)

Study Plan

How is the study designed?

Number of groups / cohorts

5

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Physiological Validation Cohort; Mechanically ventilated patients with acute respiratory distress syndrome (ARDS) receiving pressure support ventilation. Intervention: Simultaneous electrical impedance tomography (EIT) and esophageal pressure monitoring at three sequential pressure support levels (PSmin, PSbase, PSmax). Outcome measures: EIT-derived Flow Index (EFI), esophageal pressure swing (ΔPes), pressure-time product per minute (PTP/min). No HFNO administered.	Device: Mechanical Ventilation Support; Patients received pressure support ventilation at three sequentially adjusted levels (PSmin, PSbase, PSmax). Breathing parameters were continuously monitored using an electrical impedance tomography (EIT) device, and inspiratory effort was invasively measured via an esophageal pressure catheter.; Device: Electrical Impedance Tomography Monitoring; PulmoVista 500 EIT device (Dräger Medical, Lübeck, Germany) was used for continuous real-time monitoring of regional lung ventilation.
Derivation Cohort - HFNO Success; High-risk patients with acute hypoxemic respiratory failure (AHRF) initiated on high-flow nasal oxygen (HFNO) who achieved clinical stabilization without requiring escalation to noninvasive ventilation or endotracheal intubation within 72 hours. Intervention: EIT monitoring and bedside data collection (heart rate, respiratory rate, arterial blood gases, SpO₂, ROX index, EMOX index) at baseline (HFNO initiation) and at 30 minutes. No additional device intervention.	Other: High-Flow Nasal Oxygen Therapy; Patients received HFNO as part of standard clinical care for acute hypoxemic respiratory failure. The treatment was titrated by the clinical team based on physiological parameters (SpO₂, RR, ABG), aiming to maintain SpO₂ ≥ 92% and reduce signs of respiratory distress.; Device: High-Flow Nasal Oxygen Therapy With EIT Monitoring; Patients received standard-of-care HFNO for AHRF. Additionally, a PulmoVista 500 EIT device was used to monitor lung ventilation and derive the EFI at baseline and 30 minutes.
Derivation Cohort - HFNO Failure; High-risk patients with AHRF initiated on HFNO who required escalation to noninvasive ventilation or endotracheal intubation within 72 hours due to refractory hypoxemia, progressive respiratory acidosis, severe respiratory distress, or hemodynamic instability. Intervention: EIT monitoring and bedside data collection (same variables as success group) at baseline and 30 minutes. Escalation decision guided by predefined objective criteria, not by EIT data.	Other: High-Flow Nasal Oxygen Therapy; Patients received HFNO as part of standard clinical care for acute hypoxemic respiratory failure. The treatment was titrated by the clinical team based on physiological parameters (SpO₂, RR, ABG), aiming to maintain SpO₂ ≥ 92% and reduce signs of respiratory distress.; Device: High-Flow Nasal Oxygen Therapy With EIT Monitoring; Patients received standard-of-care HFNO for AHRF. Additionally, a PulmoVista 500 EIT device was used to monitor lung ventilation and derive the EFI at baseline and 30 minutes.
Validation Cohort - HFNO Success; Independent temporally separate cohort of high-risk AHRF patients initiated on HFNO who achieved clinical stabilization without escalation. Same inclusion/exclusion criteria as derivation cohort. Intervention: Identical 30-minute reassessment protocol: EIT monitoring and bedside data collection at baseline and 30 minutes. Model tested prospectively without coefficient refitting.	Device: High-Flow Nasal Oxygen Therapy With EIT Monitoring; Patients received standard-of-care HFNO for AHRF. Additionally, a PulmoVista 500 EIT device was used to monitor lung ventilation and derive the EFI at baseline and 30 minutes.
Validation Cohort - HFNO Failure; Independent temporally separate cohort of high-risk AHRF patients initiated on HFNO who required escalation to noninvasive ventilation or endotracheal intubation. Same escalation criteria as derivation cohort. Intervention: EIT monitoring and bedside data collection at baseline and 30 minutes. The fixed dual-domain model (baseline PaCO₂, 30-min EFI, ΔRR, ΔSpO₂) derived from the derivation cohort was applied without refitting to assess discrimination.	Device: High-Flow Nasal Oxygen Therapy With EIT Monitoring; Patients received standard-of-care HFNO for AHRF. Additionally, a PulmoVista 500 EIT device was used to monitor lung ventilation and derive the EFI at baseline and 30 minutes.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
HFNC Failure Rate(Early Reassessment at 30 Minutes)	HFNO failure was defined as escalation to noninvasive ventilation (NIV) or endotracheal intubation due to refractory hypoxemia, progressive respiratory acidosis, severe respiratory distress, or hemodynamic instability. Within-tier adjustments (increasing flow or FiO₂ without changing support modality) were NOT considered failure.	within 30 minutes after HFNO initiation (with monitoring of outcomes up to hospital discharge)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Physiological Validation of EFI	EFI was compared with esophageal pressure swing (ΔPes) and pressure-time product per minute (PTP/min) across pressure support levels using regression analysis and repeated within-subject comparisons.Unit of Measure No unit for R² (dimensionless ratio); Arbitrary units (a.u.) for EFI; cm H₂O for ΔPes; cm H₂O·s/min for PTP/min.	During physiological measurements in mechanically ventilated patients (performed before the clinical HFNO cohort; within 48 hours of ICU admission)
Persistent Abnormality at 30 Minutes	ANCOVA-adjusted 30-minute values of EFI, PaCO₂, heart rate, respiratory rate, pH, PaO₂ were compared between HFNO success and failure groups to identify persistent physiological burden.Unit of Measure EFI: arbitrary units (a.u.); PaCO₂ and PaO₂: mmHg; Heart rate: beats/min; Respiratory rate: breaths/min; pH: dimensionless (pH units);	within 30 minutes after HFNO initiation
Divergent Short-Term Response Trajectories	Generalized estimating equations (GEE) evaluated time-by-group interactions for EFI, respiratory rate, PaO₂, PaCO₂, pH, heart rate, ROX, to identify divergent early response trajectories.Measure of Central Tendency / Measure of Dispersion Time-by-group interaction P values; Estimated marginal means at baseline and 30 minutes for each group; Within-patient change scores (Δ values) between the two time points for each variable Unit of Measure EFI: arbitrary units (a.u.); Heart rate: beats/min; Respiratory rate: breaths/min; pH: dimensionless (pH units); PaCO₂ and PaO₂: mm Hg; ROX: dimensionless index.	Baseline to 30 minutes after HFNO initiation

Collaborators and Investigators

• Sponsor: Ruijin Hospital
• Investigators: Study Chair: Hongping Qu, Department of Critical Care Medicine，Ruijin Hospital，Shanghai Jiao Tong University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2025
• Primary Completion (Actual): March 31, 2026
• Study Completion (Actual): March 31, 2026

Study Registration Dates

• First Submitted: January 16, 2026
• First Submitted That Met QC Criteria: January 16, 2026
• First Posted (Actual): January 26, 2026

Study Record Updates

• Last Update Posted (Actual): June 17, 2026
• Last Update Submitted That Met QC Criteria: June 16, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Other Study ID Numbers: [2025]232 and [2025] 30

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No