WIN Ratio Analysis to Determine a Strategy of Non- Invasive SUpport for Respiratory Failure in the EmeRgency Department

The purpose of this clinical trial is to determine the best initial non-invasive respiratory support strategy for adults who present to the emergency department with acute hypoxemic respiratory failure, a condition in which blood oxygen levels are dangerously low and require urgent treatment. This study compares two commonly used non-invasive respiratory support strategies to evaluate their effectiveness and safety, based on important patient outcomes during hospitalization, including survival, the need for invasive mechanical ventilation, and the duration of respiratory support. Participants will be randomly assigned (with an equal chance) to receive one of the following treatments:

• Non-Invasive Positive Pressure Ventilation (NIPPV): Oxygen delivered under pressure through a face mask.
• High-Flow Nasal Oxygen (HFNO): Oxygen delivered at high-flow through a specially designed nasal cannula placed in the nostrils.

Researchers will compare the two treatment strategies using a hierarchical assessment of major pulmonary outcomes, including:

• Hospital survival
• Days on mechanical ventilation
• Duration of non-invasive respiratory support

As part of the study, researchers will collect:

• Blood and urine samples
• Physiologic measurements (such as chest movement measured through sensors placed on the skin)
• Information from participants' medical records

Acute hypoxemic respiratory failure (AHRF) is a serious medical emergency that frequently presents in the emergency department (ED) and requires immediate respiratory support to prevent further clinical deterioration. Patients with AHRF are at high risk for progression to invasive mechanical ventilation and death, and early management decisions may substantially influence outcomes.

Non-invasive respiratory support (NIRS) is widely used as first-line therapy for AHRF. Two commonly used NIRS strategies are non-invasive positive-pressure ventilation (NIPPV) and high-flow nasal oxygen (HFNO). Both modalities are accepted standards of care; however, their relative effectiveness and safety when applied early in the ED remain uncertain. Prior comparative studies have largely been conducted in intensive care settings, enrolled selected patient populations, or focused on single outcomes such as intubation or mortality. Consequently, equipoise persists regarding the optimal initial NIRS strategy for ED patients with undifferentiated AHRF.

The WINDSURFER trial (WIN ratio analysis to Determine a strategy of non-invasive SUpport for Respiratory Failure in the EmeRgency Department) is designed to compare two strategies of non-invasive respiratory support-NIPPV and HFNO-with respect to clinically meaningful outcomes in adult ED patients with acute hypoxemic respiratory failure.

Study Setting: The trial will be conducted at hospitals participating in the NIH-funded Strategies to Innovate Emergency Care Clinical Trials Network (SIREN).

Study Population: Eligible participants are adults presenting to a participating ED with acute hypoxemic respiratory failure and a clinical need for non-invasive respiratory support. Enrollment focuses on patients treated early in their ED course. Individuals with conditions requiring immediate invasive ventilation or with contraindications to study interventions are excluded. Up to a maximum of 500 adult participants will be enrolled.

Study Interventions and Randomization: Participants will be randomly assigned in a 1:1 ratio to one of two initial non-invasive respiratory support strategies: NIPPV or HFNO. Randomization is centrally managed using a secure, web-based system to ensure allocation concealment and balance across sites.

The assigned NIRS strategy will be used as the initial respiratory support approach and maintained for a protocolized treatment period of 24 hours, unless earlier clinical improvement, escalation to invasive mechanical ventilation, or death occurs. Following this initial period, subsequent respiratory management will be determined by the treating clinical team according to local standards of care.

Primary Outcome: The primary outcome is Major Adverse Pulmonary Events (MAPE), a composite outcome evaluated using the WIN Ratio method. MAPE prioritizes outcomes based on clinical importance, incorporating:

• Hospital mortality
• Duration of invasive mechanical ventilation
• Duration of non-invasive respiratory support

Secondary Outcomes: Secondary outcomes characterize potential complications and adverse clinical trajectories associated with non-invasive respiratory support, including the development or worsening of pneumonia or pneumonitis, acute respiratory distress syndrome (ARDS), or shock.

Data Collection and Follow up: Clinical data will be obtained from participant medical record and study-specific assessments to capture participant characteristics, treatment course, and outcomes. Participants will be followed through hospital discharge, death, or 28 days after randomization, whichever occurs first. Selected outcomes may be assessed through medical record review beyond hospital discharge.

Ethical Considerations: Because AHRF is a life-threatening emergency requiring immediate intervention and patients frequently lack decision making capacity at presentation, the study is conducted under Exception From Informed Consent (EFIC) in accordance with FDA regulations (21 CFR 50.24). Community consultation and public disclosure are completed prior to enrollment at each site. Participants or their Legally Authorized Representatives are informed of enrollment at the earliest feasible opportunity and may withdraw from the study at any time.