Effect of High Flow Nasal Therapy (HFNC) Weaning Protocols vs Standard of Care on Respiratory Outcomes in Patients With Acute Respiratory Failure (WHIP)

Effect of High Flow Nasal Therapy (HFNC) Weaning Protocols vs Standard of Care on Respiratory Outcomes in Patients With Acute Respiratory Failure: A Randomized Clinical Trial

High-flow nasal cannula (HFNC) is a widely used noninvasive respiratory support technique for patients with acute respiratory failure (ARF). It provides heated and humidified oxygen at high flow rates, improving oxygenation, reducing respiratory effort, and enhancing patient comfort. International guidelines recommend HFNC over conventional oxygen therapy in hypoxemic ARF. However, there is significant variability in clinical practice regarding HFNC discontinuation, and no standardized weaning criteria currently exist. Prolonged HFNC use may increase hospital stay and healthcare costs, while premature discontinuation may lead to respiratory deterioration and the need for further ventilatory support. Previous studies suggest that successful HFNC weaning may be predicted by a Fraction of inspired oxygen (FiO₂) ≤40% and a Respiratory rate-Oxygenation index (ROX index) ≥9.2. The ROX index is calculated as the ratio of peripheral oxygen saturation (SpO₂) divided by fraction of inspired oxygen (FiO₂) to respiratory rate. The primary objective of this study is to compare a standardized HFNC weaning strategy based on ROX index and FiO₂ thresholds with usual clinical practice based on physician judgment. The primary outcome is weaning failure at the first attempt, defined as the need for HFNC reinstitution, noninvasive or invasive mechanical ventilation, or death within 48 hours after discontinuation.

Study Overview

• Status: Recruiting
• Conditions: Acute Respiratory Failure (ARF)
• Intervention / Treatment: Other: Protocolized HFNC weaning

• Study Type: Interventional
• Enrollment (Estimated): 148
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Michele Mondoni, MD; Phone Number: +39 0240223025; Email: michele.mondoni@unimi.it

Study Locations

• Italy
  • Lombardy
    • Milan, Lombardy, Italy, 20142
      • Recruiting
      • Pulmonology Unit, ASST Santi Paolo e Carlo. Department of Health Sciences, University of Milan, Milan (Italy)
  • Sicily
    • Catania, Sicily, Italy, 95123
      • Not yet recruiting
      • Pulmonology Unit, University Hospital "G. Rodolico-San Marco"
      • Contact: Claudia Crimi, MD PhD; Phone Number: +39 095 3781352; Email: claudia.crimi@unict.it

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Age ≥18 years
• Presence of acute respiratory failure (ARF)
• Receiving HFNC treatment for ≥24 hours

Exclusion Criteria:

• Post-extubation HFNC use or tracheostomized patients
• Respiratory acidosis (pH <7.35) or clinically significant acute hypercapnia (pCO₂ >50 mmHg with worsening from baseline)
• Long-term home NIV or home CPAP use
• Do-not-intubate (DNI) orders precluding escalation to invasive mechanical ventilation
• Life expectancy ≤48-72 hours due to terminal non-respiratory disease
• Neurological impairment or deep sedation preventing safe HFNC use (e.g. coma or severe uncontrolled delirium)
• Technical contraindications to HFNC (i.e. facial trauma, maxillofacial surgery, severe nasal obstruction)
• Refusal to participate or inability to provide informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Non-protocolized weaning; Non-protocolized weaning according to standard clinical practice: HFNC assessment every 24 hours and discontinuation based on physician clinical judgment.
Experimental: Protocolized weaning; Protocolized weaning using ROX index + FiO₂	Other: Protocolized HFNC weaning; HFNC discontinuation based on ROX index ≥9.2 and FiO₂ ≤40%

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Weaning failure	To compare the percentage of patients who fail HFNC weaning within 48 hours after the first separation attempt using a protocolized HFNC weaning strategy based on ROX index and FiO₂ cut-offs versus standard clinical practice guided by physician judgment.	Within 48 hours after the first separation attempt

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Second-attempt weaning success	To compare the percentage of patients who fail HFNC weaning within 48 hours after the second separation attempt using a protocolized HFNC weaning strategy based on ROX index and FiO₂ cut-offs versus standard clinical practice guided by physician judgment.	Within 48 hours after the second separation attempt
Length of hospital stay	Comparison of total hospital stay and post-weaning hospital stay between the two study arms.	From the day of hospital admission until the day of hospital discharge, assessed up to 60 days; and from the day of HFNC discontinuation until the day of hospital discharge, assessed up to 60 days.
In-hospital and 30-day mortality	Comparison of in-hospital mortality and 30-day mortality after discharge between the two study arms.	From the day of admission to the day of discharge or death (in-hospital mortality) and from the day of admission to 30-day after discharge (30-day mortality)
Predictors of weaning success	Identification of clinical and respiratory variables associated with successful HFNC weaning.	From enrollment through hospital discharge, an average of 10 days.
Number of days of HFNC treatment from initiation to definitive discontinuation	Number of days of HFNC treatment from initiation to definitive discontinuation	From the date and time of HFNC initiation until the date and time of definitive HFNC discontinuation, assessed up to 30 days.
Predictors of HFNC treatment duration	Demographic, clinical, radiological and laboratory variables associated with HFNC treatment duration	From HFNC initiation through hospital discharge, an average of 10 days
Prevalence of diaphragmatic dysfunction assessed by diaphragm thickening fraction (DTF) and diaphragmatic excursion measured by ultrasound between the two study arms.	Comparison of the prevalence of diaphragmatic dysfunction assessed by diaphragmatic ultrasound between patients with successful HFNC weaning and those with weaning failure. Diaphragmatic function will be evaluated using diaphragm thickening fraction (DTF) and diaphragmatic excursion measured by ultrasound.	30 minutes before HFNC weaning initiation and 24 hours after weaning completion.
Changes in diaphragmatic function	Evaluation of diaphragmatic ultrasound parameters before and after HFNC discontinuation.	Before HFNC discontinuation and within 48 hours after weaning attempt

Collaborators and Investigators

• Sponsor: University of Milan

Study record dates

Study Major Dates

• Study Start (Estimated): May 15, 2026
• Primary Completion (Estimated): May 1, 2028
• Study Completion (Estimated): May 1, 2028

Study Registration Dates

• First Submitted: May 13, 2026
• First Submitted That Met QC Criteria: June 4, 2026
• First Posted (Actual): June 10, 2026

Study Record Updates

• Last Update Posted (Actual): June 10, 2026
• Last Update Submitted That Met QC Criteria: June 4, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: weaning; HFNC; acute respiratory failure; ARF; ROX INDEX
• Other Study ID Numbers: THE WHIP TRIAL

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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