Effects of Face Mask Continuous Positive Airway Pressure Vs. Noninvasive Ventilation Vs. High-flow Nasal Oxygen on Intubation-free Survival in Acute Hypoxemic Respiratory Failure: the TRIPOD Randomized Clinical Trial (TRIPOD)

Acute hypoxemic respiratory failure (AHRF) is a common indication for admission to an intensive care unit (ICU), with mortality exceeding 50% in cases where invasive mechanical ventilation is needed. Therefore, assessment of the most adequate oxygen strategy to avoid intubation in patients with AHRF deserves consideration.Previous studies have indicated that non-invasive oxygenation strategies, including high-flow nasal oxygen (HFNO), helmet or face mask noninvasive ventilation (NIV), and continuous positive airway pressure (CPAP), are effective in preventing endotracheal intubation in adult patients with AHRF when compared to the standard oxygen therapy. However, the optimal non-invasive oxygenation strategies remain uncertain. This study aim to determine whether CPAP, compared with HFNC or NIV, increase the intubation-free survival during study period in patients with AHRF.

Study Overview

• Status: Recruiting
• Conditions: Noninvasive Ventilation; Acute Hypoxemic Respiratory Failure; High-Flow Nasal Oxygen Therapy; Continuous Positive Airway Pressure (CPAP)
• Intervention / Treatment: Device: Continuous Positive Airway Pressure; Device: High-flow nasal oxygen; Device: Non-invasive ventilation

• Study Type: Interventional
• Enrollment (Estimated): 1300
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Yi Yang, PhD; Phone Number: +8613913966300; Email: yiyiyang2004@163.com
• Study Contact Backup: Name: Ling Liu, PhD; Phone Number: +8613851435472; Email: liulingdoctor@126.com

Study Locations

• China
  • Jiangsu
    • Nanjing, Jiangsu, China, 210009
      • Recruiting
      • Zhongda Hospital, School of Medicine, Southeast University
      • Contact: Ling Liu, PhD; Phone Number: +8613851435472; Email: liulingdoctor@126.com

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Age≥18 yrs;
2. A ratio of the partial pressure of arterial oxygen (PaO2) to the FiO2 of 300 mm Hg or less, or a ratio of pulse oximetry oxygen saturation (SpO2) to the FiO2 of 315 or less (SpO2≤97%) and the need for (1) noninvasive positive pressure ventilation with at least 5 cm H2O PEEP, or (2) high-flow nasal cannula at 30L/min or higher, or (3) standard oxygen with oxygen flow rate of at least 10 L/min;
3. Sign informed consent.

Exclusion Criteria:

1. Patients that have already received Continuous positive airway pressure, Noninvasive ventilation continuously for more than 24 hours before the screening visit.
2. Previous bout of mechanical ventilation during index hospitalization.
3. Exacerbation of chronic lung disease, including asthma or chronic obstructive pulmonary disease.
4. Moderate to severe cardiac insufficiency (New York Heart Association class >II or left ventricular ejection fraction<50%) or cardiogenic pulmonary edema.
5. Hemodynamic dysfunction, defined as vasopressor dose > 0.3 µg/kg/min of norepinephrine-equivalent to maintain systolic blood pressure > 90 mm Hg.
6. Impaired consciousness with a Glasgow coma score ≤ 12.
7. Patients with urgent need for intubation, including respiratory or cardiac arrest, respiratory pauses with loss of consciousness or gasping for air, severe hypoxemia defined as SpO2 lower than 90% despite maximal oxygen support.
8. Patients with contraindication to NIV according to the French consensus conference, patient refusal, cardiorespiratory arrest, coma, non-drained pneumothorax, unresolved vomiting, upper airway obstruction, hematemesis or severe facial trauma, thoracic or abdominal surgery in the previous 7 days.
9. A do-not-intubate order at time of inclusion.
10. Pregnancy.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Continuous Positive Airway Pressure; Patients will receive continuous positive airway pressure	Device: Continuous Positive Airway Pressure; Patients were placed at a 45-degree supine position, and noninvasive ventilation was delivered to the patient through a face mask connected to an ICU ventilator.; PEEP was started at 5 cm H2O with a FiO2 of 0.5 at initiation. PEEP and FiO2 were titrated to maintain SpO2 between 94 and 98%, remaining constant for at least 5 min.; CPAP was initiated with a first session of at least 4 h, the minimally required duration of noninvasive ventilation was 16 hours per day for at least 2 calendar days. Between noninvasive-ventilation sessions, patients received HFNO.
Active Comparator: High-flow nasal oxygen; Patients will receive high-flow nasal oxygen	Device: High-flow nasal oxygen; Oxygen was passed through a heated humidifier (MR850, Fisher and Paykel Healthcare) and applied continuously through large-bore binasal prongs, with a gas flow rate of 50 liters per minute and an FiO2 of 0.5 at initiation. HFNO heating temperature was prespecified at 37°C.; FiO2 will be titrated to maintain SpO2 between 94 and 98%, remaining constant for at least 5 min.; HFNO was applied for at least 2 calendar days.
Active Comparator: Non-invasive ventilation; Patients will receive non-invasive ventilation	Device: Non-invasive ventilation; Patients were placed at a 45-degree supine position, and noninvasive ventilation was also delivered to the patient through a face mask connected to an ICU ventilator. The mask most appropriate for the patient will be selected and adjusted to minimize leakage and pressure points.; The inspiratory positive airway pressure (pressure support plus PEEP) was initiated between 12 and 14 cm H2O, PEEP was started at 5 cm H2O with a FiO2 of 0.5 at initiation. FiO2 was titrated to maintain SpO2 between 94 and 98%, remaining constant for at least 5 min.; NIV was initiated with a first session of at least 4 h, the minimally required duration of noninvasive ventilation was 16 hours per day for at least 2 calendar days. Between noninvasive-ventilation sessions, patients received HFNO.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intubation-free survival rate	The proportion of patients who intubation-free and alive within 28 days after randomization.	From randomization to 28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
28-day mortality	The proportion of patients who are died within 28 days	From randomization to 28 days
Intubation rate within 28 days	The proportion of patients who are intubated within 28 days after randomization	From randomization to 28 days
A ranked composite score incorporating death and intubation through day 28	Priority sequence: 28-day mortality, followed by 28-day intubation	From randomization to 28 days
Meeting the prespecified criteria for intubation within 28 days.	The proportion of patients who meeting the prespecified criteria for intubation within 28 days.	From randomization to 28 days
ICU mortality	The proportion of patients who died within the ICU	From randomization to ICU discharge, assessed up to 60 days
In-hospital mortality	The proportion of patients who died within the hospital	From randomization to hospital discharge, assessed up to 60 days
Change in Discomfort scale after 1 hour of randomization	The discomfort scale are calculated using 100-mm visual-analogue scale	Time from randomization to 1hour
Invasive ventilator-free days at 28 days	Days alive without endotracheal intubation and invasive mechanical ventilation	From randomization to 28 days
Circulatory support-free days at day 28	Circulatory support defined as infusion of any vasopressor/inotrope agent for a minimum of 1 hour (i.e. norepinephrine, epinephrine, phenylephrine, vasopressin analogues, angiotensin, dopamine, dobutamine, milrinone or levosimendan)	From randomization to 28 days
Time from randomization to an improvement of two points on a seven-category ordinal scale	1, not hospitalized with resumption of normal activities; 2, not hospitalized, but unable to resume normal activities; 3, hospitalized, not requiring supplemental oxygen; 4, hospitalized, requiring supplemental oxygen; 5, hospitalized, requiring nasal high-flow oxygen therapy, noninvasive mechanical ventilation, or both; 6, hospitalized, requiring ECMO, invasive mechanical ventilation, or both; and 7, death	From randomization to 28 days
ICU-free days at day 28	The number of ICU-free days within 28 days after randomization	From randomization to 28 days
Hospital-free days at day 28	The number of Hospital-free days within 28 days after randomization	From randomization to 28 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Vomiting	The proportion of patients with vomiting, judged by the clinicians according to the clinical manifestations.	From randomization to 28 days
Aspiration of gastric contents	The proportion of patients with aspiration of gastric contents, judged by the clinicians according to the clinical manifestations.	From randomization to 28 days
Nasal/facial skin necrosis	The proportion of patients with nasal/facial skin necrosis, judged by the clinicians according to the clinical manifestations.	From randomization to 28 days
Pneumothorax	Pneumothorax detected through chest X-ray or CT scan	From randomization to 28 days
Cardiac arrest	The proportion of patients with cardiac arrest	From randomization to 28 days
Other adverse events	The proportion of other adverse events related to the interventions assessed by investigators	From randomization to 28 days

Collaborators and Investigators

• Sponsor: Southeast University, China
• Investigators: Study Director: Ling Liu, PhD, Zhongda Hospital, School of Medicine, Southeast University

Study record dates

Study Major Dates

• Study Start (Actual): January 23, 2025
• Primary Completion (Estimated): October 31, 2027
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: January 11, 2025
• First Submitted That Met QC Criteria: January 21, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 24, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Respiratory Insufficiency
• Other Study ID Numbers: TRIPOD Study

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
• product manufactured in and exported from the U.S.: No