The Effect of NOn-invasive Respiratory Support on outcoMe and Its Risks in SARS-COV-2-related Hypoxemic Respiratory Failure (NORMO2)

Effects of Early vs. Delayed Invasive Mechanical Ventilation: A Target Trial Emulation

To determine whether early endotracheal intubation compared to late endotracheal intubation affects clinical outcome (duration of invasive mechanical ventilation, mortality).

Study Overview

• Status: Recruiting
• Conditions: Target Trial Emulation, Invasive Mechanical Ventilation
• Intervention / Treatment: Procedure: endotracheal intubation

Detailed Description

Non-invasive respiratory support, especially HFNO is usually well-tolerated, especially in COVID-19 patients and can be applied for a prolonged period of time. However, there is a heated debate whether later/delayed endotracheal intubation (due to HFNO / NIV) increases the risk of lung injury, so-called patient self-inflicted lung-injury (P-SILI). The concept of P-SILI assumes that high forces applied to the lung resulting from strenuous breathing effort generated by the patient exacerbates lung-injury and is associated with adverse clinical outcome. It is therefore important to investigate if a longer period of non-invasive respiratory support before invasive mechanical ventilation is associated with adverse clinical outcome. Thus, it is unknown if delaying invasive ventilation worsens clinical outcome. In this study, the research question is whether early compared to late endotracheal intubation improves clinical outcome (duration of invasive mechanical ventilation, mortality)? The aim is to identify the optimal S/F ratio and respiratory rate thresholds for initiating intubation to either improve survival or reduce the duration of invasive ventilation without compromising survival. This is achieved by comparing 25 dynamic treatment regimes defined by combinations of S/F thresholds (<any, 250, 200, 150, 100) and respiratory rate thresholds (>any, 16, 20, 25, 30). Thresholds indicating less severe illness (e.g., S/F < 250 and RR > 16) are considered 'early intubation,' while thresholds indicating more severe illness (e.g., S/F < 100 and RR > 30) are considered 'late intubation'.

Two sensitivity analyses will be conducted:

1. Restricting to patients without hypercapnia (pCO2 < 45), excluding those with missing pCO2 values or pCO2 > 45.
2. Including only patients with non-missing Glasgow Coma Scale (GCS) values and adjusting for GCS as a confounder.

Additionally, seven subgroup analyses will be conducted:

1. Patients diagnosed with COVID-19
2. Patients with a history of COPD
3. Patients with a history of CHF
4. Patients with BMI ≤ 30
5. Patients with BMI > 30
6. Patients on high-flow nasal oxygen (HFNO) at time zero
7. Patients on non-invasive ventilation (NIV) at time zero

• Study Type: Observational
• Enrollment (Estimated): 50000

Contacts and Locations

• Study Contact: Name: Carmen A.T. Reep, MSc; Phone Number: +31628164764; Email: c.reep@erasmusmc.nl
• Study Contact Backup: Name: Evert-Jan Wils, PhD, MD; Email: e.wils@franciscus.nl

Study Locations

• Netherlands
  • Zuid-Holland
    • Rotterdam, Zuid-Holland, Netherlands, 3015GD
      • Recruiting
      • Erasmus Medical Centre
      • Contact: Carmen A.T. Reep, MSc; Phone Number: +31628164764; Email: c.reep@erasmusmc.nl

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Non-Probability Sample

Study Population

Patients from the United Stated for which data is registered in the National Covid Cohort Collaborative (N3C).

Description

Inclusion Criteria:

• Hospitalized (inpatient or ICU)
• 18 years or older
• Hypoxemic respiratory failure: S/F<250
• Not yet intubated

Exclusion Criteria:

• Do not intubate order
• Presence of tracheostomy

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
28-day RMTL of mortality	Mortality restricted mean time lost (RMTL) over the 28-day period (area under the cumulative incidence function curve)	28 days
28-day mortality risk	Mortality risk at day 28	28 days

Collaborators and Investigators

• Sponsor: Erasmus Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2018
• Primary Completion (Estimated): January 1, 2025
• Study Completion (Estimated): January 1, 2025

Study Registration Dates

• First Submitted: December 23, 2024
• First Submitted That Met QC Criteria: January 2, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 2, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Other Study ID Numbers: 50-56300-98-2113

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