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, 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