Protocol and Statistical Analysis Plan for the Waveform Capnography versus Colorimetric Carbon Dioxide Detection During Tracheal Intubation of Critically Ill Adults (WAVE) Study

Background: During emergency tracheal intubation, clinicians use waveform capnography or colorimetric carbon dioxide (CO2) detection to confirm exhaled CO2 from the endotracheal tube to determine its location. Both devices reliably yield a negative result when the tube is in the esophagus. However, in most emergency intubations the tube is correctly located in the trachea, and in this circumstance the relative diagnostic accuracy of the two devices is uncertain. If one device more often fails to detect exhaled CO2 despite correct tube placement (a false negative result), this could lead to unnecessary tube removal, repeated intubation attempts, and an increased risk of serious complications. Research Question: Among critically ill adults undergoing emergency tracheal intubation, is waveform capnography or colorimetric CO2 detection more sensitive for identifying an endotracheal tube correctly placed in the trachea? Study Design and Methods: The WAVE study is a pragmatic, prospective, paired diagnostic accuracy study conducted in emergency departments and intensive care units in the United States. The study compares waveform capnography and colorimetric CO2 detection (index tests) against a non-CO2-based reference standard for endotracheal tube location among 2,092 critically ill adults undergoing tracheal intubation. The primary outcome is the sensitivity of each index test for identifying a tube located in the trachea. The secondary outcome is specificity for identifying a tube located outside the trachea. Results: Enrollment began on April 21, 2025 and is ongoing, with completion anticipated in 2026. Interpretation: The WAVE study will provide prospective evidence comparing waveform capnography with colorimetric CO2 detection for determination of endotracheal tube location in critically ill adults. These findings may inform clinical practice and guideline recommendations regarding the optimal test of exhaled CO2 for use in the ED and ICU. Prespecifying the protocol and statistical analysis plan before completion of enrollment enhances the rigor, reproducibility, and transparency of the study.