To the Editor:
We thank Dr Lellouche and colleagues for their comments regarding our manuscript.1 Selecting an outcome measure for clinical trials in COVID-19 and other causes of hypoxemia is complex. We believe that oxygen-free days (OFD) is an important addition to the available clinical trial outcomes, but appreciate the considerations outlined by Dr Lellouche.
First, Dr Lellouche notes that variation in oxygen saturation targets could lead to differences in oxygen weaning and, therefore, differences in OFDs caused by practice patterns rather than pathophysiology. This limitation is correct but applies to all free day outcomes (eg, ventilator-free days, vasopressor-free days, and so forth), which are widely accepted in critical care research. Although practice variation may impact raw values for OFD, randomization in clinical trials would balance this variation between groups and preserve the validity of between-group comparisons.
Second, Dr Lellouche and colleagues highlight that skin pigmentation may affect the accuracy of oxygen saturation measurements using pulse oximetry (Spo 2). If pulse oximeters systematically overestimate Spo 2 compared with Sao 2 in patients with darker skin pigmentation, this could result in supplemental oxygen being weaned more quickly. Addressing this issue is critically important—more for the millions of patients affected in clinical care than for the use of OFDs as a clinical trial outcome, where randomization balances baseline patient characteristics such as skin pigmentation.
The statement by Lellouche et al that “…Spo 2 overestimates Sao 2 by 2% to 3%” in patients with darker skin may be overly simplistic. Measurement error has two components: directional bias and variability. The magnitude of the directional bias in Spo 2 measurement may differ based on the oximeter type and on the patient’s Spo 2 value. In data collected by the authors, at Spo 2 values < 92% and > 98%, no directional bias was present, and at values between 92% and 98%, Sao 2 values relative to Spo 2 were approximately 1% lower for Black patients.2 Variability is also an important, and underappreciated, contributor to error in Spo 2 measurement.2, 3, 4 At a given Spo 2 value, patients with darker skin are more likely to have either lower or high er Sao 2 values. Although directional bias could be corrected with a simple equation (eg, subtract 2% to 3% from the Spo 2), variability must be corrected by improving the device itself.
In summary, we agree with Lellouche et al that harmonizing the approach to supplemental oxygen use across participants and minimizing Spo 2 measurement error for patients of all skin pigmentations would strengthen trials using OFDs as an outcome.
Acknowledgments
Author contributions: W. H. S. is the guarantor of this work. A. Moskowitz, W. H. S., A. Mohamed, M. S. S., and M. W. S. provided essential intellectual input into the crafting of this letter response. A. Moskowitz and M. W. S. authored the first draft of the work. All the authors provided critical input into the final version and approved of the final product.
Funding/support: This research was, in part, funded by the National Heart, Lung and Blood Institute (NHLBI) of the National Institutes of Health (NIH) through awards 42-312-0217571-66406L and 1OT2HL156812.
Financial/nonfinancial disclosures: See earlier cited article for author conflicts of interest.
Role ofsponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.
Disclaimer: The views and conclusions contained in this document are those of the authors and should not be interpreted as representing the official policies, either expressed or implied, of the NIH, the National Heart, Lung, and Blood Institute, or the U.S. Department of Health and Human Services.
References
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