Perfusion-Dependent Melanin Bias in Pulse Oximetry and ICU Mortality Across 209 U.S. Hospitals: A Multicenter Retrospective Analysis of 52 Million Readings

Background: Pulse oximeters are typically validated on cohorts of 200–500 subjects under controlled conditions. Whether these cohorts capture the demographic heterogeneity of national clinical practice and whether measurement error is associated with patient outcomes has not been established at scale. Methods: We analyzed paired SpO2/SaO2 readings from three independent sources spanning 209 U.S. hospitals: MIMIC-IV (1 hospital; 12,934 ICU stays), eICU-CRD (208 hospitals; 55,178 stays), and the Open Oximetry Repository (PhysioNet; 52.4 million readings with continuous melanin and perfusion indices). Bias was defined as SpO2 − SaO2. Hidden hypoxemia (SpO2 ≥ 94% with SaO2 < 88%) was assessed per ICU stay. Mortality was compared between hidden-hypoxemia-positive and -negative stays with multivariable logistic regression adjusting for age, sex, race, and four laboratory severity markers (cluster-robust SEs by hospital). Sensitivity analyses included landmark restriction (first 48 hours), lactate stratification, alternate thresholds, and patient-level aggregation. PPG signal quality was assessed in 125 ICU patients with demographic-linked waveform data. Results: Bias was minimal at normal perfusion but amplified under low perfusion in high-melanin patients, consistent with known optics: at very low perfusion × high melanin × severe hypoxia, mean bias reached +12.8% (n=458,571), with 47% of readings constituting hidden severe hypoxemia. National bias in African American patients was +2.76% (n=529,541; 208 hospitals), 62% higher than academic estimates. Across 55,178 eICU stays, hidden hypoxemia was associated with approximately doubled mortality after adjustment for age, sex, race, and illness severity (adjusted OR 1.86, 95% CI 1.69–2.04, p < 0.001), consistent across all racial groups. Hidden hypoxemia was not a pre-terminal phenomenon: 63% of events occurred >48 hours before death (median first event: 15.3 hours; mean time to death: 151 hours), and the association persisted in landmark analysis (first 48 hours only), in patients with normal lactate (adjusted OR 1.87, 95% CI 1.61–2.16), and when both restrictions were applied simultaneously (16.5% vs. 11.1%). Waveform analysis (n=125) showed no fixed racial difference in baseline PPG AC/DC ratio (Black: 0.299, White: 0.273), suggesting the signal deficit is conditional on perfusion state. Full extraction (n=1,545) is in progress. Conclusions: In this multicenter retrospective analysis, national pulse oximetry variance exceeded published benchmarks and was associated with approximately doubled ICU mortality, replicated across 209 U.S. hospitals. Hidden hypoxemia was not a pre-terminal artifact: events occurred throughout the ICU stay at a constant rate, and mortality associations persisted in landmark and lactate-stratified analyses. These findings suggest that current regulatory validation standards may underestimate the real-world prevalence of demographic bias in pulse oximetry, and that perfusion-dependent mechanisms may offer a target for algorithmic correction.