<b><i>Background and Objectives:</i></b> Transcutaneous PCO<sub>2</sub> and PO<sub>2</sub> measurement systems offer non-invasive blood gas trend monitoring. The aim of this prospective study was to assess bias and precision of a transcutaneous PCO<sub>2</sub> and PO<sub>2</sub> measurement system incorporating a novel pO<sub>2</sub> sensor (Sentec OxiVenT™) in neonates ≥34 weeks of gestational age (GA) admitted to intensive care. <b><i>Methods:</i></b> Transcutaneous PCO<sub>2</sub> and PO<sub>2</sub> were compared to arterial and capillary blood gas measurements. Bias and precision were calculated by fitting linear mixed models to account for repeated measurements, and influence of clinical covariates on bias and precision was assessed. <b><i>Results:</i></b> We obtained 611 paired transcutaneous and blood gas measurements in 110 patients (median GA 38.3 [interquartile range 36.1–39.7] weeks; age 9 [4–15] days; weight 3,000 [2,500–3,500] g). Transcutaneous PCO<sub>2</sub> showed significant bias to arterial PCO<sub>2</sub> (+0.61; 95% confidence interval 0.46, 0.76 kPa), but not to capillary PCO<sub>2</sub> (−0.23; −0.46, 0.002 kPa). Bias of transcutaneous PO<sub>2</sub> was significant to arterial PO<sub>2</sub> (−2.50; −2.94, −2.06 kPa), while no significant bias compared to capillary PO<sub>2</sub> was observed (+0.17; −0.30, 0.64 kPa). Precision intervals were ±1.8/2.0 kPa for arterial versus capillary PCO<sub>2</sub> and ±4.9/3.3 kPa for arterial versus capillary PO<sub>2</sub> comparisons, respectively. Further, sensor operating temperature (43°C vs. 42°C), soft tissue oedema, vasoactive drugs, weight, and GA significantly altered bias (<i>p</i> < 0.05). <b><i>Conclusions:</i></b> The tested transcutaneous blood gas measurement system showed no significant bias compared to capillary PCO<sub>2</sub> and PO<sub>2</sub>, acceptable bias to arterial PCO<sub>2</sub>, and limited agreement with arterial PO<sub>2</sub>. Precision intervals were wide for all comparisons.
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