Oxygen diffusion kinetics, buffering capacity and phenotype: A narrative review of oxygen physiology and later phenotype in very preterm infants.

Clinicians often view exposure to supplementary oxygen in preterm infants as a simple reciprocal trade-off between mortality and the risk of vision-threatening retinopathy, but this perspective oversimplifies the underlying physiology. Oxygen moves through a series of spatially distinct compartments without intrinsic regulation, with Fick's law governing the entire process. We suggest that retinopathy of prematurity and cerebral palsy represent opposite ends of a shared continuum of oxygen diffusion injury. Several physiological concepts define this risk matrix. The spatial critical threshold indicates the structural limits of immature microvasculature that impact the diffusion radius. The extinction gradient marks the point at which the capillary-to-cell gradient becomes flat, leading to flux collapse and intracellular hypoxia. Conversely, the hyperoxic injury threshold identifies the point at which intracellular oxygen tension becomes harmful. Lastly, buffering capacity refers to the oxygen bound to haemoglobin in the venous circulation, downstream of metabolism, which is available to buffer temporary mismatches between delivery and consumption. These thresholds explain how hyperoxia and hypoxia can coexist within the same capillary, clarifying distinct clinical phenotypes. Framing oxygen injury this way clarifies contradictions in neonatal trials and offers a physiological model relevant to other diffusion-limited conditions.