["The Journal of Physiology, Volume 604, Issue 8, Page 3457-3475, 15 April 2026. ", "\nAbstract figure legend Clinical detection of brain injury in preterm infantsremains a significant challenge. We investigated whether evolving brain injuryafter severe hypoxia‐ischaemia (HI) in chronically instrumented preterm fetalsheep is associated with dynamic changes in arterial blood pressure variability(BPV) and tested the hypothesis that post‐HI BPV changes are mediated byalpha‐adrenoreceptor activation. HI was associated with increased low‐frequencyBPV during the latent phase, followed by sustained reduction during thesecondary phase of injury. The HI group also had a greater reading‐to‐readingcoefficient of variation during the first day. Importantly, changes in thelatent phase beat‐to‐beat and short‐term BPV were suppressed by non‐selectivealpha‐adrenoceptor inhibition. These findings suggest that alpha‐adrenergicreceptor‐mediated phase‐dependent changes in BPV could serve as an earlybiomarker of brain injury. Created with Biorender.com.\n\n\n\n\n\n\n\n\n\nAbstract\nBrain injury in preterm infants is common but often difficult to detect in the early stages. The present study investigated whether evolving preterm brain injury after exposure to hypoxia‐ischaemia (HI) is associated with dynamic changes in arterial blood pressure variability (BPV) and tested the hypothesis that it was mediated by alpha‐adrenoreceptor activity. Chronically instrumented 0.7 gestation fetal sheep received sham‐HI (n = 8) or HI induced by 25 min of umbilical cord occlusion, followed by i.v. infusion of either the alpha‐adrenergic blocker phentolamine (n = 6) or saline (n = 8) from 15 min to 8 h post‐HI. HI was associated with acutely reduced beat‐to‐beat dispersion, sequential and spectral BPV measures, which normalised by 3 h post‐HI, followed by increased low‐frequency BPV from 3 h to 4 h. From 8 h to 13 h post‐HI, there was sustained reduction in all BPV measures throughout the secondary phase of injury. Alpha‐adrenoreceptor blockade abolished the increase in low‐frequency power during the latent phase and partly influenced secondary phase BPV. The HI group also showed greater 3 hourly reading‐to‐reading BPV during the first 24 h post‐HI, which was completely suppressed with alpha‐adrenoreceptor inhibition. Based on these initial findings, in a subsequent validation cohort [sham‐HI (n = 10) and HI‐saline (n = 10)] a short‐term BPV threshold had 90% sensitivity and 80% specificity for HI. This study highlights the evolving, phase‐dependent changes in BPV after HI, that they are partly mediated by alpha‐adrenoreceptor activation, and suggests that BPV could be a potential early biomarker for brain injury.\n\n\n\n\n\n\n\n\n\nKey points\n\nBrain injury in preterm infants is common but often difficult to detect clinically, partly because of their normal low muscle tone and that seizures are typically electrographic.\nBlood pressure variation (BPV) is mediated mainly by autonomic activity, and so may be a marker for neural injury.\nIn preterm fetal sheep, hypoxia‐ischaemia was associated with evolving, phase‐dependent changes in BPV.\nChanges in BPV were partly mediated by alpha‐adrenoreceptor activation.\nThese findings support the concept that BPV could be a useful, pragmatic tool to help screen for brain injury.\n\n\n"]