Background and aims Cardiovascular compromise is associated with poor outcome in the preterm neonate, with gestational age and male sex as independent risk factors for hypotension, developmental injury and death. Recent work has highlighted the microvasculature as important in the development of cardiovascular compromise in the preterm. We aimed to further characterise microvascular changes that occur in the preterm newborn, identify potential windows for therapeutic intervention and explore the mechanisms underlying this dysfunction.

Methods Preterm neonates were studied during circulatory transition. Microvascular blood flow was characterised over time by laser Doppler. We developed a guinea pig model for studying the mechanisms underlying regulation of blood flow (delivery at GA62/71) and also undertook studies in the preterm piglet.

Results We observed significantly different patterns of microvascular tone regulation between male and female human (p = 0.01) and guinea pig (p = 0.01) neonates. Overproduction of vasodilators (carbon monoxide r = 0.495; p < 0.001; hydrogen sulphide r = 0.37, p = 0.0004), and decreased sympathetic nervous activity (r = 0.424, p = 0.025) was associated with increased microvascular flow. We were additionally able to characterise aspects of this physiology in the preterm piglet.

Conclusions We propose a paradigm shift whereby inherent physiological differences between the preterm and term, and male and female, lead to inappropriate dilatation of the microvasculature, insufficient preload to the struggling myocardium and functional hypovolaemia, thus resulting in central hypotension and cardiovascular compromise. We now have evidence of many of the mechanisms underlying this dysregulation and propose future research be directed at interventional opportunities.