Towards a molecular basis for intraventricular haemorrhage: nitric oxide and impaired cerebral autoregulation

In this issue of Acta Pædiatrica, a new hypothesis behind intraventricular haemorrhage (IVH) is presented (1). Van Bel et al. propose that endogenous production of vasodilatory nitric oxide (NO) is associated with the development and extension of IVH. Despite an impressive reduction in the proportion of very low birthweight infants developing IVH (2), from 35–50% down to 15% in the era of maternal steroid therapy, the increased survival of infants below 27 wk gestation means that there are now more candidates for IVH surviving than 15 to 20 y ago. Furthermore, IVH is not restricted just to infants with birthweights below 1500 g. Among the infants with post-haemorrhagic hydrocephalus seen by our neonatal service in Bristol over the last 4 y, 20% had gestational ages of over 32 wk. Much has been learnt about the mechanisms behind IVH at this critical phase of human development. An important anatomical factor is the highly vascular subependymal germinal matrix in the very preterm infant with vessels destined to involute before term lacking protection and support from extracellular matrix proteins (2). An important physiological factor is the limited ability to stabilize cerebral blood  ow in the sick preterm infant. Respiratory distress syndrome (RDS), mechanical ventilation, intubation and pneumothorax generate wide swings in intrathoracic, arterial and central venous pressures that are transmitted to the intracranial vasculature (2). Several studies have shown that low blood pressure or reduced cerebral blood  ow are risk factors for subsequent IVH (3, 4), as is extreme  uctuation in cerebral blood  ow velocity (5). However, our understanding of IVH is incomplete. NO vasodilates mainly via the action of guanosine cyclic 3’,5’ monophosphate (cGMP) on vascular smooth muscle. In a group of 60 infants with gestational ages below 32 wk, Van Bel et al. measured plasma cGMP serially, carried out repeated cranial ultrasound scans and showed that plasma cGMP levels were higher in infants with IVH than in infants with no IVH. Maximal cGMP values preceded the  nal extension in infants with moderate and severe IVH. The authors postulate that high levels of vasodilatory NO maintain a high cerebral blood  ow and increase the risk of germinal matrix bleeding if arterial blood pressure rises rapidly in response to treatment. Van Bel et al. also observed (as have previous investigators) that the infants with moderate and severe IVH received more circulatory support in the form of inotropes and volume than the infants with mild or no IVH. Support for this hypothesis comes from the work of Hardy et al. (6). They observed that NO synthase protein expression and activity in the cerebral microvasculature were 2 to 3 times higher in newborn pigs than in juvenile pigs. NO production was markedly increased during hypertension in newborn, but not juvenile, pigs. If they blocked NO synthase pharmacologically, the pigs were able to maintain autoregulation (stabilization) of cerebral blood  ow at higher arterial pressures. If this applies to the very preterm infant, then sudden rises in arterial pressure are associated with NO-supported rises in blood  ow through the germinal matrix. There is evidence that corticosteroids down regulate NO production (7) and this is consistent with the observation that preterm infants tend to have higher arterial pressures after maternal corticosteroid therapy (8) and the very large reduction in IVH observed in randomized trials of maternal steroid therapy (relative risk 0.57) (9). This important hypothesis and original observation from Van Bel et al. are already generating a number of other testable hypotheses. Questions remaining to be answered include: