In Premature Newborns Intraventricular Hemorrhage Causes Cerebral Vasospasm and Associated Neurodisability via Heme-Induced Inflammasome-Mediated Interleukin-1 Production and Nitric Oxide Depletion

Abstract

Background: Intraventricular hemorrhage (IVH) occurs in 60-70% of neonates weighing 500-750 g and 10-20% of those weighing 1,000-1,500 g. All forms of IVH have been associated with neurocognitive deficits. Both subarachnoid and IVHs have been associated with delayed vasospasm leading to neurological deficits. Pathways linking hemoglobin release from blood clots to vasospasm include heme-induced activation of inflammasomes releasing interleukin-1 (IL-1) that can cause calcium dependent and independent vasospasm. Free hemoglobin is a potent scavenger of nitric oxide (NO). Depletion of NO, a potent endogenous vasodilator, has been associated with features of vasospasm.

Hypothesis: In premature newborns, IVH causes cerebral vasospasm and associated neurodisability via heme-induced increased inflammasome-mediated IL-1 production and NO depletion.

Confirmation of hypothesis and implications: This hypothesis could be confirmed in the IVH animal model with visualization of any associated vasospasm by angiography and in newborns with IVH by transcranial Doppler ultrasonography and correlation with cerebrospinal fluid IL-1 and NO metabolite levels. Confirmation of the role of heme in activation of inflammasomes causing IL-1 production and NO binding could be achieved by measuring the effect of heme scavenging interventions on IL-1 levels and levels of NO metabolites. In addition to removal of the accumulated blood of an IVH by drainage, irrigation, and fibrinolytic therapy intrathecal application of vasodilators and heme scavenging agents like haptoglobin and haemopexin and systemic treatment with inhibitors of inflammasomes like telmisartan could be used to prevent and treat cerebral vasospasm, and thus reduce the risk of associated brain injury in premature neonates.

Keywords: heme; hemorrhage; inflammasome; interleukin-1; nitric oxide; vasospasm.