NACCSGBI Project Grant
Determining the role of Nitric Oxide Depletion in Early Brain Injury after Subarachnoid Haemorrhage using Multimodal Magnetic Resonance Imaging
Dr Martyn Ezra
Subarachnoid haemorrhage (SAH) is the commonest cause of stroke in young adults and is often fatal or results in serious disability. It occurs when small defects in the blood vessels of the brain called "aneurysms" rupture leading to bleeding around the brain. Because SAH predominantly affects young adults who are likely to have financial and family responsibilities, the long-term economic, social and health care implications are considerable. One of the major causes of disability is the development of secondary strokes days after the initial bleed.
Currently, it is not known exactly why these secondary strokes occur and it is difficult to predict which patients are most at risk. It is thought that changes in the brain in the initial days after the bleed may predispose patients to developing these secondary strokes; this period has been termed Early Brain Injury. Despite this, the majority of our understanding of this critical period comes from research in animals. These studies suggest that following SAH a cascade of harmful chemical reactions occurs, that result in brain cell damage. Over activation of the energy producing components of the cells called mitochondria, leading to the production of destructive chemicals, is thought to have a critical role in this process.
After SAH there is a large decrease in the level of molecule within the brain called nitric oxide; we believe that this decrease contributes to the development of early brain injury. Nitric oxide is known to play an essential role in protecting the brain after injury by stopping over activation of the mitochondria. Promisingly, studies in animals have shown that it is possible to reproduce this protective effect by giving drugs that increase the levels of nitric oxide in the brain.
We aim to investigate the effect of nitric oxide replacement in human SAH patients by using specialised magnetic resonance imaging (MRI) techniques. Using MRI it is possible to directly measure the damage to the cells of the brain during early brain injury without using injections, radiation or invasive probes.
We will examine patients, in the first 72 hours, who have had the most severe form of SAH, that require machines to help with their breathing. They will be randomly allocated to receive either, a drug to increase brain nitric oxide levels called sodium nitrite or a placebo control. We believe that increasing brain nitric oxide levels will protect the brain cells from further damage and reverse the damage that has already occurred. MRI scans will be performed before and after the drug/placebo in both groups of patients to see if there is any difference in the damage to the brain cells.
This study will for the first time test the effects of increasing brain nitric oxide levels on early brain injury in human patients. We hope this will lead to larger future studies investigating nitric oxide replacement to prevent the development of secondary strokes after SAH. The potential benefit to both patients and the NHS of this research is considerable.
