Jon Westbrook

The role of the nitric oxide pathway in brain injury and its treatment--from bench to bedside.

Nitric oxide (NO) is a key signalling molecule in the regulation of cerebral blood flow. This review summarises current evidence regarding the role of NO in the regulation of cerebral blood flow at rest, under physiological conditions, and after brain injury, focusing on subarachnoid haemorrhage, traumatic brain injury, and ischaemic stroke and following cardiac arrest. We also review the role of NO in the response to hypoxic insult in the developing brain. NO depletion in ischaemic brain tissue plays a pivotal role in the development of subsequent morbidity and mortality through microcirculatory disturbance and disordered blood flow regulation. NO derived from endothelial nitric oxide synthase (eNOS) appears to have neuroprotective properties. However NO derived from inducible nitric oxide synthase (iNOS) may have neurotoxic effects. Cerebral NO donor agents, for example sodium nitrite, appear to replicate the effects of eNOS derived NO, and therefore have neuroprotective properties. This is true in both the adult and immature brain. We conclude that these agents should be further investigated as targeted pharmacotherapy to protect against secondary brain injury.

Pseudo-continuous arterial spin labelling MRI for non-invasive, whole-brain, serial quantification of cerebral blood flow following aneurysmal subarachnoid haemorrhage.

Delayed cerebral ischaemia (DCI) is the major cause of mortality and morbidity following aneurysmal subarachnoid haemorrhage (SAH). Recent experimental evidence from animal models has highlighted the need for non-invasive and robust measurements of brain tissue perfusion in patients in order to help understand the pathophysiology underlying DCI. Quantitative, serial, whole-brain cerebral perfusion measurements were obtained with pseudo-continuous arterial spin labelling (PCASL) magnetic resonance imaging (MRI) in six SAH patients acutely following endovascular coiling. This technique requires no injected contrast or radioactive isotopes. MRI scanning was well tolerated. Artefact from endovascular coils was minimal. PCASL MRI was able to detect time-dependent and patient-specific changes in voxel-wise and regional cerebral blood flow. These changes reflected changes in clinical condition. Data obtained in healthy controls using the same experimental protocol confirm the reliability and reproducibility of these results. This is the first study to use whole-brain, quantitative PCASL to identify time-dependent changes in cerebral blood flow at the tissue level in the acute period following SAH. This technique has the potential to better understand changes in cerebral pathophysiology as a consequence of aneurysm rupture.

Calcium channel blockade with nimodipine reverses MRI evidence of cerebral oedema following acute hypoxia.

Acute cerebral hypoxia causes rapid calcium shifts leading to neuronal damage and death. Calcium channel antagonists improve outcomes in some clinical conditions, but mechanisms remain unclear. In 18 healthy participants we: (i) quantified with multiparametric MRI the effect of hypoxia on the thalamus, a region particularly sensitive to hypoxia, and on the whole brain in general; (ii) investigated how calcium channel antagonism with the drug nimodipine affects the brain response to hypoxia. Hypoxia resulted in a significant decrease in apparent diffusion coefficient (ADC), a measure particularly sensitive to cell swelling, in a widespread network of regions across the brain, and the thalamus in particular. In hypoxia, nimodipine significantly increased ADC in the same brain regions, normalizing ADC towards normoxia baseline. There was positive correlation between blood nimodipine levels and ADC change. In the thalamus, there was a significant decrease in the amplitude of low frequency fluctuations (ALFF) in resting state functional MRI and an apparent increase of grey matter volume in hypoxia, with the ALFF partially normalized towards normoxia baseline with nimodipine. This study provides further evidence that the brain response to acute hypoxia is mediated by calcium, and importantly that manipulation of intracellular calcium flux following hypoxia may reduce cerebral cytotoxic oedema

Electroencephalographic Response to Sodium Nitrite May Predict Delayed Cerebral Ischemia After Severe Subarachnoid Hemorrhage.

Objectives:Aneurysmal subarachnoid hemorrhage often leads to death and poor clinical outcome. Injury occurring during the first 72 hours is termed “early brain injury,” with disruption of the nitric oxide pathway playing an important pathophysiologic role in its development. Quantitative electroencephalographic variables, such as &agr;/&dgr; frequency ratio, are surrogate markers of cerebral ischemia. This study assessed the quantitative electroencephalographic response to a cerebral nitric oxide donor (intravenous sodium nitrite) to explore whether this correlates with the eventual development of delayed cerebral ischemia. Design:Unblinded pilot study testing response to drug intervention. Setting:Neuroscience ICU, John Radcliffe Hospital, Oxford, United Kingdom. Patients:Fourteen World Federation of Neurosurgeons grades 3, 4, and 5 patients (mean age, 52.8 yr [range, 41–69 yr]; 11 women). Interventions:IV sodium nitrite (10 &mgr;g/kg/min) for 1 hour. Measurements and Main Results:Continuous electroencephalographic recording for 2 hours. The alpha/delta frequency ratio was measured before and during IV sodium nitrite infusion. Seven of 14 patients developed delayed cerebral ischemia. There was a +30% to +118% (range) increase in the alpha/delta frequency ratio in patients who did not develop delayed cerebral ischemia (p < 0.0001) but an overall decrease in the alpha/delta frequency ratio in those patients who did develop delayed cerebral ischemia (range, +11% to –31%) (p = 0.006, multivariate analysis accounting for major confounds). Conclusions:Administration of sodium nitrite after severe subarachnoid hemorrhage differentially influences quantitative electroencephalographic variables depending on the patient’s susceptibility to development of delayed cerebral ischemia. With further validation in a larger sample size, this response may be developed as a tool for risk stratification after aneurysmal subarachnoid hemorrhage.