Phase dynamics of cerebral blood flow in subarachnoid haemorrhage in response to sodium nitrite infusion.

Aneurysmal subarachnoid haemorrhage (SAH) is a devastating subset of stroke. One of the major determinates of morbidity is the development of delayed cerebral ischemia (DCI). Disruption of the nitric oxide (NO) pathway and consequently the control of cerebral blood flow (CBF), known as cerebral autoregulation, is believed to play a role in its pathophysiology. Through the pharmacological manipulation of in vivo NO levels using an exogenous NO donor we sought to explore this relationship. Phase synchronisation index (PSI), an expression of the interdependence between CBF and arterial blood pressure (ABP) and thus cerebral autoregulation, was calculated before and during sodium nitrite administration in 10 high-grade SAH patients acutely post-rupture. In patients that did not develop DCI, there was a significant increase in PSI around 0.1 Hz during the administration of sodium nitrite (33%; p-value 0.006). In patients that developed DCI, PSI did not change significantly. Synchronisation between ABP and CBF at 0.1 Hz has been proposed as a mechanism by which organ perfusion is maintained, during periods of physiological stress. These findings suggest that functional NO depletion plays a role in impaired cerebral autoregulation following SAH, but the development of DCI may have a distinct pathophysiological aetiology.

Opioid suppression of conditioned anticipatory brain responses to breathlessness.

Opioid painkillers are a promising treatment for chronic breathlessness, but are associated with potentially fatal side effects. In the treatment of breathlessness, their mechanisms of action are unclear. A better understanding might help to identify safer alternatives. Learned associations between previously neutral stimuli (e.g. stairs) and repeated breathlessness induce an anticipatory threat response that may worsen breathlessness, contributing to the downward spiral of decline seen in clinical populations. As opioids are known to influence associative learning, we hypothesized that they may interfere with the brain processes underlying a conditioned anticipatory response to breathlessness in relevant brain areas, including the amygdala and the hippocampus. Healthy volunteers viewed visual cues (neutral stimuli) immediately before induction of experimental breathlessness with inspiratory resistive loading. Thus, an association was formed between the cue and breathlessness. Subsequently, this paradigm was repeated in two identical neuroimaging sessions with intravenous infusions of either low-dose remifentanil (0.7ng/ml target-controlled infusion) or saline (randomised). During saline infusion, breathlessness anticipation activated the right anterior insula and the adjacent operculum. Breathlessness was associated with activity in a network including the insula, operculum, dorsolateral prefrontal cortex, anterior cingulate cortex and the primary sensory and motor cortices. Remifentanil reduced breathlessness unpleasantness but not breathlessness intensity. Remifentanil depressed anticipatory activity in the amygdala and the hippocampus that correlated with reductions in breathlessness unpleasantness. During breathlessness, remifentanil decreased activity in the anterior insula, anterior cingulate cortex and sensory motor cortices. Remifentanil-induced reduction in breathlessness unpleasantness was associated with increased activity in the rostral anterior cingulate cortex and nucleus accumbens, components of the endogenous opioid system known to decrease the perception of aversive stimuli. These findings suggest that in addition to effects on brainstem respiratory control, opioids palliate breathlessness through an interplay of altered associative learning mechanisms. These mechanisms provide potential targets for novel ways to develop and assess treatments for chronic breathlessness.

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 α/δ 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 µg/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.

Early brain injury and cognitive impairment after aneurysmal subarachnoid haemorrhage.

The first 72 h following aneurysm rupture play a key role in determining clinical and cognitive outcomes after subarachnoid haemorrhage (SAH). Yet, very little is known about the impact of so called "early brain injury" on patents with clinically good grade SAH (as defined as World Federation of Neurosurgeons Grade 1 and 2). 27 patients with good grade SAH underwent MRI scanning were prospectively recruited at three time-points after SAH: within the first 72 h (acute phase), at 5-10 days and at 3 months. Patients underwent additional, comprehensive cognitive assessment 3 months post-SAH. 27 paired healthy controls were also recruited for comparison. In the first 72 h post-SAH, patients had significantly higher global and regional brain volume than controls. This change was accompanied by restricted water diffusion in patients. Persisting abnormalities in the volume of the posterior cerebellum at 3 months post-SAH were present to those patients with worse cognitive outcome. When using this residual abnormal brain area as a region of interest in the acute-phase scans, we could predict with an accuracy of 84% (sensitivity 82%, specificity 86%) which patients would develop cognitive impairment 3 months later, despite initially appearing clinically indistinguishable from those making full recovery. In an exploratory sample of good clinical grade SAH patients compared to healthy controls, we identified a region of the posterior cerebellum for which acute changes on MRI were associated with cognitive impairment. Whilst further investigation will be required to confirm causality, use of this finding as a risk stratification biomarker is promising.

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.

Acute impairment of saccadic eye movements is associated with delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage.

OBJECTIVE Delayed cerebral ischemia (DCI) causing cerebral infarction remains a significant cause of morbidity and mortality following aneurysmal subarachnoid hemorrhage (aSAH). Early brain injury in the first 72 hours following rupture is likely to play a key role in the pathophysiology underlying DCI but remains difficult to quantify objectively. Current diagnostic modalities are based on the concept of vasoconstriction causing cerebral ischemia and infarction and are either invasive or have a steep learning curve and user variability. The authors sought to determine whether saccadic eye movements are impaired following aSAH and whether this measurement in the acute period is associated with the likelihood of developing DCI. METHODS As part of a prospective, observational cohort study, 24 male and female patients (mean age 53 years old, range 31-70 years old) were recruited. Inclusion criteria included presentation with World Federation of Neurosurgical Societies (WFNS) Grades 1 or 2 ("good grade") aSAH on admission and endovascular treatment within 72 hours of aneurysmal rupture. DCI and DCI-related cerebral infarction were defined according to consensus guidelines. Saccadometry data were collected at 3 time points in patients: in the first 72 hours, between Days 5 and 10, and at 3 months after aSAH. Data from 10 healthy controls was collected on 1 occasion for comparison. RESULTS Age-adjusted saccadic latency in patients was significantly prolonged in the first 72 hours following aSAH when compared with controls (188.7 msec [95% CI 176.9-202.2 msec] vs 160.7 msec [95% CI 145.6-179.4 msec], respectively; p = 0.0054, t-test). By 3 months after aSAH, there was no significant difference in median saccadic latency compared with controls (188.7 msec [95% CI 176.9-202.2 msec] vs 180.0 msec [95% CI 165.1-197.8 msec], respectively; p = 0.4175, t-test). Patients diagnosed with cerebral infarction due to DCI had a significantly higher age-adjusted saccadic latency in the first 72 hours than those without infarction (240.6 msec [95% CI 216.7-270.3 msec] vs 204.1 msec [95% CI 190.7-219.5 msec], respectively; p = 0.0157, t-test). This difference was more pronounced during Days 5-10 following aSAH, the peak incidence for DCI (303.7 msec [95% CI 266.7-352.7 msec] vs 207.6 msec [95% CI 193.7-223.6 msec], respectively; p < 0.0001, t-test). A binary generalized linear model showed that latency in the first 72 hours was the only significant predictor of cerebral infarction (p = 0.0185). CONCLUSIONS This is the first study to use saccadometry to measure the saccadic latency of eye movements in patients with aSAH during the acute period following aneurysm rupture. The results showed that median saccadic latency is associated with the risk of developing cerebral infarction due to DCI and may act as a potential objective biomarker to guide the need for intensive care admission and treatment. Future studies will look to formally validate saccadic latency as a biomarker of DCI in a larger cohort and assess whether the addition of saccades improves current clinical models for predicting patients at risk.