Plasma nitrite as an indicator of cerebral ischemia during extracranial/intracranial bypass surgery in moyamoya patients.

BACKGROUND AND PURPOSE: Nitric oxide (NO) plays a key role in ischemia and shows potential as a biomarker for ischemia. We measured mixed venous nitrite (NO2-) as a proxy for NO, during controlled cerebral ischemia in patients with moyamoya disease (MMD) during direct extracranial/intracranial (EC/IC) bypass surgery with temporary occlusion of the M4 branch of the middle cerebral artery (MCA) to permit anastomosis with the superficial temporal artery (STA). This small, focal ischemic event is not reliably detected using cerebral oximetry, somatosensory evoked potentials (SSEPs) or electroencephalography (EEG). METHODS: We enrolled nine adult MMD patients (n=8 female, n=1 male) undergoing direct EC/IC bypass surgery. Nitrite was measured at least one hour prior to MCA occlusion, and before, during and after anastomosis. Cortical function was monitored using either multi-lead EEG and SSEPs, or frontal EEG activity. RESULTS: Mixed venous NO2- was significantly elevated (p<0.05) within 12 min following arterial occlusion vs. baseline. An M4 branch of the MCA was cross clamped for a median duration of 18 (IQR = 5) minutes during anastomosis. One patient with elevated NO2- showed a transient neurologic deficit that resolved 3 days post-operatively. CONCLUSIONS: Mixed venous NO2- was significantly elevated shortly following cerebral artery occlusion vs. baseline in a majority of the study subjects, suggesting that NO2- is a potential biomarker for ischemia. Since all patients received identical burst suppression anesthesia and vasopressors, the fact that NO2- was not elevated during cross-clamp in all patients supports the conclusion that the NO2- elevation is likely due to ischemia.

Continuous monitoring of changes in plasma nitrite following cerebral ischemia in a rabbit embolic stroke model.

In this proof-of-concept study, we investigated direct, continuous monitoring of plasma nitrite as an indicator of cerebral ischemia following clot embolization of rabbits via an indwelling carotid catheter. Two groups of rabbits were studied to compare the effects of embolization on nitrite levels. In the control group, blood was continuously obtained from a jugular venous catheter. The blood was immediately passed through an ultrafiltration filter; the filtrate was chemically reduced to convert free nitrite to nitric oxide (NO) and then measured using a NO-specific electrode. In the embolized group, after a baseline nitrite level was achieved, blood clots were injected into the brain via the carotid artery catheter, and then nitrite levels were continuously measured from jugular venous blood. The stroke group showed a significantly greater increase in nitrite as compared to controls (p=0.017). Using the area-under-the-curve (AUC) method, results reached statistical significance (p<0.05) within 3 min of embolization. In embolized rabbits, NO(2) levels increased 424±256% compared to baseline. This study shows that nitrite can be measured immediately following a stroke and that our system measures nitrite independent of the extent of the stroke. This study provides evidence for the feasibility of using nitrite as a marker of ischemic stroke.