Increased intracerebral excitatory amino acids and nitric oxide after hypothermic circulatory arrest.

BACKGROUND: Prolonged hypothermic circulatory arrest (HCA) results in neurologic injury, but the mechanism of this injury is unknown. This study was undertaken to measure quantitatively intracerebral excitatory amino acids and citrulline, an equal coproduct of nitric oxide, during HCA. We hypothesized that HCA resulted in higher levels of glutamate, aspartate, glycine, causing increased intracellular calcium, and therefore, nitric oxide and citrulline. METHODS: Ten dogs underwent intracerebral microdialysis and 2 hours of HCA at 18 degrees C. Effluent was analyzed by high performance liquid chromatography with electrochemical detection. Five dogs each were sacrificed at 8 and 20 hours after HCA. Neuronal apoptosis was scored from 0 (no injury) to 100 (severe injury). RESULTS: Time course of HCA was divided into six periods. Peak levels of amino acids in each period were compared with those at baseline. Glutamate, coagonist glycine, and citrulline, an equal coproduct of nitric oxide, increased significantly over baseline during HCA, cardiopulmonary bypass, and 2 to 8 hours after HCA. Aspartate increased significantly during HCA and 8 to 20 hours after HCA. Apoptosis score was 65.56 +/- 5.67 at 8 hours and 30.63 +/- 14.96 at 20 hours after HCA. CONCLUSIONS: Our results provide direct evidence that HCA causes increased intracerebral glutamate and aspartate, along with coagonist glycine. We conclude that HCA causes glutamate excitotoxicity with subsequent nitric oxide production resulting in neurologic injury, which begins during arrest and continues until 20 hours after hypothermic circulation arrest. To provide effective cerebral protection, pharmacologic strategies to reduce glutamate excitotoxicity require intervention beyond the initial ischemic insult.

Neuronal nitric oxide synthase inhibition reduces neuronal apoptosis after hypothermic circulatory arrest.

BACKGROUND: Neurologic injury, including choreoathetosis and learning and memory deficits, occurs after prolonged hypothermic circulatory arrest (HCA). Apoptosis, or programmed cell death, is a possible cause of the neurologic injury seen after HCA. However, the mechanism of apoptosis is unknown. Hypothermic circulatory arrest causes glutamate excitotoxicity, resulting in increased nitric oxide production. We therefore hypothesized that nitric oxide mediates apoptosis. The purpose of this study was to determine if neuronal nitric oxide synthase inhibition reduces neuronal apoptosis in an established canine model of HCA. METHODS: Fourteen male hound dogs (weight, 20 to 27 kg) were placed on closed-chest cardiopulmonary bypass, subjected to 2 hours of HCA at 18 degrees C, rewarmed to normothermia, and sacrificed 8 hours after HCA. Group 1 (n = 7) dogs were treated with the neuronal nitric oxide inhibitor 7-nitroindazole, 25 mg/kg intraperitoneally, before arrest and every 2 hours until sacrifice. Group 2 (n = 7) dogs received vehicle only. The brains were analyzed histopathologically. Apoptosis, identified by hematoxylin-eosin staining, was confirmed by DNA terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end-labeling assay and electron microscopy. Apoptosis was scored by a blinded neuropathologist from 0 (normal) to 100 (severe injury). RESULTS: Apoptosis occurred early after HCA in select neuronal populations, including the hippocampus, stria terminalis, neocortex, and entorhinal cortex. Apoptotic neurons showed a characteristic shrunken cytoplasm and nuclear chromatin condensation. 7-Nitroindazole significantly inhibited apoptosis (group 1 versus 2: 19.17 +/- 14.39 versus 61.11 +/- 5.41; p < .001). CONCLUSIONS: Our results provide evidence that apoptosis is associated with the neurologic injury that occurs after HCA and that nitric oxide mediates the apoptosis that occurs after HCA. Strategies for cerebral protection during HCA may include the inhibition of neuronal nitric oxide synthase.

Endovascular repair of abdominal aortic aneurysms in patients with congenital renal vascular anomalies.

PURPOSE: The endovascular repair of abdominal aortic aneurysms (AAAs) has been suggested as an alternative to conventional aortic reconstruction. The presence of anomalous renal vascular anatomy frequently necessitates special planning during conventional aortic replacement and may also create unique challenges for endovascular repair. We analyzed our experience with 24 patients with variant renal vascular anatomies who underwent treatment with aortic endografts to determine the safety and efficacy of this technique in this population. METHODS: During a 6-year period, 204 patients underwent aortic endograft procedures, 24 (11.8%) of whom had variations in renal vascular anatomy. There were 19 men and five women. Each of the 24 patients had variant renal vascular anatomy, which was defined by the presence of multiple renal arteries (n = 32), with or without a renal parenchymal anomaly (horseshoe or solitary pelvic kidney). Twenty patients underwent aneurysm repair with balloon expandable polytetrafluoroethylene grafts, and the remaining patients underwent endograft placement with self-expanding attachment systems. Eighteen patients underwent exclusion and presumed thrombosis of anomalous renal branches to effectively attach the aortic endograft. The decision to sacrifice a supernumerary artery was made on the basis of the vessel size (<3 mm), the absence of coexisting renal insufficiency, and the expectation for successful aneurysm exclusion. RESULTS: The successful exclusion of the AAAs was achieved in all the patients, with the loss of a total of 17 renal artery branches in 12 patients. Small segmental renal infarcts (<20%) were detected in only six of the 12 patients with follow-up computed tomographic scan results, despite angiographic evidence of vessel occlusion at the time of endografting. No evidence of new onset hypertension or changes in antihypertensive medication was seen in this group. No retrograde endoleaks were detected through the excluded renal branches on late follow-up computed tomographic scans. Serum creatinine levels before and after endografting were unchanged after the exclusion of the AAA in all but one patient with multiple renal branches. One patient had a transient rise in serum creatinine level presumed to be caused by contrast nephropathy. CONCLUSION: On the basis of this experience, we recommend the consideration of endovascular grafting for patients with AAAs and anomalous renal vessels when the main renal vascular anatomy can be preserved and when the loss of only small branches (<3 mm) is necessitated in patients with otherwise normal renal functions.