Intraoperative magnesium infusion during carotid endarterectomy: a double-blind placebo-controlled trial.

OBJECT: Recent data from both experimental and clinical studies have supported the use of intravenous magnesium as a potential therapy in the setting of cerebral ischemia. This study assessed whether intraoperative magnesium therapy improves neuropsychometric testing (NPT) following carotid endarterectomy (CEA). METHODS: One hundred eight patients undergoing CEA were randomly assigned to receive placebo infusion or 1 of 3 magnesium-dosing protocols. Neuropsychometric testing was performed 1 day after surgery and compared with baseline performance. Assessment was also performed on a set of 35 patients concurrently undergoing lumbar laminectomy to serve as a control group for NPT. A forward stepwise logistic regression analysis was performed to evaluate the impact of magnesium therapy on NPT. A subgroup analysis was then performed, analyzing the impact of each intraoperative dose on NPT. RESULTS: Patients treated with intravenous magnesium infusion demonstrated less postoperative neurocognitive impairment than those treated with placebo (OR 0.27, 95% CI 0.10-0.74, p = 0.01). When stratified according to dosing bolus and intraoperative magnesium level, those who were treated with low-dose magnesium had less cognitive decline than those treated with placebo (OR 0.09, 95% CI 0.02-0.50, p < 0.01). Those in the high-dose magnesium group demonstrated no difference from the placebo-treated group. CONCLUSIONS: Low-dose intraoperative magnesium therapy protects against neurocognitive decline following CEA.

Pre-clinical evaluation of an sLe x-glycosylated complement inhibitory protein in a non-human primate model of reperfused stroke.

BACKGROUND: Soluble complement receptor-1 (sCR1), a potent complement inhibitor, confers neuroprotection in a murine stroke model. Additional neuroprotective benefit is achieved by sLe x-glycosylation of sCR1. In an effort to translate sCR1-sLe x to clinical trials, we evaluated this agent in a primate stroke model. METHODS: Adult male baboons randomly received either sCR1-sLe x or vehicle. Stroke volume was assessed on day 3, and neurological examinations were conducted daily. Complement activity (CH50) was measured at 30 minute, 2, 6, 12 hour, 3, and 10 days post-ischemia. RESULTS: The experiment was terminated prematurely following an interim analysis. In a preliminary cohort (n = 3 per arm), infarct volume was greater in the treated animals. No difference in neurological score was found between groups. CH50 levels were significantly reduced in the sCR1sLe x-treated groups. A hypotensive response was also observed in animals treated with sCR1-sLe x. Conclusions Further work is necessary to explain the hypotensive response observed in primates prior to further clinical development of sCR1-sLe x.

Preclinical evaluation of the neuroprotective effect of soluble complement receptor type 1 in a nonhuman primate model of reperfused stroke.

OBJECT: Postischemic cerebral inflammatory injury has been extensively investigated in an effort to develop effective neuroprotective agents. The complement cascade has emerged as an important contributor to postischemic neuronal injury. Soluble complement receptor Type 1 (sCR1), a potent inhibitor of complement activation, has been shown to reduce infarct volume and improve functional outcome after murine stroke. Given numerous high-profile failures to translate promising antiinflammatory strategies from the laboratory to the clinic and given the known species-specificity of the complement cascade, the authors sought to evaluate the neuroprotective effect of sCR1 in a nonhuman primate model of stroke. METHODS: A total of 48 adult male baboons (Papio anubis) were randomly assigned to receive 15 mg/kg of sCR1 or vehicle. The animals were subjected to 75 minutes of middle cerebral artery occlusion/reperfusion. Perioperative blood samples were analyzed for total complement activity by using a CH50 assay. Infarct volume and neurological scores were assessed at the time the animals were killed, and immunohistochemistry was used to determine cerebral drug penetration and C1q deposition. An interim futility analysis led to termination of the trial after study of 12 animals. Total serum complement activity was significantly depressed in the sCR1-treated animals compared with the controls. Immunostaining also demonstrated sCR1 deposition in the ischemic hemispheres of treated animals. Despite these findings, there were no significant differences in infarct volume or neurological score between the sCR1--and vehicle-treated cohorts. CONCLUSIONS: A preischemic bolus infusion of sCR1, the most effective means of administration in mice, was not neuroprotective in a primate model. This study illustrates the utility of a translational primate model of stroke in the assessment of promising antiischemic agents prior to implementation of large-scale clinical trials.