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Ann Thorac Surg 1995;59:579-584
© 1995 The Society of Thoracic Surgeons

Articles

AMPA glutamate receptor antagonism reduces neurologic injury after hypothermic circulatory arrest

MD J. Mark Redmond, MD Kenton J. Zehr, PhD Mary E. Blue, MA Mary S. Lange, MD A. Marc Gillinov, MD Juan C. Troncoso, MD Duke E. Cameron, MD Michael V. Johnston, MD William A. Baumgartner*

Division of Cardiac Surgery, the Johns Hopkins Medical Institutions and the Kennedy-Krieger Research Institute, Baltimore, Maryland, USA

* Address reprint requests to Dr Baumgartner, Department of Surgery, The Johns Hopkins Hospital, Blalock 618, 600 N Wolfe St, Baltimore, MD 21287-4618.

Pharmacologic inhibition of the N-methyl-D-aspartate (NMDA) glutamate receptor can reduce the neurologic injury associated with hypothermic circulatory arrest; however, other receptor subtypes, such as the α-amino-3-hydroxy-5-methylisoazole-4-propionic acid/kainate or AMPA/kainate subtype, may predominate in the adult brain. In this experiment, a selective AMPA antagonist, NBQX, was used in a canine survival model of hypothermic circulatory arrest. Twelve male dogs (20 to 25 kg) were placed on closed-chest cardiopulmonary bypass, subjected to 2 hours of hypothermic circulatory arrest at 18°C, and rewarmed on cardiopulmonary bypass. All were mechanically ventilated and monitored for 20 hours before extubation and survived for 3 days. Six dogs received NBQX beginning 2 hours after arrest (3 mg/kg for 3 hours then 1.5 mg/kg for 2 hours). Control dogs received vehicle only. Neurologic recovery was assessed every 12 hours using a species-specific behavior scale that yielded a neurodeficit score ranging from 0 (normal) to 500 (brain dead). After sacrifice at 72 hours, brains were examined by receptor autoradiography and histologically for patterns of selective neuronal necrosis and scored blindly from 0 (normal) to 100 (severe injury). Dogs given NBQX had better neurologic function compared with controls (neurodeficit score, 58.6 ± 15 versus 204 ± 30; p < 0.004) and had less neuronal injury (18.2 ± 3 versus 52.5 ± 6; p < 0.004). Densitometric receptor autoradiography revealed preservation of neuronal NMDA receptor expression only in dogs given NBQX. These results suggest that antagonism of the non-NMDA glutamate receptor AMPA may be neuroprotective in adults after hypothermic circulatory arrest.




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