The N-methyl-D-aspartate antagonist memantine has no neuroprotective effect during hypothermic circulatory arrest: a study in the chronic porcine model.
BACKGROUND
Glutamate excitotoxicity has an important role in the development of brain injury after prolonged hypothermic circulatory arrest. The goal of the present study was to determine the potential efficacy of memantine, an N -methyl-D -aspartate receptor antagonist, to mitigate cerebral injury after hypothermic circulatory arrest.


METHODS
Twenty pigs (23-33 kg) were randomly assigned to receive memantine (5 mg/kg) or placebo in a blinded fashion before a 75-minute period of hypothermic circulatory arrest at 20 degrees C. Hemodynamic, electroencephalographic, and metabolic monitoring were carried out. The intracerebral concentrations of glucose, lactate, glutamate, and glycerol were measured by means of enzymatic methods on a microdialysis analyzer. Daily behavioral assessment was performed until the animals died or were put to death on day 7. Histologic analysis of the brain was carried out in all animals.


RESULTS
In the memantine group, 5 of 10 animals survived 7 days compared with 9 of 10 in the placebo group. The median behavioral score at day 7 was 3.5 in the memantine group and 7.5 in the placebo group (P >.2). Among the surviving animals, medians were 9.0 and 8.0 on day 7 (P >.2), respectively. The medians of recovered electroencephalographic bursts were equal in both groups. The median of total histopathologic score was 16 in the memantine group and 14 in the placebo group (P >.2). There was a negative correlation between glutamate levels and electroencephalographic burst recovery (tau = -0.377, P =.043). A positive correlation was found between the highest individual glutamate value and histopathologic score (tau = 0.336, P =.045).


CONCLUSIONS
The present study demonstrates that memantine has no neuroprotective effect after hypothermic circulatory arrest in the pig. In addition, we have shown the accuracy of cerebral glutamate measurements to predict histopathologic injury after hypothermic ischemia.
Rimpiläinen
J
J
Department of Surgery, University of Oulu and Oulu University Hospital, FIN 90220 Oulu, Finland.
Pokela
M
M
Kiviluoma
K
K
Vainionpää
V
V
Hirvonen
J
J
Ohtonen
P
P
Jäntti
V
V
Anttila
V
V
Heinonen
H
H
Juvonen
T
T
D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002315:Cardiopulmonary Bypass; D004569:Electroencephalography; D005260:Female; D005947:Glucose / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D005990:Glycerol / Q000378:metabolism; D006324:Heart Arrest, Induced / Q000009:adverse effects*; D007036:Hypothermia, Induced / Q000009:adverse effects*; D020925:Hypoxia-Ischemia, Brain / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D019344:Lactic Acid / Q000378:metabolism; D008559:Memantine / Q000627:therapeutic use*; D017551:Microdialysis; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D013552:Swine
D018696:Neuroprotective Agents; D019344:Lactic Acid; D018698:Glutamic Acid; D016202:N-Methylaspartate; D005947:Glucose; D005990:Glycerol; D008559:Memantine