Effect of excitatory amino acid receptor blocker MK-801 on overall, neurologic, and morphologic outcome after prolonged cardiac arrest in dogs.
Excitatory amino acids accumulating in the brain during ischemia may cause selective neuronal damage postischemia. This hypothesis was tested in a series of studies using MK-801, an N-methyl-D-aspartate (NMDA) receptor blocker, in a reproducible outcome model of prolonged cardiac arrest in dogs. After normothermic ventricular fibrillation cardiac arrest, the dogs were resuscitated with closed-chest femoral veno-arterial cardiopulmonary bypass. At 4 h they were separated from bypass, ventilation was controlled for 20 h, and intensive care was continued to 96 h. In Study I, ventricular fibrilation cardiac arrest (no-flow) was 17 min; starting immediately with reperfusion, MK-801 1200 mg/kg (n = 5) or an equal volume of placebo (n = 5) was infused over 12 h in blinded, randomized fashion. In Study II, the duration of the no-flow period was reduced to 15 min, and MK-801 2400 mg.kg-1 (n = 4) or placebo (n = 4) was infused. In Study III, no-flow lasted for 15 min, and MK-801 2400 mg/kg was started 30 min before ventricular fibrillation (n = 4); comparison was with Study II controls. In all three studies, MK-801 plasma concentrations peaked at greater than 50 ng/ml and were 15-30 ng/ml over 12 h. All 22 dogs of experiments within protocol survived with severe brain damage. MK-801 delayed return of pupillary reactivity, EEG activity, consciousness, and respiration, necessitating longer periods of controlled ventilation. Neurologic deficit scores, overall performance categories, and brain and heart morphologic damage scores at 96 h did not differ between placebo and MK-801 pretreatment or post-treatment groups. These negative outcome results after prolonged cardiac arrest do not negate the hyperexcitability hypothesis of selective vulnerability, but suggest the existance of additional mechanisms of secondary brain damage.
Sterz
F
F
Department of Anesthesiology/Critical Care Medicine, University of Pittsburgh, Pennsylvania.
Leonov
Y
Y
Safar
P
P
Radovsky
A
A
Stezoski
S W
SW
Reich
H
H
Shearman
G T
GT
Greber
T F
TF
D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use; D003986:Dibenzocycloheptenes / Q000627:therapeutic use*; D016291:Dizocilpine Maleate; D004285:Dogs; D006323:Heart Arrest / Q000628:therapy*; D008297:Male; D011379:Prognosis; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000037:antagonists & inhibitors*; D012151:Resuscitation; D013997:Time Factors
D000927:Anticonvulsants; D003986:Dibenzocycloheptenes; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D016291:Dizocilpine Maleate