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J Thorac Cardiovasc Surg 1999;118:770-771
© 1999 Mosby, Inc.

LETTERS TO THE EDITOR

A word of caution in extrapolating the spinal cord protective effects of memantine obtained in a rabbit model under ketamine anesthesia

Research Department
Kokura Memorial Hospital
Kitakyushu 803-8555, Japan

Koho-J. Miyamoto, MD

II Department of Physiology
University of the Ryukius
School of Medicine
Okinawa, Japan

To the Editor:

We read with great interest the article titled "Memantine for Prevention of Spinal Cord Injury in a Rabbit Model" by Ehrlich and associates (J Thorac Cardiovasc Surg 1999;117: 285-91). We do not doubt the protective effects exhibited by memantine, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, and we believe it is a significant contribution to central nervous system protection.

However, we would like to bring a few points to the attention of the readership:

1. The protective effects of NMDA antagonists are widely known. ¹ Part of that protection is due to the hypothermic effect of NMDA antagonists. ² In any study to assess protection, specifying only the ischemic time is not enough; specifying the temperature as well, preferably the esophageal temperature, is almost mandatory.
   
2. The temperature was monitored rectally and, although a heating pad was used to maintain normal body temperature, it would have been informative to specify the temperature itself. We have found that esophageal temperatures more closely reflect spinal cord temperatures than do rectal temperatures. ³ Rectal temperatures are usually higher than esophageal temperatures, sometimes by as much as 0.5°C to 1.2°C, and esophageal temperature differences as small as 0.5°C might result in totally different neurologic outcomes. ^2,3
   
3. Their anesthesia protocol included ketamine, which resulted in instant loss of transcranial motor-evoked potentials. This can be explained on the basis of the known NMDA receptor antagonism of ketamine, which is responsible for the reported protective effects. ^1,4 Thus the observed protective effects of memantine were the result of the effects of memantine by itself in addition to those contributed by ketamine, but their relative roles are unknown. For definitive assessment of the protective effects of memantine alone, a group of rabbits anesthetized with nonprotective concentrations of volatile agents without ketamine or barbiturates is essential before the data can be extrapolated to human application, because ketamine is no longer widely used in humans.
   
4. Obviously, slow intravenous infusion of memantine over a 30-minute period before ischemia resulted in better protection than a fast (3-minute) intra-arterial infusion into the aorta distal to the aortic crossclamp, that is, after ischemia. The different results are probably related to how fast the memantine can cross the blood-brain barrier. Had the intra-arterial infusion been performed over a 30-minute period before aortic crossclamping, which of course is impractical, the results might have been different. We have found that a 20- to 30-minute period is usually necessary for effects of pharmacologic agents (including those of adenosine and adenosine triphosphate) to significantly appear in the brain interstitial fluid after intravenous administration (bolus or infusion).
   

References

1. Robinson MB, Coyle JT. Glutamate and related acidic excitatory neurotransmitters: from basic science to clinical application. FASEB J 1987;1:446-55.[Abstract]
   
2. Buchan A, Pulsinelli WA. Hypothermia but no NMDA antagonist MK-801 attenuates neuronal damage in gerbils subjected to transient global ischemia. J Neurosci 1990;10:311-6.[Abstract]
   
3. Miyamoto TA, Miyamoto KJ, Ohno N. Objective assessment of CNS function within 6 hours of spinal cord ischemia in rabbits. J Anesth 1998;12:189-94.
   
4. Weiss J, Goldberg MP, Choi DW. Ketamine protects cultured neocortical neurons from hypoxic injury. Brain Res 1986;380:186-90.[Medline]
   

This article has been cited by other articles:

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				J. Rimpilainen, M. Pokela, K. Kiviluoma, V. Vainionpaa, J. Hirvonen, P. Ohtonen, V. Jantti, V. Anttila, H. Heinonen, and T. Juvonen The N-methyl-D-aspartate antagonist memantine has no neuroprotective effect during hypothermic circulatory arrest: A study in the chronic porcine model J. Thorac. Cardiovasc. Surg., May 1, 2001; 121(5): 957 - 968. [Abstract] [Full Text] [PDF]

				T.-A. Miyamoto and K.-J. Miyamoto A word of caution in extrapolating the riluzole spinal cord injury protective effects obtained in a rabbit model under ketamine anesthesia J. Thorac. Cardiovasc. Surg., December 1, 1999; 118(6): 1156 - 1157. [Full Text]

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