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Maturation Phenomenon in Cerebral Ischemia IV pp 189–203Cite as

Combination Drug Therapy and Mild Hypothermia: Comparison with Neurosurgical Standard Regimen in a Rat Model of Reversible Focal Cerebral Ischemia

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Summary

Temporary occlusion of cerebral arteries is a common technique to facilitate neurovascular surgery, however, it puts the patient at risk of permanent deficits caused by focal ischemia. Currently, the gold standard of cerebroprotection is barbiturate-induced burst suppression. In addition, the neurosurgical standard drug therapy involves nimodipine, mannitol, and dexamethasone. We have recently demonstrated the superior neuroprotective efficacy of combination therapy with magnesium (calcium- and glutamate-antagonist) + tirilazad (antioxidant) + mild hypothermia (33°C). In the present study we compared this pathophysiologi- cally orientated treatment strategy with the standard regimen. Furthermore, we investigated whether barbiturates provide an additional neuroprotective effect under hypothermic conditions. 142 Sprague-Dawley rats were subjected to 90 min of middle cerebral artery (MCA) occlusion by an intraluminal filament technique, and randomly assigned to the following groups. In part I of the study each drug of the standard regimen was evaluated as monotherapy and in combination. In part II of the study the most effective standard therapy (nimodipine + mannitol + dexamethasone + burst suppression by methohexital) was compared with magnesium + tirilazad + mild hypothermia (33°C). In part III of the study, burst suppression by methohexital and mild hypothermia were evaluated as monotherapy and in combination. Local cortical blood flow was measured by continuous laser Doppler flowmetry. Neurological examinations were performed daily, and infarct size was histologically assessed after 7 days. Part I: Standard drugs alone or in combination moderately limited infarct volume, with mannitol and burst suppression by methohexital being the most effective monotherapies (33% reduction of infarct volume). Most of the animals had residual neurological deficits at the end of the observation period. Part II: Again, combination therapy with standard drugs + burst suppression only moderately limited infarct volume by 36%. In contrast, combination therapy with magnesium + tirilazad + mild hypothermia abolished cortical infarction and reduced total infarct volume by 73% (P<0.05 vs. all other groups). None of the animals in this group had any residual neurological deficit at the end of the observation period (P<0.05 vs. all other groups). Part III: Again, burst suppression by methohexital moderately limited infarct volume (-32%), while hypothermia significantly reduced total infarct volume (-71%). There was no additional neuroprotection by methohexital in combination with hypothermia (-66%). The current clinical standard of neuroprotection has been overestimated. Also, combination therapy with standard drugs is only moderately effective and not more effective than mannitol or burst suppression by methohexital alone. Even the most potent therapeutic approach, mild hypothermia, can be improved by additional pharmacotheraphy with magnesium and tirilazad, but not by barbiturates. Pathophysiologically orientated combination theraphy with clinically licensed drugs such as magnesium and tirilazad + mild hypothermia seems to be a promising candidate for clinical evaluation in neurovascular surgery. A randomized clinical trial has been approved by the local ethics committee.

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Authors
  1. R. Schmid-Elsaesser
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  2. S. Zausinger
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  3. T. Westermaier
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  4. E. Hungerhuber
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  5. A. Baethmann
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  6. H.-J. Reulen
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© 2001 Springer-Verlag Berlin Heidelberg

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Schmid-Elsaesser, R., Zausinger, S., Westermaier, T., Hungerhuber, E., Baethmann, A., Reulen, HJ. (2001). Combination Drug Therapy and Mild Hypothermia: Comparison with Neurosurgical Standard Regimen in a Rat Model of Reversible Focal Cerebral Ischemia. In: Maturation Phenomenon in Cerebral Ischemia IV. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-59446-5_23

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  • DOI: https://doi.org/10.1007/978-3-642-59446-5_23

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-540-41107-9

  • Online ISBN: 978-3-642-59446-5

  • eBook Packages: Springer Book Archive

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