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Ann Thorac Surg 2002;74:632
© 2002 The Society of Thoracic Surgeons
a Department of Thoracic Surgery, Percy Military Hospital, 101 Ave Henri Barbusse B.P. 406, 92141 Clamart Cedex, France
b Institut de Pharmacologie Moléculaire et Cellulaire du CNRS, Valbonne, France
e-mail: loic.lang{at}wanadoo.fr
To the Editor
We read with interest the study by Shake and collaborators on the protective effect of diazoxide during hypothermic circulatory arrest (HCA) [1]. Ischemic preconditioning is an endogenous protective mechanism in which brief periods of ischemia and reperfusion render the brain more resistant to a subsequent more sustained ischemic insult [2]. Our group has demonstrated that the mechanism of ischemic preconditioning in the brain involved the liberation of adenosine, stimulation of adenosine A1 receptors, and, via those receptors, opening of the sulfonylurea-sensitive K+ATP channels [2]. We showed that pretreatment with the K+ATP channels openers cromakalim, nicorandil, and pinacidil mimicked the effect of a brief ischemic paradigm, prevented the expression of the early genes c-fos, c-jun, and heat shock protein 70 mRNA, and prevented neuronal cell death in rat hippocampus at 7 days of reperfusion, but only if the drugs were reinjected once each day during the reperfusion period. A single pretreatment injection resulted in temporary neuroprotection [3]. Neuroprotection was demonstrated for an interval between the brief ischemic insult and the subsequent longer ischemic insult of 3 days, but not 1 hour [3]. Others have provided evidence for a form of ischemic preconditioning in the brain which resembles the one known in the heart as "rapid preconditioning" and requires only 30 minutes of reperfusion between the conditioning short ischemic insult and the test ischemic insult [4]. They showed that neuroprotection was sustained for 3 days after the second ischemic insult, but also that neuroprotection almost disappeared when reperfusion was continued for 7 days [4]. We provided evidence that this rapid preconditioning was probably through the activation of adenosine A1 receptor, because the selective A1 receptor agonist cyclopentyladenosine injected 15 minutes prior to test ischemic insult mimicked the effects of rapid preconditioning and resulted in 70% protection of hippocampal neurons at 7 days [2]. Considering those studies, it is yet unknown whether the neuroprotection induced by rapid preconditioning is permanent or temporary.
Although the Johns Hopkins group’s article demonstrates the neuroprotective effect of diazoxide at 72 hours of reperfusion, it does not provide evidence for a more definitive protection against delayed neuronal cell death. Sacrificing some animals after 7 days of reperfusion could have addressed the question whether the protection afforded by diazoxide is permanent or not. Thus, there is now compelling evidence that neuronal protection can be temporary with some neuroprotective therapies. The TUNEL method, Bax, and caspase-3 immunohistochemical studies could have been of value to demonstrate that diazoxide can truly prevent neuronal apoptosis after HCA.
Regarding the drug itself, we have some concerns regarding its use during aortic arch surgery. Thus, diazoxide has been widely used in humans in the 1970s, with several cases of hyperglycemic hyperosmolar nonketotic coma reported in anesthetized patients [5]. Infusion of diazoxide has been demonstrated to result in a prompt hyperglycemia [6]. As hyperglycemia can dramatically worsen ischemic brain damage [7], we wonder whether diazoxide treatment would really be safe in the setting of global cerebral anoxia or ischemia triggered by prolonged HCA. Blood glucose measurements in the experimental groups could have been of value in order to verify that diazoxide infusion did not induce hyperglycemia.
References
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