Pharmacological Protection

Because deep hypothermia, including ACP, often still leads to unwanted neurological outcome in circulatory arrest, additional methods of neuroprotection are applied, including pharmacological interventions. Probably the most controversial approach is the use of barbiturates, particularly thiopentone. In theory barbiturates have an interesting protective profile including a reduction of CMR02 and cerebral blood flow, effects on free fatty acid and free-radical metabolism, reduction of cerebral edema, and suppression of seizure activity [32]. In a rat model of cerebral ischemia, thiopentone attenuated Ca2+ influx in the hippocampus and cortex, probably owing to inhibition of calcium channels and NMDA receptors [64].

Barbiturates have been extensively studied in animal models of focal ischemia [42, 43] with varying success.

CBP, with its tendency to produce substantial amounts of microemboli, may serve as a reliable human model for focal cerebral ischemia. Nussmeier et al. [49] were among the first to report beneficial effects of thiopentone in the prevention of neuropsychiatric complications in cardiac surgery, but a similar study by Zaidan et al. [65] could not substantiate this finding.

The cerebral protective effects of barbiturates in global ischemia have been studied in various models including humans after cardiac arrest [5]. All the trials failed to demonstrate an improvement in outcome. There are no randomized clinical studies showing advantageous effects of barbiturates in DHCA patients, and it has even been suggested that barbiturates may jeopardize the energy state of the brain in these conditions [55]. Still, in a survey on current practice, 35% of the respondents believed there to be sufficient evidence to support the use of barbiturates in aortic surgery with DHCA [11]. As potential support for the use of barbiturates, it could be stated that they have been shown to be protective in incomplete, focal ischemia in specific settings as are present during CBP, because of multiple emboli. In addition, they may be helpful in protecting the brain during rewarming after DHCA, particularly in the early phase, when the aforementioned observed jugular venous oxygen desaturation indicates a lack in oxygen delivery.

Since Ca2+ ions play a major role in the devastating effect of cerebral ischemia, several studies have been conducted on the effects of calcium antagonists as neu-roprotectants. Nimodipine, which has neuroprotective effects in decreasing vasospasm after subarachnoid hemorrhage, has been shown to have some efficacy in improving cognitive outcome after CBP [16], but no studies in patients undergoing DHCA have been reported. Unfortunately, a study involving patients undergoing valve replacement had to be terminated because of substantial complications in the nimodipine-treated patients [38].

Another Ca2+ channel blocker, magnesium, showed evidence of protection to the neurons of the hippocampus in rats in anoxic conditions, in contrast to nimodi-pine, which showed no protection at all [29]. This can be explained by the blockade of all voltage-sensitive and NMDA-activated neuronal Ca2+ channels by magnesium, whereas nimodipine only blocks voltage-sensitive channels.

In view of its typical local anesthetic properties, li-docaine has the potential of a powerful neuroprotective agent. It blocks selectively Na+ channels in neuronal membranes. In animal models high doses of lidocaine induce isoelectric EEG, indicating a pronounced reduction in CMR02. In this respect it mimics the effects of hypothermia, but unlike the barbiturates, lidocaine can further reduce metabolic rate by 15-20% [2]. This is mainly attributed to its capacity to reduce ion leaks and energy requirements for the Na+K+-ATPase pumps. In many respects lidocaine may be an adjuvant to hypothermia in protecting the brain during ischemia. In a dog model studying lidocaine at doses of 4 mg/kg before DHCA and 2 mg/kg at the start of reperfusion, the neurological deficit scores in the treatment group were significantly better than in the placebo group [67]. In two recent human studies, a continuous lidocaine infusion of 1 mg/min during and after cardiac surgery resulted in better short-term cognitive outcome [41, 61]. These promising results should lead to human multicenter trials on the neuroprotective effects of lidocaine during DHCA.

In the cascade of events during brain ischemia with an important role for NMDA and AMPA receptors, it is understandable that antagonists of these receptors have been extensively studied in the prevention of adverse neurological outcomes. Remacemide, an NMDA antagonist, was studied during coronary bypass surgery, and showed beneficial effects as a neuroprotective agent [1], but follow-up is lacking. It is also unknown if these results can be extrapolated to DHCA patients. 0ther studies with NMDA antagonists, including ketamine, had to be discontinued because of toxicity or hallucinogenic side effects [57].

Steroids, in particular dexamethasone and methyl-prednisolone, are routinely used during DHCA surgery [11], mainly because they counteract the systemic inflammatory response (SIRS) during and after CBP. Brain ischemia is considered to be a combination of embolization and SIRS, and steroids have previously been shown to improve neurological outcome in DHCA patients [36].

In several animal studies dexmedetomidine, a selective a2-adrenoreceptor agonist, showed strong neuroprotective properties in focal as well as global ischemia [35]. Inhibition of ischemia-induced norepinephrine release may be associated with these effects, particularly in the hippocampus, an extremely vulnerable region in the brain, as described earlier. There are no data concerning the potential protecting role of dexmedetomi-dine in brain ischemia, but its pharmacological profile makes it a very interesting compound to study in this context.

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