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Right arrow Cardiac - pharmacology
Asian Cardiovasc Thorac Ann 2007;15:167-177
© 2007 Asia Publishing EXchange Ltd

REVIEW PAPER

Pharmacological Neuroprotection During Cardiac Surgery

Yuji Kadoi, MD

Department of Anesthesiology, Gunma University, Graduate School of Medicine, Gunma, Japan

For reprint information contact: Yuji Kadoi, MD Tel: 81 27 220 8454 Fax: 81 27 220 8473 Email: kadoi{at}med.gunma-u.ac.jp, Department of Anesthesiology, Gunma University, Graduate School of Medicine, 3-39-22, Showa-machi, Maebashi, Gunma 371-8511, Japan.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 CONCLUSION
 REFERENCES
 
Despite more than 30 years of aggressive neuroprotective research by many investigators, neuropsychological deficit after cardiac surgery remains an important cause of postoperative morbidity. Although the neurological outcome is a result of a multifactorial etiology, many physicians world-wide have recognized the importance of this problem, and extensive efforts have been made in attempting to minimize the incidence of neurological and neurocognitive dysfunction. Pharmacological intervention is one of the important potential methods of neuroprotection during cardiac surgery. In vitro studies have identified drugs that are effective protectants against focal cerebral ischemia, hemorrhage, and global ischemia. However, at present there is no solid agreement on the need for prophylactic neuroprotectants in cardiac surgery. Researchers and clinicians must become more cognizant of the pitfalls and paradoxes that have arisen in attempting to translate the results of animal studies into clinical trial, with regard to neuroprotective therapy during cardiac surgery. There is an extensive need for new pharmacological approaches directed at reducing neurologic and neurocognitive injury during cardiac surgery. This article reviews past and present neuroprotective efforts and interventions during cardiac surgery.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
CONCLUSION
 REFERENCES
 
Over the past 30 years, there has been a steady increase in the average age of patients undergoing cardiac surgery.1,2 Consequently, the severity of cardiac disease at the time of surgery and the re-operation rate for recurrent disease has also increased. Nevertheless, because of many technological advances in surgery, perioperative anesthesia and cardiopulmonary bypass (CPB), there has been a steady decrease in the mortality rate associated with cardiac surgery, from 10% in the late 1970s to 4% in the late 1990s.1,2 However, the incidence of central nervous system dysfunction after cardiac surgery has remained almost constant during the past 30 years. The incidence of postoperative stroke is consistently reported to be around 3% and as high as 9% in patients older than 75 years of age.3,4 The incidence of neurocognitive dysfunction in patients undergoing coronary artery bypass graft (CABG) surgery is up to 79–88% of patients within a week of surgery. Van Dijk and co-workers5 reviewed that a pooled analysis of six highly comparative studies yielded a proportion of 22.5% (95% confidence interval, 18.7%–26.4%) of patients with a cognitive deficit at 2 months after cardiac surgery. The elderly are more likely to have reduced baseline neurocognitive functions, so that a relatively small perioperative decline may have a significant impact on independent living. In addition, perioperative neurological and neurocognitive dysfunction lead to increases in mortality rate and resource utilization, such as prolongation of intensive care unit and hospital stays and increased need for long-term rehabilitation.3

Many studies have investigated the contributory factors to neurological and neurocognitive dysfunction after cardiac surgery.2–5 It has been well established that contributory factors for adverse neurological outcome fall into two categories: those that cannot be modified (patient characteristics and preoperative co-morbidities) and those that may be modified (cerebral embolism, aortic atheroma, CPB duration and cerebral perfusion, acid-base management, and temperature).2–4 Interventions which attempt to reduce or prevent neurological and neurocognitive injury during cardiac surgery can be divided into two categories: (1) physical and (2) pharmacological.

Many physicians world-wide have recognized the importance of this problem, and extensive efforts have been made in attempting to minimize the incidence of neurological and neurocognitive dysfunction.4 Some of these efforts by physicians include the use of arterial filters and membrane oxygenators, alterations in management of the ascending aorta, surgical air-evacuation maneuvers, maintaining cerebral perfusion, hypothermia, advanced neurological monitoring (jugular venous oxygen saturation, near infrared spectroscopy, transcranial Doppler sonography, and electroencephalography etc.).2,4 Transcranial Doppler sonography studies show that these patients sustain hundreds of cerebral microemboli during surgery. Greater numbers of cerebral microemboli are associated with an incidence of postoperative neurological dysfunction.

Although cerebral embolism (gaseous or particulate) is well-established as a cause of injury, it is unknown whether all neurologic insults that occur in association with cardiac surgery can be ascribed to this mechanism. The duration of CPB time has been also consistently identified as a risk factor related to postoperative neurological dysfunction even if membrane oxygenation and arterial filtration have greatly reduced the number of microemboli produced by bypass circuits.3 Investigations reveal that progressive cerebral vasoconstriction leads to a gradual decrease in cerebral blood flow. It is important to note that bypass time may be prolonged by several factors which may contribute to cerebral injury. The complexity of the surgery (for example combined intracardiac and coronary artery procedures) leads to prolonged CPB time and has maintained a robust and consistent association with the incidence of postoperative neurological insult.3

Pharmacological cerebral protection during CPB remains one of the prime means of neuroprotection during cardiac surgery. The strategies for pharmacological cerebral protection during cardiac surgery need to be applied to all patients, regardless of co-morbidities, with the likelihood of only a small percentage of those patients either needing or benefiting from these interventions. However, the financial cost of such pharmacological interventions would be extremely high. It is not only the cost of chosen pharmacological agents that limits the routine use of cerebral protection, but also the more subtle drain that such strategies place on limited resources.2–5

Neurologic and neurocognitive dysfunction in cardiac surgery patients is believed to result from showers of air and particulate debris flushed into the cerebral circulation during CPB, the ischemia being exacerbated by periods of systemic hypoperfusion during CPB. At this point, microembolic models would seem more likely to represent the type of cerebral insults experienced by cardiac surgery patients than standard forebrain ischemia or temporary focal ischemia models. In addition, little is known about the types of microemboli that have deleterious effects on the brain; those consisting of atheromatous debris, microbubbles, or fat and small fibrin-platelet complexes.2,4 This article focuses on pharmacological interventions during CPB, with special emphasis on the effect of anesthetic preconditioning on ischemic insults.

(1) GABA (GAMMA-AMINOBUTYRIC ACID) AGENTS
(a) Barbiturates
In 1974, Michenfelder6 showed in dogs that barbiturates reduce cerebral metabolic rate for oxygen (CMRO2) by decreasing spontaneous synaptic activity. Maximal reduction of CMRO2 was coincident with a nearly flat electroencephalographic (EEG) trace. At the time, it was widely believed that barbiturate brain protection was mediated via reduction of CMRO2. Other possible neuroprotective mechanisms for cerebral ischemia by barbiturates as investigated by laboratory studies are:1. inhibition of lipid peroxidation,7 2. attenuation of brain free fatty acid liberation, especially of arachidonic and stearic acids,8 and 3. scavenging of free radicals.8

With regard to the beneficial effects of barbiturates on cerebral ischemia, Nussmeier and co-workers9 were the first to report the neuroprotective effects of barbiturates during cardiac surgery in clinical trials. A total of 89 randomly assigned patients undergoing open-ventricular operation received sufficient thiopental (an average of 39.5 mg·kg–1) to maintain EEG silence throughout the period from before atrial cannulation to termination of bypass, while 93 control patients received only fentanyl. On the first postoperative day, five thiopental (5.6%) and eight control (8.6%) patients exhibited clinical neuropsychiatric abnormalities. By the 10th postoperative day, all neuropsychiatric dysfunctions had resolved in the thiopental group, but persisted in seven (7.5%) control patients (p < 0.025). In a similar study of patients undergoing CABG, however, Zaidan and co-workers10 reported that isoelectric EEG induction with thiopental (an average of 33.1 mg·kg–1) during CPB did not have any neuroprotective effect. Recently, a retrospective evaluation of 227 open-heart surgery patients showed that thiopental (an average of 38.1 mg·kg–1) had no beneficial effect on neurological outcome.11

(b) Propofol
Propofol has been shown to have a similar effect as thiopental on CMRO2. In addition, many recent studies have shown propofol to be effective against focal cerebral ischemia, oxidative stress or glutamate toxicity in both in vitro and in vivo animal experiments.12–14 Stimulation of the GABA-A/benzodiazepine receptor complex by propofol induces a chloride influx into the neuronal cells.15 This hyperpolarization of the synaptic membrane suppresses the release of excitatory amino acids triggered by brain ischemia.13,14 In clinical studies, Roach and co-workers16 reported that the induction of EEG burst suppression with propofol during open cardiac surgery (valve replacement), did not lead to improved neurologic or neuropsychologic outcome as compared to an otherwise similar opiate-based anesthetic. Kadoi and co-workers17 reported that propofol (an average dose of 85 µg·kg–1·min–1) preserved cerebral oxygenation, as estimated by jugular venous oxygen saturation during CPB, compared with a fentanyl group, while propofol did not affect postoperative cognitive dysfunction.

(2) CALCIUM CHANNEL ANTAGONISTS, NMDA ANTAGONISTS, AND FREE RADICAL SCAVENGERS
Although several mechanisms can lead to cell death after brain ischemia, at least three interrelated pathophysiological mechanisms are important and active after ischemia and reperfusion: elevation of intracellular calcium, release of excitotoxic amino acids including glutamate, and generation of reactive oxygen species (ROS).18,19

(a) Calcium channel antagonists
Calcium channel antagonists block the flow of calcium into ischemic cells, interrupting the ischemic cascade and improving post-ischemic hypoperfusion. An L-type calcium channel antagonist, nimodipine, has been proved to be beneficial in reducing cerebral infarction and improving outcome after subarachnoid hemorrhage.20 In a small study of 35 patients undergoing CABG or valvular heart surgery,21 nimodipine preserved neuropsychometric function after CPB when administered at a dosage of 0.5 µg·kg–1·min–1, as assessed by using a battery of cognitive tests preoperatively and at 5 days and 6 months postoperatively. Significantly better postoperative cognitive functioning on tests of verbal fluency and visual retention was observed at a 6-month follow-up in nimodipine-treated patients in comparison with the control group. Conversely, Legault and co-workers22 reported a trial in which nimodipine was given to 75 patients during the perioperative period. The trial was terminated early because of both an unexpected disparity in death rates between groups and a lack of evidence of a beneficial effect of nimodipine. New deficits were observed in 72% of the placebo group versus 77% of the nimodipine group (p = 0.55). In the 6-month follow-up period, 8 deaths (10.7%) occurred in the nimodipine group (n = 75) compared with 1 death (1.3%) in the placebo group (n = 74) (p = 0.02). Major bleeding occurred in 10 patients in the nimodipine group versus 3 in the placebo group (13.3% versus 4.1%; p = 0.04). Six (46.2%) of the 13 patients with major bleeding died compared with 3 deaths (2.2%) among the 136 patients without major bleeding. Subsequently, they concluded that calcium antagonists have a prohemorrhagic effect in some patients and suggested that nimodipine use should be restricted perioperatively in patients scheduled for cardiac valve replacement.

(b) NMDA antagonists
There is much evidence to show that the release of an excessive amount of glutamate plays a pivotal role in the pathogenesis and development of cerebral injury. The administration of NMDA receptor antagonists can reduce the infarction volume and neurologic deficit after cerebral ischemia.19 Arrowsmith and co-workers23 reported that 171 patients undergoing CABG were randomized to receive remacemide (up to 150 mg every 6 hours) or placebo, from 4 days before to 5 days after their bypass procedure. They found that overall postoperative change (reflected by learning ability in addition to reduced deficits) was more favorable in the remacemide group, which demonstrated significantly greater improvement in a global z score (p = 0.028) and changes in 3 individual tests (p < 0.05). They concluded that this result supports the hypothesis that drugs acting on the excitotoxic mechanism of ischemic cerebral damage can be effective in humans. In contrast, Ikonomidou and co-workers24 reported that progressive neurodegeneration in the basal ganglia induced by the mitochondrial toxin 3-nitropropionate, or in the hippocampus by traumatic brain injury in rats, is enhanced by N-methyl-D-aspartate antagonists but ameliorated by alpha amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) antagonists. They concluded that N-methyl-D-aspartate antagonists may increase neurodestruction in mature brains undergoing slowly progressive neurodegeneration, whereas blockade of the action of glutamate at AMPA receptors may be neuroprotective.

(c) Free radical scavengers
Cardiopulmonary bypass induces the activation of complement and polymorphonuclear neutrophils (PMNs). Activated PMNs are recognized as a major extracellular source of the oxidant species, which may represent an important mechanism in the generation of tissue injury.18,19 Desferrioxamine, an iron chelator, has the ability to inhibit the iron-catalyzed generation of hydroxyl radical and also scavenges activated oxygen species (ROS).25 Menasche and co-workers26 reported that desferrioxamine was given in 12 patients undergoing cardiac surgery both intravenously, (30 mg·kg–1, starting 30 mins before and ending 30 mins after bypass), and as an additive to the cardioplegic solution. PMNs harvested from desferrioxamine-treated patients produced fewer superoxide radicals than those from control patients. However, they did not examine the neurological outcome in these patients. In a recent study, Prass and co-workers25 showed that desferrioxamine induces delayed tolerance against cerebral ischemia in vivo and in vitro. Further study is necessary to clarify the effects of desferrioxamine on neurological outcome.

Mannitol, a free radical scavenger, is widely used for neuroprotection therapy during neuroanesthesia.27 Luvisotto and co-workers28 showed the neuroprotective effect of mannitol on experimental cerebral ischemia. Korenkov and co-workers29 found that treatment with 15% mannitol (1 g·kg–1 as a bolus) revealed significant decreases in infarct size and number of apoptotic cells in rats. Until now, no data exist regarding the effects of mannitol during CPB on cognitive dysfunction. Further study is necessary to clarify the effects of mannitol on neurological outcome during cardiac surgery.

Recently, edaravone, a free radical scavenger, has become clinically available (Mitsubishi Pharma Co, Tokyo, Japan). Suzuki and co-workers30 showed that edaravone exerted a significant protective effect on the spinal cord against ischemic-reperfusion injury by suppressing the level of free radical species in a rabbit model. Further study is necessary to clarify the effects of edaravone on neurological outcome during cardiac surgery.

(3) OTHERS
(a) Prostacyclin
Prostacyclin is the vasoactive metabolite of arachidonic acid in arteries and veins, and is the most potent endogenous inhibitor of platelet aggregation. It inhibits platelet aggregation by stimulating the platelet enzyme adenylate cyclase. Microembolism in the brain by platelet aggregates may contribute to cerebral injury and postoperative cognitive dysfunction after cardiac surgery. Thus, prostacyclin has a potential role in reducing platelet aggregation-induced microembolism, resulting in a decrease in the incidence of postoperative cognitive dysfunction. Fish and co-workers31,32 examined the effects of prostacyclin on the incidence and severity of postoperative neuropsychologic dysfunction in patients undergoing CABG in a randomized double-blind manner. Psychologic testing demonstrated similar declines in postoperative performance in both the prostacyclin-treated and the control group at one week after the operation.

(b) Aprotinin
Cardiopulmonary bypass induces a state characterized by systemic endotoxin and tumor necrosis factor (TNF) release. Neutrophil integrin CD11b is rapidly upregulated by cytokines, including TNF, and is thought to be the primary neutrophil adhesive integrin response for neutrophil organ entrapment, resulting in post-CPB reperfusion injury. This aggregation and adhesion may contribute to the exacerbation of focal ischemia.33 Aprotinin, a nonspecific serine protease enzyme inhibitor with broad-spectrum anti-inflammatory properties, has been proved to significantly decrease white cell activation and transmigration during CPB.34 Low-dose aprotinin administration was found to have an anti-inflammatory effect similar to that of methylprednisolone, in blunting release of systemic tumor necrosis factor and neutrophil integrin CD11B upregulation, in comparison to untreated controls.35 Additionally, after major vascular surgery, activation of neutrophils, manifested by increased superoxide production and impaired chemotaxis, has been shown to be significantly suppressed by aprotinin administration.34,35 A meta-analysis by Smith and Muhlbaier36 showed that 2.4% of the placebo group experienced stroke compared to only 1.0% in the treatment group. Frumento and co-workers37 performed a retrospective study in cardiac surgery patients at high risk for developing stroke, to determine the relative effects of FDA (full-dose aprotinin) and HDA (half-dose aprotinin) regimens on the incidence of postoperative stroke. Records of 1,524 patients undergoing cardiac surgery over a 15-month period were reviewed. A total of 149 patients fulfilled the criteria for being at high risk for stroke. Overall, the incidence of stroke was 16% (24/149). The incidence of stroke differed (p < 0.05) among the three groups: no aprotinin 16% (9/56), HDA 22% (15/67), and FDA 0% (0/26). In addition, the stroke risk index was very similar (p = 0.56) between groups. Thus, they concluded that in this retrospective study of cardiac surgery patients at high risk for postoperative stroke, the administration of FDA but not HDA was associated with a lower incidence of stroke. To reduce the overexpression of adhesion molecule such as CD11b, use of white blood cell filters may be useful for the prevention of overproduction of immunosuppressive cytokines.38–41

(c) GM1 (Monosialoganglioside)
GM1 ganglioside is reported to be effective in prevention of apoptotic neuronal cell death potentially mediated in part by tyrosine kinase receptors.42 The Italian Acute Stroke Study indicated that GM1 ganglioside-treated patients with hemodilution during the first 15 days showed a significantly higher degree of neurological improvement during the first 10 days compared to placebo-treated patients with hemodilution. However, these differences were no longer statistically significant at day 120.43 Grieco and co-workers44 reported in a pilot study that administration of GM1 ganglioside in patients undergoing CABG tended to improve neurologic and neuropsychological outcome, despite there being no statistical difference.

(d) Corticosteroids
Steroid compounds have commonly been used in neurologically impaired patients, including those with ischemic brain injury. In contrast to limited evidence of protection in acute spinal cord injury in humans,45 traditional corticosteroids may exacerbate ischemic brain injury. Sapolsky46 reviewed the three possible types of deleterious effects in the brain: glucocorticoid-induced atrophy, neurotoxicity,47 and neuroendangerment in the hippocampus. In addition, because of disagreement between clinical studies, recommendations from the American College of Neurological Surgeons (ACNS, 1996) state that glucocorticoids should not be used in the treatment of closed head trauma.48 A recent study showed that reduced preoperative endotoxin immunity is a predictor of increased postoperative cognitive dysfunction in patients undergoing coronary artery bypass graft, particularly in those > 60 years old.49 It is known that glucocorticoids can suppress the inflammatory response induced by CPB.50 Although no data exists regarding the effects of glucocorticoids during CPB on cognitive dysfunction, interventions against the exacerbations of the pro-inflammatory response, such as use of steroids during CPB, might improve cognitive dysfunction after cardiac surgery.

(e) Beta-blockers
Atrial fibrillation (AF) is a frequent occurrence after cardiac surgery, with an incidence of 20% to 40%.51 The incidence of AF is increased in patients of advanced age, in males, in chronic obstructive pulmonary disease, and in certain electrocardiographic manifestations.51 Mathew and co-workers51 showed that patients with recurrent AF after coronary artery bypass graft surgery had longer hospital stays and suffered more neurological complications. Recently, Stanley and co-workers52 examined whether postoperative AF was associated with postoperative cognitive dysfunction and showed that those patients who developed AF postoperatively showed more cognitive decline than those who did not develop postoperative AF at 6 weeks after surgery. These results indicate that prevention of postoperative AF might result in a decreased incidence of cognitive dysfunction. Since publication of the results from Mathew and co-workers51 demonstrating that a reduced risk for AF was associated with postoperative administration of beta-blockers [odds ratio, 0.32; 95% confidential interval (CI), 0.22–0.46], there are few reports showing an association between the use of beta-blockers during the perioperative period, and postoperative cognitive dysfunction. Amory and co-workers53 retrospectively examined the impact of perioperative beta-blocker administration on neurological complications at a single medical center, and found that adverse neurologic events (stroke, coma, and transient ischemic attack) occurred in 3.9% (n = 90) of 2,296 patients who received perioperative beta-blockers and 8.2% (n = 23) of 279 patients who did not receive beta-blockers (odds ratio, 0.43: 95% CI, 0.23–0.83; p = 0.016). Although there is little evidence that use of beta-blockers was associated with a reduction in the incidence of postoperative neurologic complications, it may be a potentially important neuroprotective strategy in cardiac surgery.

(f) Sedative agents
The alpha 2-adrenergic agonists currently used in clinical practice: clonidine, dexmedetomidine, and mivazerol attenuate the surgical stress response and therefore potentially reduce cardiovascular complications. The alpha 2-adrenergic agonists dilate post-stenotic coronary vessels and attenuate the severity of perioperative hemodynamic abnormalities. The alpha 2-adrenergic agonists are conferred a grade II B recommendation in the 2002 American College of Cardiology/American Heart Association Guideline Update on Perioperative Cardiovascular Evaluation for Noncardiac Surgery. Wijeysundera and co-workers54 revealed that alpha 2-adrenergic agonists reduced myocardial ischemia (relative ratio = 0.71; 95% CI: 0.54–0.92) and were associated with trends toward lower mortality (relative ratio = 0.49; 95% CI: 0.12–1.98) and a reduced risk of myocardial infarction (relative ratio = 0.83; 95% CI: 0.35–1.96). Although no data exists regarding the effects of alpha 2-adrenergic agonists on cognitive dysfunction, interventions against the exacerbations of pro-inflammatory response, such as use of alpha 2-adrenergic agonists, might improve cognitive dysfunction after cardiac surgery.

(4) ANESTHETIC PRECONDITIONING
The term "preconditioning" was first introduced by Murry and co-workers55 in 1986. They showed that four periods of 4-minute coronary occlusion, each separated by 5 minutes of reperfusion, led to a reduction in infarct size caused by a subsequent 40 min occlusion of the coronary artery, by 29% to 7%. This phenomenon could not be explained by increased blood flow through collaterals. They called this method of enhancing ischemic tolerance in the heart "preconditioning". Extensive research in experimental animals has provided data on the potential mechanism of ischemic preconditioning in the heart, including adenosine receptor activation, opening mitochondrial ATP-sensitive potassium channels, and production of endogenous protective stress proteins.56–60 Preconditioning can exist in organs other than the heart, such as the central nervous system, in which Kitagawa and co-workers61 first demonstrated the phenomenon of ischemic preconditioning in vivo. This phenomenon of ischemic preconditioning has been confirmed in various animal models of forebrain ischemia and focal cerebral ischemia. The brain may be protected from ischemia by employing multiple mechanisms that are available for cellular survival. If preconditioning induction can be manipulated and accelerated by a drug treatment that is safe and effective enough, it could greatly improve the treatment of cerebral injury.56

Two retrospective clinical studies were conducted to demonstrate the presence of ischemic tolerance in humans. Weih and co-workers62 first demonstrated the possibility of ischemic tolerance in the brain, showing that independence (Rankin scale score of 0 to 1) and favorable outcome (Glasgow Coma Scale score of 5) were significantly associated with prior transient ischemic attack (TIA). Moncayo and co-workers63 retrospectively assessed a total of 2,490 patients admitted consecutively to a primary care center for first-ever cerebral infarction in the anterior circulation. The patients were divided into two groups on the basis of the presence or absence of prior ipsilateral TIAs. Duration of TIA was classified into three groups (< 10 minutes, 10 to 20 minutes, and > 20 minutes). The severity of the neurologic picture on admission, and functional disability after stroke were compared between patients with and without TIAs. A total of 293 (12%) of the 2,490 patients had prior ipsilateral TIAs before cerebral infarction. Risk factors did not differ between patients with or without TIAs, whereas the topography and etiology of ischemic stroke did differ (p < 0.001). Patients without prior TIAs had a more severe clinical picture on admission, with a greater reduction of consciousness (p = 0.009). Patients with previous TIAs had a more favorable outcome than those without TIAs (67% versus 58%, p = 0.004). After adjustment for confounding variables, TIAs lasting 10 to 20 minutes were still associated with a favorable outcome (odds ratio, 1.98, p = 0.002). They concluded that ischemic tolerance may play a role in patients with ipsilateral TIAs before cerebral infarction, allowing better recovery from a subsequent ischemic stroke.

Administration of volatile anesthetics during myocardial ischemia has been proved to reduce myocardial stunning and irreversible myocardial ischemic injury in vivo.57–59,64 Cope and co-workers64 first reported in their use of isolated rabbit hearts, that perfusion of isolated hearts for 5 min with 2 minimum alveolar concentration (MAC) of halothane, enflurane or isoflurane reduced infarct size by approximately 75%, even though the anesthetics were washed out of the heart 10 min before ischemia. A brief exposure to sevoflurane has also been shown to improve cardiac contractility and cardiac efficiency in isolated guinea pig hearts after global ischemia. The central mechanism underlying anesthesia-induced preconditioning is that volatile anesthetic agents activate potassium ATP-channels, adenosine A1 receptors, P38 mitogen-activated protein kinase, inducible nitric oxide synthase and protein kinase C.56,59–60,65 (Figure 1Go).


Figure 1
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  		Figure 1. Volatile anesthetic-induced preconditioning may be due to the opening of mitochondrial adenosine triphosphate-sensitive potassium channels concomitant with the modulation of mitochondrial function (early phase). Volatile anesthetics activate the protein kinase C via a stimulation of Gi-coupled receptor. Protein kinase C can stimulate the opening of k-ATP channel and mitogen-activated protein kinase (MAPK). This may induce an activation of a variety of signal transduction pathways (late phase).

 
Numerous studies from the evidence both of ischemic preconditioning in the brain and volatile anesthetic preconditioning of the heart led researchers to question whether volatile anesthetic agents might also have preconditioning effects in the brain and hence, improve neurological outcome.

(a) Volatile anesthetics
Assessing the effects of volatile anesthetics on cerebral ischemia in animal studies, there is reasonable evidence to show that volatile anesthetics have preconditioning effects on the brain.66–71 (Table 1Go) There have been several clinical studies regarding the effects of pre-administration of volatile anesthetics on the heart during cardiac surgery. In contrast, there have been no clinical studies regarding the effects of volatile anesthetics on neuroprotection during cardiac surgery. If volatile anesthetic agents prove to have neuroprotective effects, as suggested by studies in animal models, the use of volatile anesthetics for their specific anti-ischemic effect should be further explored. Extensive clinical studies are needed to determine whether volatile anesthetics are really beneficial during the perioperative period, in protecting against cerebral injury during cardiac surgery.


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  		Table 1. In Vivo and In Vitro Studies of the Effects of Preconditioning by Volatile Anesthetics on Cerebral Ischemia
 
(b) Opiate receptor stimulation
Opioids are commonly used as anesthetic agents and for the treatment of pain. Recent reports have demonstrated that opioids also possess the ability of induction of preconditioning effects in the heart and brain. Pretreatment with morphine induced cardioprotection against ischemia. This ischemic preconditioning is mediated by delta-opioid receptors. In addition, the beneficial effect of morphine is abolished by the potassium ATP-channel antagonist glibenclamide,72 which suggests a role for ATP-channel signaling transduction pathways in mediating the cardioprotective effects of morphine. In a clinical study, Tomai and co-workers73 found that the adaptation to ischemia observed in humans after two sequential coronary balloon inflations was abolished by naloxone, thus demonstrating cardioprotective effects by activating opioid-receptor signal transduction in humans. Recent reports have demonstrated that delta-opioid receptor activation also protects against cerebral ischemia. Zhang and co-workers74 demonstrated that in cortical neurons, activation of the delta-opioid receptor system protects cortical neurons against glutamate-induced stress, whereas activation of mu- or kappa-opioid receptors offers no significant neuroprotection. Lim and co-workers75 recently showed in Purkinje cells that this neuroprotection may be delta1-opioid receptor dependent and may involve mitochondrial adenosine triphosphate-sensitive potassium channel activation and free radical production. In contrast to their beneficial effects on cerebral ischemia, opioids might have deleterious effects on spinal ischemia. Faden and co-workers77 first demonstrated the possibility of the deleterious effects of opioids on spinal injury. Recently, Kakinohana and co-workers76 showed that in cases of immediate reflow following a non-injurious interval of spinal ischemia, intrathecal morphine potentiates motor dysfunction. Reversal by naloxone suggests that this effect results from an opioid receptor-mediated potentiation of a transient block of inhibitory neurons initiated by spinal ischemia. Until now there have been no clinical studies examining the effects of opioids on cerebral injury during cardiac surgery. Extensive clinical studies are needed to determine whether opioids are beneficial or deleterious to cerebral injury in cardiac surgery during the perioperative period.

(c) Need for extensive experimental studies
Reasons for the failure of so many neuroprotective agents in clinical trials, despite their apparent benefit in animal models, are becoming clear.78,79 Traditionally, animal studies have relied on reduction in infarct size or neuronal cell death within the first few hours after ischemic insult as the primary measure of therapeutic efficacy. In contrast, clinical efficacy by using neurological and functional outcomes, not infarct volume or neuronal cell death, is assessed several months after ischemic insult. Histological end points cannot tell whether surviving neurons are functional, or whether the dysfunction will proceed to death in a delayed fashion, and they are less predictive of long-term histology than are early behavioral assessments. Therefore, assessment of therapeutic efficacy in experimental studies should include, in addition to infarct size and neuronal cell death, a demonstration of benefit on functional measures of motor, sensory, or cognitive deficit. Researchers and clinicians must become more cognizant of the pitfalls and paradoxes that have arisen in attempting to translate the results of animal studies into clinical trials of neuroprotective therapy during cardiac surgery. There are extensive needs for new pharmacological approaches directed toward reducing neurologic and neurocognitive injury during cardiac surgery.


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 CONCLUSION
REFERENCES
 
Although we have no fundamental knowledge about how neurological and neurocognitive consequences occur during cardiac surgery, it is essential to improve the mortality rate and reduce the incidence of neurological and neurocognitive dysfunction after cardiac surgery. Pharmacological intervention may be one of the potential protective methods against cerebral injury. Neurologic and neurocognitive dysfunction after cardiac surgery remains a fertile area of research.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 CONCLUSION
 REFERENCES
 

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