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Brain damage in cardiac surgery patients

Wojciech Dabrowski1, Ziemowit Rzecki1, Jacek Pilat2 and Marek Czajkowski3
Neuropsychological disorders and brain injury are still a serious problem in cardiac surgery patients. Owing to multifactorial mechanism of brain injury during extracorporeal circulation, the effective and safe protection is extremely difcult. Despite several studies, the ideal neuroprotective treatment has not been found. Based on literature we analysed the main mechanisms of brain injury and new methods of brain protection.
Addresses 1 Department of Anaesthesiology Intensive Therapy, Medical University of Lublin, Poland 2 Department of General Surgery, Transplantology and Clinical Nutrition, Medical University of Lublin, Poland 3 Department of Cardiac Surgery, Medical University of Lublin, Poland Corresponding author: Dabrowski, Wojciech (wojciechdabrowski@interia.pl, w.dabrowski5@yahoo.com)

intellectual deterioration and memory decits [10]. All these disorders were also divided into focal, multifocal or global. The brain injury after cardiac surgery is multifactorial. Global or focal ischaemia appears to be the main factor leading to brain injury, and may result from cerebral hypoperfusion, macroembolisation or microembolisation, massive inammatory responses, perioperative disorders in oxygen delivery resulting from prolonged anaemia and postoperative cerebral hyperthermia, cardiac arrhythmias and genetic predisposition [1,1117]. Several clinicians and researchers suggest that intraoperative and postoperative cerebral embolisms connected with global or focal hypoperfusion are the crucial factors leading to postoperative neurocognitive disorders [11,12,15,18]. About 3050% of postoperative strokes result from cerebral macroembolism, whereas encephalopathy and neuropsychological disorders develop owing to microemboli [11,12,19,20]. There is strong evidence that a signicant number of cerebral embolisms result from the disrupted atherosclerotic aorta, opened left-side cardiac chamber or extracorporeal machine [12,1820]. Indeed, atherosclerosis of the ascending aorta is the predictive factor of brain injury in cardiac surgery patients [12,21]. A fragment of atherosclerotic plaque liberated by surgical manipulation of the aorta (clamping or cannulation) and translocated into the brain vessel induces ischaemia and causes transient or permanent cellular dysfunction in the vital centres of the brain. Such cerebral emboli may contribute to the postoperative morbidity or mortality. Importantly, similar disorders are observed after fat embolism associated with extracorporeal circulation and uncritical cardiotomy suction. Fat embolism causes brain oedema with haemorrhage [22]. Unfortunately, the arterial and venous lters routinely used inadequately protect patients from fat microemboli [23]. Disorders in cerebral blood ow are another important factor resulting in postoperative neuropsychological dysfunction. Physiologically, the cerebral blood ow ranges from 40 to 60 mL/100 g brain tissue per min. It is mainly regulated by the mean artery pressure. A traditional extracorporeal machine with roller pumps produces the pulsatile blood ow with the index of cardiac output between 2 and 2.4 L min1 m2. Despite this, the cerebral blood ow decreases to 2060 mL/100 g of brain tissue per min [24]. Additionally, this low brain perfusion may be reduced by carotid artery stenosis, which strongly
Current Opinion in Pharmacology 2012, 12:189194

Current Opinion in Pharmacology 2012, 12:189194 This review comes from a themed issue on Cardiovascular and renal Edited by Jamie Y Jeremy, Kai Zacharowski, Nilima Shukla and Song Wan Available online 9th February 2012 1471-4892/$ see front matter # 2012 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coph.2012.01.013

Postoperative brain damage and neuropsychological disorders are frequent complications of cardiac surgery and elevate mortality, morbidity and hospital costs, as well as signicantly impair the quality of life [13]. They occur in 3080% of patients undergoing extracorporeal circulation (ECC) and in 3050% of patients undergoing cardiac surgery without ECC [4,58]. In many cases, they subside within three postoperative months; however, in 17 35% of cardiac surgery patients, the disorders can persist for even one year [2,5,8]. Their incidences are age-related and are signicantly higher in patients aged 65 years or more [9]. For instance, the incidence rate of the most serious brain damage stroke, is less than 1% in younger patients compared to 65.5% in patients aged 6575, and more than 7% in patients over the age of 75. The American College of Cardiology/American Heart Association classied the brain injury following cardiac surgery into two main categories: type 1 severe neurological dysfunction, stupor and coma, and type 2
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predicts the postoperative brain injury. The moderate carotid artery diseases are noted in 1722% and severe stenosis (higher than 80%) is observed in 612% of cardiac surgery patients [25,26]. In patients over the age of 65, past transient ischaemic attack (TIA), smoking, peripheral artery diseases and female sex are associated with severe carotid stenosis [26]. For this reason many clinicians perform carotid endarterectomy preoperatively or synchronously with cardiac surgery [25,27]. Others suggest that the use of centrifugal pumps signicantly reduces adverse outcomes after cardiac surgery [28,29]. Moreover, some other factors such as anaesthetic agents or low carbon dioxide tension reduce the possibility of brain vessels autoregulation and have a strong impact on the cerebral blood ow. Therefore, the method of anaesthesia and correction of arterial carbon dioxide tension according to body temperature play a crucial role in intraoperative brain protection. The role of venous outow from the brain seems interesting, yet not well documented. Several experimental and clinical studies present the adverse effects of raised venous pressure in brain circulation [30,31]. Decreased venous outow from the brain impairs cerebral circulation, declines cerebral perfusion pressure (CPP) and increases brain blood barrier (BBB) permeability, which raises vascular water shift into the extracellular space resulting in cytotoxic and vasogenic oedema and extensive haemorrhagic cerebral infarction [28]. Moreover, increased brain venous pressure may cause transient ischaemia, which manifests as a transient ischaemic attack [30]. Interestingly, the elevated central venous pressure during cardiac surgery increases the risk of postoperative neurological complications [31]; however, the effect of brain venous hypertension has not been described and requires further studies. Postoperative hyperthermia is another risk factor of brain injury. Many clinicians focus on intra-operative hypothermia and disregard the re-warming period at the end of extracorporeal circulation. Fast re-warming of the brain and postoperative hyperthermia predispose to total cerebral ischaemia and stroke [13]. Therefore, the avoidance of full re-warming at the end of extracorporeal circulation is the main strategy to reduce the number of hypothermia events [2]. Systemic inammatory responses are also serious problems after extracorporeal circulation. Several authors suggest that an inammatory response following cardiac surgery with extracorporeal circulation plays a crucial role in the development of brain injury [16,32,33]. It has been well documented that cardiac surgery increases the plasma and cerebrospinal levels of cytokines, which strongly correlates with severe postoperative encephalopathy and other adverse neuropsychological disorders [3234]. The prolonged contact with an articial material surface of the
Current Opinion in Pharmacology 2012, 12:189194

extracorporeal circuit and ischaemia-reperfusion injury of organs activate the immunological reaction leading to disorders of vascular permeability and cellular structures [3336]. Interestingly, the use of anti-inammatory agents, such as corticosteroids, signicantly reduces postoperative neuropsychological disorders and brain injury [36]. Different cardiac arrhythmias, particularly atrial brillation, are a serious problem in patients after cardiac surgery. Atrial brillation episodes occur in 1040% of such patients, their frequency increases with age and the peak of its incidence is on the rst postoperative day. It potentially leads to many serious complications such as thromboembolism with its worst forms neurological disorders, haemodynamic disturbances, shock and higher early and late postoperative mortality [37,38]. There is strong evidence that atrial brillation precedes stroke in 36.5% of patients with cerebral ischaemic events [39]. Importantly, atrial brillation is not associated with the risk of postoperative stroke but it is the major independent predictor of brain injury during the postoperative period. Recently, several authors have studied the genetic predisposition to postoperative brain injury in cardiac surgery patients [4042]. The presence of the apolipoprotein E e4 allele is the highest genetic risk factor of postoperative stroke [40]. Additionally, minor alleles of C-reactive protein, a variant of the platelet glycoprotein IIb/III receptor and interleukin-6 are postulated as independent risk factors [41,42]. Nevertheless, our knowledge of genetic predisposition to postoperative brain injury is limited and further studies are needed to determine the mechanism and risk stratication for cardiac surgery. The main aims of brain protection are to reduce the number of sources leading to brain injury and to increase the brain tolerance to ischaemic events. Generally, there are two kinds of brain protection: non-pharmacologic and pharmacologic. The shortened duration of articial circuit and time spent in the operating theatre, reduced cardiac suction and avoidance of hyperthermia may strongly reduce adverse neurological disorders in the non-pharmacologic way. Several experimental studies documented that mild hypothermia reduced the risk of brain injury; however, clinical trials did not conrm that nding [43,44]. Nevertheless, many clinicians use mild hypothermia during extracorporeal circulation. A decrease in body temperature reduces cellular metabolism and energy consumption, inhibits the release of neurotransmitters and decreases the calcium inux into brain cells [45 47]. Moreover, deep hypothermia signicantly decreases the cerebral blood ow and number of microemboli [48,49,50]. On the contrary, patients re-warming favours brain injury and is associated with worse outcomes [50]. The maintenance of arterial carbon dioxide tension (alpha-stat acidbase management) at the level of
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Brain injury and heart surgery Dabrowski et al. 191

3538 mmHg prevents spasms of cerebral arteries and reduces postoperative neuropsychological disorders [51]. Similar effects are achieved by maintaining the adequate mean artery pressure of 5060 mmHg [52,53]. The pressure higher than 80 mmHg and lower than 50 should be avoided, irrespective of the disease and age. This pressure should be maintained at the undisturbed level, because the cerebral perfusion pressure strongly depends on the mean artery pressure. Rapid changes in mean artery pressure strongly predispose to brain injury, particularly during the disconnection of the extracorporeal machine. During the recent years, the cerebral oxygen saturation monitored continuously using near infrared spectroscopy is frequently used to maintain the adequate cerebral oxygen delivery during cardiac surgery. Increasing evidence reveals that decreased oxygen saturation below 50% associates with worse neurological outcomes [54,55]. This simple measurement gives much information about the brain status, especially its oxygen metabolism during extracorporeal circulation. Moreover, the continuous measurement of brain saturation allows fast correction of disturbances in brain oxygen delivery. Despite the non-pharmacologic protection, some anaesthetic agents should be used for brain protection. The volatile anaesthetics are one of them. The proposed mechanisms of volatile anaesthetics related neuroprotection are based on an increase in cerebral blood ow, slight increase in intracellular calcium, upregulation of bioenergy metabolism in brain, nitric oxide synthase and antiapoptotic factors as well as reduction in oxidative stress [56]. The use of volatile anaesthetics increases mitochondrial adenosine triphosphate-sensitive potassium channels (mitoKATP) activity leading to mild hyperpolarisation [5759]. The opened mitoKATP channel decreases mitochondrial energy consumption by ATP sparing, enlarging mitochondrial energy. Moreover, moderately increased intracellular calcium prevents large intracellular calcium inux and plays a crucial role in neuronal survivability after hypoxia/ ischaemia events [58]. Volatile anaesthetics cause the membrane depolarisation in the presynaptic mitochondria, also after the removal of extracellular calcium [57]. This increase in intracellular calcium concentration results from a decrease in ischaemic activity of calcium-calmodulin receptors, inhibition of N-methylD-aspartate (NMDA) and a decrease in glutamate release [5760]. Moreover, the use of volatile anaesthetics signicantly reduces the concentration of brain injury markers [61]. Similar effects are observed in patients receiving magnesium infusions. Magnesium plays an important role in the central nervous system. Its decline affects a number of secondary brain injury factors, including neurotransmitter release, ion changes, oxidative reaction and energy metabolism. Numerous studies have
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shown that magnesium is essential in CNS injuries [62]. Indeed, magnesium decreases after brain trauma, which is correlated with neuronal cell dysfunction. The moderate brain injury results in a decrease in intracellular brain free magnesium up to 60% [63]. Recently, several magnesium disorders in brain circulation have been documented during extracorporeal circulation [64]. Importantly, continuous supplementation of magnesium reduces substantially the plasma S100b protein concentration [65]. Moreover, intravenous infusions of magnesium reduce the incidence of atrial brillation, improve cardiac function and postoperative neuropsychological outcomes [64,66]. Nevertheless, the neuroprotective effect of magnesium is still open to debate, particularly in cardiac surgery patients. Moreover, the neuroprotective effect of lidocaine is still controversial. Indeed, infusion of antiarrhythmic dose of lidocaine before ischaemia onset increases the number of surviving neurons in the CA1 region of the hippocampus and preserves cognitive functions in experimental studies [67]. Some randomised, double-blind prospective clinical studies conrm neuroprotective effects of intra-operative infused lidocaine in cardiac surgery patients [68]. Some other studies document lack of them [69]. Therefore, the neuroprotective effect of lidocaine requires further clinical studies. Propofol is another interesting agent used for neuroprotection in cardiac surgery patients. It strongly inhibits the NMDA receptor, activates gamma amino-butyric acid (GABA) receptors and slightly modulates the intracellular calcium inux. By decreasing the internalisation of Dacid amino-3-hydroxy-5-methyl-4-isoxazole-propionic (AMPA) receptor glutamine R2 (GluR2) subunit, it reduces infarct size, promotes neurogenesis and improves spatial learning and memory in rats [70]. Likewise, clinical studies demonstrate its neuroprotective effect [71]. Contrarily, there is experimental evidence that propofol activates the mechanisms leading to cell death in the cortex and thalamus of the developing brain [72]. From this reason, propofol is recommended as an anaesthetic of choice in adult patients undergoing cardiac surgery. Several studies document the neuroprotective effect of barbiturates [73]. Barbiturates depress the brain metabolism, inhibit mitoKATP channel, facilitate protein synthesis, activate GABA receptors, and present antioxidative activity. Similarly to propofol, barbiturates cause a dosedependent neurodegeneration in the developing brain. The use of pentobarbital alters synaptic plasticity and leads to a long-lasting spatial learning decit [74]. Interestingly, the perioperative use of b-blockers improves postoperative neurological outcomes in cardiac surgery patients. b-blockers are known to have many
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benets during non-cardiac and cardiac surgery. The neuroprotective action of this drug has been not fully known. However, several authors reported a signicant reduction of postoperative neuropsychological disorders in patients receiving b-blockers during the perioperative period [75,76]. It is recommended to continue b-blockers therapy until surgery with the last dose included as a part of oral premedication. Moreover, this effect is intensied by preoperative statin administration [75]. The analysis of 6813 patients undergoing cardiac surgery showed that such a combination has a strong neuroprotective effect. Therefore, it can be suggested to include statins to bblockers therapy, however their neuroprotective effect requires future studies. Several other drugs have been studies as potential neuroprotective agents in cardiac surgery patients. Amantadine and memantine, the antagonists of NMDA receptor, appear to have promising neuroprotective effects. They bind to NMDA with a higher afnity than magnesium and thus decrease the prolonged inux of calcium into the cellular space. Moreover, they increase dopamine release and block dopamine reuptake. Memantine moderately decreases clinical deterioration and protably affects the mood, behaviour and cognitive function [77]. Therefore, they can improve neuropsychological outcome, however, their neuroprotective effect has been completely undocumented in cardiac surgery patients. The ideal brain protection has been not specied in cardiac surgery patients. Despite several adverse effects of extracorporeal circulation, cardiac surgery is the only method of treatment of many cardiac diseases. Many neuroprotective techniques and pharmacologic methods are used to improve the quality of life; however, a signicant reduction of brain injury is still the subject of many experimental and clinical studies. Therefore, neuropsychological disorders and brain injury remain the main problem of cardiac surgery patients.

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