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Brain damage in cardiac surgery patientsWojciech Dabrowski1, Ziemowit Rzecki1, Jacek Pilat2 andMarek 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 difficult. 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.

Addresses1Department of Anaesthesiology Intensive Therapy, Medical Universityof Lublin, Poland2Department of General Surgery, Transplantology andClinical Nutrition,

Medical University of Lublin, Poland3Department of Cardiac Surgery, Medical University of Lublin, Poland

Corresponding author: Dabrowski, Wojciech([email protected], [email protected])

Current Opinion in Pharmacology2012, 12:189194

This review comes from a themed issue on

Cardiovascular and renalEdited 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 dis-

orders are frequent complications of cardiac surgery and

elevate mortality, morbidity and hospital costs, as well assignificantly 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 sub-

side within three postoperative months; however, in 17

35% of

cardiac

surgery

patients,

the

disorders

can

persistfor even one year [2,5,8].Their incidences are age-related

and are significantly 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 classified the brain injury following cardiac

surgery into two main categories: type 1 severe neuro-logical dysfunction, stupor and coma, and type 2

intellectual deterioration and memory deficits [10].

All these disorders were also divided into focal, multi-

focal 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 cerebralhypoperfusion, macroembolisation or microembolisation,

massive inflammatory 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 intraopera-

tive 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 encephalo-

pathy and neuropsychological disorders develop owing to

microemboli [11,12,19,20]. There is strong evidence that

a significant number of cerebral embolisms result from

the disrupted atherosclerotic aorta, opened left-side car-

diac 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 bysurgical manipulation of the aorta (clamping or cannula-

tion) 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 circula-

tion and uncritical cardiotomy suction. Fat embolism

causes brain oedema with haemorrhage [22]. Unfortu-

nately, the arterial and venous filters routinely used

inadequately protect patients from fat microemboli [23].

Disorders in cerebral blood flow are another important

factor resulting in postoperative neuropsychological dys-

function. Physiologically, the cerebral blood flow ranges

from 40 to 60 mL/100 g brain tissue per min. It is mainlyregulated by the mean artery pressure. A traditional

extracorporeal machine with roller pumps produces the

pulsatile blood flow with the index of cardiac outputbetween 2 and 2.4 L min1m2. Despite this, the

cerebral blood flow 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

Available online at www.sciencedirect.com

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predicts the postoperative brain injury. The moderatecarotid 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, periph-

eral artery

diseases

and

female

sex

are

associated

withsevere carotid stenosis [26]. For this reason many clin-

icians perform carotid endarterectomy preoperatively or

synchronously with cardiac surgery [25,27]. Others

suggest that the use of centrifugal pumps significantly

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 flow. Therefore, the method of anaes-

thesia and correction of arterial carbon dioxide tension

according to body temperature play a crucial role in

intraoperative brain protection.

The role of venous outflow from the brain seems inter-

esting, yet not well documented. Several experimental

and clinical studies present the adverse effects of raisedvenous pressure in brain circulation [30,31]. Decreased

venous outflow from the brain impairs cerebral circula-

tion, 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 exten-

sive haemorrhagic cerebral infarction [28]. Moreover,

increased brain venous pressure may cause transient

ischaemia,whichmanifests as a transient ischaemic attack

[30]. Interestingly, the elevated central venous pressure

during cardiac surgery increases the risk of postoperativeneurological 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 hypother-

mia and disregard the re-warming period at the end ofextracorporeal circulation. Fast re-warming of the brain

and postoperative hyperthermia predispose to total

cerebral ischaemia and stroke [13]. Therefore, the avoid-

ance of full re-warming at the end of extracorporeal

circulation is the main strategy to reduce the number

of hypothermia

events

[2].

Systemic inflammatory responses are alsoseriousproblems

after extracorporeal circulation. Several authors suggest

that an inflammatory 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 pro-longed contact with an artificial material surface of the

extracorporeal circuit and ischaemia-reperfusion injury oforgans activate the immunological reaction leading to

disorders of vascular permeability and cellular structures

[3336]. Interestingly, theuseof anti-inflammatory agents,

such as corticosteroids, significantly reduces postoperative

neuropsychological

disorders

and

brain

injury

[36].

Different cardiac arrhythmias, particularly atrial fibrilla-

tion, are a serious problem in patients after cardiac

surgery. Atrial fibrillation episodes occur in 1040% of

such patients, their frequency increases with age and the

peak of its incidence is on the first 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 fibrillation precedes stroke in

36.5% of patients with cerebral ischaemic events [39].

Importantly, atrial fibrillation is not associated with the

risk of postoperative stroke but it is themajor independent

predictor of brain injury during the postoperative period.

Recently, several authors have studied the genetic pre-

disposition to postoperative brain injury in cardiac surgery

patients [4042].The presence of the apolipoproteinE 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 re-

ceptor 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 stratification 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 artificial circuit

and time spent in the operating theatre, reduced cardiacsuction and avoidance of hyperthermia may strongly

reduce adverse neurological disorders in the non-pharma-

cologic way. Several experimental studies documented

that mild hypothermia reduced the risk of brain injury;

however, clinical trials did not confirm that finding

[43,44]. Nevertheless,

many

clinicians

use

mild

hypother-mia during extracorporeal circulation. A decrease in body

temperature reduces cellular metabolism and energy

consumption, inhibits the release of neurotransmitters

and decreases the calcium influx into brain cells [4547]. Moreover, deep hypothermia significantly decreases

the cerebral blood flow 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

190 Cardiovascular and renal

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3538 mmHg prevents spasms of cerebral arteries andreduces postoperative neuropsychological disorders [51].

Similar effects are achieved by maintaining the adequate

mean artery pressure of 5060 mmHg [52,53]. The pres-

sure higher than 80 mmHg and lower than 50 should be

avoided, irrespective

of

the

disease

and

age.

This

pressureshould 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 evi-

dence reveals that decreased oxygen saturation below

50% associates with worse neurological outcomes

[54,55]. This simple measurement gives much infor-

mation about the brain status, especially its oxygen

metabolism during extracorporeal circulation. Moreover,

the continuous measurement of brain saturation allowsfast correction of disturbances in brain oxygen delivery.

Despite the non-pharmacologic protection, some anaes-

thetic 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 flow, slight increase in intracellular

calcium, upregulation of bioenergy metabolism in brain,

nitric oxide synthase and antiapoptotic factors as well asreduction in oxidative stress [56]. The use of volatile

anaesthetics increases mitochondrial adenosine tripho-

sphate-sensitive potassium channels (mitoKATP) activity

leading to mild hyperpolarisation [5759]. The opened

mitoKATP channel decreases mitochondrial energy con-

sumption by ATP sparing, enlarging mitochondrial

energy. Moreover, moderately increased intracellularcalcium prevents large intracellular calcium influx and

plays a crucial role in neuronal survivability after hypoxia/

ischaemia events [58]. Volatile anaesthetics cause the

membrane depolarisation in the presynaptic mitochon-

dria, also after the removal of extracellular calcium [57].

This

increase

in

intracellular

calcium

concentrationresults from a decrease in ischaemic activity of

calcium-calmodulin receptors, inhibition of N-methyl-

D-aspartate (NMDA) and a decrease in glutamate release

[5760]. Moreover, the use of volatile anaesthetics sig-

nificantly reduces the concentration of brain injury mar-

kers [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, in-

cluding neurotransmitter release, ion changes, oxidativereaction and energy metabolism. Numerous studies have

shown that magnesium is essential in CNS injuries [62].Indeed,magnesium decreases afterbrain 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 magnes-

ium disorders

in

brain

circulation

have

been

documentedduring extracorporeal circulation [64]. Importantly, con-

tinuous supplementation of magnesium reduces substan-

tially the plasma S100b protein concentration [65].

Moreover, intravenous infusions of magnesium reduce

the incidence of atrial fibrillation, improve cardiac func-

tion and postoperative neuropsychological outcomes

[64,66].Nevertheless, the neuroprotective effect ofmag-

nesium 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 clinicalstudies confirm 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 neuropro-

tection in cardiac surgery patients. It strongly inhibits the

NMDA receptor, activates gamma amino-butyric acid

(GABA) receptors and slightlymodulates the intracellular

calcium influx. By decreasing the internalisation of D-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid

(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 deathin the cortex and thalamus of the developing brain [72].

From this reason, propofol is recommended as an anaes-

thetic of choice in adult patients undergoing cardiac

surgery.

Several

studies

document

the

neuroprotective

effect

ofbarbiturates [73]. Barbiturates depress the brain metab-

olism, inhibit mitoKATP channel, facilitate protein syn-

thesis, activateGABA receptors, and present antioxidative

activity. Similarly to propofol, barbiturates cause a dose-

dependent neurodegeneration in the developing brain.

The use of pentobarbital alters synaptic plasticity and

leads to a long-lasting spatial learning deficit [74].

Interestingly, the perioperative use of b-blockers

improves postoperative neurological outcomes in cardiacsurgery patients. b-blockers are known to have many

Brain injury and heart surgery Dabrowski et al. 191


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benefits during non-cardiac and cardiac surgery. Theneuroprotective action of this drug has been not fully

known. However, several authors reported a significant

reduction of postoperative neuropsychological disorders

in patients receiving b-blockers during the perioperative

period [75,76].

It

is

recommended

to

continue

b-blockerstherapy until surgery with the last dose included as a part

of oral premedication. Moreover, this effect is intensified

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 b-

blockers therapy, however their neuroprotective effect

requires future studies.

Several other drugs have been studies as potential neu-

roprotective agents in cardiac surgery patients. Amanta-

dine and memantine, the antagonists of NMDA receptor,

appear to have promising neuroprotective effects. They

bind to NMDA with a higher affinity than magnesium

and thus decrease the prolonged influx of calcium into the

cellular space. Moreover, they increase dopamine releaseand block dopamine reuptake. Memantine moderately

decreases clinical deterioration and profitably affects the

mood, behaviour and cognitive function [77]. Therefore,

they can improve neuropsychological outcome, however,

their neuroprotective effect has been completely undo-

cumented in cardiac surgery patients.

The ideal brain protection has been not specified in

cardiac surgery patients. Despite several adverse effects

of extracorporeal circulation, cardiac surgery is the only

method of treatment of many cardiac diseases. Manyneuroprotective techniques and pharmacologic methods

are used to improve the quality of life; however, a sig-

nificant reduction of brain injury is still the subject of

many experimental and clinical studies. Therefore, neu-

ropsychological disorders and brain injury remain the

main problem of cardiac surgery patients.

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