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British Journal of Anaesthesia 84 (3): 37893 (2000)


Central nervous system complications of cardiac surgery

J. E. Arrowsmith1*, H. P. Grocott2, J. G. Reves2 and M. F. Newman2

1Department of Anaesthesia, Papworth Hospital, Papworth Everard, Cambridge CB3 8RE, UK.
2Division of Cardiothoracic Anesthesia, Department of Anesthesiology, Box 3094,
Duke University Medical Center, Durham, NC 27710, USA
*Corresponding author

Br J Anaesth 2000; 84: 37893

Keywords: surgery, cardiovascular; surgery, postoperative period; heart, cardiopulmonary
bypass; brain, function; psychological responses, postoperative; complications, neurological;
complications, stroke

While the number of patients undergoing surgery for Adverse neurological outcome from cardiac surgery is
valvular and other types of heart disease has remained the result of damage to the brain, spinal cord and/or
fairly constant, the number undergoing coronary revascu- peripheral nerves. CNS injury ranges in severity from subtle
larization procedures is increasing (Fig. 1). Because of changes in personality, behaviour and cognitive function to
many technological advances over the past four decades, fatal brain injurythe cerebral catastrophe (Table 1). A
there has been a steady decrease in the mortality and major neurological complication after otherwise successful
morbidity associated with these procedures. Nevertheless, surgery represents a devastating outcome for patient and
neurological injury remains an important cause of post- their family. The social and economic impact is enormous.
operative morbidity91 and is responsible for an increasing
proportion of perioperative deaths.44 158 Since the introduc- Measures of neurological outcome after cardiac
tion of cardiopulmonary bypass (CPB) in the early
1950s, the neurological sequelae of cardiac surgery have
been a major concern. Identification of risk factors for A wide variety of techniques have been used to assess
adverse neurological and neuropsychological outcomes adverse neurological events after cardiac surgery (Table 2)
has led to the development of physical and pharmaco- with the incidence of stroke and cognitive dysfunction
logical neuroprotective strategies targeted at the at risk being the most frequently used outcome measures. Early
population.111 123 retrospective studies in this area could only detect what they
set out to look forneurological (e.g. coma, hemiparesis,
Neurological injury after cardiac surgery seizures, blindness) and psychological (e.g. depression,
disorientation and confusion)problems that were suffi-
Advances in medical care and the introduction of broader ciently obvious to be noticed and documented.
indications for surgery has meant that patients previously The introduction of psychometric testing, typically
deemed inoperable are now considered suitable candidates measures of memory, attention, visuospatial ability and
for surgery. Over the past 20 yr, there has been a steady motor speed, broadened the scope and power of investi-
increase in the average age of patients undergoing cardiac gations.17 Prospective studies not only demonstrated the
surgery.123 This increase has been accompanied by a rise value of a multimodal (i.e. neurological and neuropsycho-
in both the severity of cardiac disease at the time of logical) approach, but highlighted the need for investigators
surgery and the reoperation rate for recurrent disease.67 to have the appropriate training and background.135
Nevertheless, the likelihood of dying or sustaining a major Several difficulties associated with perioperative neuro-
complication after cardiac surgery in the late 1990s is cognitive testing continue to challenge the research
significantly lower than that in the 1950s. Not unreasonably, community. There is as yet no gold standard against which
most patients expect to survive cardiac surgery intact, make to compare new tests. In addition, there is neither agreement
a good functional recovery and live longer. A significant
number of patients however suffer a perioperative complica-
tion involving the central nervous system (CNS). This article is accompanied by Editorial II.

The Board of Management and Trustees of the British Journal of Anaesthesia 2000
CNS complications of cardiac surgery

Table 1 Types and initial incidence of neurological complications after cardiac

surgery (reproduced and modified with permission from Shaw and colleagues135)

Complication Incidence

Fatal brain injury 0.3%

Non-fatal diffuse encephalopathy
Depressed conscious level 3%
Behavioural changes 1%
Intellectual/cognitive dysfunction 3079%
Choreoathetosis 0.3%
Visual field defects 25%
Fig 1 The UK Society of Cardiothoracic Surgeons (SCTS) register 1977 Reduced visual acuity 4.5%
1998. Summary of procedures carried out for ischaemic, valvular and Focal brain injury (stroke) 25%
miscellaneous acquired heart disease, and overall operative mortality. Primitive reflexes 39%
Spinal cord injury 00.1%
Adapted from data obtained from the SCTS web site (
doc/2104) and reproduced with permission. Peripheral nerve injury
Brachial plexopathy 7%
Other peripheral neuropathy 6%
on which tests or groups of tests should be used, nor what
is (are) the optimal time(s) for administration.151 There is
broad agreement that using a large number of tests is
reducing cerebral injury. Furthermore, if the degree of
preferable to using only a few. The incidence of cognitive
elaboration of a biochemical marker can be shown to
decline is reported to be higher in studies in which a larger
correlate with clinical (neurological and cognitive) outcome,
number of tests were used than in those where only a few
large interventional studies could be designed that do
tests were used. Using a larger number of tests however,
not rely on costly and time consuming neurological and
increases both administration time and the likelihood that
neuropsychological testing.
some patients will not be able to complete all tests. The
Although a marker of neuronal injury may provide an
number of tests used and their timing in relation to surgery
indication of the severity of a cerebral injury, it cannot
affects measured outcome.17
provide information on the anatomical distribution and
There is no universally accepted method of analysing
clinical impact of that injury. A small infarct in the internal
neurocognitive test results and therefore no standard for
capsule may be associated with modest release of a marker
defining the incidence and severity of cognitive decline
substance yet produce a disabling hemiplegia, whereas a
based on changes in test performance.16 By focusing solely
considerably larger infarct in a frontal lobe, accompanied
on a decline in cognitive function, most investigators
by massive release of marker, may produce few symptoms
have ignored the fact that, with repeated testing, normal
or physical signs.
volunteers tend to show improvement in performance, a
Brain-specific creatine phosphokinase (CPK-BB) was
phenomenon known as the practice effect.113 Cognitive
one of the first markers to be evaluated.156 Marked
impairment should perhaps more correctly be defined as
increases in cerebrospinal fluid (CSF) concentrations were
decline and failure to improve.49 84 Furthermore, if an age-
detected in dogs subjected to 60 min of CPB. Incorporation
matched control group is not used in late follow-up studies,
of a 40-m arterial line filter resulted in significantly
it may be impossible to distinguish persistent perioperative
lower CSF CPK-BB concentrations compared with those
neurological problems from the effects of normal ageing
in unfiltered animals. In a clinical study conducted at the
processes, depression or dementia.40
Cleveland Clinic, 413 of 421 (98%) patients undergoing
Many confounding factors make it difficult to attempt
coronary artery bypass surgery (CABS) had increased
direct comparisons between studies that have used different
blood concentrations of CPK-BB after surgery. There was,
methodologies.78 In an effort to address these problems,
however, no correlation between CPK-BB concentration
a consensus on the use of these tests is beginning to
and the occurrence of encephalopathy or stroke.21
emerge.97 98
The use of CSF adenylate kinase (CSF-AK) as a marker
of cerebral injury after cardiac surgery was reported by
Markers of neuronal injury berg and colleagues.2 A subsequent publication reported
In addition to neurocognitive testing, proteins released by a significant correlation between CSF-AK and performance
the injured brain have been used to measure brain injury. in psychometric tests.1 Further work characterizing CSF
After cerebral hypoxiaischaemia, numerous substances markers has been limited because of the methodological
have been shown to be released from neurones, glia, problems of lumbar puncture in patients who have been
endothelium, platelets and leucocytes (Table 3). Quantifica- heparinized for CPB.
tion of these substances offers the potential for rapid The marker that has received the most interest recently
diagnosis, making possible early interventions aimed at is astroglial protein S100. The numerous functions of

Arrowsmith et al.

Table 2 Investigational methods used in the study of adverse neurological outcome after cardiac surgery

Pathological Gross and microscopic postmortem examination

Clinical Retrospective chart review for mortality and gross neurological, psychiatric, cognitive complications
Prospective neurological and psychiatric examination
Neuropsychological/cognitive function testing, anxiety and depression inventories
Subjective (patientspouse) reports of cognitive function
Financial Duration of intensive care
Length of hospital stay
Patient charges
Social Activities of daily living
Return to work
Resumption of sexual activity
Ultrasound Transoesophageal echocardiographyepiaortic ultrasound assessment of aortic atheromatous disease
Carotid and transcranial Doppler quantification of microemboli
Brain imaging Brain computed tomography (CT)
Magnetic resonance imaging and spectroscopy (MRS)
Positron emission tomography (PET)
Electrophysiological Electroencephalography (EEG)
Processed EEG (cerebral function analysing monitorCFAM), somatosensory evoked potentials (SSEP)
Biochemical Blood and cerebrospinal fluid markers of cerebral injury
Blood glucose, arterial pH and blood gases
Others Cerebral near infra-red spectroscopy (NIRS)
Jugular bulb oxygen saturation
Retinal fluorescein angiography
Regional cerebral blood flow (rCBF)

Table 3 Potential biochemical markers of brain injury or aortic valve procedures) is associated with a greater
Source Marker(s) postoperative increase in S100 than CABS.154

Glia S100b, myelin basic protein (MBP)

Glial fibrillary acidic protein (GFAP)
Neurone specific enolase (NSE), adenylate kinase (AK)
Risk factors for adverse neurological outcome
Creatine phosphokinase brain isoform (CPK-BB) Soon after the introduction of CPB into clinical practice,
Guanine nucleotide binding protein G0, calbidin-D reports of neurological injury after cardiac surgery began
Lactate dehydrogenase (LDH), glutamate
Inflammatory cells Interleukin-6, transforming growth factor- to appear in the literature. Early reports were small and
Adhesion molecules (ICAM-1, E-selectin, neural cell retrospective, focusing on clinical manifestations in
adhesion moleculeNCAM) survivors and neuropathological findings in non-survivors.
Metabolic Lactate, Cu-Zn superoxide dismutase (CuZn-SOD)
The late 1960s and early 1970s heralded the publication of
several large, retrospective studies and the recognition of
S100 include promotion of axonal growth, glial prolifera- the importance of patient age, cerebral hypoperfusion and
tion, neuronal differentiation and calcium homeostasis.73 cerebral embolism. During the next decade, the focus of
Increased concentrations of S100 in both blood and CSF prospective investigation moved away from stroke and
have been found after acute stroke, transient ischaemic coma (which were becoming increasingly uncommon) to
attacks, head injury, intracranial haemorrhage and post- more subtle psychological, cognitive and behavioural out-
cardiac arrest coma, in addition to Alzheimers disease and comes. More recently, investigators have examined the
Downs syndrome.73 In acute stroke, the degree of S100 causes and mechanisms of neurological injury, developed
elevation correlates well with infarct volume and neuro- indices of risk by defining predictive perioperative risk
logical outcome.73 factors, and tested the beneficial effects of physical and
Several studies have demonstrated an increase in S100 pharmacological interventions.
after cardiac surgery. Westaby and colleagues reported a Arguably one of the most significant contributions in
relationship between S100 concentrations and age, aortic recent years is the prospective, observational study con-
cross-clamp time and CPB duration.166 Patients with carotid ducted by the Multicenter Study of Perioperative Ischemia
artery stenosis had higher concentrations of S100 than (McSPI) group at 24 US medical institutions between 1992
those who did not and patients who had CABS without and 1994. The study sought to determine the incidence
CPB showed no increase in S100. Peak postoperative of neurological injury after CABS, identify independent
concentrations of S100 have been shown to correlate predictors of these adverse outcomes and assess their
with intraoperative cerebral microemboli quantified with impact on resource utilization. Two categories of adverse
transcranial Doppler sonography.50 The Oxford group has neurological outcome were defined: type Inon-fatal
shown that, compared with controls, the use of an arterial stroke, transient ischaemic attack (TIA), stupor or coma at
line filter decreased the number of patients who had the time of discharge, or death caused by stroke or hypoxic
abnormal increases in S100 after surgery.153 The same encephalopathy; and type IInew deterioration in intellec-
group has also shown that intracardiac surgery (e.g. mitral tual function, confusion, agitation, disorientation, memory

CNS complications of cardiac surgery

Table 4 Adjusted odds ratios [95% confidence intervals] for type I and type II cerebral outcomes associated with selected risk factors from the McSPI and IREF
study. IABPintra-aortic balloon pump; AParterial pressure; CABScoronary artery bypass surgery (reproduced with permission from Roach and colleagues123)

Risk factor Type I outcomes Type II outcomes

Proximal aortic atherosclerosis 4.52 [2.528.09]

History of neurological disease 3.19 [1.656.15]
Use of IABP 2.60 [1.215.58]
Diabetes mellitus 2.59 [1.464.60]
History of hypertension 2.31 [1.204.47]
History of pulmonary disease 2.09 [1.143.85] 2.37 [1.344.18]
History of unstable angina 1.83 [1.033.27]
Age (per additional decade) 1.75 [1.272.43] 2.20 [1.603.02]
Admission systolic AP 180 mm Hg 3.47 [1.418.55]
History of excessive alcohol intake 2.64 [1.275.47]
History of CABS 2.18 [1.144.17]
Arrhythmia on day of surgery 1.97 [1.123.46]
Antihypertensive therapy 1.78 [1.023.10]

deficit or seizure without evidence of focal injury. More

than 30% of patients were 70 yr or older and there was a
high prevalence of hypertension, unstable angina, cardiac
failure and diabetes mellitus. In all, 129 of 2108 (6.1%)
patients had an adverse neurological outcome in the peri-
operative period. Type I outcomes occurred in 66 of 2108
(3.1%) patients and included eight deaths as a result of
cerebral injury, 55 non-fatal strokes, two TIA and one case
of stupor at the time of discharge. Type II outcomes occurred
in 63 of 2108 (3.0%) patients and included 55 patients with
intellectual dysfunction and eight with seizures. The wide
variation in institutional outcome rates for both type I
(113.8%) and type II (09.3%) outcomes is cause for
concern and has yet to be fully addressed.
Stepwise logistic regression analysis identified eight
significant, independent predictors of type I outcomes and
seven significant, independent predictors of type II outcomes
(Table 4). Although similar, the predictors for the two
outcome types were not identical.
Factors found not to be significant predictors were: Fig 2 Multicentre preoperative stroke risk index for patients undergoing
perioperative hypotension (systolic arterial pressure 40 mm coronary artery bypass graft surgery. Definitions: diabetes mellitus
history of either type I or type II diabetes or insulin use on admission
Hg during CPB or 80 mm Hg at other times for more than
or before operation; neurological diseaseprevious stroke or transient
10 min), intraoperative use of an apical vent to decompress ischaemic attack; vascular diseaseperipheral vascular disease, known
the left ventricle, congestive cardiac failure on the day of carotid vascular disease, claudication or vascular surgery; pulmonary
surgery and a history of peripheral vascular disease. Adverse diseaseemphysema, chronic bronchitis, asthma, restrictive lung disease.
neurological outcome was associated with higher in hospital CABScoronary artery bypass surgery, CNScentral nervous system.
Adapted with permission from Newman and colleagues.111
mortality, increased duration of intensive care and post-
operative hospital stay, increased patient charges and
increased likelihood of being discharged to an intermediate
or long-term care facility.
Patient age
Using data obtained from the McSPI study, the Duke
group went on to develop a model to predict the development Of all the factors thought to be predictive of neurological
of stroke after CABS.111 Using preoperative patient factors, and neuropsychological injury in cardiac surgery, age is
the so-called stroke index allows rapid assessment of risk probably the most robust32 43 108 123 158 (Fig. 3). Although
(Fig. 2). the elderly appear to retain cerebral autoregulation, they
More recently, the McSPI group have reported adverse are at increased risk of stroke, particularly in the presence
neurological outcomes in 43 of 273 (16%) patients of severe aortic atherosclerosis and occult cerebrovascular
undergoing combined intracardiac and coronary artery disease.15 105 The elderly are more likely to have reduced
procedures.168 The authors concluded that this surgical baseline cognitive function so that a relatively small
population was at extraordinary risk of adverse cerebral perioperative decline may have a significant impact on
outcome. independent living.

Arrowsmith et al.

Fig 3 Effect of age on the risk of stroke (left) and mortality (right) after coronary artery bypass surgery. Reproduced with permission from Cosgrove
and colleagues32 and the US Society of Thoracic Surgeons (, respectively.

Sex have reduced the impact of poor cardiac function on

Few studies have specifically examined the influence of sex neurological outcome.
on neurological outcome after cardiac surgery.43 The main
reason for this is that men greatly outnumber women in the Cerebrovascular disease
adult cardiac surgical population. Data from the US Society Patients with a history of stroke or TIA are more likely
of Thoracic Surgeons ( for the to sustain a perioperative stroke.80 148 159 Patients with
years 1995 to 1996 suggest that operative mortality was significant but asymptomatic atheromatous disease in the
significantly greater in females after both repeat and/or extracranial cerebral arteries may be at increased risk on
emergency CABS (4.30% vs 2.63%; P0.0001) and primary the grounds that they will be more vulnerable to regional
elective CABS (2.9% vs 1.5%; P0.0001). A recent report ischaemia during periods of hypoperfusion. Although pre-
from the Bypass Angioplasty Revascularization Investi- operative detection of a carotid bruit is associated with a
gation (BARI) group however, suggests that the higher two-fold increase in absolute perioperative stroke risk after
mortality observed in women is a product of higher risk CABS, it is a poor measure of the severity of stenosis and
profiles rather than increased gender susceptibility.65 When has been shown not to correlate well with angiographic
risk factors are controlled for, female sex was an independent findings.37 In the presence of carotid disease detected by
predictor of improved 5-yr survival. Doppler sonography, the risk of stroke is increased three-
Laboratory evidence suggests that oestrogens have a vital fold.20 As expected, the risk of stroke increases with the
role in neuronal growth, differentiation and survival.141 severity of carotid disease. In a follow-up study of 4047
Furthermore, oestrogens also appear to play an important patients examined before CABS, Brener and colleagues
and specific role in cognitive function in women.136 The demonstrated that in the presence of 50% carotid stenosis,
finding that oestrogen administration reverses memory the risk of stroke increased from 1.9% to 6.3%.19 In 32
deficits in women rendered hypo-oestrogenic with leu- patients with complete carotid occlusion, the stroke rate
prolide acetate (a gonadotrophin releasing hormone was 15.6%.
agonist) suggests that a study of oestrogen replacement In a study of 47 patients undergoing CABS at the
in postmenopausal women undergoing cardiac surgery is Middlesex Hospital, studied with i.v. digital subtraction
warranted.137 carotid angiography, 51% had evidence of atheroma and
17% had stenosis of at least one carotid artery in the neck.57
Severity of cardiac disease and cardiac function The incidence of cognitive deficit at 8 days and 8 weeks
An early study by Blachly and Kloster suggested that low after surgery was not significantly greater in those patients
postoperative cardiac output was related to the occurrence with angiographically visible carotid artery disease.
and severity of a postoperative brain syndrome or A retrospective study at the Cleveland Clinic revealed
hallucinosis.12 Lee and colleagues reported that patients that the incidence of new stroke after open-heart surgery
who had symptoms of cardiac disease for more than 6 was 13.4% in 126 patients with previous stroke.128 The
months were more likely to develop neurological damage likelihood of a new perioperative stroke was not related to
after coronary artery surgery.74 Poor preoperative left ventri- the time interval between the previous stroke and surgery.
cular function and/or episodes of left ventricular failure Furthermore, the presence of extracranial occlusive disease
have been reported to be associated with worse neurological appeared to be non-contributory. Patients who had had a
outcome.131 134 Interestingly, the McSPI study found that stroke in the 3 months before surgery were more likely to
neither congestive cardiac failure nor arrhythmia on the have worsening of a prior deficit whereas those with a more
day of surgery were associated with adverse neurological remote history of stroke were more likely to have a stroke
outcome.123 It is possible that improvements in critical care, in a different brain region. Intraoperative hypotension was
anti-arrhythmic therapy and support of the failing heart found to be more frequent in those patients with recent

CNS complications of cardiac surgery

preoperative stroke, suggesting persistent haemodynamic disease and early re-stenosis after coronary angioplasty,
vulnerability. independent of serum cholesterol, may also be associated
Current evidence suggests that asymptomatic extracranial with APOE4.62
cerebrovascular disease represents a modest increase in the APOE was evaluated as a predictor of postoperative
risk of perioperative stroke, but other factors, such as cognitive dysfunction in 65 patients undergoing CABS.155
embolism or hypoperfusion, are probably more important. A significant association was found between the APOE4
allele and decline in four of nine measures of cognitive
Diabetes mellitus and hyperglycaemia function at discharge from hospital and 6 weeks after
For many years, the use of glucose-containing priming surgery.
solutions in the extracorporeal circuit was commonplace. The notion that APOE isoforms may have a role in
Although there is evidence that outcome from stroke in dictating the expression of early immediate genes after
humans is worse in diabetics, there are no data unequivocally neuronal injury, and thus the balance between neuronal
implicating hyperglycaemia as the cause.138 The higher repair and neuronal death, is attractive but requires further
incidence of hypertension, renal impairment and vascular investigation.
disease may partly explain a worse outcome in diabetic
patients. In a study of 70 patients conducted at the Education level, socioeconomic status and mood
Middlesex Hospital, allocated randomly to either electrolyte An interesting observation is that a higher number of
or dextrose prime, neuropsychological outcome was found years of formal education appears to protect patients from
to be worse in the latter group.112 In a recent study using cognitive decline.106 Level of educational achievement how-
133Xe clearance, the Duke group demonstrated that insulin- ever, correlates poorly with baseline (preoperative) cognitive
dependent diabetic patients had impaired cerebral blood function test scores.
flow autoregulation, characterized by increased oxygen Depression is commonly reported after cardiac surgery.
extraction, during CPB.33 Several reports have suggested The use of non-standard measures of depression, however,
that diabetes mellitus is a risk factor for poor neurological may have overestimated its frequency. A presumed
outcome after CPB.84 111 123 association between postoperative depression and poor
In recent years, there has been a re-evaluation of the performance on psychometric tests has meant that mood
use of glucose-containing priming solutions in cardiac assessment has become an integral component of many
surgery.139 On the grounds that hyperglycaemia appears to studies. In a recent study, the Center for Epidemiological
worsen neurological outcome in both focal and global Study of Depression (CES-D) depression questionnaire and
cerebral ischaemia,76 101 some investigators claim that a battery of neuropsychological tests were used to assess
hyperglycaemia during cardiac surgery is detrimental and outcome in 124 CABS patients 1 month and 1 yr after
should be avoided.140 Others, however, suggest that glucose surgery.82 Depression was defined as a CES-D score 16.
administration may be beneficial.88 89 Only 12 (13%) patients not depressed before surgery were
In our experience, most centres avoid deliberate hyper- depressed 1 month afterwards, whereas 18 (53%) of those
glycaemia and treat intraoperative hyperglycaemia with who were depressed before surgery were depressed at 1
insulin. The critical glucose concentration at which treat- month (P0.001). One year after surgery, values were eight
ment should be instituted is unknown. (9%) and 16 (47%), respectively (P0.001). There was
little or no correlation between depression and changes in
Genetic susceptibility cognitive function. The inference is that cardiac surgery
It is known that patients with similar physical characteristics, neither causes nor cures depression.
identical medical histories and cardiac disease of equivalent
severity have markedly differing neurological and neuro- Cerebral microembolization
psychological outcomes from uneventful cardiac surgery. Emboli, which may be gaseous or particulate, can be
This observation led investigators at Duke University to conveniently divided into macro and micro according to
speculate that genetic factors may account for this size. Macroemboli occlude flow in arteries 200 m or
variability.105 106 155 Concurrent laboratory studies, focusing greater in diameter, whereas microemboli occlude flow in
on apolipoprotein E, prompted a clinical investigation. small arteries, arterioles and capillaries.14
Apolipoprotein E (APOE), a 34 kD glycosylated lipid- Air may reach the systemic circulation from the bypass
binding protein, is expressed as three common isoforms circuit via the venous cannula, or as an inevitable con-
(2, 3 or 4) in humans. Possession of the APOE4 allele sequence of left-heart surgery.149 Not surprisingly, systemic
is now known to be a risk factor for the development of embolization is more common during valve surgery than
late-onset and sporadic forms of Alzheimers disease.129 130 CABS.72 The ultimate fate of bubbles depends on their
It may also be associated with a worse outcome after initial size, the partial pressure of gases in solution and
subarachnoid haemorrhage3 and increased severity of temperature, which dictates the solubility of gases in liquids.
chronic neurological deficits in boxers exposed to chronic Because of high surface tension forces, small bubbles are
head trauma.68 Interestingly, accelerated aortic atheromatous unstable and tend to collapse. Bubbles are more likely to

Arrowsmith et al.

grow in size during rewarming when gas solubility the technique in adults.10 99 Recent comparisons between
decreases. Although bubbles are known to traverse the intraoperative TOE and epiaortic ultrasound showed con-
cerebral vasculature, they may cause endothelial injury.14 clusively that TOE underestimated the presence and severity
Particulate matter can also be categorized according to of aortic atherosclerosis.39
composition and origin. Biological particles arise from Several centres are currently investigating the efficacy
components of the circulation (aggregates of erythrocytes, of alterations in surgical technique based on ultrasonic
leucocytes, platelets, denatured protein, fibrin) and the evaluation of the aorta. Such alterations include aortic
operative site (thrombus, fat, calcium, cellular aggregates, cannulation at a different site, avoidance of aortic can-
atheroma, valve debris, muscle fragments, hair). Non- nulation altogether, avoidance of aortic cross clamping and
biological particles arise from the extracorporeal circuit and replacement of the ascending aorta and/or aortic arch.
cardiotomy reservoir (polyvinyl chloride, silicone rubber,
antifoam, priming solutions, cardioplegia solutions) and Duration of cardiopulmonary bypass
from foreign material introduced into the operative field The suggestion that CPB is associated with progressive,
(fibres from swabs, glove talc, dust). embolic cerebral microvascular obstruction suggests a
Considerable histological,92 angiographic13 and ultra- relationship between duration of bypass and adverse neuro-
sonographic118 152 evidence suggests that cerebral logical outcome.100 146 Many investigators have either
embolization occurs in all patients subjected to CPB. observed or suggested that neurological outcome is related
Although it is not clear which types of microemboli cause to the duration of bypass18 45 83 162 while others have
most damage to the brain, a correlation between intra- suggested otherwise.53 The finding that progressive cerebral
operative cerebral microembolic load and postoperative vasoconstriction leads to a gradual decrease in cerebral
neuropsychological dysfunction has been demonstrated.28 119 blood flow during prolonged non-pulsatile hypothermic
The finding, in a recent animal study, that the use of bypass117 127 may be an additional factor, but has not been
cardiotomy suction was associated with histological evidence substantiated.36 132
of increased cerebral microembolization suggests that blood It is important to note that bypass time may be
aspirated from the surgical field can be a major source of prolonged by several factors which may themselves
microemboli.23 contribute to cerebral injury. A slow (meticulous) or
delayed surgeon may occasionally increase bypass time. It
Aortic atheromatous disease is more usual, however, that complicated surgical procedures
Although the possibility of atheromatous cerebral embolism (e.g. combined valve and CABS), complications or technical
during aortic surgery was recognized many years ago,56 it problems (e.g. haemorrhage, aortic dissection) and difficulty
is only in recent years that this problem has been revisited. weaning from bypass are the main causes of prolonged
The severity of aortic atheromatous disease increases sharply bypass. It is clear that all of these factors may reflect a
with age.15 Postmortem studies indicate a prevalence of greater severity of cardiac disease in a population of surgical
20% in the fifth decade increasing to 80% in the eighth patients that have a higher incidence of adverse neurological
decade.164 The prevalence of ulcerated aortic arch atheroma outcomes.
at autopsy has been shown to be higher (26% vs 5%) in
patients with cerebrovascular disease but appears not to be Perfusion: pressure, flow and pulsation
correlated with the presence of extracranial internal carotid Few would doubt that prolonged periods of profound arterial
artery stenosis.4 Surgical manipulations of the proximal hypotension and cerebral hypoperfusion are bad for the
aorta, cannulation through an atheromatous plaque or brain and that certain areas, at the boundaries of cerebral
sandblasting of the aortic wall during perfusion may artery territories (so-called watersheds), are particularly
cause atheroembolism. The advent of transoesophageal vulnerable.45 The influence of systemic (arterial or pump)
echocardiography (TOE) and intraoperative epiaortic ultra- blood flow, flow character and cerebral perfusion pressure
sonography has allowed a more detailed view of the aorta (CPP) on CBF during CPB and neurological outcome has
during surgery and quantification of atheromatous plaques been the subject of considerable debate.
according to thickness and the presence of mobile com- In addition to pressure and flow, actual CBF during
ponents. CPB is determined by other factors including: acidbase
The importance of aortic atheroembolism has been high- management strategy, temperature, depth of anaesthesia,
lighted by Katz and colleagues69 who found that the packed cell volume and oxygen saturation.132 During
incidence of stroke was 25% in patients with a mobile moderate hypothermia, cerebral autoregulation remains
plaque of the aortic arch compared with 2% in those with intact at a mean arterial pressure (MAP) as low as 30 mm Hg
sessile plaque. A strong association between severe aortic such that, in -stat managed patients, CBF remains virtually
atheroma and postoperative stroke or death has been con- constant within the range 30100 mm Hg.95 Children appear
firmed by others.8 38 59 123 to tolerate a MAP as low as 15 mm Hg.48 Recent evidence
The successful use of intraoperative epicardial ultrasound suggests that MAP in the range 5175 mm Hg has a small
in surgery for congenital heart lesions160 stimulated use of effect on CBF during both hypothermic (0.086 ml

CNS complications of cardiac surgery

100 g1 min1 mm Hg1) and normothermic (0.178 ml Non-pulsatile perfusion is associated with diminished
100 g1 min1 mm Hg1) CPB.106 107 These findings are endothelial shear stress and a reduction in endothelial nitric
supported by the observation that at constant pump flow, oxide production leading to increased vascular resistance
jugular venous oxygen saturation (SjO2) correlates with CPP and end-organ dysfunction.77 Furthermore, it is suggested
during hypothermic, pulsatile CPB.52 that non-pulsatile flow may cause stasis of cerebral inter-
Although maintenance of a perfusion pressure 50 mm Hg stitial fluid167 and also the cerebral swelling demonstrated
during hypothermic CPB appears to be tolerated by the after hypothermic54 and normothermic55 bypass. In a canine
majority of patients, the safety of this practice has been model of extracorporeal perfusion after 15 min of cardiac
questioned.24 The obvious question is, could higher perfusion arrest, non-pulsatile perfusion was associated with worse
pressures (i.e. 70 mm Hg) improve outcome?58 In an cerebral hyperaemia and lower oxygen consumption com-
attempt to answer the question, Gold and colleagues pared with pulsatile perfusion.5 In a prospective study of
prospectively compared cardiac and neurological outcome 316 patients undergoing CABS, however, Murkin and
variables in 248 patients undergoing elective CABS, colleagues were unable to demonstrate any influence of
allocated randomly to either lower (5060 mm Hg) or higher mode of perfusion on neurobehavioural outcome.96
(80100 mm Hg) perfusion pressures.46 Six months after Despite considerable research, the characteristics of
surgery, the overall incidence of combined cardiac and neuro- optimal CPB perfusion remain to be defined. Within the
logical complications was significantly lower in the higher bounds of usual CPB conduct, pressure, flow and flow
pressure group (4.8% vs 12.9%; P0.026) as was the stroke character appear to have little influence on CBF.132 In the
rate (2.4% vs 7.2%). There were no differences in cognitive absence of unequivocal evidence suggesting otherwise,
and functional outcomes. The small study population, unusu- there seems little reason to alter perfusion practices that are
ally high baseline stroke rate (7.2%) and method of data tolerated by the vast majority of patients.
analysis makes it hard to reach any definite conclusion.70 121
The observed differences in outcome could have occurred by Temperature
chance but may be accounted for by the greater number of Since the early days of cardiac surgery, systemic and
patients with aortic atherosclerosis in the lower pressure regional hypothermia has been the mainstay of organ
group. protection during CPB. Hypothermia is unique among
During CPB, systemic flow rate is usually based on neuroprotective modalities in that it reduces energy
body surface area and the degree of hypothermia (typically consumption (about 7% per C) associated with both
1.62.4 litre min1 m2) and adjusted according to indices electrophysiological function and maintenance of cellular
of the adequacy of organ perfusion (e.g. arterial blood integrity. At modest hypothermia, autoregulation of CBF is
gases). Although it is well established that low pump flow such that CBF is tightly coupled to cerebral metabolic rate
with concomitant arterial hypotension results in decreased (CMRO2). With decreasing temperature, the CBF:CMRO2
CBF, the independent effects of low flow and low pressure ratio increases resulting in luxury brain blood flow. At
are less well characterized. In a baboon model of non- temperatures of 1520C (deep hypothermia), pressure
pulsatile hypothermic (28C) CPB, Schwartz and colleagues flow autoregulation is lost. In animal models of cerebral
showed that, regardless of pump flow, CBF was governed ischaemia, mild hypothermia reduces neuronal adenosine
by mean arterial pressure (2060 mm Hg). Furthermore, triphosphate (ATP) depletion,169 and both delays the onset
when mean arterial pressure was maintained constant, and reduces the rate of excitatory amino acid release.102
changes in pump flow (0.752.25 litre min1 m2) did not Hypothermia does, however, have several distinct
alter CBF.133 These findings are at odds with the results of disadvantages, not least of which is the requirement for
several other studies of CBF during CPB.47 125127 147 rewarming the patient at the end of the procedure. Place-
Govier and colleagues showed no correlation between ment of the arterial cannula in the ascending aorta results
CBF and either mean arterial pressure (30110 mm Hg) or in cerebral perfusion with blood at a temperature close to
pump flow rate (1.02.2 litre min1 m2) in 67 patients that of blood leaving the heat-exchanger. For this reason it
undergoing CABS.47 In contrast, Soma and colleagues is easy to produce inadvertent cerebral hyperthermia during
reported that CBF was directly dependent on pump flow rewarming. The observation that warming from moderate
rate (4070 ml kg1 min1).147 The Bowman Gray group hypothermic CPB is associated with jugular venous
have reported the effects on CBF of alterations in arterial desaturation (SjO2 50%) suggests that cerebral oxygen
pressure with administration of sodium nitroprusside126 and extraction during this period exceeds supply.29 34 In a series
phenylephrine127 (measured by 133Xe clearance) at constant of 255 patients studied at Duke University, the cerebral
pump flow. In -stat managed patients, changes in arterial arteriovenous oxygen difference (CaO2CvO2) on rewarming
pressure had no effect on CBF whereas in pH-stat managed was significantly associated with overall cognitive decline
patients, CBF was correlated positively with pressure. A (P0.0013).35
subsequent study showed that modest changes in pump Rapid rates of warming, using temperatures 41C, have
flow rate (1.752.25 litre min1 m2) had no influence on long been considered a potential cause of neurological
arterial pressure or CBF.125 injury during CPB.22 Hyperthermia increases CMRO2 and

Arrowsmith et al.

may cause protein denaturation and air embolism, in addition focal neurological deficits came from the normothermic
to tissue ischaemia.30 In a recent study, nasopharyngeal group. One patient died as a result of cerebral infarction.
temperature (TNP) monitoring was compared with continu- In contrast, there were no significant differences in neuroc-
ous jugular venous temperature monitoring.51 Although ognitive test performances, although the study was not
there was a high degree of precision between the two sufficiently powered to detect a difference.
monitoring sites, there was a marked difference in bias. Hypothermic neuroprotection is consistent with the find-
This was most pronounced during rewarming when jugular ings of Regragui and colleagues120 who prospectively
venous temperature was 3.4C higher than TNP. The authors investigated the effect of perfusion temperature (28C, 32C
concluded that TNP monitoring underestimated brain or 37C) on postoperative cognitive function in 96 adults
temperature during rewarming and speculated that as a undergoing elective CABS with CPB. Compared with
result, the brain may be at increased risk of neurological patients perfused at 32C, the incidence of cognitive deficits
injury. However, in an unrandomized and unblinded study was significantly higher in patients perfused at 37C (P
of 28 CABS patients, von Knobelsdorff and colleagues 0.021). Cooling to 28C appeared to offer no additional
suggested that the use of a slow rewarming regimen benefit.
did not attenuate reductions in SjO2.163 An accompanying Despite suggestions that normothermic bypass does not
editorial raised several methodological issues and advised increase risk,85 it is interesting to note that at a meeting of
caution in interpreting these findings.110 researchers in the field, held in Oxford at the end of 1996,
The finding that even mild hyperthermia (3839C) the majority of participants indicated that they would rather
increases excitotoxic neurotransmitter release during cereb- undergo hypothermic (32C), rather than normothermic,
ral hypoxia and delays recovery of energy metabolism is bypass if they required cardiac surgery (personal commun-
cause for concern.93 The use of mild hypothermia (34C) ication)!
after CPB and in the early postoperative period has been
shown not to be associated with increased bleeding, cardiac Acidbase management
morbidity or time to tracheal extubation.103 Any neuro- The importance of maintaining normocapnia before the
protective effect of this strategy remains to be established onset of CPB was highlighted by Nevin and colleagues in
in prospective, randomized studies. 1987. Three days after surgery, patients who had been
In recent years, studies have suggested that normothermic inadvertently hyperventilated (PaCO2 4.7 kPa) had a higher
cardioplegia may improve myocardial protection during incidence of neurological (46% vs 27%) and psychometric
heart operations.93 As interest in these so-called warm- (71% vs 40%) deficits than patients who were normocapnic
heart techniques has increased, their use has become (PaCO2 4.76.0 kPa).104
widespread. The immediate concern was that abandonment The solubility of gases in a liquid, including blood,
of hypothermic perfusion during CPB would compromise increases as temperature decreases. When arterial blood
cerebral protection and lead to a higher incidence of gases are analysed with a temperature correction during
neurological morbidity. hypothermia, patients appear to have a respiratory alkalosis
To date, studies that have examined the effect of (decreased PaCO2 and increased pH). Addition of carbon
normothermic cardioplegia and CPB on myocardial and dioxide to normalize PaCO2 and maintain a pH of 7.40 is
neurological outcome have yielded conflicting results. Singh known as pH-stat acidbase management. The use of
and colleagues,142 143 the Warm Heart Investigators165 and arterial blood gases without temperature correction is known
McLean and colleagues86 reported no increase in neuro- as -stat management.
logical complications. Martin and colleagues79 however, During moderate hypothermic CPB, pressureflow auto-
demonstrated a marked increase in neurological injury in regulation of CBF is maintained when -stat blood-gas
patients maintained at normothermia during CPB. Directly management is used but lost when pH-stat management is
comparing these studies is difficult because actual brain used. The inability to autoregulate CBF at low perfusion
temperature was not measured and small variations in the pressures, the possibility of steal in patients with intracra-
conduct of CPB and operative technique may have had a nial cerebrovascular disease and the presence of acidosis
crucial influence on temperature. This is further confounded during rewarming associated with the pH-stat strategy
by relatively low mean patient ages and the deliberate increase the potential for brain injury. Furthermore, the
exclusion of patients with increased risk of perioperative excessive CBF associated with pH-stat may substantially
stroke. increase the delivery of emboli to the brain.94
In an attempt to resolve the issue, Mora and colleagues93 The influence of pH management has been assessed by
compared neurological and neuropsychological outcomes in several groups. In a study of 86 patients undergoing CABS,
138 patients allocated randomly to receive either intermittent Bashein and colleagues reported that the pH manage-
cold oxygenated crystalloid cardioplegia during hypo- ment strategy had no influence on either cardiac or
thermic (28C) bypass or continuous retrograde neurocognitive outcome.11 Stephan and colleagues, in a
normothermic blood cardioplegia during normothermic prospective, randomized study of 65 patients undergoing
(35C) bypass. All seven patients found to have new CABS with hypothermic (26C) CPB, reported that use of

CNS complications of cardiac surgery

the pH-stat strategy was associated with cerebral hyperaemia standard for assessment of neurological and cognitive out-
(191% vs 18%) and a higher incidence of neurological comes, reduces its use as an experimental model.
dysfunction 7 days after surgery (P0.036).150 In a study The observation that certain barbiturates could reduce
of 316 patients undergoing CABS, cognitive dysfunction at CMRO2 led to extensive research into their neuroprotective
2 months was less prevalent after 90 min of CPB in patients potential. In 1986, Nussmeier, Arlund and Slogoff were
managed with -stat than with the pH-stat strategy (27% first to report barbiturate neuroprotection in humans.114 One
vs 44%; P0.047).96 Similar findings have been reported hundred and eighty-two patients undergoing open-ventricle
in a study of 70 patients undergoing CABS at St Thomas procedures were randomized to either thiopental (an initial
Hospital (20% vs 48.6%; P0.05).161 bolus followed by a continuous infusionmean total dose
In patients66 and animals6 71 undergoing deep hypothermic 39.5 mg kg1), sufficient to maintain electroencephalo-
cardiac arrest (DHCA) however, pH-stat management before graphic silence throughout the period from before aortic
the onset of circulation arrest appears to improve neurolo- cannulation to termination of bypass (n89) or fentanyl
gical outcome. Using magnetic resonance spectroscopy in (n93). On the first postoperative day, clinical neuro-
an immature piglet model of DHCA, Aoki and colleagues psychiatric abnormalities were found to be more common
have shown that recovery of cerebral ATP and intracellular in the control group (5.6% vs 8.6%). By day 10 after
pH in the initial 30 min of reperfusion is faster in pH-stat operation, all neuropsychiatric dysfunction had resolved in
managed animals.6 In -stat managed animals, cerebral the thiopental group but persisted in seven (7.5%) control
intracellular pH decreased during early reperfusion, whereas patients (P0.025). The incidence of complications was
it showed continuous recovery in pH-stat managed animals. related significantly to calcification of replaced valves,
Postoperative brain water content (oedema) was also signi- aortic valve replacement, advanced age and prolonged
ficantly lower in pH-stat managed animals. Possible reasons bypass, but not to hypotension during perfusion. It is curious
for these observations include improved brain cooling by to note that in a later publication by the same group, the
increased blood flow to subcortical areas, improved oxygen background incidence of new neurological deficit was much
delivery and reduction of reperfusion injury, in addition to lower.90 144 In a similar study of patients undergoing CABS,
an alkaline shift in intracellular pH with hypothermia in however, no protective effect could be demonstrated.170
spite of a stable blood pH.6 Mortality in the thiopental; group was, however, lower than
in controls (0.7% vs 2.6%; P0.018). More recently, a
retrospective evaluation of 227 open-heart surgery patients
Neuroprotective interventions
revealed that thiopental (mean dose 38.1 mg kg1) had no
It is clear that risk factors for adverse neurological outcome beneficial effect on neurological outcome although mortality
fall into two categories: those that cannot be modified (i.e. was significantly lower in the thiopental group (1.2% vs
age, sex, genotype and medical history) and those that may 9.6%; P0.034).115
(i.e. cerebral embolism, aortic atheroma, CPB duration and Propofol has similar effects to thiopental on CMRO2
cerebral perfusion). Interventions designed to reduce or and CBF.26 Although in vitro evidence suggests a direct
prevent neurological injury during cardiac surgery can be neuroprotective action, perhaps via GABAA receptors,63 it
divided into two categories: (1) physical and (2) pharmaco- is suggested that a propofol-induced reduction in CBF
logical. Table 5 summarizes some of the physical interven- reduces the delivery of microemboli to the cerebral circu-
tions that have been used or advocated. lation.109
Calcium channel antagonists have stimulated consider-
Pharmacological interventions able research. Of these, nimodipine, an L-type calcium
A greater understanding of the pathophysiology of channel blocker, has shown considerable promise in the
neurological injury offers the hope of pharmacological management of subarachnoid haemorrhage116 but not acute
neuroprotection. At present, however, there is no agreement head injury.157 A prospective, double-blind, randomized
on the need for prophylactic neuroprotectants in cardiac study of nimodipine in 400 patients undergoing valve
surgery, much less the choice of drug.122 124 surgery was terminated because of lack of efficacy and
With the exception of some anaesthetic drugs, many of significant adverse events.75 The incidence of new neurolo-
the prototype neuroprotective agents studied in cardiac gical deficits was no different to placebo (72% vs 77%;
surgery were developed originally for the treatment of P0.55). In the 6-month follow-up period, mortality was
stroke. In many ways, cardiac surgery is a convenient significantly higher in the nimodipine group (10.7% vs
model with which to test these agentsa large number of 1.3%; P0.02). Major haemorrhage was also significantly
patients sustaining a cerebral injury at a predictable time. more common in the nimodipine group (13.3% vs 4.1%;
Unfortunately, disagreement over the precise nature of heart P0.04).
surgery related brain injury (focal vs diffuse micro-focal Prostacyclin has been used in addition to, or as a
vs diffuse), the confounding influences of other standard replacement for, heparin during CPB. It is known to reduce
neuroprotective strategies (hypothermia, blood-gas manage- platelet aggregation during extracorporeal circulation and
ment, arterial line filtration, etc.) and the lack of a gold may therefore be neuroprotective.42 In 1987, Fish and

Arrowsmith et al.

Table 5 Potentially neuroprotective physical interventions in cardiac surgery

General considerations Expeditious surgery

Attention to myocardial preservation and haemostasis
Maintaining cerebral perfusion Avoid prolonged/profound arterial hypotension
Avoid prolonged systemic hypoperfusion
Avoid prolonged superior vena caval obstruction
Consider retrograde cerebral perfusion during DHCA
Reducing cerebral embolization Adequate anticoagulation
Minimize aortic manipulation/instrumentation
Careful (de)cannulation of the aorta
Avoid venous air entrainment
Use of arterial line filter
Avoid CPB altogether (i.e. beating heart procedures)
Use of exhaustive deairing/debridement procedures
Avoid or reduce use of cardiotomy suction
Consider heparin-bonded circuits
Temperature management Moderate hypothermia (i.e. 32C)
Avoid rapid/excessive rewarming
Acidbase management Alpha-stat regimen (pH-stat during cooling before DHCA and in patients with significant aorto-pulmonary
Avoid hypercapnia and hypocapnia
Other Avoid/treat hyperglycaemia
Advanced neurological monitoring Jugular venous oxygen saturation
Near infrared spectroscopy (NIRS)
Electroencephalography (EEG)
Transcranial Doppler sonography

colleagues reported the results of a randomized, double- laboratory evidence suggests that they may worsen neuro-
blind study designed to evaluate the effect of prostacyclin logical outcome.81
on the incidence and severity of postoperative neuropsycho- Indications that free radical production increases during
logical dysfunction in 100 patients undergoing CABS.41 Of CPB9 64 and in cerebral ischaemia27 suggests a possible
96 patients who completed the psychological and neurolo- neuroprotective role for free radical scavengers.25 Desferri-
gical evaluations 1 week after surgery, 74 were evaluated oxamine, which may reduce iron-catalysed free radical
psychologically 2 months after surgery. There were no production, has been evaluated in 24 adult patients (12
differences in neurological outcome or psychological test controls, 12 treated) undergoing CPB for various cardiac
performance. operations.87 Desferrioxamine was given both i.v. and with
Grieco and colleagues have recently reported the results the cardioplegic solution. Polymorphonuclear neutrophils
of a double-blind, placebo-controlled pilot study of GM1 (PMN) harvested from desferrioxamine-treated patients pro-
ganglioside in patients undergoing cardiac surgery.49 duced significantly fewer superoxide radicals than those of
Although there was a trend towards improved neurological control patients. It was concluded that desferrioxamine-
and neuropsychological outcome in the ganglioside treated exposed PMN had decreased oxidative responsiveness.
group, the differences did not reach statistical significance. These results were thought to be consistent with the
hypothesis that desferrioxamine reduces free radical-
The systemic inflammatory response associated with
mediated amplification of the inflammatory response to
CPB, characterized by the release of cytokines in response
CPB. Although this could be effective in reducing the
to activation of the coagulation, fibrinolytic and complement
harmful effects of extracorporeal circulation, no evaluation
cascades, has been the subject of recent discussion.60 The
of any neuroprotective effect has been reported.
bovine serine protease inhibitor, aprotinin, has been shown
In light of experimental evidence indicating a role for
to significantly reduce intraoperative bleeding and transfu- excitatory amino acid neurotransmission in the pathogenesis
sion requirements in a variety of settings, including cardiac of brain injury occurring during cardiac surgery with CPB,
surgery with CPB. Despite an early report suggesting an several compounds have reached phase II clinical trials. Of
increased incidence in perioperative myocardial infarction31 these, the competitive glutamate antagonist, remacemide
there is now a suggestion, from a meta-analysis of several hydrochloride, has been shown to improve neuropsycho-
studies, that high-dose aprotinin may actually reduce the logical outcome in a prospective, randomized, double-blind
incidence of perioperative stroke.145 Whether or not this study in patients undergoing CABS.7 Compared with the
action is a result of the non-specific anti-inflammatory placebo group, patients treated with remacemide showed
properties of antiproteases remains unclear. Nafamostat significantly superior performance on three of 10 neuro-
mesilate (FUT-175), a synthetic serine protease inhibitor, is psychological tests. Furthermore, the remacemide group
currently under investigation in cardiac surgery. Although had significantly greater improvement in performance on a
it is known that glucocorticoids can suppress some of composite measure (total z score) of neuropsychological
the inflammatory cytokines liberated during CPB,61 recent performance (P0.028).

CNS complications of cardiac surgery

Numerous drugs are currently being evaluated in stroke, psychometric, and radiologic methods. J Thorac Cardiovasc Surg
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9 Barsacchi R, Pelosi G, Maffei S, et al. Myocardial vitamin E is
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psychometric testing and the definition of cognitive decline ascending aorta. Circulation 1989; 80: I-2759
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17 Borowicz LM, Goldsborough MA, Selnes OA, McKhann GM.
Acknowledgements Neuropsychologic change after cardiac surgery: a critical review.
We gratefully acknowledge the support of the National Institutes of
J Cardiothorac Vasc Anesth 1996; 10: 10511
Health, National Institute on Aging, Claude D. Pepper Older Americans
Independence Center, No. 5 P60-AG-11268; National Institutes of Health 18 Branthwaite MA. Neurological damage related to open-heart
Grant RO1-AG-09663; National Institutes of Health Leadership and surgery. A clinical survey. Thorax 1972; 27: 74853
Excellence Award No. 5 R35-AG-07922; National Institutes of Health 19 Brener BJ, Brief DK, Alpert J, Goldenkranz RJ, Parsonnet V. The
Alzheimers Disease Research Center No. 5 P50-AG-05128; National risk of stroke in patients with asymptomatic carotid stenosis
Institutes of Health Grant 1RO3-AG-1419401; National Institutes of
undergoing cardiac surgery: a follow-up study. J Vasc Surg 1987;
Health Grant 1RO1-HL-5431601; American Heart Association Grant-In-
Aid 95010970; The Lord Amulree Traveling Studentship (UCH); and a 5: 26979
grant from the Anesthesia Patient Safety Foundation. 20 Breslau PJ, Fell G, Ivey TD, Bailey WW, Miller DW, Strandness
DE. Carotid arterial disease in patients undergoing coronary
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