www.thelancet.com Vol 368 August 19, 2006
Central nervous system injury associated with cardiac
Mark F Newman, Joseph P Mathew, Hilary P Grocott, G Burkhard Mackensen, Terri Monk, Kathleen A Welsh-Bohmer, James A Blumenthal,
Daniel T Laskowitz, Daniel B Mark
Millions of individuals with coronary artery or valvular heart disease have been given a new chance at life by heart
surgery, but the potential for neurological injury is an Achilles heel. Technological advancements and innovations in
surgical and anaesthetic technique have allowed us to off er surgical treatment to patients at the extremes of age and
infi rmity—the group at greatest risk for neurological injury. Neurocognitive dysfunction is a complication of cardiac
surgery that can restrict the improved quality of life that patients usually experience after heart surgery. With a broader
understanding of the frequency and eff ects of neurological injury from cardiac surgery and its implications for
patients in both the short term and the long term, we should be able to give personalised treatments and thus preserve
both their quantity and quality of life. We describe these issues and the controversies that merit continued
The great reduction in overall cardiac morbidity and
mortality associated with cardiac surgery has focused
attention on central nervous system (CNS) complications,
such as stroke, that can arise.1–5 Studies suggest that
elderly patients with comorbidities and advanced
cardiovascular disease benefi t more from cardiac surgery
than from medical therapy alone,6 yet these patients have
greater morbidity and mortality, especially neurological
dysfunction, after cardiac surgery.4,7–12 CNS complications
caused 7·2% of all deaths after cardiopulmonary bypass
surgery in the 1970s, but rose to almost 20% by the mid-
1980s, and it continues to increase.5,13 Postoperative
neurological dysfunction is also a concern because it
aff ects quality of life and has implications for health
Neurological injury describes a range of disorders, from
incapacitating or lethal stroke or coma to encephalopathy,
delirium, and neurocognitive decline.2,16–18 Although stroke
after cardiac surgery is an important concern for both
short term and long term disability, more subtle
neurological eff ects, such as encephalopathy and neuro-
cognitive dysfunction, are associated with increased
medical costs and decreased cognitive function and
quality of life.2,16 Patients, their family members, and the
medical teams fi nd upsetting the situation of an operation
being successful in its cardiac outcome, but resulting in
substantial neurological or neurocognitive defi cits that
subsequently restrict the patient’s ability to function
To defi ne the extent of perioperative neurological injury
as a disease process, we reviewed studies that explored
the type, incidence, and consequences of neurological
injury. We excluded articles on surgery for congenital
heart defects and clinical trials with a biochemical marker
as the primary endpoint. We discuss the possible reasons
for variability in the results of these assessments, examine
the causes of neurological injury resulting from cardiac
surgery, and debate the factors aff ecting the likelihood
and the severity of injury. We conclude by examining
controversial issues that need further investigation.
Incidence of perioperative central nervous
To identify the incidence of neurological injury associated
with cardiac surgery, we divided our discussion by the
clinical outcomes that we previously mentioned, including
stroke or coma, encephalopathy, and neurocognitive
decline. The most frequently cited data on stroke and
encephalopathy come from Roach and colleagues’2
prospective observational study. Of 2108 patients
undergoing elective coronary artery bypass grafting
(CABG) in 24 institutions in the USA, there was a 6·1%
incidence of adverse cerebral outcomes. Patients were
assessed for two types of neurological outcome: type I
outcome, which included fatal or non-fatal stroke, stupor,
or coma at discharge, occurred in 3·1%; and 3% of
patients had type II outcomes that included deterioration
in intellectual function, memory defi cit, or seizures.
Lancet 2006; 368: 694–703
Department of Anesthesiology,
(Prof M F Newman MD,
J P Mathew MD, H P Grocott MD,
G B Mackensen MD,
Prof T M Monk MD) and
Department of Psychiatry and
(Prof K A Welsh-Bohmer PhD,
Prof J A Blumenthal PhD), and
Department of Medicine, Duke
University Medical Center,
Durham, NC, USA
(D T Laskowitz MD,
Prof D B Mark MD)
Prof Mark F Newman,
Department of Anesthesiology,
Box 3094, Duke University
Medical Canter, Durham,
NC 277110, USA
Search strategy and selection criteria
We searched PubMed of the National Library of Medicine for the years 1985–2005. The
following search terms were used: “neurologic injury”, “stroke”, “cerebral injury”, “cerebral
complication”, “cognitive disorders”, “neurocognitive decline”, and “neuropsychologic
tests”, combined with “heart surgery”, “coronary artery bypass”, “extracorporeal
circulation”, “cardiopulmonary bypass”, or “CABG”. This search was done to support a
review of the subject area, and was not a formal meta-analysis. Although there was
overlap in the articles on neurological and neurocognitive decline, we used separate
criteria to assess the articles that were mainly included in our Review. We prioritised
articles on “neurologic injury” on the basis of the assessment methodology used:
prospective neurological evaluation, prospective data collection, or retrospective
endpoint adjudication. Large-scale one-centre and multicentre databases were included,
as well as frequently cited review articles or articles regarded as classic in their specialty.
We limited our consideration of both neurological and neurocognitive decline to adult
cardiac surgery not requiring circulatory arrest. Surgery for congenital heart defects and
clinical trials with a biochemical marker as the primary outcome were also excluded. We
prioritised articles on “neurocognitive decline” according to these criteria: primary
assessment of cognition by well described neuropsychological tests, assessment both
preoperatively and at least 1 month postoperatively, and studies published after 1980.
www.thelancet.com Vol 368 August 19, 2006 695
In a retrospective review of 2972 consecutive cardiac
surgery patients (including those with valvular surgery),
Hogue and colleagues19 showed a 1·6% incidence of
stroke. 65% of these strokes happened in the postoperative
period, whereby patients who had initially awakened
from surgery without a defi cit later had a stroke. In
a report, published in 2001 based on data from the Society
of Thoracic Surgery national cardiac surgery data-
base (1996–1997), which contained information for
416 347 patients, the incidence of neurological events
(stroke, transient ischaemic attack, or coma) was 3·3%.20
Although the risk factors for perioperative stroke, which
include age, presence of vascular disease, and diabetes,
have increased substantially, the frequency of injury is
falling in most prospective databases.21
Patients undergoing open-chamber procedures, such
as mitral valve or aortic surgery, are believed to be at
higher risk for adverse cerebral outcomes than patients
whose hearts are not opened during surgery.1,5 These
patients generally have an increased risk of embolisation
from vegetations, thrombi, and gaseous bubbles that
are created by the intraoperative entrapment of air
within the cardiac chambers. In prospective studies of
patients undergoing combined intracardiac and
coronary artery surgery there was a 16% incidence of
adverse cerebral outcomes, divided equally between
type I (8·4%; 5·9% non-fatal strokes and 1·8% death
from cerebral injury) and type II (7·3%) outcomes.5
Although retrospective evaluations show a lower rate of
stroke than prospective studies, these retrospective
analyses also show a two to three times higher rate of
stroke in patients undergoing combined procedures
than those undergoing one procedure.19,20 Thus, patients
undergoing combined intracardiac and revascularisation
procedures should be judged at greatest risk for adverse
CABG done on a beating heart (off -pump) has been said
to have fewer neurological complications than other
cardiac surgeries.22 In a retrospective multivariable
analysis of 16 184 adult patients undergoing cardiac
surgery, Bucerius and colleagues23 recorded a lower
incidence of stroke in patients who underwent off -pump
CABG than those who had other cardiac surgery. The
overall frequency of stroke was 4·6% and varied between
procedures: double valve or triple valve surgery, 9·7%;
mitral-valve surgery, 8·8%; CABG and valve surgery,
7·4%; aortic valve surgery, 4·8%; CABG, 3·8%; off -pump
CABG, 1·9%. Cleveland and others1 reported data from
the Society of Thoracic Surgeons database that showed a
substantial reduction in stroke in patients who had off -
pump CABG procedures. However, despite attempts to
control for demographic and perioperative diff erences,
the demographics for patients in the on-pump versus
off -pump surgical groups make the results inconclusive.
In the Octopus (Octopus Device, Medtronic, Minneapolis,
MN, USA) study done in the Netherlands, the largest
randomised trial to compare off -pump with on-pump
CABG, there was no substantial diff erence between
groups in neurological or neurocognitive injury.24,25 Yet,
despite its size (n=281), the trial was underpowered to
identify neurological and neurocognitive outcome
because of the inclusion of a lower-risk population.
Overall, there has been insuffi cient randomised pros-
pective controlled study of on-pump or off -pump CABG
to assess whether either procedure is associated with
improved cerebral outcome.
Perioperative neurocognitive decline
Although there is some variance in reported incidence of
perioperative stroke and encephalopathy, that of perio-
perative neurocognitive decline shows striking variability
according to the measurements included, the surgical
procedure done, the inclusion and exclusion criteria for a
specifi c study, and the criteria used to defi ne neuro-
cognitive decline or dysfunction.26 A standard deviation
or a percentage decline yields early dysfunction rates
from 50% to 70% within the fi rst postoperative week,
which falls to 30–50% after 6 weeks, and 20–40% at
6 months and 1 year.
We examined the eff ect of diff erent defi nitions of
cognitive decline on the incidence of postoperative
neurocognitive decline and noted large diff erences in
event rates based on the defi nitions of defi cit or decline.26
Measurement of periprocedural change in neurological
score is consistent with recommendations from consensus
statements for assessment of neurocognitive decline, but
other investigators have criticised the approach on the
basis of statistical concerns about diff erences in baseline
scores or absence of comparison with patients of normal
neurological function.27–29 Whichever statistical method is
used, the rates of neurocognitive decline vary, dependent
on the sensitivity of the test used and the degree of
representation of the most sensitive and time-specifi c
domains assessed. Neurocognitive dysfunction in the
Not impaired at discharge
Impaired at discharge
6 weeks 6 months
Time of evaluation
Change in composite cognitive
index from baseline
Figure 1: Change in composite cognitive index from baseline
The composite cognitive index is the sum of the scores for the four domains and includes cognitive decline, as well
as increases in scores as a result of learning. Positive change represents an overall improvement (learning), whereas
negative values indicate overall decline. Reproduced with permission of the authors16 and the publisher.
www.thelancet.com Vol 368 August 19, 2006
immediate perioperative period could be related to the
benzodiazepines, or other anaesthetic drugs. Many
investigators have therefore eliminated testing in the
early postoperative period. However, later decline might
be associated with factors other than perioperative
neurological injuries, including recurrent injury,
depression, or other neurological disorders that might
not be directly related to cardiac surgery.
Precise measurement of incidence of neurocognitive
decline related to cardiac surgery needs an appropriate
control group. However, there has been no consensus as
to whether an age-appropriate group, a group matched
for coronary artery disease, or an additional surgical
control is most appropriate for comparison. A substantial
incidence of cognitive decline associated with non-cardiac
surgery has been reported.30,31 Therefore patients who
need cardiac surgery might be appropriately compared
with controls, matched by age and extent of coronary
artery disease, to assess the degree of cognitive decline
related to surgery compared with patient characteristics.
Several groups16,18,32 have reported an association between
early postoperative decline and long-term cognitive
deterioration—both 1 and 5 years after cardiac surgery.
Individuals who had cognitive decline after surgery were
much more likely to have continued or increased
deterioration over time, even if they showed improvement
in the intervening period (fi gure 1).16 There is debate as to
the source of cognitive decline—ie, is the decline in
function seen years after cardiac surgery directly related
to the surgery or do some patients progress to cognitive
deterioration, irrespective of whether they had had
surgery and anaesthesia?33 A longitudinal study is needed
to ascertain the importance of both patient characteristics
eff ects of narcotics,
and surgical intervention in assessment of progression of
Cost of perioperative central nervous system
Stroke is the third leading cause of death in the USA and
will continue to be a challenge as the population ages.
The frequency of stroke after CABG makes this surgical
procedure the leading cause of iatrogenic stroke in that
country.34 Perioperative stroke has a great cost to both the
patient and to the health care system. In the early 1990s,
Tuman and co-workers35 clearly showed that perioperative
CNS dysfunction increased intensive care unit stays from
3 (SD 3) days to 9 (11) days, and also resulted in a nine
times greater perioperative mortality (36% vs 4%) than in
patients without neurological injury. Similarly, Roach and
colleagues2 reported that patients with adverse cerebral
outcomes had higher in-hospital mortality, longer hospital
stay, and a higher rate of discharge to extended care
facilities than did patients with no neurological defi cit.
Despite improvements in medical and surgical technology,
data continue to show that postoperative stroke lengthens
hospital length of stay (11 [SD 4] days vs 7  days), days
spent in the intensive care unit (2  days vs 1  days),
and is associated with higher in-hospital mortality (14·4%
vs 2·7%).34 Treatment of perioperative stroke accounts for
about 25% of the resources expended annually for stroke
treatment in the USA.36,37
Although few people would question the importance of
stroke in the perioperative period, the importance of
cognitive decline after surgery has long been debated
because such cognitive decline is transient in many
patients. In a study using several standardised, validated
assessments14 in patients undergoing cardiac surgery, we
recorded that lower cognitive function was associated
with reduced quality of life measures at 5 years follow-up.
Furthermore, multivariable logistic regression on a two-
way classifi cation of employment status—adjusted for
age, sex, number of years in education, and diabetes
showed the 5-year overall cognitive function score to be
strongly correlated with productive employment (fi gure 2).
Perception of general health also varied directly with
cognitive functioning, whereby patients with lower
cognitive function score at 5 years self-reported a lower
quality of general health. A subsequent study in
732 patients that underwent assessment of cognitive
function before and one year after coronary artery surgery
noted that quality of life improved after cardiac surgery,
but cognitive decline limited the improvement in activities
of daily living and self-reported health.38 Daily activities
such as driving are also aff ected by postoperative cognitive
decline. Cognitive impairment after cardiac surgery
therefore can lead to various long-term consequences.39,40
Causes of neurological dysfunction
Understanding of risk factors patients have that are
associated with perioperative CNS injury is an important
–2·00–1·50 –1·00 –0·50 0·000·501·001·502·00
5-year cognitive function score
Homemaker: n=14, 8%
Retired: n=96, 55%
Part time: n=11, 6%
Full time: n=32, 18%
Figure 2: Patient employment status and 5 year composite cognitive index
The 5 year cognitive function score is the sum of the overall cognitive scores, including cognitive decline and
learning eff ects. Reproduced with permission of the authors14 and the publishers.
www.thelancet.com Vol 368 August 19, 2006 697
fi rst step in beginning to understand the range of
neurological dysfunctions that can occur. Several
studies18,41,42 have eff ectively defi ned stroke risk on the
basis of patient characteristics and intraoperative
echocardiography. The value of the use of preoperative
characteristics to identify patients who are at greatest risk
is the potential to alter care and give appropriate
information to clinicians and patients in their treatment
decisions. A stroke risk index (table 1, fi gure 3), on the
basis of preoperative characteristics has been developed
to predict a patient’s risk of perioperative stroke. However,
because of changes in clinical practice, the index might
now overestimate true stroke risk. Nevertheless, the
index does identify the key risk factors for stroke in this
group of patients.
Aortic atherosclerosis and cerebral embolisation
Many investigators have identifi ed proximal aortic
atherosclerosis as a factor associated with a great increase
in the risk of stroke.43–45 Embolisation of aortic atheroma
or other debris from the surgical area is an important
causal factor in stroke and major neurological injury after
cardiac surgery. In studies completed by Roach2 and
Waring42 and their colleagues before the widespread use
of transoesophageal echocardiography, overall risk of
stroke in patients with surgeon-palpated aortic athero-
sclerosis was increased fi ve-fold. Studies that used
epiaortic ultrasonography confi rmed the association of
aortic atherosclerosis with perioperative stroke with rates
increasing by fi ve times if there was atherosclerosis in
the ascending aorta.45
Further support for embolisation as a major factor in
neurological injury has come from studies in which
transcranial Doppler and carotid ultrasonography were
used that have shown high rates of cerebral emboli,
especially during aortic interventions, including can-
nulation, aortic cross-clamping or unclamping, use of
partial occlusion clamps, and other non-aortic cardiac
manipulations.46–48 However, the correlation between
neurological injury and the number of emboli is not as
reliable as the correlation for aortic atherosclerosis
measured by transoesophageal or epiaortic imaging.49–52
This could be attributable to our inability to distinguish
less harmful air emboli from the more dangerous
Post-mortem examinations have revealed small
capillary arteriolar dilatations53–56 (fi gure 4) in the brains
of patients who had recently undergone cardiac surgery
with cardiopulmonary bypass.57,58 These dilatations
occur in large numbers and are the result of micro-
embolisation of lipids or other substances that could
cause perioperative neurological injury.55
Additional evidence showing that embolisation is an
important factor in neurological injury includes studies
that used MRI, which recorded that up to 45% of
patients will have new diff usion-weighted magnetic
resonance imaging lesions after CABG or aortic
surgery.50,51 This fi nding supports the arguement that
persisting neurological injury happens with these
procedures; however, such injury has yet to be directly
linked to neurocognitive decline. Location of the
neurological injury might help to predict its sequelae.
For example, a small injury in the internal capsule
could produce a profound stroke, whereas a large
frontal or cerebellar infarct might not be detected
without detailed functional investigation.
Since the classic study by Gilman was published in 1965,57
the presence of non-pulsatile perfusion and low blood
pressure during cardiac surgery has been blamed for
much of the neurological injury we have described.
Features of watershed infarcts in elderly patients,
especially those with carotid disease, have been important
in identifying this association. Furthermore, Caplan and
colleagues58 recorded that low blood pressure can be
associated with reduced washout of small emboli from
Diabetes mellitus (history of either type I or type II diabetes or insulin use on admission
History of neurological disease (previous stroke or transient ischaemic attack)
Previous coronary artery bypass surgery
History of vascular disease (peripheral vascular disease, known carotid vascular disease,
claudication, or vascular surgery
History of pulmonary disease (emphysema, chronic bronchitis, asthma, restrictive lung
Stroke risk is established by addition of the scores associated with the defi ned patient characteristic and then
comparing that risk score with the predicted CNS injury risk in fi gure 3 (eg, risk score of 120 predicts a probability of
CNS injury of 10%, about 3 times normal risk).41
Table 1: Risk factors for neurological injury after cardiac surgery
204060 80100120140 160
Stroke risk index (points)
CNS injury risk (%)
Figure 3: The relation between stroke risk index and risk of adverse
For example, 100 total points predicts a risk of CNS injury of 5%. Reproduced with
permission of the authors96 and the publisher.
www.thelancet.com Vol 368 August 19, 2006
the watershed areas, increasing the possibility that
hypoperfusion contributes to watershed infarcts seen in
Gold and colleagues59 did a randomised prospective trial
of high (mean arterial pressure, 80–100 mm Hg) versus
low perfusion pressure (50–70 mm Hg) during
cardiopulmonary bypass for patients (n=240) under going
CABG. The results of this trial did not show a signifi cant
diff erence in myocardial or neurological outcomes
between the two groups. However, when the cardio-
vascular outcomes (myo cardial and neurological) were
combined, a greater benefi t was shown for the high
pressure group, suggesting that cardiovascular injury was
associated, with low perfusion pressure. Hartman and
colleagues44 measured aortic athero sclerosis severity in a
subset (n=189) and noted that high perfusion pressure
was associated with a reduced frequency of neurological
injury in individuals with severe aortic atherosclerosis.
This fi nding suggests that in patients at high risk for
embolisation, perfusion pressure could aff ect the severity
or extent of measurable injury.
Atrial fi brillation is common after cardiac surgery, with a
prevalence of 20–40%.2,60 The incidence of atrial fi brillation
is increased in patients with advanced age,2,60,61 of male
sex,61 with chronic obstructive pulmonary disease,62,63 and
with specifi c electrocardiographical dis orders.64 Atrial
fi brillation increases intensive care unit and hospital
lengths of stay, and increases the intensity of nursing care
needed.2,60,61,65,66 Atrial fi brillation is also associated with an
increased incidence of postoperative neurological
abnormalities (eg, stroke or transient ischaemic
attack).2,19,61,67 However, the association between atrial
fi brillation and neurocognitive decline is less clear.
We investigated the association in a prospective trial of
308 patients who underwent CABG surgery and who
completed cognitive testing both preoperatively and
6 weeks after surgery; 69 patients (22%) had postoperative
atrial fi brillation.68 Patients who developed atrial
fi brillation showed more cognitive decline than those
who did not (p=0·036). The mechanisms for this
association have not been defi ned, but are postulated to
relate to an increased risk of cerebral embolisation or
hypoperfusion caused by a reduced cardiac output state.
Prevention of atrial fi brillation could result in a reduced
incidence of neurological injury.
Systemic infl ammatory response
Cardiac surgery is associated with a profound systemic
infl ammatory response, especially when cardiopulmonary
bypass is used. Systemic infl ammatory response might
contribute to the overall severity of neurological injury,69
but there are few data to lend support to infl ammatory
response alone as the causative factor. Westaby and co-
workers70 recorded no signifi cant association between
infl ammatory markers and neurocognitive injury in a
group of patients who underwent CABG. However,
infl ammation is probably a contributory factor, and not
causal; thus, as we better understand the variables that
aff ect severity of neurological injury and susceptibility
factors, we can further ascertain the importance of these
factors in neurological and neurocognitive injury.
Two trials that evaluated the use of a C5 complement
inhibitor in cardiac surgery showed a small, but
measurable benefi cial eff ect on neurocognitive decline
when complement inhibitor was given during surgery
and for 24 h postoperatively.71,72 Overall decline in
neurological or neurocognitive function were not
signifi cantly changed; however, another study has shown
an association between low baseline endotoxin immunity
(increased susceptibility to endotoxin and subsequent
infl ammatory response) and cognitive decline after
surgery, providing indirect evidence that individuals at
heightened risk of infl ammation have an increased risk
of cognitive decline after cardiac surgery.73
Figure 4: Small capillary-arteriolar dilatations.
Arrows show small capillary-arteriolar dilatations. Reproduced with permission of the authors97 and the publisher.
www.thelancet.com Vol 368 August 19, 2006 699
Our group and other investigators have noted that
depression is an independent predictor of long-term
survival after surgery.74,75 In Blumenthal’s study of
817 patients, moderate-to-severe depression before CABG
surgery that persisted afterwards, or postsurgical onset
depression increased the risk of death to twice that of
non-depressed patients74 (fi gure 5). Although these
fi ndings have important implications for management of
patients undergoing CABG, depression has not proved a
major factor in neurocognitive decline caused by cardiac
surgery.18 Notwithstanding, depression aff ects patients’
perceptions of their cognitive functioning, with depressed
patients reporting more subjective complaints about their
memory and other cognitive abilities than non-depressed
An intriguing development in the specialty of neuro-
protection is in the identifi cation of genetic predisposition
or susceptibility in cerebral injuries associated with
cardiac surgery. In the PEGASUS study of 1635 patients
who underwent cardiac surgery with cardiopulmonary
bypass, DNA was isolated from preoperative blood and
analysed for 26 diff erent single-nucleotide polymorphisms.
Multivariable logistic regression modeling was used to
identify the association of clinical and genetic
characteristics with stroke. Permutation analysis was used
to adjust for multiple comparisons inherent in genetic
association studies. Of 1635 patients, 28 (1·7%) had stroke
and were included in the fi nal genetic model. The
combination of the two minor alleles of C-reactive protein
(CRP; 3_UTR and 1846C/T) and interleukin 6 (IL-6;
174G/C) polymorphisms, occurring in 583 (35·7%)
patients, was signifi cantly associated with stroke (odds
ratio 3·3; 95% CI 1·4–8·1; p=0·0023). In a multivariable
logistic model adjusted for age, the CRP and IL-6 single-
signifi cantly associated with stroke (p=0·0020). Genetic
factors associated with infl ammation predicted a three-
fold increase in stroke rate over and above other clinical
risk factors, suggesting that genetic factors could possibly
be used to identify patients for whom neuroprotective
strategies would be eff ective.
That one’s genetic makeup might alter neurocognitive
outcome after cardiac surgery was fi rst suggested in a
1997 study.76 In that study, patients with the apolipoprotein
ε4 allele had worse cognitive
cardiopulmonary bypass. Subsequent studies have not
been able to replicate the results of this study, making the
fi ndings controversial.77 Nevertheless, the 1997 study
probably represents the start of our understanding of the
complex role of individual genetic variations in
perioperative brain injury.
Mathew and co-investigators78 characterised PlA2, a
polymorphism of the glycoprotein (GP) IIIa constituent
of the platelet integrin receptor GP IIb/IIIa, and
examined its eff ect on cognitive outcome after cardiac
surgery. In their study, a multivariate analysis revealed
that the PlA2 genotype was signifi cantly associated with
greater decline on the mini-mental state examination
(p=0·036) than other genotypes. The mechanism of this
association with adverse cerebral outcome might be
related to an increased prothrombotic activity, which has
been shown in investigations of coronary artery
thrombosis and myocardial infarction.79,80 As technology
has advanced, genetic association research has been
moving from investigation of single candidate genes to
multiple candidate genes to genome wide scans. Mathew
and colleagues81 have presented data related to identifying
genes that better defi ne the risk and mechanism of
perioperative neurocognitive decline.
Cognitive impairment that happens up to 6 weeks after
cardiac surgery has been likened to the cognitive decline
after non-cardiac surgery reported by the International
Study for Post-Operative
(ISPOCD) group.30 The incidence of cognitive impair-
ment with non-cardiac surgery originally seemed lower
than that shown with cardiac surgery, and is comparable
with the incidence in cardiac surgery patients younger
than 60 years. However, there has been an increased
recognition of the neurocognitive decline occurring in
elderly patients after general anaesthesia for all
Although surgical stress and other factors aff ecting
neurological outcome probably apply in cardiac and non-
cardiac surgery, anaesthesia as a possible causal factor
2468 10 12
Years after surgery
Non-depressed (CES-D <16)
Mildly depressed (CES-D 16 –26)
Moderately to severely depressed (CES-D ≥27)
Numbers at risk
Figure 5: Kaplan-Meier survival curves for all cause mortality by baseline depression status
Reproduced with permission of the authors74 and the publisher.
www.thelancet.com Vol 368 August 19, 2006
has been incriminated by cell culture and whole animal
studies.82–84 General anaestheic agents, especially inhaled
agents, could aff ect either short-term or long-term
cognitive function, or both, by changing β amyloid
deposition, protein-folding, or cholinergic receptors.82–84
However, there are few clinical data to support the idea
that repeated exposure to general anaesthesia greatly
aff ects subsequent cognitive function.85 Animal research
and clinical trials are needed to establish whether any
anaesthetic agents cause neurocognitive changes or if
they aff ect ageing-related cognitive decline.
Pre-existing cerebrovascular disease
Studies using preoperative MRI or computer axial
tomography scanning in asymptomatic elderly patients
who were scheduled for cardiac surgery identifi ed that
the presence of silent infarcts could be associated with
later decline in cognition or dementia.86 The largest study,
by Goto and colleagues,86 consisted of 421 candidates
scheduled for CABG; of those, 126 (30%) had small brain
infarctions identifi ed preoperatively and 83 (20%), had
multiple infarctions. Half the patients had evidence of
brain abnormalities before surgery; therefore, patient
characteristics are probably important determinants of
the probability for neurological injury seen after surgery.
The fi ndings suggest that severity of pre-existing athero-
sclerotic disease and amount of preoperative cognitive
and neurological reserve aff ect postoperative cognitive
In addition to the controversies discussed thus far, there
are other issues surrounding the role of postoperative
neurological injury in the risk of long term neuro-
cognitive decline. These include the eff ect of surgical or
cardiopulmonary bypass management, and the role of
patient characteristics and risk factors.
Off -pump cardiac surgery
Many regard cardiopulmonary bypass as the culprit in
organ dysfunction, especially neurological injury.
However, the superiority of off -pump CABG in prevention
of neurological or neurocognitive injury is controversial.
Preliminary data suggest there is less cognitive decline
and stroke associated with off -pump CABG than with on-
pump CABG, but those studies were often fl awed by non-
random enrolment bias.1,87 Skeptics note that many other
factors are involved in triggering infl ammatory processes
including sternotomy, heparin administration, and wide
haemodynamic swings during surgery. In addition,
off -pump procedures still involve the manipulation of the
ascending aorta, which is known to cause embolisation.
Van Djik and colleagues25 showed that although there
was less cognitive decline seen shortly after surgery in the
off -pump group than in the on-pump group, at 1 year, no
signifi cant diff erence was found. There was a trend
toward improvement in their low-risk trial. The failure to
see a signifi cant diff erence at 1 year could be because the
study was underpowered.88
Concerns that off -pump CABG is associated with
incomplete revascularisation or graft patency have added
to the controversy.89 Patients at high risk of neurological
injury might accept a compromise, off -pump surgery to
prevent debilitating stroke. A younger patient who has a
lower risk of neurological complications, on the other
hand, might instead choose to have conventional CABG to
increase the chances of complete revascularisation and
longer graft patency. This and other issues remain to be
Whereas there is clear radiological, pathological, and
functional evidence of perioperative neurological injury
after cardiac surgery,16,50,51,53 and though we have shown an
association between perioperative cognitive decline and
long-term cognitive dysfunction, controversy surrounds
the implications of the neurological injury and the rationale
for the association. From results of 1 year and 3 year follow-
up studies, Selnes33 and McKhann90 and their co-workers
suggested that cognitive function changes in CABG
patients are similar to those seen in a control group with
risk factors for coronary artery disease who were followed
over the same period. We investigated neurocognitive
function 5 years after patients were randomised to CABG
or angioplasty as part of the Bypass Angioplasty
Revascularization Investigation (BARI) trial.91 In that
investigation, no diff erence was noted in cognitive function
after 5 years; however, conclusions were limited by the lack
of preoperative testing, substantial crossover between
groups in the study, and patient drop-out.91 Another small
trial comparing CABG with angioplasty also failed to show
a substantial diff erence in neurocognitive decline in
patients with severe coronary artery disease undergoing
revascularisation.92,93 These trials underscore the possibility
that patient characteristics might be more relevant than
the type of intervention in prediction of neurological
Genetic and environmental factors are often impossible
to characterise; thus, Potter and colleagues94 used twins as
controls and found no evidence that CABG was adversely
related to cognitive function. By contrast, fi ndings in
younger patients (aged 63–70 years) revealed improvements
in cognitive function after CABG. The most important
issue for further longi tudinal trials is whether cardiac
surgery and anaesthesia interact with environmental and
genetic factors to change the slope of ageing-related
cognitive decline. Lyketsos and colleagues’ longitudinal
Cache County study95 noted that CABG surgery increased
the slope of age-related cognitive decline as measured by
the mini-mental status examination. This association
remained after controlling for vascular disease, but was
only signifi cant at 5 year follow-up, not at earlier milestones.
Further investigation of this question will hopefully allow
us to choose the most appropriate treatment for individual
patients, preserving both the quantity and quality of life
usually enjoyed with surgical repair of cardiac disease.
www.thelancet.com Vol 368 August 19, 2006 701
Almost 40 years have passed since cardiopulmonary
bypass allowed the development of modern cardiac
surgery. Questions immediately arose about the impact of
cardiopulmonary bypass and cardiac surgery on
neurological outcome. Clearly cardiac surgery has
improved the quality of life of millions of patients, but
despite substantial improvements in cardiopulmonary
bypass technology, surgical and anaesthetic techniques,
neurological injury remains a concern for the increasingly
elderly patients undergoing cardiac surgery and the
physicians that care for them. Large, prospective,
longitudinal trials with appropriate controls remain
necessary to identify how patient characteristics, disease
progression, and surgical and anaesthetic technique
contribute to ageing-related neurocognitive decline after
anaesthesia and surgery. The brain is our most sensitive
indicator of subtle organ injury. Strategies now under
development to reduce perioperative neurological injury
therefore not only hold the promise of protecting patients’
neurocognitive function, but also of reducing the overall
morbidity and mortality associated with these pro-
Confl ict of interest statement
We declare that we have no confl ict of interest.
We thank Susan Goble for editorial assistance and the Duke Clinical
Research Institute Communications Group.
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