Mind injuries after cardiac surgery

C

CE: ; JCM-D-13-00296; Total nos of Pages: 9;

JCM-D-13-00296

Narrative review

Mind injuries after cardiac surgeryDaniele Rovaia, Daniela Giannessib, Maria G. Andreassib, Claudio Gentilic,Alessandro Pingitorea, Mattia Glauberd and Angelo Gemignanic

After cardiac surgery, delirium, cognitive dysfunction,

depression, or anxiety disorders frequently occur, and

profoundly affect patients’ prognosis and quality of life.

This narrative review focuses on the main clinical

presentations of cognitive and psychological problems

(’mind injuries’) that occur postoperatively in absence of

ascertainable focal neurologic deficits, exploring their

pathophysiological mechanisms and possible strategies for

prevention and treatment. Postoperative cognitive

dysfunction is a potentially devastating complication that can

involve several mechanisms and several predisposing,

intraoperative, and postoperative risk factors, which can

result in or be associated to cerebral microvascular damage.

Postoperative depression is influenced by genetic or

psychosocial predisposing factors, by neuroendocrine

activation, and by the release of several pro-inflammatory

factors. The net effect of these changes is neuroinflammation.

opyright © Italian Federation of Cardiology. Una

1558-2027 � 2014 Italian Federation of Cardiology

These complex biochemical alterations, along with an

aspecific response to stressful life events, might target the

function of several brain areas, which are thought to represent

a trigger factor for the onset of depression.

J Cardiovasc Med 2014, 15:000–000

Keywords: coronary artery bypass grafts, genetics, genomics, inflammatorymediators, neurocognitive deficits

aCNR, Institute of Clinical Physiology, bBiomedicine, CNR, Institute of ClinicalPhysiology, cClinical Psychology, Department of Surgery, Medical, Molecular andCritical Area Pathology, University of Pisa, Pisa and dCardiothoracic Department,Fondazione Toscana G. Monasterio, G. Pasquinucci Heart Hospital, Massa, Italy

Correspondence to Daniele Rovai, MD, FESC, CNR, Clinical Physiology Institute,Via Moruzzi 1, 56124 Pisa, ItalyTel: +39 050 3152216; fax: +39 050 315 2166; e-mail: [email protected]

Received 14 May 2013 Revised 6 October 2013Accepted 7 April 2014

IntroductionCardiovascular disease and mind are closely related. It is

widely acknowledged that various psychosocial factors

(such as acute and chronic stress, depression, or social

isolation) are closely associated with an increased risk of

acute myocardial infarction,1 anxiety disorders are associ-

ated with an increased prevalence of coronary artery

disease (CAD),2 and anxiety in youth predicts sub-

sequent coronary heart disease events.3 The relationship

between psychosocial factors and cardiac events is even

closer in patients who have suffered from cardiac disease.

Specifically, depression after acute myocardial infarction

or unstable angina is associated with a worse event-free

survival,4,5 and anxiety disorders and depression in

patients with stable CAD predict greater cardiac events.6

Finally, depressive symptoms are associated with an

increased risk of all-cause and cardiovascular death,

and this risk is particularly marked in depressive indi-

viduals with comorbid CAD.7

After cardiac surgery, impairment in cognitive

function, depression, and anxiety disorders frequently

occur, profoundly affecting patients’ prognosis and

quality of life. For these reasons, we undertook this

narrative review in order to focus on the main clinical

presentations of cognitive and psychological compli-

cations (’mind injuries’) that occur after cardiac surgery

in the absence of focal neurologic deficits, and to

investigate neural correlates of their pathophysio-

logic mechanisms. Finally, we will consider current

achievements that may shed light on possible strategies

for prevention and treatment.

Materials and methodsA literature search of Medline was conducted on the basis

of the following medical subheadings: coronary artery

bypass surgery, cardiac surgical procedures, depression,

delirium, anxiety disorders, and posttraumatic stress dis-

orders. We selected the articles published in English,

French, or Italian language from January 1962 through

November 2012; we supplemented this information

with articles obtained from journal archives and from

personal files. Out of more than 700 papers screened,

pertinent articles were selected favoring prospective

studies, randomized controlled trials, meta-analysis, or

large-scale studies.

Cognitive dysfunction after cardiac surgeryPostoperative deliriumCognitive dysfunction is a common complication after

cardiac surgery, and mainly includes postoperative

delirium and cognitive decline.8 Postoperative delirium

is a confusional state of acute onset characterized by a

precipitous drop in attention and cognitive function,

including impaired vigilance, memory dysfunction, and

delusions. In a recent meta-analysis on 25 selected pub-

lications, the incidence of delirium following cardiac

surgery was on average 25%.9 In another recent study,

out of 8474 patients undergoing coronary artery bypass

graft (CABG) surgery at a single center, 6% were reported

uthorized reproduction of this article is prohibited.

DOI:10.2459/JCM.0000000000000133

mailto:[email protected]

http://dx.doi.org/10.2459/JCM.0000000000000133

Co


JCM-D-13-00296

2 Journal of Cardiovascular Medicine 2014, Vol 00 No 00

to develop postoperative delirium.10 This variability

likely reflects different diagnostic criteria and patients’

selection. Although generally considered a short-term,

transient disorder, delirium can have long-term sequelae.

It has been shown that the presence of this disturbance is

associated with an increase in perioperative stroke, all-

cause mortality, prolonged hospitalization, and increased

health costs.9

Postoperative cognitive declineAn early, short-term impairment in cognitive perform-

ance, characterized by a reduction in memory, attention,

language, executive functions, and motor speed, can

occur after cardiac surgery. This cognitive decline is

subtle and sometimes subthreshold. Thus, it can often

be detected only by careful neuropsychological testing by

a trained and experienced examiner. Postoperative cog-

nitive decline improves over the following months, being

present in 53% of patients at hospital discharge, in 36%

at 6 weeks, and in 24–33% of patients at 1 year

postoperatively.11,12 The link between postoperative

delirium and cognitive decline has been recently demon-

strated. On the one hand, the patients in whom delirium

developed postoperatively had lower preoperative

cognitive function than those in whom delirium did

not develop; on the other hand, postoperative delirium

was followed by a significant decline in cognitive ability

during the first year after surgery.13

Causes of postoperative cognitivedysfunctionPredisposing and precipitating factorsSeveral factors are related to the pathogenesis of post-

operative cognitive dysfunction. Compared with patients

without postoperative delirium, those with delirium share

several predisposing factors, including older age, history

of diabetes, history of previous stroke or transient

ischemic attack, more depressive symptoms, or lower

cognitive function preoperatively.9,14 The precipitating

risk factors are related to both the operative phase (as

the duration of surgery, prolonged intubation, or intra-

operative hyperglycemia) and the postoperative phase (as

red blood cell transfusion, elevation in inflammatory

markers and plasma cortisol level, or postoperative

complications).9,14

The predictors of postoperative cognitive decline can be

related to greater comorbidity and fragility, and include

preexisting cerebral disease, peripheral vascular disease,

postoperative complications, the condition of living

alone, and lower levels of education.15 Several intra-

operative aspects able to affect postoperative cognitive

dysfunction deserve greater attention.

Cerebral microemboliAs autopsy of patients who died after cardiac surgery

revealed evidence of microemboli in all brains examined,16

pyright © Italian Federation of Cardiology. Unau

cerebral microemboli due to gaseous, organic, or inorganic

particles generated during extracorporeal circulation have

been hypothesized to be a primary predictor of postopera-

tive cognitive impairment. To measure intraoperative

microemboli, transcranial or carotid Doppler ultrasound

has been utilized by the analysis of high-intensity

transient signals, assumed to reflect particulate or gaseous

microembolic particles. However, counting the total

number of emboli did not provide a cut-off value, below

which there was no risk and above which there was a high

risk of postoperative cognitive dysfunction.17 Despite

these results, a silent organic brain injury can occur

after cardiac surgery, as demonstrated by diffusion-

weighted magnetic resonance imaging, which has

shown brain lesions in 29% of patients studied

postoperatively.18 Characteristically, these lesions were

multiple and very small, located in all cerebrovascular

territories, but more frequently in frontal and watershed

border zones. A few of these lesions were associated

with overt clinical signs of stroke, whereas other lesions

were not.

Another open issue is that of the effects of extracorporeal

circulation on postoperative cognitive dysfunction.

Although several studies reported improved cognitive

outcome after off-pump cardiac surgery, no difference

in cognitive performance has been found between

patients randomized to on-pump and those randomized

to off-pump bypass surgery, including a meta-analysis

of eight prospective randomized controlled trials.19,20

Conversely, aortic atheroma burden, studied via trans-

esophageal and epiaortic echocardiography, has been

shown to predict postoperative cognitive dysfunction

at 1 week after surgery.21 Accordingly, a surgical

strategy designed to minimize aortic manipulation

can significantly reduce the incidence of cognitive

deficits in patients with CABG compared with traditional

techniques.22

Anesthetic managementOther pathogenetic factors involve the anesthetized

patient’s management. In a randomizedtrial of180patients

undergoing CABG, propofol anesthesia was associated

with an increased incidence of early cognitive dysfunc-

tion as compared with desflurane anesthesia, without

significant difference in the incidence of postoperative

delirium.23 A positive correlation has also been found

between early postoperative cognitive dysfunction

and intraoperative cerebral oxygen desaturation24 or

systemic hypoxia 5 days after CABG.25 Finally, several

pieces of evidence suggest a similar pathophysiologic

mechanism underlying postsurgical cognitive impair-

ment and Alzheimer’s disease. Similar changes in bio-

markers such as amyloid-b beta peptide, tau protein, and

S100b have been detected in both plasma and cerebro-

spinal fluid of patients with Alzheimer’s disease and

those with postsurgical cognitive decline.26,27

thorized reproduction of this article is prohibited.

C


JCM-D-13-00296

Mind injuries after cardiac surgery Rovai et al. 3

In conclusion, cognitive dysfunction after cardiac surgery

in the absence of focal neurologic signs is a potentially

devastating complication that can involve several

mechanisms and several predisposing preoperative,

intraoperative, and postoperative risk factors, which often

result in cerebral microvascular damage. The latter can

trigger changes in anatomical and functional connec-

tivity, the condicio sine qua non for generating cognitive

alterations (Fig. 1).

Depression and anxiety disorders aftercardiac surgeryDepression and depressive symptomsUndergoing cardiac surgery remains a significant life

event that has an important emotional impact on patients

and their families. After CABG, from 31 to 60% of

patients refer depressive symptoms, whereas 16 to

23% of patients present the clinical picture of major

depression.28,29 Although depressive symptoms can be

assessed by questionnaires, the diagnosis of major

depression is clinical and is based on the observation

of several symptoms, including a depressed mood,

psychomotor retardation, loss of interest or pleasure in

normally enjoyable activities, hopelessness, feelings of

failure, and low self-esteem.

From a prognostic point of view, postoperative

depressive symptoms are associated with a lack of func-

tional improvement 6 months after surgery,30 and DSM

IV diagnosis of major depression is associated with an

increased risk of new cardiac events during follow-up,31

and with increased mortality up to 5–10 years

after CABG.29,32 Furthermore, postoperative depressive


Fig. 1

Predisposing risk factorsOlder age, diabetes, previous stroke or TIA,aortic atheroma burden, peripheral vasculardisease, comorbidity, fragility, depressivesymptoms, lower cognitive function, lowlevels of education, living alone

Intraoperative risk factorsProlonged duration of surgery, prolongedintubation, aortic manipulation, propofolanesthesia, intraoperative cerebral oxygendesaturation, intraoperative hyperglycemia,extracorporeal circulation

Postoperative risk factorsRBC transfusion, increased inflammatorymarkers, increased plasma cortisol levels,postoperative complications, systemichypoxia

Schematic diagram of the factors involved in the pathogenesis of postoper

symptoms are associated with poorer quality of life,

and with an earlier degeneration of venous grafts.33

The negative effects of depression also affect patients

undergoing cardiac valve surgery.34 On the contrary,

patients with personality traits characterized by optimism

show a lower rate of rehospitalization after CABG.35

Anxiety disordersAnxiety disorders are common after cardiac surgery;

they include post-traumatic stress disorder (PTSD),

generalized anxiety disorder, and panic disorders. PTSD

is a severe anxiety disorder often described in combat

veterans. It is induced by exposure to an event that

involves death or serious injury, and generates intense

fear or helplessness. In patients with PTSD, this

traumatic event is persistently re-experienced, the

stimuli that may trigger such experience are avoided,

and symptoms of increased arousal (such as difficulty

falling or staying asleep, or concentrating) appear. These

symptoms are associated with significantly impaired

social or occupational functioning. PTSD can be present

in up to 18% of patients after cardiac surgery, and is

associated with a poorer quality of life.36

Anxiety symptoms (worry, apprehension, and fear-

fulness) are very frequent in the preoperative phase of

cardiac surgery, involving on average 40% of patients;

these symptoms tend to decline weeks and months after

surgery. Although the relationship between anxiety and

outcome has been less investigated, higher anxiety

scores, generalized anxiety disorder (characterized by

excessive and uncontrollable anxiety, often dispropor-

tionate to the actual source of worry), and panic attack


Postoperative cognitivedysfunction

Cerebral microvasculardamage

ative cognitive dysfunction. RBC, red blood cell.

Co


JCM-D-13-00296


disorder are associated with a worse outcome after CABG

or valve surgery.37

Pathophysiology of postoperative depressionand anxietyRole of somatic illnessAlthough the cause and pathophysiology of major depres-

sion and other mental disorders are not well clarified,

converging evidence suggests that several mechanisms

are involved in their pathogenesis. Among the risk factors

for depression, a role is played by concomitant physical

illness. Patients with a greater degree of depressive

symptoms after CABG were more likely to have more

comorbid conditions, higher Canadian Cardiovascular

Society angina class, higher cardiovascular risk factors,

lower physical function, and were to be operated on more

often on an emergency basis than those with lower levels

of postoperative depressive symptoms.30,33,34 It is note-

worthy that left ventricular function, history of cardiac

disease, including previous myocardial infarction, angina

pectoris, and previous coronary angioplasty procedures,

were associated with severity of depression.30 To indicate

that the psychological reaction is related to the somatic

illness, the term secondary depression has been uti-

lized.38 However, it is a frequent clinical observation

that the distress experienced by the patient is often

uncorrelated to the severity of physical illness. Thus,

factors beyond the somatic illness should be considered

to explain the complex pathogenetic mechanisms of

postoperative depression.

Psychosocial factorsA review of 46 studies has shown that the most

commonly identified psychological predictors of post-

operative depression and anxiety after CABG were

preoperative depression and anxiety.39 Furthermore,

the patient’s beliefs about their illness before cardiac

surgery was an independent predictor of disability,

physical functioning, and depressive symptoms 3 months

after cardiac surgery.40 Finally, social factors do play a

role, because patients who developed postoperative

depression were more likely to be less educated, to have

less social support, and to live alone than patients who did

not develop postoperative depression.30

Neuroendocrine activationOpen heart surgery is associated with the activation of

several neuroendocrine systems, such as the hypothala-

mic–pituitary–adrenal (HPA) axis. HPA activation, with

increased cortisol release, has been documented during

cardiac surgery, mainly in patients operated with cardio-

pulmonary bypass.41 A modest association has also been

found between major depressive disorder and HPA acti-

vation.42 However, a relationship between cortisol con-

centration and depressive symptoms after CABG has not

been consistently demonstrated.43


After cardiac surgery, thyroid hormone changes

frequently occur, consisting mainly of decreased triio-

dothyronine (T3) levels.44 Several studies have docu-

mented that altered thyroid hormone profile is a

predictor of a worse prognosis in cardiac patients,45 and

that the outcome can be counteracted by hormone

supplementation.46 Independently of heart disease, low

T3 levels are associated with depressive symptoms in

psychiatric patients,47 and T3 administration is used as an

add-on therapy for depression resistant to serotonin selec-

tive reuptake inhibitors in nonhypothyroid patients.48

Despite the above considerations, thyroid homeostasis

after CABG has received little attention so far, and its

role in postoperative mood disorders is still under inves-

tigation.

InflammationMajor depression has been associated with increased

inflammatory biomarkers in the peripheral blood.49,50 A

meta-analysis of 24 studies measuring cytokine concen-

tration in patients with major depression has found sig-

nificantly higher concentrations of tumor necrosis factor

(TNF)-a and interleukin (IL)-6 in depressed individuals

compared with controls.51 In another meta-analysis,

depression was positively associated with both IL-6

and with high-sensitivity C-reactive protein in clinical

and community samples.52 Finally, in a small series of

depressed patients showing elevated TNF-a and leuko-

cyte count on admission, both TNF-a and leukocyte

count decreased to levels comparable to those of controls

following antidepressant treatment with selective sero-

tonin reuptake inhibitors (SSRIs).53 Thus, several studies

suggest a link between major depression and inflam-

mation.

In cardiac surgery, the immune reaction associated

with surgical trauma, like other forms of aseptic trauma,

initiates a systemic inflammatory response characterized

by increased plasma levels of pro-inflammatory and anti-

inflammatory cytokines, produced by blood cells, the

myocardium, and the endothelium.54 In experimental

animals, this inflammatory response to surgical trauma

has been shown to profoundly affect brain function by

inducing neuroinflammation.55 In patients undergoing

CABG, preoperative elevated serum levels of high-

sensitivity C-reactive protein were an independent

predictor of postoperative depression.56 Thus, a relation-

ship has been proposed that links surgical trauma, general

inflammatory response, neuroinflammation, and depress-

ive symptoms.57 For developing a major depressive

episode, these alterations should also interact with a

specific multifactorial genetic pattern.

Genetic predispositionPostoperative depression has a genetic component, which

should not be regarded as an all-or-nothing phenomenon

that is manifested regardless of external conditions.


C


JCM-D-13-00296


Genetic predisposition is to be understood as a type of

reaction (genetically influenced) that occurs when the

individual is exposed to stressful events.

In the last few decades, alterations in several central

nervous system neurotransmitters, including seroto-

nergic neurotransmission, have been shown to play a

key role in both the pathophysiology of depression

and the mechanisms of action of antidepressant drug

treatment.58 The genetic variability in two serotonin-

related gene polymorphisms that influence central

nervous system serotonin turnover, and their relation-

ship to depression and adverse cardiac events, has been

studied in a group of 427 patients undergoing CABG.59

Neither candidate polymorphism was significantly

predictive of postoperative depression in the studied

population, which was likely not powered enough to

test such a hypothesis (P¼ 0.06 for each gene poly-

morphism). However, depressed patients who carry

the long (L) allele of the 5HTTLPR polymorphism

were more likely than the short/short (S/S) carriers

to have an event during follow-up, including repeat

coronary revascularization by CABG surgery or percuta-

neous coronary intervention, myocardial infarction,

cardiac arrest, or all-cause mortality.

In response to various stimuli, cortisol coordinates meta-

bolic, endocrine, immune, and nervous system responses.

The effects of cortisol are mainly mediated by the

glucocorticoid receptor, which is expressed throughout

the body, including the brain.60 In a cross-sectional

genetic association study of 526 patients with chronic

CAD, four glucocorticoid receptor gene polymorphism

and haplotype analyses were conducted and correlated

with current or past depression. The prevalence of

depression was 24% in the noncarriers, 34% in hetero-

zygotes, and 53% in homozygous for the haplotype 3

allele; these associations persisted after adjusting for

confounding factors.61 Finally, an association between

polymorphism of the glucocorticoid receptor gene

and anxiety, traumatic memories, PTSD symptoms, and

health-related quality of life has been shown in 126

patients undergoing cardiac surgery and intensive care

unit therapy.62 Specifically, the homozygous carriers of

the BcL G allele were more likely to present anxiety and

PTSD symptoms than heterozygous carriers or non-

carriers. Furthermore, homozygous carriers did not

show any significant improvement in health-related

quality of life 6 months after cardiac surgery, whereas

heterozygous carriers or noncarriers did. Finally, genetic

variants of the binding protein that modulates the glu-

cocorticoid receptor function (FK506) and brain-derived

neurotrophic factor (BDNF) are suggestively associated

with depression in a Swedish population-based cohort.63

All of the above considerations support the concept that

genetic predisposition is a risk factor for developing

elevated depressive symptoms and for greater adverse

events after cardiac surgery.


Brain and abnormal response to stressWithin the brain, a complex neural network determines

what is threatening and thus stressful to the individual.

This network includes some subcortical structures such

as hypothalamus, hippocampus, and amygdaloid com-

plex, as well as cortical areas such as the prefrontal cortex.

Recently, it has been pointed out that the hippocampus

seems to be a crucial structure for linking abnormal stress

reaction (allostatic load) to mental dysfunctions. The

hippocampus is a complex and highly organized brain

structure involved in learning and memory, in processing

the contextual aspects of emotional events, and regulat-

ing visceral functions, including the HPA axis.64,65 The

hippocampus contains receptors for adrenal steroids and

for major metabolic hormones, and it appears to be

particularly vulnerable to the effects of stress. Mild

and short-lasting stress often enhances hippocampal

function, whereas prolonged or severe stress may alter

the structure and function of the hippocampus. This

altered hippocampal function includes a reduction

(retraction) in the branching of cell dendrites and a

reduction in the formation of new neurons in the adult

hippocampus, a phenomenon referred to as adult hippo-

campal neurogenesis.66 Recently, several studies have

provided evidence that the hippocampus is a specific

target of various hormones and pro-inflammatory sub-

stances induced by stressful experiences, thus supporting

the idea that the hippocampus is involved in the regu-

lation of mood.67,68 Thus, a neurogenesis hypothesis of

depression has been put forward linking a suppressed rate

of adult hippocampal neurogenesis to the pathophysio-

logy of depression. In conclusion, the complex bio-

chemical changes that occur during cardiac surgery,

including neuroendocrine activation and inflammation,

along with an aspecific response to stressful life events,

might target hippocampal function and represent a risk

factor or a trigger factor for the onset of depression in

these patients (Fig. 2).

Possible strategies for prevention andtreatmentAntidepressantsBecause of their favorable risk profile and effects on

depression, anxiety disorders, and PTSD, SSRIs are

considered the antidepressants of choice in patients with

CAD. In a meta-analysis of six randomized controlled

trials, CAD patients on SSRIs showed a significantly

greater improvement in depression symptoms compared

with controls, without significant differences in mortality

or CHD readmission rates.69 Despite these premises,

studies on SSRIs in patients undergoing CABG have

generated conflicting results. In a retrospective study

on 4794 patients who underwent CABG, 5% of whom

were already receiving SSRIs before surgery, the SSRI

group had an increased risk of mortality after adjustment

for baseline differences.70 In a more recent study on

4136 patients who underwent CABG, 2.5% of whom


Co


JCM-D-13-00296


Fig. 2

Postoperative depression

NeuroinflammationHippocampus, amygdala,prefrontal cortex

Neuroendocrine activationHPA axis activation →cortisol releaseLow T3 syndrome

InflammationPro-inflammatory cytokinesHigh-sensitivity-CRP

Predisposing psychological risk factorsPre-operative depression and anxiety,patient’s beliefs about their illness

Predisposing genetic factorsSerotonin-related gene and glucocorticoidreceptor gene polymorphism

Surgical trauma

Somatic illnessComorbidity, angina class, CV risk factors,low physical function, emergency operations

Predisposing social risk factorsLow levels of education, low socialsupport, living alone

Schematic diagram of the factors involved in the pathogenesis of postoperative depression. CRP, C-reactive protein; CV, cardiovascular; HPA,hypothalamic–pituitary–adrenal; T3, triiodothyronine.

were on SSRIs or serotonin–noradrenaline reuptake

inhibitors, the antidepressant treatment was not associ-

ated with cardiac mortality or all-cause mortality.

However, the use of the above medications was signifi-

cantly associated with an increased risk of renal dys-

function requiring dialysis and prolonged ventilation

after CABG.71 In a previous study on 1380 patients

who received either SSRIs (78% of patients) or non-SSRI

antidepressant (22% of patients) before CABG, the pre-

operative use of SSRIs was not associated with increased

risk for bleeding or inhospital mortality after CABG.72

Faced with these diverging results, prospective random-

ized trials on the optimal medical treatment of mood

disorders after cardiac surgery would be desirable.

StatinsAn interesting association between postoperative

depression and statin therapy has been observed in a

small sample of 193 patients hospitalized for angioplasty,

myocardial infarction, or CABG. The use of statins

(in 81% of patients) was associated with significantly

decreased risk of depression.73 As statins have known

effects on inflammatory cytokines, and they also reduce

markers of oxidative stress, this observation could support

the inflammatory and oxidative hypothesis of depression.

In a larger study on 1059 cardiac surgical patients,

the preoperative use of statins had a protective effect

on the risk of early postoperative delirium.74 These

findings suggest the possibility of novel therapies differ-

ent from conventional antidepressants in the prevention


and treatment of postoperative depression and cognitive

dysfunction. However, further studies are needed to

prove such a hypothesis.

Cognitive behavioral therapyInteresting results on the prevention and treatment of

postoperative mind injuries involve nonpharmacological

treatment tailored to improve patient knowledge and

stress management. In a recent study, 100 patients with

symptoms of depression or anxiety before CABG were

randomly assigned to receive the usual treatment or a

brief cognitive behavioral therapy. This intervention

improved depressive symptoms at time of discharge, as

well as quality of life after 1 month.75 In another study,

123 patients with major or minor depression within 1 year

after surgery were randomized to cognitive behavioral

therapy, supportive stress management, or usual

care. Even after surgery, the two nonpharmacological

strategies were efficacious for treating depression after

CABG, compared with the usual care.76 Recently, the

effectiveness of telephone-delivered collaborative care

has been evaluated in 302 patients after CABG.77 Com-

pared with usual care, telephone-delivered care resulted

in improved health-related quality of life, physical func-

tioning, and depressive symptoms at 8-month follow-up.

Enriched environment hypothesisSeveral studies have shown that exposure to a cogni-

tively and socially stimulating environment (a combina-

tion known as ‘enriched environment’) and physical


C


JCM-D-13-00296


exercise exert beneficial effects on brain function.

Specifically, exercise and exposure to an enriched

environment improve cognitive performance, slow

down decline in the elderly, increase cortical synaptic

plasticity, and reduce the risk of developing dementia

and depression.78–80 Furthermore, it has been shown

that an enriched environment yields a significant increase

in hippocampal neurogenesis, counterbalancing the detri-

mental effects of stress-related substances.78 Because of

the similarities in pathophysiological mechanisms, one

might propose translating the enriched environment

strategy to the postoperative theatre. In this view, inter-

action between patient and family members, nurses, and

medical personnel should be encouraged as much as

possible. Furthermore, the patient might take advantage

of being exposed to pleasant visual stimuli and to

pleasant acoustic stimuli or odors. Finally, the patient’s

mental recovery might be favored by an early rehabilita-

tion program, so as to train the patient’s body and mind.

LimitationsBecause of the complexity of this issue and the large

amount of literature available, an in-depth analysis of

individual studies could not be reported in this narrative

review. This wide topic was chosen to underlie the

continuum and possible interrelationship between

different types of cognitive dysfunction and mood

disorders, as well as any common favoring factors,

precipitating factors, and pathogenetic mechanisms.

ConclusionThe relationship between cardiovascular disease and men-

tal disorders is close and bidirectional. On the one hand,

stress, depression, and social isolation are independent risk

factors for the development of CAD. On the other hand,

heart disease and cardiac surgery produce a stress reaction

that induces the activation of several neuroendocrine

pathways, and the release of several pro-inflammatory

factors. The net effect of these changes is neuroinflamma-

tion. Consequently, a reduction in the function of several

brain areas occurs, and is thought to be responsible for

depressive mood. Furthermore, postoperative mind inju-

ries are influenced by factors that existed prior to the

intervention, such as genetic predisposition or psycho-

social factors. Prevention of postoperative mental disorders

through optimization of pre and/or postsurgery treatment

by new pharmacological and/or nonpharmacological strat-

egies could be worthwhile for improving patient’s prog-

nosis and quality of life.

AcknowledgementsThis study was supported by institutional grants of the

CNR Institute of Clinical Physiology.

The authors gratefully acknowledge Ms Alison Frank for

the English revision of the article.

There are no conflicts of interest.


References1 Rosengren A, Hawken S, Ounpuu S, et al., INTERHEART investigators.

Association of psychosocial risk factors with risk of acute myocardialinfarction in 11 119 cases and 13 648 controls from 52 countries(the INTERHEART study): case-control study. Lancet 2004; 364:953–962.

2 Vogelzangs N, Seldenrijk A, Beekman AT, et al. Cardiovascular disease inpersons with depressive and anxiety disorders. J Affect Disord 2010;125:241–248.

3 Janszky I, Ahnve S, Lundberg I, Hemmingsson T. Early-onsetdepression, anxiety, and risk of subsequent coronary heart disease: 37-yearfollow-up of 49 321 young Swedish men. J Am Coll Cardiol 2010; 56:31–37.

4 Frasure-Smith N, Lesperance F, Talajic M. Depression followingmyocardial infarction. Impact on 6-month survival. JAMA 1993;270:1819–1825.

5 Whang W, Shimbo D, Kronish IM, et al. Depressive symptoms and all-cause mortality in unstable angina pectoris (from the CoronaryPsychosocial Evaluation Studies [COPES]). Am J Cardiol 2010;106:1104–1107.

6 Martens EJ, de Jonge P, Na B, et al. Scared to death? Generalized anxietydisorder and cardiovascular events in patients with stable coronary heartdisease: the Heart and Soul Study. Arch Gen Psychiatry 2010; 67:750–758.

7 Nabi H, Shipley MJ, Vahtera J, et al. Effects of depressive symptoms andcoronary heart disease and their interactive associations on mortality inmiddle-aged adults: the Whitehall II cohort study. Heart 2010; 96:1645–1650.

8 Fox HM, Rizzo ND, Gifford S. Psychological observations of patientsundergoing mitral surgery: a study of stress. Am Heart J 1954; 48:645–670.

9 Lin Y, Chen J, Wang Z. Meta-analysis of factors which influence deliriumfollowing cardiac surgery. J Card Surg 2012; 27:481–492.

10 Martin BJ, Buth KJ, Arora RC, Baskett RJ. Delirium: a cause for concernbeyond the immediate postoperative period. Ann Thorac Surg 2012;93:1114–1120.

11 Newman MF, Kirchner JL, Phillips-Bute B, et al., Neurological OutcomeResearch Group and the Cardiothoracic Anesthesiology ResearchEndeavors Investigators. Longitudinal assessment of neurocognitivefunction after coronary-artery bypass surgery. N Engl J Med 2001;344:395–402.

12 Van Dijk D, Jansen EW, Hijman R, et al., Octopus Study Group. Cognitiveoutcome after off-pump and on-pump coronary artery bypass graft surgery:a randomized trial. JAMA 2002; 287:1405–1412.

13 Saczynski JS, Marcantonio ER, Quach L, et al. Cognitive trajectories afterpostoperative delirium. N Engl J Med 2012; 367:30–39.

14 Mu DL, Wang DX, Li LH, et al. High serum cortisol level is associated withincreased risk of delirium after coronary artery bypass graft surgery: aprospective cohort study. Crit Care 2010; 14:R238.

15 Ho PM, Arciniegas DB, Grigsby J, et al. Predictors of cognitive declinefollowing coronary artery bypass graft surgery. Ann Thorac Surg 2004;77:597–603.

16 Newman SP, Harrison MJ. Coronary-artery bypass surgery and the brain:persisting concerns. Lancet Neurol 2002; 1:119–125.

17 Martin KK, Wigginton JB, Babikian VL, et al. Intraoperative cerebralhigh-intensity transient signals and postoperative cognitive function: asystematic review. Am J Surg 2009; 197:55–63.

18 Sun X, Lindsay J, Monsein LH, et al. Silent brain injury after cardiac surgery:a review. J Am Coll Cardiol 2012; 60:791–797.

19 Kozora E, Kongs S, Collins JF, et al. Cognitive outcomes after on- versusoff-pump coronary artery bypass surgery. Ann Thorac Surg 2010;90:1134–1141.

20 Marasco SF, Sharwood LN, Abramson MJ. No improvement inneurocognitive outcomes after off-pump versus on-pump coronaryrevascularisation: a meta-analysis. Eur J Cardiothorac Surg 2008;33:961–970.

21 Evered LA, Silbert BS, Scott DA. Postoperative cognitive dysfunction andaortic atheroma. Ann Thorac Surg 2010; 89:1091–1097.

22 Hammon JW, Stump DA, Butterworth JF, et al. Single crossclamp improves6-month cognitive outcome in high-risk coronary bypass patients: the effectof reduced aortic manipulation. J Thorac Cardiovasc Surg 2006;131:114–121.

23 Royse CF, Andrews DT, Newman SN, et al. The influence of propofol ordesflurane on postoperative cognitive dysfunction in patients undergoingcoronary artery bypass surgery. Anaesthesia 2011; 66:455–464.

24 Slater JP, Guarino T, Stack J, et al. Cerebral oxygen desaturation predictscognitive decline and longer hospital stay after cardiac surgery. Ann ThoracSurg 2009; 87:36–44.


Co


JCM-D-13-00296


25 Browne SM, Halligan PW, Wade DT, Taggart DP. Postoperative hypoxia isa contributory factor to cognitive impairment after cardiac surgery. J ThoracCardiovasc Surg 2003; 126:1061–1064.

26 Evered LA, Silbert BS, Scott DA, et al. Plasma amyloid beta42 and amyloidbeta40 levels are associated with early cognitive dysfunction after cardiacsurgery. Ann Thorac Surg 2009; 88:1426–1432.

27 Palotas A, Reis HJ, Bogats G, et al. Coronary artery bypass surgeryprovokes Alzheimer’s disease-like changes in the cerebrospinal fluid.J Alzheimers Dis 2010; 21:1153–1164.

28 Glassman AH, Shapiro PA. Depression and the course of coronary arterydisease. Am J Psychiatry 1998; 155:4–11.

29 Blumenthal JA, Lett HS, Babyak MA, et al., NORG Investigators.Depression as a risk factor for mortality after coronary artery bypasssurgery. Lancet 2003; 362:604–609.

30 Mallik S, Krumholz HM, Lin ZQ, et al. Patients with depressive symptomshave lower health status benefits after coronary artery bypass surgery.Circulation 2005; 111:271–277.

31 Connerney I, Shapiro PA, McLaughlin JS, et al. Relation betweendepression after coronary artery bypass surgery and 12-month outcome:a prospective study. Lancet 2001; 358:1766–1771.

32 Connerney I, Sloan RP, Shapiro PA, et al. Depression is associated withincreased mortality 10 years after coronary artery bypass surgery.Psychosom Med 2010; 72:874–881.

33 Wellenius GA, Mukamal KJ, Kulshreshtha A, et al. Depressive symptomsand the risk of atherosclerotic progression among patients with coronaryartery bypass grafts. Circulation 2008; 117:2313–2319.

34 Ho PM, Masoudi FA, Spertus JA, et al. Depression predicts mortalityfollowing cardiac valve surgery. Ann Thorac Surg 2005; 79:1255–1259.

35 Scheier MF, Matthews KA, Owens JF, et al. Optimism and rehospitalizationafter coronary artery bypass graft surgery. Arch Intern Med 1999;159:829–835.

36 Stoll C, Schelling G, Goetz AE, et al. Health-related quality of life andposttraumatic stress disorder in patients after cardiac surgery and intensivecare treatment. J Thorac Cardiovasc Surg 2000; 120:505–512.

37 Szekely A, Balog P, Benko E, et al. Anxiety predicts mortality and morbidityafter coronary artery and valve surgery: a 4-year follow-up study.Psychosom Med 2007; 69:625–631.

38 Bech P. Mood and anxiety in the medically ill. Adv Psychosom Med 2012;32:118–132.

39 McKenzie LH, Simpson J, Stewart M. A systematic review of preoperativepredictors of postoperative depression and anxiety in individuals who haveundergone coronary artery bypass graft surgery. Psychol Health Med2010; 15:74–93.

40 Juergens MC, Seekatz B, Moosdorf RG, et al. Illness beliefs before cardiacsurgery predict disability, quality of life, and depression 3 months later.J Psychosom Res 2010; 68:553–560.

41 Hoda MR, El-Achkar H, Schmitz E, et al. Systemic stress hormoneresponse in patients undergoing open heart surgery with or withoutcardiopulmonary bypass. Ann Thorac Surg 2006; 82:2179–2186.

42 Vreeburg SA, Hoogendijk WJ, van Pelt J, et al. Major depressive disorderand hypothalamic–pituitary–adrenal axis activity: results from a largecohort study. Arch Gen Psychiatry 2009; 66:617–626.

43 Dowlati Y, Herrmann N, Swardfager W, et al. Relationship between haircortisol concentrations and depressive symptoms in patients with coronaryartery disease. Neuropsychiatr Dis Treat 2010; 6:393–400.

44 Sabatino L, Cerillo AG, Ripoli A, et al. Is the low tri-iodothyronine statea crucial factor in determining the outcome of coronary artery bypasspatients? Evidence from a clinical pilot study. J Endocrinol 2002;175:577–586.

45 Iervasi G, Molinaro S, Landi P, et al. Association between increasedmortality and mild thyroid dysfunction in cardiac patients. Arch Intern Med2007; 167:1526–1532.

46 Pingitore A, Galli E, Barison A, et al. Acute effects of triiodothyronine (T3)replacement therapy in patients with chronic heart failure and low-T3syndrome: a randomized, placebo-controlled study. J Clin EndocrinolMetab 2008; 93:1351–1358.

47 Premachandra BN, Kabir MA, Williams IK. Low T3 syndrome in psychiatricdepression. J Endocrinol Invest 2006; 29:568–572.

48 Abraham G, Milev R, Stuart Lawson J. T3 augmentation of SSRI resistantdepression. J Affect Disord 2006; 91:211–215.

49 Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the roleof cytokines in the pathophysiology of major depression. Biol Psychiatry2009; 65:732–741.

50 Schmidt HD, Shelton RC, Duman RD. Functional biomarkers ofdepression: diagnosis, treatment, and pathophysiology.Neuropyschopharmacology 2011; 36:2375–2394.

51 Dowlati Y, Herrmann N, Swardfager W, et al. A meta-analysis of cytokinesin major depression. Biol Psychiatry 2010; 67:446–457.


52 Howren MB, Lamkin DM, Suls J. Associations of depression with C-reactiveprotein, IL-1, and IL-6: a meta-analysis. Psychosom Med 2009; 71:171–186.

53 Tuglu C, Kara SH, Caliyurt O, et al. Increased serum tumor necrosis factor-alpha levels and treatment response in major depressive disorder.Psychopharmacology 2003; 170:429–433.

54 Franke A, Lante W, Fackeldey V, et al. Proinflammatory andantiinflammatory cytokines after cardiac operation: different cellularsources at different times. Ann Thorac Surg 2002; 74:363–370.

55 Terrando N, Eriksson LI, Ryu JK, et al. Resolving postoperativeneuroinflammation and cognitive decline. Ann Neurol 2011; 70:986–995.

56 Yang L, Wang J, Zhang L, et al. Preoperative high-sensitivity C-reactiveprotein predicts depression in patients undergoing coronary artery bypasssurgery: a single-center prospective observational study. J ThoracCardiovasc Surg 2012; 144:500–505.

57 Poole L, Dickens C, Steptoe A. The puzzle of depression and acutecoronary syndrome: reviewing the role of acute inflammation. J PsychosomRes 2011; 71:61–68.

58 Risch SC, Nemeroff CB. Neurochemical alterations of serotonergicneuronal systems in depression. J Clin Psychiatry 1992; 53:3–7.

59 Phillips-Bute B, Mathew JP, Blumenthal JA, et al. Perioperative Geneticsand Safety Outcomes Investigative Team. Relationship of genetic variabilityand depressive symptoms to adverse events after coronary artery bypassgraft surgery. Psychosomat Med 2008; 70:953–959.

60 DeRijk R, de Kloet ER. Corticosteroid receptor genetic polymorphisms andstress responsivity. Endocrine 2005; 28:263–270.

61 Otte C, Wust S, Zhao S, et al. Glucocorticoid receptor gene anddepression in patients with coronary heart disease: the Heart and SoulStudy-2009 Curt Richter Award Winner. Psychoneuroendocrinology2009; 34:1574–1581.

62 Hauer D, Weis F, Papassotiropoulos A, et al. Relationship of a commonpolymorphism of the glucocorticoid receptor gene to traumatic memoriesand posttraumatic stress disorder in patients after intensive care therapy.Crit Care Med 2011; 39:643–650.

63 Lavebratt C, Aberg E, Sjoholm LK, Forsell Y. Variations in FKBP5 andBDNF genes are suggestively associated with depression in a Swedishpopulation-based cohort. J Affect Disord 2010; 125:249–255.

64 McEwen BS, Gianaros PJ. Central role of the brain in stress and adaptation:links to socioeconomic status, health, and disease. Ann N Y Acad Sci2010; 1186:190–222.

65 Maras PM, Baram TZ. Sculpting the hippocampus from within: stress,spines, and CRH. Trends Neurosci 2012; 35:315–324.

66 Lucassen PJ, Meerlo P, Naylor AS, et al. Regulation of adult neurogenesisby stress, sleep disruption, exercise and inflammation: implications fordepression and antidepressant action. Eur Neuropsychopharmacol 2010;20:1–17.

67 Samuels BA, Hen R. Neurogenesis and affective disorders. Eur J Neurosci2011; 33:1152–1159.

68 Juster RP, McEwen BS, Lupien SJ. Allostatic load biomarkers of chronicstress and impact on health and cognition. Neurosci Biobehav Rev 2010;35:2–16.

69 Pizzi C, Rutjes AW, Costa GM, et al. Meta-analysis of selective serotoninreuptake inhibitors in patients with depression and coronary heart disease.Am J Cardiol 2011; 107:972–979.

70 Xiong GL, Jiang W, Clare R, et al. Prognosis of patients taking selectiveserotonin reuptake inhibitors before coronary artery bypass grafting. Am JCardiol 2006; 98:42–47.

71 Tully PJ, Cardinal T, Bennetts JS, Baker RA. Selective serotonin reuptakeinhibitors, venlafaxine and duloxetine are associated with in hospitalmorbidity but not bleeding or late mortality after coronary artery bypass graftsurgery. Heart Lung Circ 2012; 21:206–214.

72 Kim DH, Daskalakis C, Whellan DJ, et al. Safety of selective serotoninreuptake inhibitor in adults undergoing coronary artery bypass grafting.Am J Cardiol 2009; 103:1391–1395.

73 Stafford L, Berk M. The use of statins after a cardiac intervention isassociated with reduced risk of subsequent depression: proof of conceptfor the inflammatory and oxidative hypotheses of depression? J ClinPsychiatry 2011; 72:1229–1235.

74 Katznelson R, Djaiani GN, Borger MA, et al. Preoperative use of statins isassociated with reduced early delirium rates after cardiac surgery.Anesthesiology 2009; 110:67–73.

75 Dao TK, Youssef NA, Armsworth M, et al. Randomized controlled trial ofbrief cognitive behavioral intervention for depression and anxiety symptomspreoperatively in patients undergoing coronary artery bypass graft surgery.J Thorac Cardiovasc Surg 2011; 142:e109–e115.

76 Freedland KE, Skala JA, Carney RM, et al. Treatment of depression aftercoronary artery bypass surgery: a randomized controlled trial. Arch GenPsychiatry 2009; 66:387–396.


C


JCM-D-13-00296


77 Rollman BL, Belnap BH, LeMenager MS, et al. Telephone-deliveredcollaborative care for treating post-CABG depression: a randomizedcontrolled trial. JAMA 2009; 302:2095–2103.

78 Cotman CW, Berchtold NC. Exercise: a behavioral intervention toenhance brain health and plasticity. Trends Neurosci 2002; 25:295–301.


79 Fratiglioni L, Paillard-Borg S, Winblad B. An active and socially integratedlifestyle in late life might protect against dementia. Lancet Neurol 2004;3:343–353.

80 Nithianantharajah J, Hannan AJ. Enriched environments, experience-dependent plasticity and disorders of the nervous system. Nat RevNeurosci 2006; 7:697–709.


Mind injuries after cardiac surgery

Documents

Transcript of Mind injuries after cardiac surgery