Postoperative Delirium and Dementia in Patients

Undergoing Cardiac Surgery: A Review of

Randomized Controlled Trials

Venus Shahabi Raberi1, Morteza Solati Kooshk Qazi2, Ali Zolfi gol3, Rahil GhorbaniNia4, Ozra Kahourian1, Reza

Faramarz Zadeh1 

1 Seyed-Al-Shohada cardiology Hospital, Urmia University of Medical Sciences, Urmia, Iran

2 School of Nursing and Midwifery, Shiraz University of Medical Sciences, Shiraz, Iran

3 Department of Pediatric Cardiology, Shahid Motahari Hospital, Hospital, Urmia University of Medical Sciences, Urmia, Iran

4 Noncommunicable Diseases Research Center, Bam University of Medical Sciences, Bam, Iran

GMJ.2023;12:e3045

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 Correspondence to:

Reza Faramarz Zadeh, Seyed-Al-Shohada ccardiology-

Hospital, Urmia University of Medical Sciences, Urmia,

Iran.

Telephone Number: +989146048919

Email Address: Faramarzzadehreza76@gmail.com

Received 2023-05-06

Revised 2023-05-15

Accepted 2023-05-30

Abstract

Delirium and dementia are considered to be the most signicant postoperative neurocognitive

complications in patients undergoing cardiac surgery, particularly those aged 60 years and older,

which reduces the post-surgery quality of life, prolongs hospitalization, increases costs, and ele-

vated the rates of mortality. Nevertheless, the etiology, risk factors, and predictive biomarkers,

have not been well elucidated particularly, in patients with unmanifested underline cognitive im-

pairments. The present study aimed to review the ndings on the etiology, factors increasing the

risk of incidence, and predictive biomarkers of postoperative delirium and dementia after cardiac

surgery, and to describe the suggested pharmacological and non-pharmacological interventions.

[GMJ.2023;12:e3045] DOI:10.31661/gmj.v12i0.3045

Keywords: Dementia; Postoperative Complications; Cardiac Surgery

Introduction

Postoperative cognitive decline (POCD) is

a common sub-clinical condition follow-

ing cardiac and non-cardiac surgery [1, 2].

POCD is widely considered to be the most

prominent in people over the age of 65 [3],

and as the population all over the world is ag-

ing at an unprecedented rate, POCD has be-

come more common [4]. Patients with POCD

will generally experience a variety of neuro-

logical symptoms including anxiety, memory

impairment, personality change, and mental

confusion all of which lead to increased med-

ical costs, reduced life independence, and are

associated with mortality [4]. Currently, sev-

eral types of POCD-related disorders have

been listed, of which delirium and dementia

are the most well-known. In addition, the cog-

nitive decline caused by anesthesia or surgery

could be followed by delirium or dementia [5,

6].

Delirium is considered an acute uctuating al-

teration in mental state that manifests as a dis-

turbance in consciousness and cognitive func-

tion. There is a suggestion that delirium has

a high incidence rate in hospitalized patients

and is followed by increased rates of morbid-

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Shahabi Raberi V, et al. Postoperative Dementia and Cardiac Surgery

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ity and mortality, and prolonged residence in

the intensive care unit (ICU) and the hospital,

thereby higher costs for both the patient and

the government [7]. Postoperative delirium

(POD) is described as a common complica-

tion after cardiac surgery [8] in which geri-

atric patients, cardiac surgery patients, and

patients hospitalized in ICU are highly at risk

of developing POD [9, 10]. POD patients are

widely believed to have longer hospital stays,

a higher risk of dementia, and a higher risk of

mortality [11].

Delirium can progress to dementia, which is

characterized by the loss of cognitive func-

tions including remembering, thinking, and

reasoning. The development of dementia after

delirium is of great concern to both third lead-

ing cause the patient and public health since

the signicant morbidity, mortality, and care-

giver burden associated with dementia have

been documented [12, 13].

Importantly, dementia has recently ranked as

the third leading cause of death in the United

States [14]. Annually, more than 47 million

people suer from dementia which is equiv-

alent to 5% of the world’s elderly population

[15].

More importantly, it is expected that the inci-

dence of dementia will increase substantially

in the following years due to an aging popu-

lation [14].

Recent studies have demonstrated that cardi-

ac surgery could be associated with increased

levels of biomarkers related to neurodegen-

eration including neurolament light chain

and Tau [16-18]. Despite the mentioned im-

portance of postoperative delirium and de-

mentia after cardiac surgery, the etiology of

its occurrence has not been elucidated, and

contradictory propositions have been hypoth-

esized. Therefore, the present study attempted

to clarify the main causes of postoperative de-

lirium and dementia after cardiac surgery and

compensatory pre-, intra-, and post-operative

proceedings to prevent/reduce its incidence

by reviewing the randomized controlled trials.

Cardiac Surgery Leads to Delirium and De-

mentia

In general, the pre-surgery cognitive state, the

application of anesthetics, procedures and in-

juries during surgery, along with induced in-

ammation and stress are the most important

assumptions about the etiology of cardiac sur-

gery-related cognitive impairment. However,

contradictions still exist in this regard, as new

ndings consistently weaken certain hypothe-

ses and strengthen others. Thereby, the current

study will review randomized controlled trials

to analyze the assumptions about the etiolo-

gy of postoperative delirium and dementia in

patients undergoing cardiac surgery and then

will assess the necessary proceedings to con-

front it.

Initially, it was thought that anesthetics used

beforecardiac surgery would be the most im-

portant cause of POCD and subsequent POD

and post-operative dementia, although sub-

sequent studies have shown that the surgi-

cal process is associated with inammation,

oxidative stress, hypoxemia, and damage to

the blood-brain barrier (BBB) as a causative

agent, too [5, 6]. It seems that patients who

have an underlying neurodegenerative com-

plication, although not manifested yet, are

more susceptible to experiencing a condition

known as a second hit. In fact, second hits are

able to accelerate the process of neurodegen-

eration by the induction of cognitive decline

after cardiac surgery [19]. The measurement

of pre-and post-surgery levels of a critical bio-

marker of Alzheimer’s disease, cerebrospinal

uid (CSF) amyloid-β42 (Aβ42), in patients

with POCD can be considered the most im-

portant nding supporting this hypothesis

[20].

Induction of inammation can be described

as a common feature of surgical procedures,

especially cardiac surgery, which can be

assumed as a bridge between surgery and

POCD, POD, and postoperative dementia

due to the involvement of inammation in

the development of neurodegenerative disor-

ders [21-23]. C-reactive protein (CRP), for

example, is an appropriate marker of inam-

mation in patients with delirium particularly

those undergoing surgery [24]. Moreover, a

dramatic elevation in the levels of inamma-

tory markers including interleukin-6 (IL-6),

broblast growth factor 21 (FGF21) and 23,

and CC-chemokine ligand 2 (CCL2) is re-

ported [25-27]. Furthermore, glial brillary

acidic protein (GFAP) is a neuroinammatory

marker that could represent the link between

Postoperative Dementia and Cardiac Surgery Shahabi Raberi V, et al.

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inammation and neurodegenerative compli-

cations [28].

Risk Factors of Postoperative Delirium and

Dementia after Cardiac Surgery

The determination of the association between

the operative procedure, anesthetics, inam-

mation, and so forth, also postoperative neu-

rological complications could benet the

understanding of the etiology of POD and

postoperative dementia, however, it requires

comprehensive studies. Indeed, multidis-

ciplinary studies are needed to explore the

overlap between preexisting cognitive im-

pairment and POCD, POD, and postoperative

dementia in the elds of anesthesia, surgery,

and old age psychiatry and neurology. The in-

tradisciplinary alignment of the terminology

and diagnostic criteria may improve our un-

derstanding of the etiology, biomarkers, and

preventive strategies [5, 29].

Understanding the cause of cognitive impair-

ment after cardiac surgery can lead to the de-

termination of relevant biomarkers. As a re-

sult, the potential biomarkers might estimate

the probability of POD and the development

of POD to dementia in patients undergoing

cardiac surgery before and after the procedure

[30, 31].

Although the relevant biomarkers have not

been fully understood, it is documented that

elder hospitalized patients with delirium rep-

resent a remarkable 12-fold increase in de-

veloping dementia, hence delirium could be

considered a reliable marker of postoperative

dementia [32, 33]. Along with that, several

attempts have recently been made to identify

risk factors associated with POD and demen-

tia after cardiac surgery. Although scientists

believed that underlying cognitive impair-

ments before surgery, whose symptoms did

not manifest were responsible for POD and

dementia after cardiac surgery, Lewis et al.

reported evidence against this belief [34].

By examining 320 patients who underwent

cardiac surgery, it was found that 15.6% of

patients had depression before surgery and

13.4% of patients experienced depression af-

ter surgery. Interestingly, preoperative depres-

sion was mainly associated with increased

anxiety and decreased self-ratings on several

quality-of-life domains, while the experience

of postoperative depression four weeks after

surgery was associated with neurocognitive

complications including as poor memory, at-

tention, processing speed, verbal uency, and

ne motor speed [34]. As a result, it can be as-

sumed that although preoperative depression

does not cause further neurocognitive disor-

ders, postoperative depression could be re-

lated to several cognitive impairments, hence

following the patients’ condition in terms of

depression after surgery can be a preventive

approach to confront delirium and dementia.

In addition, a 5-year follow-up study of 114

elderly patients aged 70 and over who under-

went cardiac surgery showed that preopera-

tive mild cognitive impairment might be a risk

factor for delirium and dementia after cardiac

surgery [35].

Also, 87% of the patients who had experi-

enced dementia within 5 years after surgery

had experienced POD, too [35]. Therefore,

POD can be considered a potential risk factor

for the development of dementia after cardiac

surgery. In fact, assessment of the preopera-

tive cognitive function in elderly patients un-

dergoing cardiac surgery should be screened.

Moreover, patients who have experienced

POD should be followed up to enable the

early detection of dementia symptoms and to

prevent the subsequent drastic consequences.

In addition to pre- and postoperative cognitive

status, a number of cardiac and inammato-

ry biomarkers can be considered risk factors

for POD and subsequent dementia. CRP,

for example, is considered the most reliable

preoperative biomarker for the prediction of

POD in patients undergoing noncardiac sur-

gery [36]. Similarly, the increased levels of

IL-2 and TNF-α were signicantly associat-

ed with POD in patients undergoing coronary

artery bypass grafting, and more importantly,

researchers have provided cuto scores for in-

creased risk [37].

In patients undergoing cardiac surgery, par-

ticularly those experiencing cardiopulmonary

bypass, a systematic stress and subsequently

systematic inammatory response occurs ac-

companied by elevated levels of inammatory

markers including cytokines and chemokines.

Also that could contribute to devastating pro-

cesses including the dysfunction of endothelial

and the disruption of BBB [38]. Consequently,

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Shahabi Raberi V, et al. Postoperative Dementia and Cardiac Surgery

these processes could be followed by the sus-

ceptibility of the brain to neuronal damage by

neuroinammatory mediators and the activa-

tion of microglia leading to the development

of POD [39]. In addition, plasma levels of

several neurotransmitters including reduced

cholinesterase and increased dopamine could

be considered biomarkers of POD [39, 40].

On the contrary, Wiberg et al., by studying

193 patients undergoing coronary artery by-

pass grafting and/or aortic valve replacement,

demonstrated that higher (70-80 mmHg) or

lower (40-50 mmHg) scores of mean arterial

pressure during cardiopulmonary bypass had

no signicant association with cerebral injury

biomarkers including neuron-specic enolase,

tau, neurolament light, and the glial marker

known as glial brillary acidic protein [41]. In

this sense, it is encouraged to conduct further

randomized controlled trials measuring pre,

inter, and postoperative heart-related markers

and assess their association with biomarkers

of cerebral injury and outcomes of pre and

post surgery brain imaging tests.

Preventive Interventions for Delirium and De-

mentia after Cardiac Surgery

Although the etiology, risk factors, and bio-

markers of delirium and dementia after car-

diac surgery are still not fully understood,

interventions have been conducted in several

randomized controlled trials to prevent post-

operative cognitive impairment in patients

undergoing cardiac surgery. In addition to

addressing undesirable neurocognitive conse-

quences after surgery, such interventions can

elucidate the causes of occurrence and make

available risk factors. The randomized con-

trolled trials conducted so far have attempted

to prevent delirium and dementia after heart

surgery through two types of interventions,

including pharmacological interventions and

non-pharmacological (operative) interven-

tions reviewed below.

Pharmacological Interventions

Anesthesia and cardiac surgery procedures

have been hypothesized as the main possible

causes of cognitive post surgery impairments

due to inducing systematic inammation and

oxidative stress. Therefore, in several stud-

ies, researchers have attempted to reduce or

eliminate the neurocognitive adverse eects

of surgery through pharmacological interven-

tions capable of reducing inammation and

stress. Ketamine is an anesthetic with anti-in-

ammatory properties that can reduce POD in

animal studies [42, 43]. Moreover, a human

study revealed that adding ketamine to rou-

tine anesthetics could reduce POD from 31%

in the placebo group to 3% [44]. A random-

ized controlled trial on patients aged 65 years

and older undergoing cardiac surgery with

cardiopulmonary bypass demonstrated that

during cardiopulmonary bypass the infusion

of ketamine (31.25%) signicantly reduced

24-h POD after surgery compared to propofol

(56.25%) [45].

The application of sedative compounds is an-

other pharmacological intervention that has

been studied to reduce or eliminate neurocog-

nitive consequences. Dexmedetomidine, an

α2 adrenoceptor agonist, is frequently admin-

istered to patients in the intensive care unit

due to its sedative and analgesic properties

[46, 47]. Perioperative administration of dex-

medetomidine was accompanied by desired

outcomes including reduction of opioid uti-

lization, improvement of postoperative anal-

gesia, and suppression of inammation all of

which are considered possible causes of cog-

nitive impairment [48, 49]. In addition, post-

operative administration of dexmedetomidine

led to a lower risk of suering from mental

complaints in patients who underwent cardiac

surgery [50].

A single-center, double-blind, randomized

controlled clinical trial on 508 patients under-

going cardiac surgery, of which 251 people

received dexmedetomidine and 257 partici-

pated in the placebo group, revealed that psy-

chological impairment could be signicantly

reduced in the dexmedetomidine group rela-

tive to the placebo group [51]. Similarly, an-

other single-blinded, prospective, randomized

controlled trial in 183 elder patients 60 years

or older undergoing cardiac surgery, of which

91 patients in the dexmedetomidine group

and others received propofol, demonstrated

that this sedative agent compared to propofol

reduced the incidence (17.5% compared to

31.5%), delayed onset (day 2 versus day 1),

and shortened duration of POD (2 days versus

3 days) [52].

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Postoperative Dementia and Cardiac Surgery Shahabi Raberi V, et al.

Moreover, the participation of 46 patients who

underwent coronary artery bypass graft sur-

gery participated in a randomized controlled

trial, suggested that dexmedetomidine com-

pared to typical anesthesia could increase the

levels of neural protective biomarkers includ-

ing matrix metalloproteinase-12 and myelin

basic protein [53]. However, a higher rate of

hypotension was reported as an adverse eect

of dexmedetomidine administration requiring

further studies to elucidate other possible side

eects [51].

Piracetam is a derivative of the neurotransmit-

ter γ-aminobutyric acid with cerebroprotective

properties that its administration leads to bet-

ter cognitive function in patients undergoing

coronary artery bypass surgery and reduces

the early postoperative substantial decline of

neuropsychological performances [54]. Mel-

atonin is a pineal gland hormone thought to

be important in sleep/wake regulation which

has been used in a wide range of studies from

neurological disorders to environmental im-

provements [55, 56].

Several studies over the past decade have

shown that the administration of this hormone

can signicantly reduce POD and post-surgery

sleep/wake complications [55]. However, a

randomized double-blind controlled clinical

trial 7 days of treatment with melatonin start-

ing 2 days before the surgery did not support

the prophylactic application of this hormone

to prevent POD [57].

Similarly, a double-blind, randomized, con-

trolled study showed that dietary melatonin

therapy in patients with mild cognitive im-

pairment can signicantly increase hippo-

campal volume and signicantly reduce CSF

T-tau protein levels [58].

Because mild cognitive impairment is a tran-

sitory state to dementia, while delirium is a

reliable risk factor for progression to demen-

tia, administration of melatonin is associated

with cardiac surgery, although no conrmato-

ry studies have been performed. Insulin is an-

other hormone its administration at normogly-

cemia during cardiac surgery may lead to the

prevention of short- and long-term memory

decline postoperatively [59].

A randomized, double-blind controlled trial

revealed that the administration of insulin in-

tranasally during cardiac surgery in patients

with type 2 diabetes does not cause hypogly-

cemia which could be important for neural

cells [60].

Non-pharmacological Interventions

Non-pharmacological interventions to reduce

delirium and dementia after cardiac surgery

can be divided into three categories: pre-, in-

tra-, and post-surgery interventions. Howev-

er, most of the interventions are related to the

procedures during and after surgery.

Cognitive training is a well-studied peri and

intraoperative intervention though to be able

to durably improve cognitive reserve in POCD

and POD and thereby could potentially reduce

the risk of postoperative cognitive impairment

in patients undergoing cardiac surgery. A ran-

domized, single-center, controlled trial studied

the perioperative cognitive training ecacy in

65 patients elderly aged 60-90. The ndings

showed that this program could signicantly

reduce the risk of POCD and POD although

further studies were encouraged [61].

In addition, another randomized clinical tri-

al on 60 elderly patients revealed that post-

operative cognitive training could improve

health-related quality of life and reduce cog-

nitive failure three months after heart valve

surgery [62]. Early mobilization was anoth-

er strategy that Shirvani et al. introduced to

reduce POD via a double-blind randomized

clinical trial on 92 patients undergoing coro-

nary artery bypass grafting [63].

Other interventions have been focused on ce-

rebral oxygenation. A randomized controlled

pilot study on 82 patients, older than 65, who

underwent coronary artery bypass graft sur-

gery on cardiopulmonary bypass revealed that

the incidence of POD in the intervention group

of patients, was signicantly lower (2.4%)

compared to controls (20%) in patients whose

regional cerebral tissue desaturations of more

than 15% of the pre-induction value or below

50% were avoided [64].

Similarly, the optimization of cerebral ox-

ygenation and observance of intraoperative

oxygen concentration are considered strat-

egies for reducing the risk of postoperative

impairment of cognitive ability in elderly pa-

tients undergoing cardiac surgery [65, 66]. In

addition, hemodilution during coronary artery

bypass grafting using cardiopulmonary by-

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Shahabi Raberi V, et al. Postoperative Dementia and Cardiac Surgery

pass (maintaining the hematocrit above 25%

by transfusion of packed red blood cells), per-

forming an aortic o-pump coronary artery

bypass instead of conventional procedure, and

the application of conservative strategies (cor-

onary angiogram only if recurrent ischemia or

heart failure) instead of invasive approaches

(routine coronary angiogram) are among the

most important interventions conducted to re-

duce the risk of delirium and dementia after

heart surgery [67-69].

Conclusion

Delirium and dementia are among the most

important neurocognitive complications after

cardiac surgery. However, the major caus-

ative factors are not fully understood, nor are

the risk factors and biomarkers. The present

References

study revealed that despite the valuable eorts

during recent years, the etiology and deni-

tive diagnosis of these complications, espe-

cially in elderly people who do not manifest

symptoms of precognitive disorders, requires

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cological interventions including sedative

agents or adjuvant anesthetics along with

non-pharmacological interventions such as

cognitive training, cerebral oxygenation, nov-

el surgical approaches, and hemodilution can

signicantly reduce the risk of postoperative

delirium and dementia.

Conict of Interest

The authors declare that there are no conicts

of interests.

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