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anathip Suenghataiphorn, M.D.*, Sakdipat Songwisit, M.D.*, Surapa Tornsatitkul, M.D.**, Pawit Somnuke,
M.D., Ph.D.***
*Faculty of Medicine Siriraj Hospital, **Department of Pharmacology, Faculty of Pharmacy, ***Department of Anesthesiology, Faculty of Medicine,
Siriraj Hospital, Mahidol University, Bangkok 10700, ailand.
An Overview on Postoperative Cognitive
Dysfunction; Pathophysiology, Risk Factors,
Prevention and Treatment
ABSTRACT
Postoperative cognitive dysfunction (POCD) is an event that alarms medical personnel owing to its adverse
eects, including heightened morbidity and mortality rates, prolonged recovery times, and increased lengths of
hospital stay and healthcare expenditure. e populations at high risk are elderly, critical patients, or complicated
cases that need prolonged surgery in which the hemodynamics are not stable. Although guidelines have been
established to facilitate the early diagnosis of POCD, its prevention is recommended for good patient outcomes. A
preoperative assessment is a prerequisite for patient optimization before surgery. Intraoperative, enhanced-recovery
protocols have been widely adopted to promote recovery following surgery. Frequent, postoperative assessments of
patients’ vital signs and cognitive functions are required for early POCD detection. Patients diagnosed with POCD
need regular follow-up, and proper patient counselling is paramount.
Keywords: Diagnostic and Statistical Manual of Mental Disorders (DSM-5); Enhanced Recovery Aer Surgery
(ERAS); Montreal Cognitive Assessment Scale (MoCA); Neurocognitive disorder, Postoperative cognitive dysfunction
(POCD) (Siriraj Med J 2022; 74: 705-713)
Corresponding author: Pawit Somnuke
E-mail: Pawit-pup@hotmail.com
Received 5 June 2022 Revised 5 July 2022 Accepted 6 July 2022
ORCID ID:http://orcid.org/0000-0002-6773-1882
http://dx.doi.org/10.33192/Smj.2022.83
All material is licensed under terms of
the Creative Commons Attribution 4.0
International (CC-BY-NC-ND 4.0)
license unless otherwise stated.
INTRODUCTION
Postoperative cognitive dysfunction (POCD) is
a condition that can occur during the postoperative
or postanesthetic periods.
1
Previous study reported
that upon discharge, 41.4% of patients aged over 60
years developed POCD and, notably, up to 12.7% of
those patients were detected with POCD at 3 months.
1
Morbidity of the patients with POCD at 3 months and
1 year aer surgery was 25.8% and 10%, respectively.
2
e etiologies can be categorized into (1) patient factors:
age > 60 years old, low education level, American Society
of Anesthesiologists (ASA) physical status ≥ 3, and
comorbidities, for example, cerebrovascular disease,
anemia (preoperative hemoglobin ≤ 11 g/dl), preexisting
cognitive dysfunction, poor functional capacity, severe
illness, postoperative respiratory complications and
postoperative infection (2) surgical factors: complex and
complicated surgeries or complications during surgery,
type of surgery and time of surgery ≥ 4 hours and (3)
anesthetic factors: intraoperative use of benzodiazepines
and Isourane volatile anesthetic agent, intraoperative
hypotension and oxygen desaturation during anesthetic
induction.
3-7
POCD contributes to declined general
health, longer length of hospitalization, longer length
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706
of postsurgical recovery, and an increase in 1-year post-
surgical mortality rate.
8,9
e prevention of POCD requires
cooperation between medical specialties throughout the
preoperative, perioperative and postoperative periods.
9
e best strategy for combatting POCD is to prevent
before it occurs. It is paramount that medical personnel
have a thorough understanding about POCD so that they
are capable of planning how to prevent POCD and also
to enhance patients’ postoperative recovery and quality
of life.
is review discusses and summarizes the details of
POCD by using evidence-based medicine covering POCD
denitions, clinical symptoms, diagnosis, pathophysiology,
risk factors, prevention, treatment, and prognosis.
Denition
e Diagnostic and Statistical Manual of Mental
Disorders (DSM-5) has yet to issue a formal denition of
POCD. However, the International Society of Postoperative
Cognitive Dysfunction (ISPOCD) denes it as a condition
that can develop when ≥ 1 abnormality in a discrete
area of mental state such as memory, consciousness
or attention is discovered, which can occur anytime
from immediate postoperative period to 6 months later.
Usually, the onset of impaired memory and intellectual
disability ranges from weeks to months postoperatively
while recovery is within days to weeks.
1,10
POCD can be
diagnosed by comparing the dierences in the results of
baseline preoperative and postoperative psychometric
testing.
9
In 2018, the new consensus among international
medical doctors and scientists was published in the
British Journal of Anesthesia.
11
e clearer denition of
POCD was introduced to facilitate research and education
endeavors: (1) delayed neurocognitive recovery (within 30
days postoperatively) and (2) postoperative neurocognitive
disorder (between 30 days and 12 months postoperatively).
POCD can be dierentiated from other diseases, such
as delirium or dementia, as outlined in Table 1.
1,12-14
Pathophysiology
Although the pathophysiology of POCD is still
not elucidated, it is, by evidence-based, associated with
neuroinammation, disruption of blood-brain barrier
(BBB) integrity, neurosynaptic damage, mitochondrial
dysfunction and oxidative stress.
15-19
Other mechanisms
including hyperventilation, hypotension or cerebral
microemboli were also proposed to involve POCD.
10
Surgical stimuli induce the expression of the inammatory
mediator, high mobility group box-1 (HMGB1), which
interacts with the pattern recognition receptor (PRR) on
macrophages causing downstream activation of innate
immunity. Also, the S100 calcium-binding protein
A12 (S100A12) level increases aer the operation and
thus resulting in intracephalic signal transduction and
inammation.
20
Upon surgical stimulation, intracellular
RNA released from the damaged tissue is detected by the
immune cells therefore inammatory process is initiated.
Proinammatory cytokines from macrophages including
tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6)
TABLE 1. Dierential diagnoses of postoperative cognitive dysfunction.
Parameters Delirium POCD Dementia
Onset
Duration
Attention
Consciousness
Symptoms
Activities of
daily living
Within 3 days
Days to weeks
Decreased
Altered
Fluctuation within the day;
alteration of consciousness;
can be hypoactive or hyperactive
Increased risk of functional
decline
Within a few months
Weeks to months
Decreased
Normal
Memory decline or cognitive
decline
No risk of functional decline
Months to years
Months till death
Decreased
Normal
Memory decline; executive
function decline; changes in
behavior and abilities
Increased risk of functional
decline
Abbreviation: POCD, Postoperative cognitive dysfunction
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and IL-1β are upregulated in the blood circulation.
21-24
ese
cytokines can breach through the BBB via vagus nerve
or paraventricular areas of the BBB leading to activation
of cerebrovascular endothelial cells which will produce
secondary messenger to secrete more proinammatory
cytokines.
25
An increase in brain-specic inammatory
markers such as serum S100 calcium-binding protein B
(S100B) and neuron-specic enolase (NSE) aer surgery
also supports that brain inammation could lead to
POCD.
10,12,26,27
Albeit playing smaller role than surgery,
anesthesia is involved in the pathophysiology of POCD.
Past study demonstrated that isourane caused apoptosis
in human neuronal cell lines and mouse brain potentially
through the accumulation of amyloid β peptide. Randomized
controlled studies also reported higher incidence of
POCD and level of proinammatory markers in groups
anesthetized under volatile anesthesia implying that
volatile might involve in POCD mechanism.
28,29
Risk factors
e risk factors of POCD can be divided into patient,
surgical, and anesthetic factors.
1. Patient factors
Old age
1,30
Age is a major factor of POCD especially in the
elderly aged > 60 years old. Studies have shown that
older age has various eects on the brain, for instance,
decreased brain volume, decreased BBB density, decreased
neurogenesis, reduced cognitive reserve, increased brain
inammation, and increased brain-vessel degeneration.
e medial temporal lobe atrophy as well as the white
matter hyperintensity as seen by magnetic resonance
imaging (MRI) in the elderly were well correlated with
clinical cognitive decline.
31
Low level of education
9,32
Many higher-educated people are prone to engage in
greater levels of complex thinking, leading to heightened
usage of the brain neural network. is extra utilization
may result in the prevention of brain decay due to a
corresponding increase in the cognitive reserve and
improvements to the eciency of neuronal replacement.
Education levels may therefore be employed to indicate
cognitive reserves as each additional year of study has
been demonstrated to result in around a 10% reduction
in the incidence of POCD.
Preexisting cerebrovascular disease
1,33
e patients with preexisting cerebral infarction
were reported to be 18.2% at risk of POCD compare with
4.9% in the control group. erefore, cerebrovascular
disease was considered the potential non-modiable
risk factors of POCD.
Preexisting Systemic Lupus Erythematosus (SLE)
34
A correlation between cognitive impairment and
underlying SLE had been reported previously. However,
the incidence of cognitive dysfunction was not dependent
on SLE duration, activity or evidence of preexisting
neuropsychiatric involvement.
Presence of insulin resistance
35
Preexisting insulin resistance was independently
associated with the incidence of POCD. It has been shown
that insulin resistance reects metabolic disease which
is related to neuropathological process regarding aging
and cognitive function. A reduction in insulin receptor
on the BBB according to insulin resistance results in
decreased insulin transport into the brain causing POCD
and Alzheimer’s disease.
Genetics
36
The Human Apolipoprotein E (ApoE) gene is
located on chromosome 19. E4 allele of the APOE gene is
evidenced to account for Alzheimer’s disease, cognitive
dysfunction and atherosclerosis. To date there are no
studies conrming the eect of sex dierence on POCD.
However, men who are the carriers of APOE4 alleles were
reported to have higher risk of POCD than women with
APOE4.
Alcoholism
37
e elderly with history of alcohol abuse could
pose a higher risk for POCD especially in the domains
related to visuospatial and executive functions.
2. Surgical factors
1,6,38
Complicated and prolonged surgeries > 4 hours,
complications during the peri- or postoperative periods,
and procedures needing multiple surgeries are all risk
factors which could result in POCD. Cardiac surgery
with the application of cardiopulmonary bypass pump
(CPB) is a predisposing factor to POCD. Prolonged
arterial cross clamping time in cardiac surgery plays
an important role in POCD according to poor cerebral
hypoperfusion.
3. Anesthetic factors
Factors such as a prolonged anesthetic period causing
disequilibrium of uids and electrolytes, acute blood
loss, oxygen desaturation, and peri- or postoperative
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anesthetic complications account for POCD. Studies
have also demonstrated that various anesthetic agents
can aect POCD; for example, midazolam may lead to
memory impairment than propofol or remifentanil.
39
Medications aecting the cholinergic system can increase
the POCD risk. On the other hand, previous studies have
found that the perioperative usage of dexmedetomidine
may result in a lower POCD risk by reducing the levels
of IL-6 and S100B.
40-42
Intraoperative use of volatile
anesthesia especially isourane and sevourane had
been reported to inuence higher risk of POCD when
compared with intravenous propofol.
29
Assessment
Assessment of POCD is not straightforward. Variations
among assessors, dierent POCD denitions or diagnostic
tools used, the timing of evaluation, emotion, degree of
pain, medication prole, and environmental setting are
common factors contributing to dierent assessment
results. 43 Many studies have assessed POCD by observing
changes in patients’ neuropsychological signs. e Mini-
Mental State Examination (MMSE) assesses orientation
(time and place), memory (immediate and short-term),
calculation, language (naming, repetition, listening, reading
comprehension, and writing), visuospatial awareness,
concentration, and attention while the Montreal Cognitive
Assessment tool (MoCA) focuses on visuospatial and
executive function (alternate trail-making test, copy the
cube, and clock drawing), language ability, attention
and calculation, delayed recall, and abstract thinking.
44
ese tools are the most common clinical screening
tests for POCD. However, they are not suitable for
cognitive follow-up evaluation.
45
Other test batteries
that are designed to evaluate cognitive status include
various neuropsychological tests (NPT) which determine
specied cognitive domains such as Digit span test, Trail
Making Test, Groove Pegboard Test, etc.
Several screening tests for POCD with comparable
sensitivity and specicity at dierentiating mild cognitive
impairment (MCI) from dementia are Addenbrooke’s
Cognitive Exam (ACE-III), Quick Mild Cognitive
Impairment Screening (Qmci), Saint Louis University
Mental Status (SLUMS), Mini-cog, Rowland Universal
Dementia Assessment Scale (RUDAS) and Abbreviate
Mental Test (AMT) (Table 2).
3,46-55
e new consensus for POCD diagnosis recommends
applying the diagnostic criteria for a neurocognitive
disorder from DSM-5.
11
Neurocognitive assessment relies
on a subjective test (based on the responses of the patient
or close relatives), an objective test (standardized NPT)
as well as an assessment of the patient’s ability to perform
the activities of daily living (ADL). is new approach
provides a more accurate POCD diagnosis compared with
the previous recommendation where only an objective
test was considered. Recent publication reported the use
of the ai version of RUDAS to screen for POCD at
postoperative day 5-9 through real-time video stream
over mobile phone internet connection. Even though the
test consumed longer time, almost 30 minutes per each
patient, than usual face-to-face evaluation, this method
encouraged the use of telemedicine in geriatric patients
especially who were not well complied with clinical
follow-up.
56
Prevention
ere are currently 2 main strategies for POCD
prevention:
1,9
1. Patient factors
Comprehensive geriatric assessment and preoperative
assessment to stratify and optimize risks before proceeding
to operations are recommended during the preoperative
period.
2. Surgical and anesthetic factors
The Enhanced Recovery after Surgery (ERAS)
protocol has been reported to improve postoperative
recovery and to reduce rate of postoperative hospitalization
and morbidity. e general principles of ERAS involve
limited uid intake, preference of laparoscopic surgery,
appropriate anesthetic agent administration, adequate pain
medications, early feeding, and early mobilization. e
ERAS protocol covers the preoperative, intraoperative,
and postoperative states, as outlined below.
3,42,57-64
a. Preoperative state
• Controlling patients’ underlying diseases,
optimizing the risk factors, and providing
preoperative counselling and prehabilitation.
• Recognizing the risks contributing to worsening
outcomes such as major surgery, immobilization,
and prolonged hospitalization.
• Encouraging social and moderate physical
activities to improve cognitive function.
• Implementation of prehabilitation program
at 6-8 weeks preoperatively which involves
processes designed to improve the preoperative
functional status of the patients by:
- Adequate and appropriate exercise including breathing
exercises or resistance training.
- Supplementary dietary intake to improve malnutrition.
- Giving education and advice especially to elderly patients.
- Treatment of comorbidities e.g., atrial brillation which
could relate to POCD.
b. Immediate preoperative state
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TABLE 2. Neuropsychological tests for the assessment of postoperative cognitive dysfunction.
Parameters MMSE MoCA ACE-III Qmci
Parameters SLUMS Mini-cog RUDAS AMT
Total score
Cut off Score for
MCI
Average time to
complete
Sensitivity (%)
Specicity (%)
Advantages
Disadvantages
Total score
Cut off Score for
MCI
Average time to
complete
Sensitivity (%)
Specicity (%)
Advantages
Disadvantages
30
< 24
10 min
79.8%
81.3%
- Less time consuming
- Easy to use
- Low sensitivity and
not suitable to screen
for MCI
30
< 27
7 min
98
98
- High sensitivity and
specicity
- May be affected in
patients with ≤ 6 years
of education and non-
white ethnicity
- New tool, not widely
used
30
< 26
15 min
90
87
- High sensitivity
- Can identify MCI and
cognitive dysfunction
in Alzheimer’s and
Parkinson’s diseases
- Designed for MCI
rather than dementia
5
< 4
3 min
85.7
79.4
- Less time consuming
- Can be used in pri-
mary care setting
- Cannot be used in
patients with visual
impairment or difculty
to hold the pen/pencil
100
< 82–88
16 min
84–93
100
- Can differentiate MCI
from early dementia
- Provides scores for
different cognitive do-
mains with correlation
to NPT
- Cannot differentiate
dementia subtypes
100
< 25
10 min
76.2
75
- Can differentiate MCI
from dementia and
normal cognition
- May be affected in
patients with ≤ 6 years
of education
100
< 62
5 min
90
87
- Less time consuming
- High sensitivity
- Useful test to detect MCI
and dementia
- Maybe inaccurate when
used in certain subgroups
e.g., post stroke patients
10
< 9
3-5 min
91.5
82.4
- Less time consuming
- Can be used as rst line
screening in acute setting
- Normal AMT may not
exclude MCI therefore it
cannot be used as a rule-
out test
Abbreviations: ACE-III, Addenbrooke's Cognitive Examination III; AMT, Abbreviated Mental Test; MCI, Mild cognitive impairment;
MOCA, e Montreal Cognitive Assessment tool; NPT, Neuropsychological test; Qmci, e Quick Mild Cognitive Impairment; RUDAS,
Rowland Universal Dementia Assessment Scale; SLUMPS, Saint Louis University Mental Status
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• Reducing the fasting time is benecial since
prolonged starvation stimulates stress and
anxiety. Maintaining patients in an euvolemic
state is recommended.
• Oral carbohydrate preloading is suggested to
stimulate the neuroendocrine response to
stress.
• romboprophylaxis is recommended for all
patients either by intermittent pneumatic
compression devices, compression stockings
or encouraging early mobilization. e risk
of bleeding needs to be evaluated before
anticoagulant administration.
• Antibiotic prophylaxis should be given 60
minutes before skin incisions.
c. Intraoperative state
• Preanesthetic sedatives and anxiolytics are
not routinely administered.
Short-acting opioids are recommended.
• Sevourane, desurane, intravenous thiopental,
and propofol infusions are recommended to
reduce risks for POCD.
• Monitoring of anesthetic depth and cerebral
oxygenation during surgery.
• Anesthetic agents with small molecular
structures, isourane and desurane, could
create amyloid β-oligomerization which
involve POCD. A large molecular agent like
propofol, if administered with smaller molecular
agents, could also result in amyloid
β-oligomerization production.
• Avoidance of prolonged nitric oxide usage.
• Laparoscopic surgeries are recommended,
given the decreased levels of bowel distention
and lower incidences of postoperative nausea
and vomiting.
• Low tidal volume ventilation (5–7 mL/kg) and
real-time hemodynamic monitoring via an
esophageal doppler are recommended.
• A high level of oxygen can increase blood ow
to the anastomotic site, lessen the risk of delayed
wound healing, and lower the incidences of
postoperative nausea and vomiting.
• Epidural analgesia is recommended for open
surgical procedures.
• Avoidance of drains or nasogastric tubes as
they hinder early mobilization.
• Administration of a local anesthetic around
the wound helps reduce pain and urinary
retention.
• Fluids overloading should be avoided according
to poor intestinal anastomosis, prolonged
bowel ileus, and systemic edema.
• Balanced salt solutions are recommended
because saline overload leads to metabolic
acidosis and hyperchloremia.
• Hypotension from central neuraxial blockade
and general anesthesia should be resolved by
vasoconstrictors rather than uid resuscitation.
• Keeping normothermia as hypothermia may
result in increased metabolic demand, altered
drug metabolism, and impaired immunity
and coagulation.
d. Postoperative state
• Opioids should be used rationally. Paracetamol
and NSAIDs are encouraged for pain control.
• Epidural anesthesia should be given continuously.
• Oral uids should be given 2 hours aer surgery,
and intravenous uids should be administered
cautiously to reduce anastomotic dehiscence
and infection.
• Maintenance of blood glucose between 180–200
mg/dl.
• Early mobilization is encouraged. Nasogastric
tubes, abdominal drains, opioids, and epidural
catheters should therefore not be used from
the second day onwards unless necessary.
• The patients should be settled in a calm
environment and properly advised before
their discharge.
Treatment
POCD treatment is usually based on 2 major
principles:
1,10
1. POCD can be mimicked by POCD-like conditions
(e.g., myocardial infarction, septic shock, medication or
toxic-substance abuse, electrolyte imbalance, a hypo- or
hyperglycemic state, endocrine or liver dysfunction, and
neurological decits). Hypoglycemia can be treated with
an intravenous glucose solution. iamine is the proper
treatment if Wernicke encephalopathy is suspected.
2. e general principles of surgical patient care can be
adapted for POCD patients. Some essential methods include
the provision of adequate ventilation and oxygenation,
hemodynamic support, or adequate postoperative pain
control. Pain control is critical and consequently requires
sucient patient counselling. Monitoring of vital signs,
electrolytes, and the cardiovascular and pulmonary
functions is suggested for enhanced recovery. When
POCD is resolved, patients may recall fragments of
memories during their POCD episodes which may create
stress. It is therefore necessary that medical personnel
give appropriate advice and counselling.
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CONCLUSION
POCD is a condition that warrants early detection
and treatment. e best measure to is to prevent it before
the resulting cognitive dysfunction develops. Proper
pre-, intra- and postoperative patient care should be
considered to reduce the risks of POCD. Preoperative
assessments are necessary to identify patients at risk and
to optimize patients’ condition for particular surgical
procedures. According to the ERAS protocol, hemodynamic
stabilization, adequate uid administration, avoidance of
excessive anesthetic agents, and appropriate management
of hypotension or hypothermia are measures for POCD
risk reduction. Adequate postoperative pain control,
breathing exercise, and early mobilization are essential
to prevent POCD and improve patients’ outcomes.
Additionally, appropriate environmental settings and
frequent postoperative POCD assessments are encouraged.
Once POCD develops, patients should be treated promptly,
scheduled for regular follow-ups, and given proper
counselling.
ACKNOWLEDGMENTS
e authors thank Dr. Arunotai Siriussawakul,
M.D., for her advice and support with the content review
and development of the nal revision. We also gratefully
acknowledge the administrative assistance provided by
Miss Chanita Janoonsong.
Conicts of interest: e authors declare that there are
no conicts of interest.
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