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Original article 361

Effect of midazolam, propofol, and dexmedetomidine on

postoperative cognitive dysfunction after cardiac surgery in the
elderly
Mofeed A. Abdelmaboud
Department of Anesthesia and Intensive Care, Background
Al-Azhar Faculty of Medicine for Boys, Cairo, Postoperative cognitive dysfunction (POCD) is among the most prevalent and
Egypt
serious life-threatening postoperative complications.
Correspondence to Mofeed A. Abdelmaboud, Aim
MD, El-Shiiekh El-Shami Street, Seqil Ausim,
The primary outcome was to compare the efficacy of dexmedetomidine, propofol,
Giza 12992, Egypt. Tel: 01114985409,
01006780507; and midazolam on prevention of POCD during cardiac surgery in the elderly. The
e-mail: rodymofy2012@yahoo.com secondary outcome is to determine possible complications during the first
Received: 19 June 2019
postoperative day.
Revised: 2 September 2019 Patients and methods
Accepted: 14 October 2019 Ninety elderly patients undergoing cardiac surgery were randomly divided
Published: 14 February 2020 during the cardiopulmonary bypass period into three equal groups. group M:
Al-Azhar Assiut Medical Journal 2019, received midazolam 0.1 mg/kg/h, group P: received propofol 1 mg/kg/h, and
17:361–366 group D: received dexmedetomidine 0.5 μg/kg/h. Mini-Mental State Examination
(MMSE), incidence of POCD, and interleukin 6 (IL-6) were recorded on the day
before surgery (M0, F0, L0, respectively), 1 h after extubation (M1, F1, L1,
respectively), and 1 week postoperatively (M2, F2, L2, respectively). POCD
was diagnosed when the MMSE score decreased two points or more
from the preoperative value. Adverse effects (hypotension, bradycardia,
laryngospasm, postoperative nausea and vomiting, and hypertension) were
recorded.
Results
As regards MMSE, there were no significant differences among groups except at
M1 where it was higher in group D than the other two groups. In groups M and P
only, MMSE was significantly higher at M1 than M0 and returned to near
preoperative value at M2 in the same group. There were no significant
differences regarding the incidence of POCD at F0, F1, and F2. There were no
significant differences with respect to blood IL-6, among groups except at L1 where
it was significantly higher in both group M and group P than group D. In groups M
and P only, IL-6 was significantly higher at L1 than L0 and then returned to near
preoperative value at L2 in the same group.
Conclusion
Dexmedetomidine was a good choice for reducing POCD in cardiac surgery in
elderly patients with less side effects.

Keywords:
cardiac surgery, elderly, midazolam, postoperative cognitive dysfunction, propofol and
dexmedetomidine
Al-Azhar Assiut Med J 17:361–366
© 2020 Al-Azhar Assiut Medical Journal
1687-1693

Several factors can influence the incidence of POCD

Introduction
such as aging, genetics, comorbidities, education, type
Postoperative cognitive dysfunction (POCD) is a
of anesthesia, type of surgery, and preoperative
common complication frequently observed after
cognition. This is why there is no specific drugs that
general anesthesia in the immediate postoperative
can prevent POCD or treating it once it develops [5].
period or sometimes up to 4 weeks postoperatively
and can persist for months or even be lifelong [1,2].
Benzodiazepines are sedative, hypnotic, and anxiolytic
drugs due to their effects on GABA receptors [6].
Clinical evidence has shown higher incidence of
POCD in elderly patients following surgery [3].
This is an open access journal, and articles are distributed under the terms
of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0
Several studies have noted that the incidence of POCD
License, which allows others to remix, tweak, and build upon the work
was 53% following on-pump coronary artery bypass non-commercially, as long as appropriate credit is given and the new
grafting surgery [4]. creations are licensed under the identical terms.

© 2020 Al Azhar Assiut Medical Journal | Published by Wolters Kluwer - Medknow DOI: 10.4103/AZMJ.AZMJ_87_19
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362 Al-Azhar Assiut Medical Journal, Vol. 17 No. 4, October-December 2019
Midazolam is a benzodiazepine used immediately
before anesthesia induction and causes loss of ability
to form new memories. However, it does not relieve
pain and a high dosage can lead to delayed recovery,
respiratory depression, and decreased oxygen
saturation (SpO2) [7].
Propofol is 2,6-diisopropylphenol that introduced in
1989. It has a very short half-life with rapid recovery.
Propofol produces a dose-dependent decrease in
cerebral metabolic rate and cerebral blood flow [8].
Dexmedetomidine is a highly selective α2-
adrenoceptor agonist with analgesic, sedative, and
sympatholytic effects. It is widely used as an adjunct
sedative in elderly patients [9]. Adrenergic pathway
plays an important role in the formation of cognition.
Moreover, α2-adrenoceptors regulate the formation of
learning, memory, and selective attention by the dorsal
ascending noradrenergic bundles from the locus
ceruleus in the brain stem. It has been confirmed
that dexmedetomidine provides its neuroprotective
effects by inducing extracellular signaling-regulated
kinase phosphorylation [10].
An association between inflammatory response and
POCD has been reported. Surgical trauma
stimulates the immune cascade with release of
inflammatory cytokines, which may induce POCD.
A number of animal studies have shown that
dexmedetomidine can reduce inflammation and
incidence of POCD [11].
Aim
The primary outcome was to compare the efficacy of
dexmedetomidine, propofol, and midazolam on the
prevention of POCD during cardiac surgery in
elderly patients. The secondary outcome is to
determine possible complications [hypotension,
bradycardia, laryngospasm or bronchospasm,
postoperative nausea and vomiting (PONV), and
hypertension] during the first postoperative day.
Sample size justification
Med Cal, Version 12.3.0.0 program (Ostend,
Belgium) was used for sample size calculation,
statistical calculator based on confidence interval
95%, and power of study 80% with an α error of
5%, according to a previous study by Rajaei et al. [12],
so this study can be relied, and based on this
assumption, and according to this value, minimum
sample size of 84 cases was enough to find such
difference. Assuming a 5% dropout, the sample
size will be 90 cases, subdivided into three equal
groups.
Patients and methods
After taking approval from Anesthesia and Intensive
Care Department, Al-Azhar Faculty of Medicine and
from local ethics committee and informed written
consent from each participant, this study was done
at El-Hussein University Hospital in the period from
March 2018 to May 2019.
Inclusion criteria
Age more than or equal to 65 years of both sexes,
American Society of Anesthesiologists physical status
of II or III, scheduled for valve surgeries or on-pump
coronary artery bypass grafting with operative time
within 4–5 h, no significant serious cerebral,
cardiovascular, respiratory, hepatic disease or renal,
no history of benzodiazepine, antidepressant use,
alcohol or drug dependence, no allergy to study
medications, with the ability to understand Mini-
Mental State Examination (MMSE), and
preoperative MMSE scores of more than 23.
Exclusion criteria
Emergency cases, MMSE of less than or equal to 23,
central nervous system or mental disease, need for
moderate hypothermia, and patient’s refusal.
After reaching the operating room, 18 G intravenous
cannula and arterial cannula were inserted to all
participants and the patients were monitored with
ECG, SpO2, end-tidal CO2 (ETCO2), and invasive
blood pressure.
MMSE [1], incidence of POCD, and IL-6 were
recorded on the day before surgery (M0, F0, L0,
respectively).
POCD was diagnosed when there was a decrease in
MMSE score of two points or more from preoperative
value (Table 1).
Anesthesia was standardized to all patients. Following
preoxygenation for 5 min with 100% oxygen anesthesia
was induced with intravenous thiopental 5 mg/kg,
intravenous fentanyl 5 μg/kg, and intravenous
atracurium 0.5 mg/kg followed 3 min later by
intubation with appropriate size cuffed endotracheal
tube. Anesthesia was maintained with isoflurane
(1.2%) in oxygen, intravenous atracurium (0.15 mg/
kg) as needed, and fentanyl infusion at a rate of 1–3 μg/
kg/h (500 μg diluted in 40 ml normal saline 0.9% with a
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Effect of medication on postoperative cognitive dysfunction after cardiac surgery in elderly Abdelmaboud
Table 1 Mini-Mental State Examination test [13]
Category Points Description
Orientation to 5 From broadest to narrowest.
time Orientation to time has been correlated
with future decline
Orientation to 5 From broadest to narrowest. This is
place sometimes narrowed down to street
and sometimes to the floor
Registration 3 Repeating named prompts
Attention and 5 Serial sevens or spelling ‘world’
calculation backwards. It has been suggested that
serial sevens may be more appropriate
for a population where English is not
the first language
Recall 3 Registration recall
Language 2 Naming pencil and watch
Repetition 1 Speaking back a phrase
Complex 6 Varies; can involve drawing figure
commands shown
concentration of 10 μg/ml). Ventilation was adjusted to
maintain an ETCO2 of between 35 and 40 mmHg.
Oropharyngeal thermometer was inserted for
temperature monitoring. Central venous line was
inserted to all patients under complete aseptic condition.
Continuous monitoring in the form of invasive blood
pressure, heart rate, SpO2, ETCO2, oropharyngeal
temperature, urine output, and arterial blood gases
were recorded on demand.
Once patients were connected to cardiopulmonary
bypass (CPB), and separated from anesthesia
machine, 90 patients fulfilling the inclusion criteria
were randomly divided during the CBP period using
computer randomization into three equal groups (30
patients each):
(1) Midazolam group (group M): received midazolam
(Amoun Pharmaceuticals Co, El-Obour City,
Cairo, Egypt) at an infusion rate of 0.1 mg/kg/h
(50 mg in 50 ml syringe with a concentration of
1 mg/ml).
(2) Propofol group (group P): received propofol
(Fresenius Kabi Deutschland GmbH, Bad
Homburg vd.H., Germany) at an infusion rate
of 1 mg/kg/h (500 mg in 50 ml syringe with a
concentration of 10 mg/ml).
(3) Dexmedetomidine group (group D): received
dexmedetomidine (RL-4409; Hospira Inc., Lake
Forest, Illinois, USA) at an infusion rate of 0.5 μg/
kg/h.
During CPB, the blood flow was adjusted to maintain a
mean blood pressure of between 50 and 60 mmHg, the
363
temperature was kept at 34°C during cooling, the
PaCO2 between 36 and 45 cmH2O, the pH was
kept above 7.36, and hematocrit at about 30. Any
changes in these parameters were adjusted by the
perfusionist.
Once patients are weaned from CPB, dexmedetomidine,
propofol, and midazolam infusions were discontinued
and the patients are reconnected to the anesthesia
machine with 1.2% isoflurane in 100% O2 and the
lungs are re-expanded manually and anesthesia was
maintained till skin closure.
The patients were extubated in the cardiac surgical
unit. MMSE test, incidence of POCD, and plasma
levels of interleukin 6 (IL-6) (pg/ml) at 1 h after
extubation (M1, F1, L1, respectively) and 1 week
after surgery (M2, F2, L2, respectively) were taken.
IL-6 was measured by enzyme-linked immunosorbent
assay, using the kit supplied by the Bioscience Company
(Schloss-Rahe-Str. 1552072 Aachen, Germany) (IL-6
enzyme-linked immunosorbent assay kit product,
ABIN365163).
Possible complications (including hypotension,
bradycardia, laryngospasm or bronchospasm, PONV,
and hypertension) during the first postoperative day
were recorded.
Results
The three groups were comparable regarding patient
characteristics (Table 2).
Group M: midazolam group, group P: propofol group,
group D: dexmedetomidine. Data are represented as
mean±SD and n (%). P value more than 0.05,
statistically not significant; P value less than 0.05,
statistically significant; P less than 0.001, highly
significant.
As regards MMSE, there were no significant
differences among groups except at M1 where it was
higher in group D than the other two groups. In group
M and group P only, MMSE was significantly higher
at M1 than M0 and returned to near preoperative value
at M2 in the same group. There were no significant
differences regarding incidence of POCD at F0, F1,
and F2 (Table 3).
There were no significant differences with respect to
blood IL-6, among groups except at L1 where it was
significantly higher in both group M and group P than
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364 Al-Azhar Assiut Medical Journal, Vol. 17 No. 4, October-December 2019

Table 2 Patient characteristics group D. In group M and group P only, IL-6 was
Group M Group P Group D P significantly higher at L1 than L0 and then returned to
(N=30) (N=30) (N=30) value near preoperative value at L2 in the same group
Age (years) 67.4±3.2 68.6±4.5 66.7±5.7 0.273 (Table 4).
Sex (male/ 16 (53.3)/ 15 (50)/15 13 (43.3)/ 0.733
female) 14 (46.7) (50) 17 (56.7)
As regard adverse effects among groups, there were no
Weight (kg) 77.5±11.3 79.3±12.5 80.4±14.5
ASA (II/III) 15 (50)/15 14 (46.7)/ 13 (43.3)/ 0.875
significant differences except PONV where it was
(50) 16 (53.3) 17 (56.7) significantly higher in group P than the other two
History of 13 (43.3) 14 (46.7) 14 (46.7) 0.956 groups (P=0.041, 0.017, respectively) (Fig. 1).
hypertension
History of DM 12 (40) 11 (36.7) 13 (43.3) 0.870
History of 10 (33.3) 9 (30) 11 (36.7) 0.861 Discussion
hyperlipidemia
The current study showed that there were no significant
Type of surgery
MVR 12 (40) 11 (36.7) 12 (40) 0954
differences among groups regarding MMSE except at
AVR 8 (26.7) 8 (26.7) 9 (30) 0.946 1 h after extubation where it was higher in the
On-pump 10 (33.3) 11 (36.7) 9 (30) 0.861 dexmedetomidine group than both midazolam and
CABG propofol groups. It was significantly higher in both
AVR, aortic valve replacement; MVR, mitral valve replacement. midazolam and propofol groups only at 1 h after
Data are represented as mean±SD and n (%). ASA, American extubation than preoperative level and returned to
Society of Anesthesiologists; CABG, coronary artery bypass
grafting; DM, diabetes mellitus; group D: dexmedetomidine group; near preoperative value at 7 days postoperatively in the
group M, midazolam group; group P, propofol group. P value more same group. Yang et al. [13] observed that perioperative
than 0.05, statistically not significant. P value less than 0.05,
dexmedetomidine improved MMSE score on first
statistically significant. P value less than 0.001, highly significant.
postoperative day. Zhang et al. [14] demonstrated that
dexmedetomidine increased the MMSE score on first,
third, and seventh postoperative days after sevoflurane
Table 3 Surgical details among groups
anesthesia in elderly patients. Zhou et al. [15] showed
Group M Group P Group D P
(N=30) (N=30) (N=30) value that dexmedetomidine improved MMSE on the first
postoperative day and after the first postoperative day in
Operation time 266.3 272.5 276.8 0.185
(min) ±22.6 ±19.8 ±23.6 elderly patients after general anesthesia. Mansouri et al.
Aortic cross- 64.6±13.5 67.4±14.3 70.3±15.2 0.311 [16] showed that there were no significant differences
clamping time (min) between dexmedetomidine and midazolam groups in the
CBP time (min) 175.5 178.9 181.5 0.452
MMSE score at 1 and 7 days postoperatively (P>0.05),
±18.6 ±16.8 ±19.7
Aortic declamping 208.5 213.7 216.4 0.55
but it was significantly higher in these two groups than
time (min) ±12.1 ±14.6 ±11.2 control (P<0.05). Rajaei et al. [12] observed that the
Data are represented as mean±SD. Group D, dexmedetomidine MMSE results were not statistically different between
group; group M, midazolam group; group P, propofol group. P the midazolam and dexmedetomidine groups at 5 days
value more than 0.05, statistically not significant. P value less than
0.05, statistically significant. P value less than 0.001, highly
postoperatively (24.8076±3.16 vs. 22.4±4.9,
significant. respectively) (P=0.12). Metry et al. [1] demonstrated

Table 4 Mini-Mental State Examination test and incidence of cognitive dysfunction among groups
Group M (N=30) Group P (N=30) Group D (N=30) P value
MMSE
Preoperative (M0) 27.8±1.4 28.3±1.2 27.9±1.3 0.295
1 h after extubation (M1) 25.8±1.2 25.9±1.1 26.8±1.1 0.001
Group M vs. group P Group M vs. group D Group P vs. group D
0.738 0.001 0.002 0.916
1 week after surgery (M2) 27.4±1.2 28.1±1.0 27.5±1.2
Frequency of cognitive dysfunction
Preoperative (F0) 0 0 0 1.0
1 h after extubation (F1) 12 (40) 12 (40.7) 10 (33.7) 0.828
1 week after surgery (F2) 9 (30) 10 (33.3) 7 (23.3) 0.685
Data are represented as mean±SD and n (%). Group D, dexmedetomidine group; group M, midazolam group; group P, propofol group;
MMSE, Mini-Mental State Examination. P value more than 0.05, statistically not significant. P value less than 0.05, statistically significant.
P value less than 0.001, highly significant.*Significant difference between group M and group D.
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Effect of medication on postoperative cognitive dysfunction after cardiac surgery in elderly Abdelmaboud
Figure 1
Adverse effects among groups.
that with respect to MMSE at 1 h postoperatively, there
was a decrease in both dexmedetomidine and propofol
groups (32.3±0.408 vs. 23.2±0.41) but without
significant difference (P=1.0) and returned back to
baseline (30) at 7 days postoperatively (P=1.0).
This study showed no significant differences regarding
the incidence of POCD among three groups. Yang et al.
[13] observed that perioperative dexmedetomidine
significantly reduced the incidence of POCD on first
postoperative day. Zhang et al. [14] demonstrated that
dexmedetomidine could improve POCD caused by
sevoflurane in elderly patients by decreasing IL-6 and
TNF-α concentration at the first, third, and seventh
postoperative days. Zhou et al. [15] showed that
dexmedetomidine significantly reduced the incidence
of POCD in elderly patients after general anesthesia on
the first postoperative day and after the first
postoperative day. Man et al. [17] observed that
perioperative dexmedetomidine was associated with
significant better postoperative neurocognitive
function in comparison with both saline controls and
anesthetics predominantly midazolam. Chen et al. [18]
demonstrated that dexmedetomidine significantly
reduces the incidence of POCD compared with
control group (9.2 vs. 21.31%, respectively, with
P<0.05) by reducing the increase of postoperative
TNF-α and IL-6 levels (P<0.05). Mansouri et al.
[16] showed that regarding the incidence POCD at
1 and 7 days postoperatively, there were no significant
differences between dexmedetomidine groups (12 and
12%, respectively) and midazolam (14 and 8%,
respectively) (P>0.05) but there was significant
differences between both groups and control (it was
24 and 20%, respectively, in the control group)
(P<0.05). Wang et al. [19] showed that the
incidence of POCD at 5–7 postoperative days was
24.5% in the dexmedetomidine group and 28.0% in
the midazolam group but with no significance
(P=0.575).
365
Dexmedetomidine reduces the incidence of POCD
and improves MMSE by acting at the locus ceruleus
in the brain stem which contain the highest
concentration of α2-adrenoceptors thus inhibiting
neuronal discharge and activity of the sympathetic
nervous system [20].
The current study demonstrated that, regarding blood
IL-6, there were no significant differences among
groups except at 1 h after extubation where it was
significantly higher in both midazolam and propofol
groups than dexmedetomidine group, and it was
significantly higher in midazolam and propofol
groups only at 1 h after extubation than preoperative
level and then returned to near preoperative value at 7
days postoperatively in the same group. Yang et al. [13]
observed that perioperative dexmedetomidine
significantly reduced IL-6 on the first postoperative
day compared with the control group.
The present study showed that there were no
significant differences among groups respecting
adverse effects except PONV where it was higher in
the propofol group than the other two groups. Zhang
et al. [14] observed that, in propofol group, the
incidence of hypotension was 13.3%, bradycardia
3.1%, laryngospasm or bronchospasm 3.1%, PONV
31.3%, and hypertension 10.3%. Lu et al. [21]
demonstrated that, in the dexmedetomidine group,
the incidence of bradycardia is 0%, postoperative
nausea is 9.2%), and vomiting is 6.6%.
Conclusion
First dexmedetomidine was more effective than
midazolam and propofol in reducing the incidence
of POCD in elderly patients in cardiac surgery with
better MMSE score and lower blood level of IL-6.
Second midazolam and dexmedetomidine showed a
lower incidence of PONV. So, this study concluded
[Downloaded free from http://www.azmj.eg.net on Monday, June 13, 2022, IP: 112.215.242.112]
366 Al-Azhar Assiut Medical Journal, Vol. 17 No. 4, October-December 2019
that dexmedetomidine was a good choice for reducing
POCD in cardiac surgery in elderly patients with less
side effects.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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