Journal of Clinical Anesthesia xxx (xxxx) xxxx

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Journal of Clinical Anesthesia

journal homepage: www.elsevier.com/locate/jclinane

Original Contribution

A randomized control trial comparing prophylactic dexmedetomidine versus

clonidine on rates and duration of delirium in older adult patients
undergoing coronary artery bypass grafting
⁎
Hoda Shokri (MD, PhD) , Ihab Ali (MD, FRCS (C-TH))
Ain Shams University, Cairo, Egypt

A R T I C LE I N FO A B S T R A C T

Keywords: Study objective: Postoperative delirium occurs in 20–50% of elderly patients undergoing cardiac surgery and
Clonidine increases morbidity and mortality. We investigated whether prophylactic dexmedetomidine could reduce de-
Coronary artery bypass grafting lirium incidence in elderly patients after coronary artery bypass grafting (CABG), compared with clonidine.
Dexmedetomidine Design: Prospective observational trial.
Elderly patients
Setting: Academic university hospital.
Haloperidol
Participants: Patients (60–70 years old) who underwent CABG and received either dexmedetomidine or clonidine
infusion postoperatively.
Interventions: Patients were randomly allocated to dexmedetomidine or clonidine groups. In the dexmedeto-
midine group, patients received an initial infusion of 0.7–1.2 μg/kg/h; sedation and analgesia were evaluated
after 45–60 min. If the Richmond assessment sedation score (RASS) increased from +1 to +4, the infusion rate
was increased by 0.1–0.2 μg/kg/h every 30 min, up to 1–1.4 μg/kg body-weight/h. Dexmedetomidine infusion
was not discontinued pre-extubation; thereafter, infusion was reduced by 0.1 μg/kg/h until 0.2 μg/kg/h. The
maximum infusion duration was 72 h. In the clonidine group, patients received an initial infusion of 0.5 μg/kg,
followed by 1–2 μg/kg/h, if the RASS changed from +1 to +4. This was continued throughout mechanical
ventilation.
Measurements: Patients were followed up to 5 days post-surgery. Delirium incidence, extubation time, lengths of
intensive care unit (ICU) and hospital stay, need for inotropic support or vasopressors, mean arterial blood
pressure and heart rate, hospital mortality rate, total postoperative morphine dose, number of patients receiving
haloperidol, and adverse events were recorded.
Main results: Two-hundred-and-eighty-six patients (dexmedetomidine, 144; clonidine, 142) were studied.
Dexmedetomidine was associated with lower risk and duration of delirium, shorter mechanical ventilation
duration and ICU stay, lower mortality rate, and lower morphine consumption than the clonidine group.
Dexmedetomidine significantly decreased heart rates after ICU admission.
Conclusions: Postoperative infusion of dexmedetomidine provides a feasible option for postoperative control of
delirium after CABG in adult patients.

1. Introduction
The World Health Organization has defined delirium as “an etiolo-
gically nonspecific organic cerebral syndrome, characterized by con-
current disturbances of consciousness, perception, attention, memory,
thinking, psychomotor behavior, the sleep-wake schedule, and emo-
tion.” The degree of severity ranges from mild to very severe, and the
duration is variable [1]. The American Psychiatric Association used a
similar definition in the 5th edition of the Diagnostic and Statistical
Manual (DSM-V). The DSM-V criteria for diagnosis of delirium includes
a disturbance of attention, awareness and cognition in addition to that
represents an acute change from the cognitive baseline and which is not
caused directly by another medical condition, or which had not been
previously established [2].
Postoperative delirium is the most common undiagnosed compli-
cation, with an incidence of 20–80%, in older patients following major
surgical procedures; it is a mixed form of hyperactive delirium and
hypoactive delirium. Hyperactive delirium features irritability,

⁎
Corresponding author.
E-mail address: Drhoda10@yahoo.com (H. Shokri).

https://doi.org/10.1016/j.jclinane.2019.09.016
Received 10 May 2019; Received in revised form 14 August 2019; Accepted 10 September 2019
0952-8180/ © 2019 Elsevier Inc. All rights reserved.

Please cite this article as: Hoda Shokri and Ihab Ali, Journal of Clinical Anesthesia, https://doi.org/10.1016/j.jclinane.2019.09.016
H. Shokri and I. Ali
agitation, and restlessness and patients may pull out intravenous lines,
catheters, or intubation tubes. Patients may experience visual halluci-
nations and think that the medical staff are trying to harm them, ag-
gravating their aggression. In hypoactive delirium, the patient presents
with delayed recovery, decreased alertness and lethargy [3]. It is im-
portant to remember that patients with delirium have fluctuations
throughout their course [3].
Delirium is caused by many stressors, including a neurotransmitter
imbalance (particularly a cholinergic deficiency), inflammation, and
electrolyte or metabolic disturbances [4]. However, the pathophy-
siology of delirium is not yet well understood.
The incidence of postoperative delirium (POD) in patients under-
going cardiac surgery was reported as 20–50%, particularly in elderly
patients admitted to intensive care units (ICUs), who are at the greatest
risk, and in those undergoing major orthopedic (51%) or cardiac sur-
gery (46%) [5]. It is associated with a higher incidence of morbidity
and mortality, lengthy hospital stay, increased financial burden, and
hospital acquired complications [6].
The diagnosis of delirium involves using delirium assessment
methods. The Confusion Assessment Method–Intensive Care Unit (CAM-
ICU) is a brief, easy, reliable, and valid tool for assessing delirium, and
can be administered by both physicians and nurses. Compared to a
psychiatrist's diagnosis of delirium, the CAM-ICU showed high sensi-
tivity and specificity (90–100%) [7]. The CAM-ICU assesses the pa-
tient's sedation level, mental status, disorganized thinking, inattention,
and altered level of consciousness [8]. The CAM-ICU is used to evaluate
patients for delirium when the Richmond Agitation and Sedation Score
(RASS) is −3 or higher. The RASS is a 10-point scale that provides
criteria for levels of sedation and agitation [9], as follows: +4: Com-
bative, +3: Very agitated, +2: Agitated, +1: Restless, 0: Alert and
calm, −1: Drowsy, −2: Light sedation, −3: Moderate sedation, −4:
Deep sedation, −5: Unarousable. The CAM-ICU is typically used to
screen patients admitted to ICU, particularly those patients who are
mechanically ventilated. It can be administered if the patient responds
to verbal stimuli without any physical stimulation. It included a four-
step algorithm: (1) an acute onset of changes or fluctuations in the
course of mental status, (2) inattention (reduced ability to focus), (3)
disorganized thinking, and (4) an altered level of consciousness (dis-
orientation). Patients are considered delirious if both points (1) and (2)
are present in addition to either features (3) or (4). Patients are con-
sidered either CAM-positive (delirium present) or CAM-negative (de-
lirium absent).
There is a strong link between the type of sedation used in the ICU
and the risk of incidence of postoperative delirium [10]. A recent meta-
analysis that included 14 prospective randomized clinical trials (RCTs)
showed that dexmedetomidine reduced the incidence of delirium in
critically ill patients when compared with midazolam sedation [11].
This resulted in shorter duration of mechanical ventilation and reduced
the length of ICU stay [11]. Additionally, a review from 2013 showed
that dexmedetomidine could be suitable for prevention and treatment
of ICU-associated delirium [12]. Dexmedetomidine causes sedation,
and thus provides a natural sleep-like sedation pattern, which may re-
duce the risk of delirium [13]. A study by Su and colleagues concluded
that treatment with dexmedetomidine in elderly patients admitted to
the ICU after non-cardiac surgery decreased the incidence of delirium
from 23% to 9% [14]. A published randomized controlled trial (RCT)
showed that prophylactic low-dose dexmedetomidine significantly de-
creased the risk of post-operative delirium [15], and it is now clinically
used in the USA and Europe [16].
Additionally, orally administered clonidine has similar pharmaco-
logical properties to dexmedetomidine [17], although its alpha-2-
adrenergic selectivity is lower [18]. Rubino et al. [15] found that in-
travenous clonidine (loading dose: 0.5 μg/kg, maintenance drip of
1–2 μg/kg/h) could be used to reduce the severity of delirium (delirium
drug scale [DDS] score, 0.6 ± 0.7 vs. 1.8 ± 0.8, additional clonidine
vs. standard, p < 0.001); it also resulted in a higher partial pressure of
2
Journal of Clinical Anesthesia xxx (xxxx) xxxx
arterial oxygen to fractional inspired oxygen concentration and a
shorter hospital stay.
In this prospective randomized study, we compared the use of
prophylactic dexmedetomidine infusion vs. clonidine infusion for the
safe reduction of the risk and duration of delirium in elderly patients
undergoing coronary artery bypass grafting (CABG).
2. Methods
The institutional ethics committee approved the study (approval
number FMASU R 16/2018, Clinical trial.gov. number NCT03477994);
written informed consent was obtained from every patient. This pro-
spective, double-blind, parallel-group clinical trial was conducted in
294 patients. The following inclusion criteria were used: (1) RCT; (2)
adult (age: 60–70 years) patients with ASA physical status II and III,
scheduled for elective isolated CABG; (3) sedation with dexmedetomi-
dine versus clonidine either for prevention or treatment of postoperative
delirium; (4) incidence of delirium as a mandatory outcome measure-
ment regarding incidence comparison; (5) ejection fraction 50–60%; (6)
absence of any associated comorbidities or history of myocardial in-
farction. The study was performed in Ain Shams University Hospital,
cardiothoracic academy, from December 2018 to February 2019. The
exclusion criteria included: (1) patients with a history of mental illness;
(2) severe dementia, delirium, or who were undergoing emergency
procedures; (3) patients treated with haloperidol; (4) patients who had
any contraindications to the study drugs; (5) a history of drug or alcohol
abuse; (6) impaired renal or hepatic functions. A detailed medical
history, including medications used, and full investigations were as-
sessed on the night of the surgical procedure. In addition, all patients
underwent the Mini-Mental State Examination (MMSE) [19] in con-
junction with a neuropsychiatric consultant.
Anesthesia management was standardized to minimize any effect of
anesthetic type on neurological outcomes. Premedication with mid-
azolam was limited to a maximum of 0.05 mg/kg. Anesthesia was in-
duced with 12 μg/kg fentanyl, 5–7 mg/kg thiopental sodium, and
0.15 mg/kg pancuronium and was maintained with 1–2.0% isoflurane.
Heart rate and blood pressure were maintained within 20% of the
baseline values. Anticoagulation was achieved with heparin 300 U/kg
administered into the right atrium to maintain an activated clotting
time above 480 s. Cardiopulmonary bypass (CPB) was conducted with
non-occlusive roller pumps, membrane oxygenators, arterial line fil-
tration, and cold blood-enriched hyperkalemic arrest. The CPB circuit
was primed with 1.8 l lactated Ringer's solution and 50 ml of 20%
mannitol. Management of CPB included systemic hypothermia (to an
esophageal temperature of 32 °C) during aortic cross-clamping, targeted
mean perfusion pressure between 60 and 80 mmHg, and pump flow
rates of 2.2 l/min/m2. Myocardial protection was achieved with ante-
grade cold blood cardioplegia. A 32-μm filter (Avecor Affinity,
Minneapolis, MN, USA) was used in the arterial perfusion line. Before
separation from CPB, patients were warmed to 36–37 °C. After se-
paration from CPB, heparin was neutralized with protamine sulfate and
1 mg/100 U heparin to reach an activated clotting time within 10% of
baseline. All patients were transferred to the ICU after surgery.
Patients were randomly allocated to either dexmedetomidine or
clonidine (control) groups according to a computer-generated rando-
mization code, with allocation ratio 1:1. Opaque sealed envelopes were
prepared according to the randomization schedule, and were opened by
a resident not involved in any part of the study. Upon arrival at the ICU,
a standardized protocol for postoperative care was implemented for all
patients by well-trained, qualified bedside nurses supervised 1:1 by
well-trained ICU consultants. The study medications were calculated
and prepared by ICU residents who were not a part of the research
team. To ensure blinding of study drug administration, the medication
vials were kept in opaque bags. Trial bags were blinded and marked
with a unique number. The allocation of trial drugs was determined by
the web-based randomization system by the allocation of the bag
H. Shokri and I. Ali
number. Both end-point assessors of the outcomes and patients were
blinded to the study drugs. All staff were blinded to treatment alloca-
tion excluding the ICU consultant and resident who were not part of the
research team.
Patients were managed by the ICU staff, who were not included in
the study. All patients were extubated when deemed clinically appro-
priate according to the local ICU protocol, by ICU staff, when the pa-
tient was able to maintain spontaneous breathing for 48 h, according to
normal weaning parameters, after which they were encouraged to sit on
a chair and mobilize with the assistance of health care providers in the
ICU then the physiotherapist became responsible for improving mobi-
lity and rehabilitation of the patients till discharge from the hospital.
The criteria of weaning were as follows: Hemodynamic stability, ap-
propriate oxygenation, appropriate neurological state, preserved ability
to protect airways and remove secretions, acceptable hemoglobin le-
vels, absence of bleeding.
For sedative protocols, infusion rates were titrated to achieve and
maintain light sedation (RASS −2 to +1) before extubation and (RASS
0) after extubation. In the dexmedetomidine group, patients received an
initial continuous infusion of 0.7–1.2 μg/kg/h; then, adequacy of se-
dation and analgesia were evaluated after 45–60 min. If the RASS score
ranged from +1 to +4, the infusion rate of dexmedetomidine was in-
creased by 0.1–0.2 μg/kg/h every 30 min up to the maximum dose of
1–1.4 μg/kg/h based on the patient's actual body weight. If sedation
was inadequate, a bolus dose of midazolam 15 μg/kg was administered.
The medication was prepared as follows. Dexmedetomidine (Precedex
200 μg per 2 ml; Abbott Laboratories, Abbott Park, IL, USA) was pre-
pared in 0.9% saline and was drawn up in a 50-ml syringe to a con-
centration of 1 μg/ml. The infusion of dexmedetomidine was continued
for a period of 24 h or until discharge from ICU (72 h) if necessary. If
the heart rate was < 60 per min, or if there was persistent hypotension,
the infusion rate was reduced by 0.2 μg/kg/h. Dexmedetomidine infu-
sion was not discontinued before extubation. When the patient was
extubated, the infusion was reduced by 0.1 μg/kg/h until it reached
0.2 μg/kg/h. The weaning rate was reduced if there was an evidence of
withdrawal reactions, such as agitation or hypertension. The loading
dose of dexmedetomidine was omitted to avoid the risk of hypotension.
In the clonidine group, the patients received 0.5 μg/kg in-
travenously (IV) slowly, over a period of 10–15 min, followed by a
continuous IV infusion of 1–2 μg/kg/h if the RASS ranged from +1 to
+4, which was continued until tracheal extubation. It was prepared as
follows: Clonidine (Catapres ampoules 150 μg/ml, Boehringer
Ingelheim Ltd, Berkshire, UK) was diluted in 0.9% saline and drawn up
in 50-ml syringe to a concentration of 15 μg/ml. Patients received
1–2 mg of morphine as rescue analgesic. Opioids were titrated to reach
a visual analogue pain score (VAS) of 3 out of 10. Pain was assessed
using a standard 10-cm visual analogue scale (0: no pain; 10: worst and
unbearable pain).
The primary end-point of the study included the incidence of de-
lirium, which was defined as a disturbed level of consciousness that
develops over a period of hours or days and fluctuates over time.
Delirium was assessed preoperatively (baseline) and postoperatively in
the ICU every 4 h in the first day, then every 8 h for the next day using
the RASS. If RASS > 3, delirium was assessed using the CAM-ICU every
8 h. When patients were discharged from the ICU to the ward, delirium
was assessed using CAM every 8 h throughout the 5 postoperative days
after discharge from ICU [19]. The incidence of delirious attacks was
recorded at the bedside by qualified nurses received intensive training
about 2 weeks in the use of delirium assessment sheets (CAM-ICU) as
part of their education courses, it took about 7 min to fill, and the di-
agnosis was confirmed by a well-trained geriatric consultation expertise
in screening and managing delirium using the Diagnostic and Statistical
Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR)
[20] which is a reference together with Mini-Mental state examination
to assess cognition, attention and level of consciousness at every shift.
DSM-IV-TR included the following criteria:
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Journal of Clinical Anesthesia xxx (xxxx) xxxx
A- Disturbance of consciousness with reduced ability to focus
B- Change of cognition
C- The disturbance develops over short period (hours to days)
D- The disturbance results from the direct physiological consequences
of a general medical condition as evidenced by history, physical
examination and investigations.
Delerium was present if criteria A, B and C were found according to
DSM-IV-TR.
IV haloperidol (2.5–5 mg PRN) was used as a first-line treatment
after failure of extubation due to persistence of agitation or incidence of
delirium after extubation, despite the use of the maximum dose of the
study drugs. A regular dose (1 mg) was used until symptoms resolved; if
deemed necessary, other antipsychotics, such as quetiapine 50 mg/12 h,
were used if the patient did not respond to haloperidol. Delirious pa-
tients were managed by a neuropsychiatric team until the delirium
subsided. Patients were considered delirium-free when they were CAM-
negative for > 24 h and alive.
The secondary endpoints included the duration of delirium de-
termined by a positive CAM-ICU result, which was determined by fol-
lowing delirious patients until 8 days after surgery. Moreover, the
duration of extubation, the length of ICU stay, need for inotropic sup-
port or vasopressors, hospital-stay length, mean arterial blood pressure,
heart rate, hospital mortality rate, total postoperative morphine dose,
and the number of patients receiving additional doses of haloperidol;
finally, adverse events, such as bradycardia, hypotension, nausea, and
vomiting were recorded. Hypotension was defined by a 25% decrease
below the baseline for mean arterial blood pressure, and it was man-
aged with intravenous ephedrine (3–6 mg IV bolus). Bradycardia
(HR < 55 beats/min) was managed with intravenous atropine
(0.1–0.2 mg/kg). An alert, successfully extubated patient, with stable
hemodynamic parameters, and absence of delirium or bleeding were
discharged from the ICU to the ward. The decision to discharge the
patient was made by both the ICU consultant and the cardiac surgeon,
there is not a printed discharge protocol. Then, patients were followed
up by qualified nurses in the use of CAM-test who were supervised by
cardiac surgery consultants, and diagnosis of any attacks of delirium
was confirmed and managed by a neuropsychiatric or geriatric con-
sultation. After hospital discharge, patients who had experienced in-
hospital delirium could be at risk of developing new symptoms for
6 months after discharge; thus, they were referred to post-hospitaliza-
tion health care services for follow-up and to ensure complete recovery.
Additionally, their family members were educated about possible
symptoms of delirium.
2.1. Statistical analysis
Using Power Calculations and Sample Size software (PASS; NCSS,
LLC, East Kaysville, UT, USA) revealed that 294 patients, 147 per arm,
was needed after considering a 5% drop out (power of 80%; alpha error
at 5%). These calculations were based on a previous study [21] that
showed that the postoperative delirium incidence rate among the
dexmedetomidine group was 17.5%, while for the propofol group it was
31.5%; CI 95%, p = 0.028.
Data were analyzed using SPSS Statistics version 23 (IBM© Corp.,
Armonk, NY, USA). Normally distributed numerical data were pre-
sented as mean and SD, and skewed data were presented as median and
interquartile range. Qualitative data were presented as number and
percentage or ratio. Normally distributed numerical data were com-
pared using the unpaired t-test. Skewed numerical data were compared
using the Mann–Whitney test and categorical data were compared using
Fisher's exact test. P-value < 0.05 were considered statistically sig-
nificant.
We also conducted regression analysis in which binary logistic re-
gression models could be fit using either a logistic regression procedure
or a multinomial logistic regression procedure to identify statistically
H. Shokri and I. Ali Journal of Clinical Anesthesia xxx (xxxx) xxxx

Fig. 1. Study flow chart.

significant predictors of postoperative delirium, which had com- Table 1

plementary options. The logistic regression procedure produces all Demographic and surgical data.
predictions, residuals, influence statistics, and goodness-of-fit tests DEX group Clonidine group P-value
using data at the individual case level, regardless of how the data are (n = 144) (n = 142)
entered and whether or not the number of covariate patterns is smaller
Sex
than the total number of cases. The multinomial logistic regression
Female 67(46.5%) 80(57.7%) 0.097
procedure internally aggregates cases to form subpopulations with Male 77(53.5%) 62(43.7%)
identical covariate patterns for the predictors, producing predictions, Age (years) 63.75 ± 3.29 64.38 ± 4.81 0.196
residuals, and goodness-of-fit tests based on these subpopulations. If all ASA (American Association of Anesthesiologists)
predictors are categorical or if any continuous predictors take on only a II 92(63.9%) 87(60.4%) 0.647
III 52(36.1%) 55(38.2%)
limited number of values—so that there are several cases at each dis-
Bypass time 144.65 ± 5.67 143.94 ± 4.81 0.254
tinct covariate pattern—the subpopulation approach can produce valid Surgical procedure duration 453.19 ± 24.38 455.28 ± 25.64 0.480
goodness of fit tests and informative residuals, which the individual HTN (number of patients) 35(24.3%) 40(27.8%) 0.458
case level approach cannot. Weight (kg) 77.2 ± 10.8 82 ± 10.2 0.12
DM 32(22.2%) 38(26.4%) 0.372
Number of red blood cell units 3.12 ± 0.87 3.24 ± 0.72 0.205
3. Results Cross clamp time (minutes) 65.77 ± 10.84 68.21 ± 12.35 0.076
Number of grafts
Single graft 40(27.8%) 35(24.3%) 0.832
A group of 294 patients were randomized (Fig. 1), of which 286
2 grafts 54(37.5%) 55(38.2%)
patients were analyzed (144 patients received dexmedetomidine and 3 grafts 50(34.7%) 52(36.1%)
142 received clonidine). The research team decided on the removal of
patients from the study either because of their clinical condition or All data were presented as percentage except age, weight, bypass time, surgical
violation of the protocol. There was no significant difference in terms of procedure duration, number of blood units and cross clamp time were pre-
demographic data, ASA status, comorbidities, and surgical data be- sented as Mean ± SD. HTN: hypertension; DM: diabetes mellitus; CABG: cor-
tween the two study groups (Table 1). onary artery bypass grafting.
The intention-to-treat analysis of the primary outcome revealed an
incidence of delirium for the entire study population of 12% (35/286). (Table 2). Postoperative mortality was significantly higher in the clo-
It showed an incidence of delirium of 8.3% (12/144) in patients re- nidine group than in the dexmedetomidine group (p = 0.048;
ceiving dexmedetomidine and 16.2% (23/142) in those receiving clo- 0.049–1.131) (Table 2). The length of ICU stay was significantly longer
nidine (p = 0.042; 95% CI 0.224–0.986) (Table 2). The duration of in the clonidine group than in the dexmedetomidine group (p < 0.001;
delirium was significantly longer in the clonidine group compared to 95% CI 0.18–0.42) (Table 2). There was no statistically significant
the dexmedetomidine group (p < 0.001; 95% CI 2.149–2.471) difference in the number of patients who had heart block or the

4
H. Shokri and I. Ali Journal of Clinical Anesthesia xxx (xxxx) xxxx

Table 2
Comparison of the incidence of postoperative complications, length of ICU and hospital stay, postoperative morphine dose and the need for a pacemaker among study
groups.
DEX group Clonidine group P-value 95% CI
(n = 144) (n = 142)

Incidence of delirium (no. of patients) 12(8.3%) 23(16.2%) 0.042⁎ 0.224-0.986

Duration of delirium (days) 2.04 ± 0.67 4.35 ± 0.71 < 0.001⁎ 2.149-2.471
Postoperative mortality 2(1.4%) 8(5.6%) 0.048⁎ 0.049-1.131
ICU stay length (days) 2.74 ± 0.59 3.04 ± 0.43 < 0.001⁎ 0.18-0.42
Incidence of hypotension (no. of patients) 7(4.9%) 6(4.2%) 0.796 0.379–3.535
Postoperative extubation time (hours) 5.32 ± 0.66 7.15 ± 0.48 < 0.001⁎ 1.696-1.964
Number of patients receiving haloperidol 3(2.1%) 5(3.5%) 0.461 0.136–2.486
Total Postoperative morphine dose (mg) over 3 days 18.24 ± 8.62 22.37 ± 10.73 < 0.001⁎ 1.866-6.394
Bradycardia 3(2.1%) 2(1.4%) 0.663 0.245–9.05
Nausea 4(2.8%) 6(4.2%) 0.505 0.178–2.345
Vomiting 7(4.9%) 12(8.3%) 0.223 0.211–1.449
Hospital stay length (days) 8.04 ± 2.16 10.18 ± 1.84 < 0.001⁎ 1.673-2.607

All data were presented as percentage except duration of delirium, ICU stay, extubation time, postoperative morphine dose and length of hospital stay were presented
as Mean ± SD. no.: number; CI: confidence interval.
⁎
P value < 0.001 was considered highly significant between the study groups.

incidence of bradycardia (p = 0.796 and p = 0.663, respectively) Table 4

(Table 2). Postoperative extubation time was significantly shorter in Comparison of heart rate values between the study groups.
dexmedetomidine group than in the clonidine group (p < 0.001; 95% Heart rate DEX group Clonidine group P-value
CI 1.696–1.964) (Table 2). (n = 144) (n = 142)
Total postoperative morphine consumption was significantly higher
in the clonidine group compared to the dexmedetomidine group Baseline 95.46 ± 3.34 96.05 ± 3.06 0.120
1st day 83.19 ± 1.67 87.26 ± 1.84 < 0.001a
(p < 0.001; 95% CI 1.866–6.394) (Table 2). There was no significant 2nd day 77.5 ± 2.34 84.2 ± 1.62 < 0.001a
difference between the study groups in terms of nausea (p = 0.505; 3rd day 76.4 ± 1.48 82.8 ± 2.17 < 0.001a
95% CI 0.178–2.345) and vomiting (p = 0.223) (Table 2). The length of
hospital stay was significantly longer in the clonidine group than in the All data were presented as mean ± SD.
a
dexmedetomidine group (p < 0.001; 95% CI1.673–2.607) (Table 2). Highly significant.
There was no significant difference between the study groups in
terms of mean arterial blood pressure at any of the time points morphine consumption with a relatively lower incidence of complica-
(Table 3). Heart rate values were significantly higher in the clonidine tions with dexmedetomidine than clonidine. Our results are consistent
group than in the dexmedetomidine group in the first 3 days post- with the findings of a RCT by Jose et al., conducted on patients un-
operatively (p < 0.001); however, baseline values were similar be- dergoing valve replacement surgery, which concluded that the in-
tween the two groups (Table 4). cidence of delirium in patients receiving dexmedetomidine was about
Logistic regression analysis of delirium showed that increased age 3% as compared with those receiving propofol (50%) and those re-
(p < 0.001), increasing number of grafts (p = 0.045), and use of clo- ceiving midazolam (50%) [22].
nidine were associated with a higher incidence of delirium (p = 0.022), Moreover, a meta-analysis by Xu and his colleagues revealed that
but sex (p = 0.502) and ASA status (p = 0.802) were not associated 9.3% of 193 patients in the dexmedetomidine group, while 23.5% of
with an increased incidence of delirium (Table 5). 200 patients in the propofol group suffered from delirium. This study
presented that dexmedetomidine sedation significantly reduced post-
4. Discussion operative delirium (POD: RR, 0.40: 95% CI, 0.24–0.64; p = 0.0002)
[23]. Consistent with the findings of Shehabi and his colleagues [24],
We compared the use of prophylactic dexmedetomidine infusion for who concluded that the duration of delirium was significantly shorter in
safely reducing the risk and duration of delirium in elderly patients the dexmedetomidine (IV infusion of 0.1 to 0.7 μg/kg/h) than in the
undergoing CABG, in comparison with the use of clonidine. We found propofol group (2 ± 4 vs. 5 ± 8 days, respectively, p = 0.032), there
that dexmedetomidine had a lower incidence of delirium than cloni- was no significant difference among dexmedetomidine, propofol, and
dine. midazolam, regarding the mortality rate. The incidence of hypotension
The results of this prospective study showed that postoperative in- and bradycardia was significantly higher in the dexmedetomidine
fusion of dexmedetomidine is a feasible option for prevention and group, and patients in the dexmedetomidine group required sig-
treatment of postoperative delirium in elderly patients undergoing nificantly more supplemental propofol (64% of patients), midazolam
CABG. This was evident by the decreased incidence and duration of (3%), or both (7%); these findings were different from those of our
delirium, the length of hospital stay, extubation time, and postoperative study.
Rubino et al. [15] suggested that supplemental clonidine (loading
Table 3 dose: 0.5 μg/kg followed by IV infusion of 1–2 μg/kg/h) significantly
Comparison of the mean arterial blood pressures between the study groups. reduced the incidence of delirium (DDS, 0.6 ± 0.7 vs. 1.8 ± 0.8, ad-
ditional clonidine vs. standard dose, P < 0.001) Our results differed
MAP DEX group Clonidine group P-value
(n = 144) (n = 142)
from those of Lin et al. [25], who showed that dexmedetomidine se-
dation caused a significant increase in the incidence of delirium in
Baseline 90.62 ± 15.07 91.27 ± 17.28 0.734 patients undergoing cardiac surgery. On the other hand, a meta-analysis
1st day 85.64 ± 12.91 88.61 ± 16.81 0.094 by Tan and colleagues [26] found that the use of dexmedetomidine in
2nd day 84.24 ± 18.54 88.22 ± 17.92 0.066
3rd day 83.16 ± 16.49 86.27 ± 15.27 0.099
elderly adult patients had no significant effect on the incidence of de-
lirium, which was also contrary to our findings. However, our results
All data were presented as mean ± SD. MAP: mean arterial blood pressure. were in agreement with the findings of Joey et al., who showed that the

5
H. Shokri and I. Ali Journal of Clinical Anesthesia xxx (xxxx) xxxx

Table 5
Results of multivariable regression analysis with delirium as dependable variable.
Unstandardized coefficients Standardized coefficients t P-value

B Std. error Beta

(Constant) −0.202 0.134 1.509 0.133

Dex versus clonidine groups 0.087 0.038 0.136 2.303 0.022a
Age 0.021 0.006 0.217 3.766 < 0.001⁎⁎
Sex 0.026 0.039 0.040 0.673 0.502
ASA 0.010 0.038 0.015 0.251 0.802
Number of grafts (GABG) 0.055 0.027 0.119 2.015 0.045a
Dependent variable: delerium

ASA: American society of Anesthesia; CABG: coronary artery bypass grafting; Dex: dexmedetomidine.
a
Significant.
⁎⁎
Highly significant.

incidence of postoperative delirium in the ICU was significantly lower
in a dexmedetomidine group (54%) than in a midazolam group (76%);
the dexmedetomidine group also had significantly shorter extubation
time [27].
A previous study showed that, by exerting anti-inflammatory ef-
fects, stabilizing the sympathetic nervous system and attenuating
ischemia/reperfusion injury, dexmedetomidine reduced isoflurane-in-
duced delirium, in addition to decreasing the time spent on the venti-
lator [28]. Our findings were also consistent with the findings of a
randomized clinical trial by Su et al. [14], in which 700 patients were
randomly assigned to receive either dexmedetomidine or placebo after
non-cardiac surgery. In the dexmedetomidine group, the incidence of
postoperative delirium was significantly lower (9% of 350 patients)
than in the placebo group (23% of 350 patients; p < 0.0001).
Additionally, our findings agreed with a previous study that showed
that the incidence of hypotension and bradycardia were similar in a
placebo and dexmedetomidine group [10]. In contrast, a meta-analysis
by Julian et al. showed that administration of dexmedetomidine was
associated with significantly lower incidence of delirium compared
with placebo (RR 0.52; 95% CI 0.39–0.70; I2 = 37%), but had a sig-
nificantly higher incidence of hypotension and bradycardia [29].
Dexmedetomidine improves the quality of sleep in ICU patients
[30], particularly the non-rapid eye movement sleep pattern [17]. It
causes sedation associated with a degree of arousability among patients
in the ICU. This resulted in a shorter time to extubation [31], decreased
incidence of delirium [32], and a lower mortality than other agents,
particularly in certain populations [33].
In addition to its α2-adrenergic receptor agonist effects, it has also
been shown to have an opioid-sparing effect [34]. Dexmedetomidine
has been shown to attenuate the inflammatory response of CPB [35].
These unique characteristics of dexmedetomidine may have reduced
the incidence and duration of postoperative delirium in our study. A
review from 2013 suggested dexmedetomidine could be suitable for
both prevention and treatment of ICU-associated delirium [36]. A meta-
analysis by Reade et al. concluded that a significantly rapid resolution
of delirium in patients of dexmedetomidine group (median, 23.3 h;
n = 39 vs. 40.0 h; p = 0.01) [37].
Consequently, it is not surprising that the use of dexmedetomidine
during the postoperative period has also been associated with reduced
mortality. To ensure that the use of dexmedetomidine could reduce
mortality in patients undergoing CABG, we should rely on high-level
evidence based on a large number of RCTs and their meta-analysis.
Many factors contribute to mortality, including old age, an increased
need of transfusion, hemodilution, heart block, and myocardial in-
farction.
The major limitation of our study was that it had a single-center
design with a possible bias by institutional standards of care. Further
evaluations, using larger multi-center studies, are required. The in-
sufficient number of previous studies comparing the effects of dexme-
detomidine compared with clonidine for prevention of postoperative
delirium in addition to the poor review of the effects of clonidine for
reducing the risk of postoperative delirium hinders our ability to
compare the results of this study with other similar studies.
Additionally, we were unable to obtain sufficient data to determine the
exact incidence rate of postoperative delirium in the Egyptian popula-
tion as compared to the global population. We did not consider placebo
as a third arm for the study, as postoperative sedation is essential after
cardiac surgery according to the institutional protocol in which patients
have been ventilated for < 10 h and are liable to develop delirium. In
addition, in the instance of delirium occurring, the patient requires
appropriate treatment.
5. Conclusion
Dexmedetomidine sedation provides a feasible option for post-
operative control and treatment of delirium, reducing the length of
hospital stay, extubation time, and postoperative morphine consump-
tion, with a lower incidence of complications as compared with cloni-
dine.
Declaration of competing interest
Not applicable.
Acknowledgement
Not applicable.
Funding sources
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
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