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Retrospective Clinical Research Report
Dexmedetomidine is superior
to midazolam for sedation
and cerebral protection in
postoperative hypertensive
intracerebral hemorrhage
patients: a retrospective study
Weiyi Gong*, Shuguang Zhang*, Xiaoliang Li*
and Lei Shi
Abstract
Objective: Dexmedetomidine has a good sedative effect and does not affect the judgment of the
patient’s consciousness level. However, its effectiveness for sedation and cerebral protection
after craniotomy in hypertensive intracerebral hemorrhage (HICH) patients is unknown.
Methods: A retrospective study of 164 postoperative HICH patients who underwent sedation
with dexmedetomidine or midazolam was conducted. The Ramsay sedation score, mean arterial
pressure (MAP), heart rate (HR), pulse oxygen saturation (SpO
2
), and respiratory rate were
measured at the indicated time points. Human soluble protein-100b(S-100b) and neuron-specific
enolase (NSE) levels were also compared between the two groups.
Results: Dexmedetomidine treatment showed a significantly better effect than midazolam on
decreasing the frequency of apparent agitation. The MAP and HR, but not the SpO
2,
were
significantly decreased and lower than those in midazolam group. Detection of plasma S-100b
and NSE proteins revealed a significant decrease in the dexmedetomidine group compared with
the midazolam group. The 6-month follow-up evaluation indicated a significantly better prognosis
of postoperative HICH patients treated with dexmedetomidine than for those treated with
midazolam.
Conclusions: Dexmedetomidine is effective for sedation in postoperative HICH patients and
may be beneficial for their outcome.
Department of Neurosurgery, Affiliated Kunshan Hospital
of Jiangsu University, Suzhou, P.R. China
*These authors contributed equally to this work.
Corresponding author:
Lei Shi, Department of Neurosurgery, No. 91 Qianjin
West Road, Kunshan City, Affiliated Kunshan Hospital of
Jiangsu University, Suzhou 215300, P.R. China.
Email: SL1012002322@126.com
Journal of International Medical Research
48(9) 1–9
!The Author(s) 2020
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DOI: 10.1177/0300060520957554
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as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
Keywords
Dexmedetomidine, midazolam, hypertensive intracerebral hemorrhage, prognosis, sedation,
cerebral protection
Date received: 11 May 2020; accepted: 19 August 2020
Introduction
Hypertensive intracerebral hemorrhage
(HICH) refers to rupture and hemorrhage
of small arteries because of pathological
changes in the brain caused by prolonged
hypertension and cerebral arteriosclerosis.
1
Among the various causes of non-traumatic
intracerebral hemorrhage, hypertension
accounts for approximately 60% of cases.
HICH is one of the most serious complica-
tions of hypertension
2
and is common in
50- to 60-year-old patients, and the inci-
dence in men is slightly higher than that in
women. HICH is one of the most serious
diseases that threaten the health of the
elderly.
3
Treatment of HICH is usually con-
servative. However, some patients suffer
from excessive bleeding and coma, often
requiring surgical treatment; that is, hema-
toma removal is performed to relieve the
hematoma, brain tissue compression, and
secondary brain injury.
4
Postoperative rest-
lessness is a common clinical symptom in
HICH patients. Restlessness can lead to
sympathetic activation, increased oxygen
consumption and brain metabolism, and
even cardiovascular events in elderly
patients, which are not conducive to disease
recovery.
5
Severe agitation can cause great
fluctuation of blood pressure, which results
in repeat rupture of the blood vessel, lead-
ing to increased brain hematoma and even
the risk of brain hernia.
6
Proper sedation
can improve patient comfort, prevent
severe fluctuations in blood pressure, and
reduce re-bleeding.
6
Therefore, it is neces-
sary to select reasonable sedative drugs to
relieve stress and restlessness.
The benzodiazepine sedative midazolam
is widely used in clinical practice. However,
in recent years, dexmedetomidine has
attracted increasing attention from anes-
thetic and intensive care unit clinicians
because it can produce the approximate
sedative effect of natural sleep and
exhibits weak respiratory depression.
7
Dexmedetomidine is a highly selective and
specific a
2
adrenergic receptor agonist and a
common adjuvant anesthetic in clinical
practice. It mainly acts within the locus coe-
ruleus, produces sedative, hypnotic and
anxiolytic effects, activates presynaptic
membrane a
2
receptors, inhibits the release
of norepinephrine, terminates the transmis-
sion of pain signals, and inhibits sympathet-
ic activity and the stress response.
8
Some
studies have shown that dexmedetomidine
also has certain neuroprotective effects.
Zhao et al.
9
confirmed that dexmedetomi-
dine has protective and hemodynamic
effects in HICH patients during the periop-
erative period. Therefore, we analyzed the
effects of dexmedetomidine on sedation and
reducing recurrence after hematoma remov-
al in postoperative HICH patients.
Materials and methods
Statement regarding human participants
All methods and treatments in this study
were performed in accordance with the
Declaration of Helsinki and the relevant
regulations. The protocols for the study
and the written consent form were
approved by the ethics committee of the
First People’s Hospital of Kunshan, China
2Journal of International Medical Research
(201907621). The study was approved by
the Ethics Committee of each hospital.
Written informed consent was obtained
from all patients providing tissue specimens
prior to surgery, and all patients consented
to the submission of this report for
publication.
Inclusion and exclusion criteria
Patients were enrolled based on the follow-
ing inclusion criteria: primary hypertension,
evidence of basal ganglia cerebral hemor-
rhage by computed tomography (CT), and
evacuation of hematoma. The exclusion
criteria were as follows: (1) patients with
hemorrhage in other parts of the brain;
(2) patients complicated with chronic liver
disease, heart disease or arrhythmia, and
diseases of the kidney, lung, and other vital
organs; (3) patients complicated with severe
coagulation abnormalities; (4) patients com-
plicated with malignant tumors or hemato-
logic diseases.
Design and therapeutic process
All HICH patients underwent surgical
intervention, including trepanation of a
single burr hole and irrigation of the hema-
toma with urokinase two times a day or
removal of the hematoma through a small
bone window. The former procedure was
performed on 80 patients, and the latter
procedure was performed on 84 patients.
All patients underwent general anesthesia.
A routine cranial CT examination was per-
formed on the first and second days after
surgery. If the patient’s condition worsened,
cranial CT was performed again. The drain-
age tube was usually removed at 2 to 3 days
after surgery according to the patient’s
condition.
Patients in the dexmedetomidine group
were first given a loading dose of 1 lg/kg
of dexmedetomidine and then maintained
on a dosage of 0.3 to 0.6 lg/kg/h. Patients
in the control group were first given a load-
ing dose of 0.05 mg/kg of midazolam and
then maintained on a dosage of 0.02 to
0.10 mg/kg/h. The medication was adjusted
to achieve and maintain a Ramsay sedation
score of 2 to 4 for a satisfactory sedation
effect. The use of sedative drugs was
continued until the patient had no obvious
irritability. Labetalol hydrochloride and
urapidil were routinely used to control
hypertension after the operation.
Labetalol hydrochloride (100 mg) was dilut-
ed in 250 mL of a 5% glucose and 0.9%
sodium chloride solution and administered
with an intravenous drip rate of 1 to 4 mg/
minute. According to recommendations,
urapidil was initially delivered at 2 mg/
minute, and the maintenance rate of deliv-
ery was 9 mg/hour. The degree of blood
pressure decline was determined by the
dose of the drug administered within the
first 15 minutes, and then drug delivery
was maintained at a low dose.
Routine follow-up was generally con-
ducted twice a month until 6 months after
the operation.
Ramsay sedation score
The Ramsay sedation score criteria are as
follows: 1, the patient is anxious and agitat-
ed, restless, or both; 2, the patient is coop-
erative, oriented, and tranquil; 3, the
patient responds to commands only; 4, the
patient is asleep and shows a brisk response
to a light glabellar tap or loud auditory
stimulus; 5, the patient is asleep and
shows a slow response to a light glabellar
tap or loud auditory stimulus; 6, the patient
is asleep and shows no response to a light
glabellar tap or loud auditory stimulus.
Monitoring index
The Ramsay sedation score, mean arterial
pressure (MAP), heart rate (HR), pulse
oxygen saturation (SpO
2
), and respiratory
Gong et al. 3
rate (RR) were recorded before and after
the medication was administered. The
amount of fentanyl used and the degree of
respiratory depression and agitation during
the course of sedation were also recorded.
An enzyme-linked immunosorbent assay
was used to detect the human soluble pro-
tein-100b(S-100b) and neuron-specific eno-
lase (NSE) levels in the plasma of the two
groups of patients before (0 hours) and
after surgery (6 hours and 12 hours).
Glasgow Outcome Scale (GOS) scores
GOS scores were evaluated at the 6-month
follow-up evaluation after surgery as fol-
lows: 1, death; 2, persistent vegetative
state; 3, severe disability; 4, moderate dis-
ability; 5, mild or no disability. GOS scores
of 4 or higher indicated a good outcome.
Statistical analysis
The data were analyzed using SPSS version
15.0 (SPSS Inc., Chicago, Illinois).
Quantitative variables such as age and
body temperature are expressed as the
mean SD. We used the v
2
or Fisher’s
test to analyze associations between cate-
gorical variables and the t-test to analyze
continuous variables. Multiple logistic
regression analysis was adopted to analyze
correlations between variables. A value of
P<0.05 was considered statistically
significant.
Results
Patients
A total of 164 HICH patients with dyspho-
ria after neurosurgery (Ramsay score of 1)
who were admitted to various hospitals
from 2015 to 2017 were selected as subjects,
including 98 men and 66 women. The pre-
operative Glasgow Coma Scale (GCS)
ranged from 8 to 12 points. According to
whether dexmedetomidine was used after
the operation, the patients were divided
into a dexmedetomidine group (86 patients)
and a midazolam group (78 patients).
No significant differences in routine
monitoring indexes were observed
between the two groups
The demographic and clinical characteris-
tics of the two groups are shown in
Table 1. No significant differences of mon-
itoring indexes, including age, sex, and
weight, MAP, temperature (C), HR, and
RR were found between the dexmedetomi-
dine group and the midazolam group after
the operation and before dexmedetomidine
or midazolam administration (Table 1).
Table 1. The demographic and clinical characteristics of patients in the dexmedetomidine and midazolam
groups before drug administration.
Characteristics Dexmedetomidine group Midazolam group P-value
Age (years) 67.3 9.95 66.9 9.64 0.785
Men/women 51/35 47/31 0.901
Weight (kg) 75.40 10.29 76.83 9.95 0.365
MAP (mmHg) 119.51 5.52 118.26 13.08 0.417
Temperature (C) 37.18 0.58 37.06 0.55 0.184
HR (n/min) 111.0 6.63 109.1 7.35 0.075
RR (n/min) 25.58 4.17 26.54 4.21 0.146
Preoperative GCS 10.5 1.28 10.4 1.38 0.398
Preoperative hematoma volume (mL) 27.8 6.12 25.5 5.61 0.659
MAP, mean arterial pressure; HR, heart rate; RR, respiratory rate; GCS, Glasgow Coma Scale.
4Journal of International Medical Research
Additionally, the preoperative GCS scores
and hematoma volume were also compared
and showed no differences (P >0.05).
Sedative effect of dexmedetomidine and
midazolam
As shown in Table 2, to achieve a satisfac-
tory sedation effect with a Ramsay sedation
score of 2 to 4, dexmedetomidine adminis-
tration for 17.97 6.59 minutes was
required, while midazolam administration
for 16.72 6.01 minutes was required.
Statistical analysis showed no difference in
sedation between the two groups. However,
during the 48 hours following sedation, the
frequency of apparent agitation in the dex-
medetomidine group was 4.53 2.48
events, which was significantly lower than
that in the control group (9.50 4.22
events) (P <0.05). Respiratory depression
is a frequent occurrence during sedation.
We further analyzed the frequency of respi-
ratory depression during sedation and
found no cases in the dexmedetomidine
group, but six cases were found with mid-
azolam treatment (P <0.05). These data
suggest that dexmedetomidine is more
effective and safer for sedation after crani-
otomy in HICH patients.
Changes in vital signs after
dexmedetomidine or midazolam
treatment
Postoperative HICH patients were immedi-
ately administered dexmedetomidine or
midazolam. As shown in Table 3, after dex-
medetomidine administration for 1 hour or
2 hours, the MAP and HR were more obvi-
ously decreased than those in the midazo-
lam group (P <0.05) when neither group of
patients was given oral or intravenous anti-
hypertensive drugs. However, both of these
variables could be controlled within the
normal ranges. Additionally, the RR was
lower after treatment than before treatment
in both groups (P <0.05); however, no sig-
nificant differences in RR were found after
dexmedetomidine or midazolam treatment.
There was also no obvious difference in the
SpO
2
at various time points between the
dexmedetomidine and midazolam treat-
ment groups. These data showed that dex-
medetomidine treatment could affect the
MAP and HR of HICH patients after sur-
gery. Considering that patients with
Table 2. The Sedative effects of dexmedetomidine and midazolam.
Characteristics Dexmedetomidine group Midazolam group P-value
Sedation time (min) 17.97 6.59 16.72 6.01 0.209
Dysphoria frequency (n) 4.53 2.48 9.50 4.22 0.000
Respiratory depression (n) 0/86 6/78 0.010
Table 3. Changes in vital signs after dexmedetomidine or midazolam treatment.
Characteristics
Dexmedetomidine
group (1 h)
Midazolam
group (1 h) P-value
Dexmedetomidine
group (2 h)
Midazolam
group (2 h) P-value
MAP (mmHg) 86.71 6.62 96.81 7.16 0.043 76.15 6.17 101.89 10.81 0.000
HR (n/min) 71.6 8.86 97.6 10.16 0.000 79.7 7.60 103.9 11.31 0.000
RR (n/min) 16.65 3.18 18.72 2.76 0.065 17.31 2.87 19.61 3.11 0.051
SpO
2
(%) 98.17 1.07 99.07 0.68 0.617 99.01 0.70 98.76 1.16 0.720
MAP, mean arterial pressure; HR, heart rate; RR, respiratory rate; SpO
2
, pulse oxygen saturation.
Gong et al. 5
primary HICH usually suffer from exces-
sive blood pressure after surgery, we sug-
gest that dexmedetomidine is a good
choice for sedation.
Dexmedetomidine decreased the plasma
S-100band NSE protein levels in
postoperative HICH patients
S-100band NSE are known outcome pre-
dictors of cerebral damage.
10
Here, these
two markers were used to confirm whether
dexmedetomidine has neuroprotective
effects on postoperative HICH patients.
We compared the plasma S-100band NSE
protein levels at the indicated times after
dexmedetomidine or midazolam adminis-
tration. Our results showed no statistically
significant difference in plasma S-100band
NSE protein levels between the two groups
before the operation. However, the plasma
S-100band NSE protein levels at 6 and 12
hours after surgery were significantly
decreased in dexmedetomidine-treated
patients compared with midazolam-treated
patients (Table 4).
Dexmedetomidine was beneficial for the
outcome of postoperative HICH patients
A GOS score of 4 or 5 was considered to be
a good outcome for patients. After 6
months, two patients in the midazolam
group were lost to follow-up. In total, 72/
86 patients in the dexmedetomidine group
had a GOS score of 4 or 5 compared with
53/76 patients in the midazolam group.
Additionally, the v
2
test showed a signifi-
cant difference in the prognosis between
the dexmedetomidine and midazolam
groups (P <0.05), which indicates that dex-
medetomidine administration is beneficial
for the outcome of postoperative HICH
patients (Table 5).
Discussion
Midazolam is a medication used for anes-
thesia, procedural sedation, sleep disorders,
and severe agitation that produces its effect
by inducing sleepiness, decreasing anxiety,
and causing a loss of the ability to create
new memories.
11
Dexmedetomidine is an a
2
adrenergic receptor agonist that is used in
veterinary medicine because of its analgesic
and sedative properties. Dexmedetomidine
is notable for its ability to provide sedation
Table 4. Changes in plasma human soluble protein-100band neuron-specific enolase protein levels in
postoperative hypertensive intracerebral hemorrhage patients.
Group 0 hours 6 hours 12 hours
S-100b(lg/L)
Dexmedetomidine 3.19 0.13 1.90 0.14 1.75 0.11
Midazolam 3.17 0.09 3.55 0.21 3.64 0.97
P-value 0.283 0.000 0.000
NSE (lg/L)
Dexmedetomidine 16.53 0.26 12.78 1.01 10.34 0.20
Midazolam 16.47 0.27 20.28 1.13 22.37 0.23
P-value 0.098 0.000 0.000
S-100b, human soluble protein-100b; NSE, neuron-specific enolase.
Table 5. Evaluation of the long-term prognosis of
patients in the two groups via the Glasgow
Outcome Scale score.
Group Dexmedetomidine Midazolam P-value
GOS score 1–3 72 53
GOS score 4–5 14 23 0.034
GOS, Glasgow Outcome Scale.
6Journal of International Medical Research
without risk of respiratory depression,
unlike other commonly used sedatives
such as midazolam, and can produce coop-
erative or semi-arousable sedation.
12
As
two commonly used sedative drugs, many
studies have been conducted to evaluate the
sedative effects of dexmedetomidine and
midazolam. In a systematic review of its
efficacy and safety, Barends et al. reported
that dexmedetomidine is a promising alter-
native to midazolam for use in procedural
sedation and provides increased comfort
during the procedure for the patient and
clinician.
13
A prospective randomized trial
comparing dexmedetomidine and midazo-
lam for conscious sedation conducted by
Elnabtity and Selim showed that dexmede-
tomidine was an effective analgesic alterna-
tive to midazolam during oocyte retrieval
for in vitro fertilization.
14
Gupta et al.
15
noted that when dexmedetomidine was
added to intravenous regional anesthesia,
it provided a longer duration of analgesia
than midazolam. In contrast, Kumari
et al.
16
found that oral midazolam was
superior to oral dexmedetomidine, with
faster onset of sedation, a higher sedation
score, and a lower anxiety score in children.
Additionally, midazolam and dexmedeto-
midine showed no significant differences in
reduction of brain activation in the audito-
ry cortex.
17
Srivastava et al.
18
found that
dexmedetomidine was safe and equally
effective for sedation of mechanically venti-
lated neurosurgical patients compared with
midazolam. However, a comparison of the
effects of dexmedetomidine and midazolam
in postoperative HICH patients had not
been performed.
In this study, we compared the effects of
dexmedetomidine and midazolam on seda-
tion in HICH patients and found no differ-
ence in the time required to achieve a
satisfactory sedative effect with a Ramsay
sedation score of 2 to 4. However, the
results also suggested that dexmedetomi-
dine has a greater hemodynamic impact
on postoperative patients than midazolam.
The MAP and HR decreased more signifi-
cantly in the dexmedetomidine group than
in the midazolam group, and the degree of
decrease depended on the concentration of
dexmedetomidine (data not shown).
Dexmedetomidine is an effective a
2
adre-
nergic receptor agonist, and its affinity for
a
2
adrenergic receptors is eight times higher
than that of clonidine. Therefore, dexmede-
tomidine can lower blood pressure.
However, midazolam has no such pharma-
cological mechanism. Bhana et al.
19,20
found that this effect was induced by a
reduction in plasma catecholamines, which
further resulted in peripheral vasoconstric-
tion and sympatholytic properties.
Consistent with the study by Bhana et al.,
we found no clinically apparent respiratory
depression during dexmedetomidine admin-
istration in postoperative patients.
19
The
SpO
2
also showed no apparent decrease.
Considering that many studies have
noted that dexmedetomidine has neuropro-
tective effects, we examined the plasma
expression of the S-100band NSE proteins
after dexmedetomidine administration.
21,22
S-100bprotein and NSE are confirmed
markers of cerebral injury.
23
Consistent
with our hypothesis, dexmedetomidine
effectively reduced the S-100band NSE
protein levels in patients compared with
midazolam, indicating that dexmedetomi-
dine plays a more beneficial role in brain
protection. The potential mechanism
might be that dexmedetomidine reduces
the release of inflammatory mediators and
neuroendocrine hormones.
24
Zhang et al.
25
reported that dexmedetomidine improved
the short-term outcome of lung tissues of
rats with sepsis. However, until now, the
effects of dexmedetomidine on the outcome
of postoperative HICH patients were
unknown.
In the present study, all patients were
followed up for 6 months, and the good
prognosis rate in the dexmedetomidine
Gong et al. 7
group (83.72%) was higher than that in the
midazolam group (69.74%), suggesting that
dexmedetomidine administration improved
the outcome of postoperative HICH
patients. However, this study is limited by
its small sample size.
Conclusion
Our study shows that dexmedetomidine is
more effective for sedation and is more ben-
eficial for brain protection and the long-
term outcome in postoperative HICH
patients than midazolam.
Author contributions
L.S. conceived and designed the study. W.G. col-
lected the data. S.Z. and X.L. analyzed the
results. W.G. and L.S. drafted the manuscript.
All authors participated in the discussion of
results and reviewed the manuscript.
Data availability
The datasets generated and analyzed during the
current study are available from the correspond-
ing author on reasonable request.
Declaration of conflicting interest
The authors declare that there is no conflict of
interest.
Funding
This work was supported by the Brain Clinic and
Basic Research Team Program of the First
People’s Hospital of Kunshan (KYC004). The
funders had no role in the study design, data
collection and analysis, decision to publish, or
preparation of the manuscript.
ORCID iD
Lei Shi https://orcid.org/0000-0001-9258-
9454
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