European Journal of Anaesthesiology 2008; 25: 403–409

r 2007 Copyright European Society of Anaesthesiology

doi: 10.1017/S0265021507003079

Original Article

The efficacy and neurotoxicity of dexmedetomidine

administered via the epidural route

S. Konakci*, T. Adanir*, G. Yilmaz*, T. Rezankoy

Ataturk Training and Research Hospital, Departments of *Anaesthesiology, y Pathology, Izmir, Turkey

Summary
Background: a2-Adrenoceptor agonists administered into the intrathecal and epidural space have been found to
be effective in the treatment of chronic pain. Moreover, it was shown that they increase the analgesic effects of
local anaesthetics and provide sedation, anxiolysis and haemodynamic stability. Dexmedetomidine, a potent
and highly selective a2-adrenoceptor agonist, is in current clinical use, particularly in the intensive care unit.
Our aim was to investigate whether dexmedetomidine produced motor and sensory blockade and neurotoxic
effects when administrated via the epidural catheter in rabbits. Methods: Twenty-one New Zealand white
rabbits were included in the study. Animals were randomized into three groups. In Group L: lidocaine (2%),
in Group LD: lidocaine (2%) 1 dexmedetomidine (5 mg) and in Group D: dexmedetomidine (10 mg) were
administered by epidural catheter. Motor and sensory blockade were evaluated. After the evaluation of block,
the animals were euthanized and their spinal cords removed for neuropathological evaluations. Results: Motor
and sensory blockade were lower in Group D than in Group L and Group LD (P , 0.01). Although there were
no differences between the groups for ischaemia of the medulla spinalis, evidence of demyelinization of the
oligodendrocytes in the white matter in Group D was significantly higher than in Group L (P 5 0.035).
Conclusions: We observed that dexmedetomidine does not have motor and sensory effects, but it may have a
harmful effect on the myelin sheath when administered via the epidural route.

Keywords: ANAESTHETIC TECHNIQUES; ANAESTHESIA EPIDURAL; DEXMEDITOMIDINE; SPINAL CORD

ISCHAEMIA; MYELIN.

Introduction a2-adrenoceptor agonists predominantly result from

supraspinal actions [4]. An a2-adrenergic compound
In order to provide ideal analgesia via the epidural
that diffuses poorly through the blood–brain barrier
route, the antinociceptive side-effects should be
and within the central nervous system might provide
minimal. Because there is no such ideal local
effective locally mediated antinociception with minor
anaesthetic, many drugs (e.g. opioids, benzodiaze-
side-effects after intrathecal or epidural administra-
pines, magnesium, ketamine, clonidine, baclofen,
tion. a2-Adrenoceptor agonists have been used in
somatostatin, neostigmine and steroids) have been
association with local anaesthetics to increase the
used as adjuvants. a2-Adrenoceptor agonists have
duration of spinal anaesthesia. Intrathecal or epidural
antinociceptive effects [1–3]. This antinociception
administration of clonidine prolongs motor blockade
is in part caused by action on spinal a2-adreno-
induced by local anaesthetics. Since the affinity of
ceptors. In contrast, the sedative side-effects of
dexmedetomidine to a2-adrenoceptors is eight times
greater than clonidine, it is expected that dexmede-
Correspondence to: Tayfun Adanir, P.B. 12 Hatay, 35370 Izmir, Turkey. E-mail:
tadanir@tnn.net; Tel: 190 232 2444444 380; Fax: 190 232 2434848
tomidine could be advantageous in regional anaes-
Accepted for publication 16 October 2007 EJA 4302
thesia. Establishing the safety of neuroaxial drugs is
First published online 19 December 2007 very important before these drugs are given to
404 S. Konakci et al
humans. Despite extensive use in animal experi-
mentation, dexmedetomidine has not been tested
clinically by the epidural or intrathecal route, or
evaluated for neurotoxicity.
The purpose of this prospective, randomized,
double-blind study was to investigate whether
dexmedetomidine has motor and sensory blockade
and side-effects when it was administered via an
epidural catheter in rabbits.
Methods
This study was approved by the Institutional Animal
Investigation Ethics Committee of Izmir Ataturk
Training and Research Hospital. Twenty-eight New
Zealand White Rabbits weighing 1650–2100 g were
planned to be included in the study; however, seven
rabbits were excluded for failure of placement of
epidural catheter at the beginning of the study.
Twenty-one rabbits were studied. All procedures were
performed between 4:00p.m. and 12:00p.m. Each
animal was used for only one set of studies to elim-
inate possible interactions between different doses and
routes of drugs. The animals were kept in the animal
research laboratory for 10 days and fed a standard diet
before the procedures started.
Before the placement of the epidural catheter,
ketamine 50 mg kg21 (Ketalar-Eczacibasi Warner
Lambert 39780, Luleburgaz, Turkey) was admi-
nistered intramuscularly. The hair on the tails
and the waist regions of the animals were shaved
after they were prone-positioned. The tail regions
were scrubbed with 10% povidone iodine. A skin
incision was performed 1 cm distal to the anus,
following sterile coverage and the subcutaneous
injection of 1% lidocaine. After skin incision,
connective tissue and paraspinal muscles were dis-
sected and the sacral hiatus was opened. An 18-G
epidural catheter (Minipack SIMS Portex Ltd,
Hyde, Kent, UK) was inserted to the epidural space
through the sacral canal up to 4–5 cm cranially.
Following catheter placement into the sacral canal,
we tested whether the dura matter was punctured or
not by aspiration. Then the free edge of the catheter
was placed in a subcutaneous tunnel using a Tuohy
needle, it was shortened and connected to a screw
connector for subsequent use. Then the catheter was
fixed to the skin and the incision was sutured.
Neurological injury associated with the use of the
epidural catheter was evaluated after recovery from
the ketamine. Paraplegia and the absent flexion
reflex of both the lower extremities following
painful stimuli on the toes of the animals were
accepted as positive signs of neurological injury.
Any animals exhibiting signs of a neurological or
motor deficit were eliminated from the study.
r 2007 Copyright European Society of Anaesthesiology, European Journal of Anaesthesiology 25: 403–409
Five hours after the insertion of the epidural
catheter, in order to verify that the catheter was
within the epidural space, 1 mL of 1% lidocaine was
administered via the epidural catheter and flushed
with 0.2 mL of 0.9% NaCl. If any motor or sensory
blockade was observed within 5 min, it was concluded
that the catheter was in the subdural space, not in
the epidural space. It was verified that motor or
sensory blockade was observed after 20 min of drug
administration.
The ear lobe veins of the animals were cannulated
with 24-G catheters and 0.9% NaCl was admi-
nistered (5 mL kg21) 24 h after the placement of
the epidural catheter. The animals were sedated
with intravenous (i.v.) midazolam (0.2 mg kg21)
(Dormicum, Roche, Fontenay, France). Arterial
cannulation of the other ear was performed after
sedation. Invasive blood pressure (BP) and heart rate
(HR) monitoring (KMA 275; Petas Corporation,
kara, Turkey) were performed through this catheter.
We waited for the sedation effect to resolve. On the
second day, we performed the main drug study.
Animals were assigned to three groups with seven
animals in each group chosen by computer-gener-
ated random numbers.
Group L: Lidocaine 2% (Aritmal Biosel amp,
Beykoz, Turkey) 0.8 mL and NaCl 0.9% 0.2 mL
were administered through the epidural catheter
and the catheters were flushed with NaCl 0.9%
0.2 mL.
Group LD: Lidocaine 2% 0.8 mL and dexmedeto-
midine (5 mg) 0.2 mL (Precedex flacon, Abbott
Laboratory, North Chicago, IL, USA) were adminis-
tered through the epidural catheter and the
catheters were flushed with NaCl 0.9% 0.2 mL.
Group D: Dexmedetomidine (10 mg) 0.8 mL and
NaCl 0.9% 0.2 mL were administered through the
epidural catheter, and the catheters were flushed
with NaCl 0.9% 0.2 mL.
We did not create another group using only
saline for control since lidocaine and saline injec-
tions through the catheter would inevitably verify
that the catheter was within the epidural space.
Therefore this group would be identical to the
lidocaine group.
Mean arterial pressures (MAP) and HR of the
animals were recorded during the study. Arterial
blood samples were obtained at 0, 5, 15, 30 and
60 min to evaluate pH, PaO2, PaCO2 and SaO2.
Motor function was assessed according to the cri-
teria of Drummond and Moore [5] by an investi-
gator blind to the treatment (0: free motion without
limitation at lower extremities; 1: asymmetry and
limitation in providing body support and walking
at lower extremities; 2: inability to provide body

support by lower extremities; and 3: paralysis of
both the lower extremities).
A painful stimulus was applied by nipping the tail,
lower extremities, upper and lower abdomen, upper
extremities and ear using a surgical clamp by a
blinded investigator. If there was no response to the
surgical clamp, the response to surgical painful
stimulus was evaluated by an incision on the abdomen.
After the surgical stimulus, if there was no response
to the painful stimulus the peritoneum was incised
and intestinal loops were exposed similar to a sur-
gical operation. Sedation was assessed by placing the
rabbit on its back – if it spontaneously recovered to
the prone position, there was no sedation.
After the evaluation of sensory blockade, the
animals were euthanized using thiopental
(120 mg kg21, i.v.) and then the perfusion fixation
method was applied with 10% formaldehyde. The
spinal cords of the animals were removed en bloc
from their spinal columns and fixed in 4% para-
formaldehyde solution. After fixation, the sections
of spinal cords were embedded in paraffin. In total,
five segments (at the catheter tip level and two
segments up and down) were examined in each
rabbit and two sections of each segment were
examined. The blocks were cut at a thickness of
5 mm and stained with haematoxylin–eosin to
examine the ischaemic injury and immunestaining
with antibodies to myelin basic protein (MBP)
(Clone RB-1460 R7; Neomarker Inc., Fremont,
CA, USA) [6] for evaluation of the myelin damage.
Immunohistochemical staining was performed
using the Strept–Avidin–Biotin Peroxidase method.
Neuropathologic assessment was provided by a
pathologist, blinded to the study group. Ischaemic
neurons were identified by cytoplasmic eosinophilia
with loss of Nissl substance and pyknotic nuclei. To
evaluate the amount of myelin loss in white matter on
immunostained sections for MBP, the scoring system
of Petersson and colleagues [7] was modified. The
whole mounted coronal sections were scored by a
pathologist, who was not aware of each group. The
pathologist scored the most severely injured area of
each section using the following scoring system:
0 – no myelin loss;
1 – myelin loss between 1% and 25% (minimal
myelin loss);
2 – myelin loss between 26% and 50% (moderate
myelin loss);
3 – myelin loss between 51% and 100% (severe
myelin loss).
The percentage of myelin loss was calculated as
the number of unstained oligodendrocytes for MBP
in the total oligodendrocytes count of white matter
for each section.
r 2007 Copyright European Society of Anaesthesiology, European Journal of Anaesthesiology 25: 403–409
Dexmedetomidine neurotoxicity 405
Statistical analysis
Statistical analyses were carried out using SPSS for
Windows version 11.0. Data were expressed as
mean 6 SD. As three of the groups had n , 30 and
were independent of each other and variables had
been measured at equal intervals, statistical analyses
were performed with non-parametric tests. HR,
MAP, motor block, painful stimuli, intestinal loops
if exposed, pH, PaO2, PaCO2 and SaO2 were com-
pared with the Kruskal–Wallis test according to
time in each group. U-test with Bonferroni’s cor-
rection and Wilcoxon signed rank sum test were
used to assess differences found between the three
groups. Comparison of the neuropathological eva-
luations between the three groups was made using
Fisher’s exact x2 test. The tolerance of intestinal
loops that were exposed to evaluate the response to
painful stimuli was also compared with Fisher’s
exact x2 test. P , 0.05 was considered as the
threshold of significance.
Results
MAP, HR and blood gas data did not change in any
of the groups (Fig. 1). Although epidural admin-
istration of lidocaine and lidocaine combined with
dexmedetomidine produced clear motor block,
dexmedetomidine alone did not produce the same
effect. There were significant differences at 2, 3, 4,
5, 15 and 30 min between Group D and the other
two groups (P , 0.01). The motor block that was
seen in Group LD was similar to that in Group L
(P . 0.05) (Fig. 2).
Epidural administration of dexmedetomidine
(10 mg dose) did not produce antinociception to the
painful stimulus that was produced by surgical
clamp. In the evaluation of painful stimuli that
were applied on the tail, lower extremities and
upper and lower abdomen, there were significant
differences at 2, 3, 4, 5, 15, 30 and 45 min between
Group D and the other two groups (P , 0.01)
(Fig. 3). No differences were observed between
Group L and Group LD in the evaluation of the
response to the surgical stimulus produced by an
incision on the abdomen. For ethical reasons, the
stimulus could not be applied because of possible
intolerance of the animals in Group D. In the eva-
luation of the intestinal loop tolerance that was
exposed to evaluate response to painful stimuli,
there were no significant differences between Group
LD and Group L. We did not find any differences
between groups for painful stimuli that were
applied on the upper extremities and the ear by
pinprick test.
There were no statistically significant differences
between the three groups for the degree of ischaemic
406 S. Konakci et al
Figure 1.
Mean arterial pressure (MAP, mmHg) and heart rate (HR, beats min21).
Figure 2.
Motor block. There were significant differences between Group D
and the other two groups (P , 0.01).
injury. Mild, diffuse and parenchymatous swell-
ing of the white matter was observed in all cases
(Fig. 4). The oligodendrocytes in the white matter
showed evidence of moderate or severe demyelin-
ization in three cases in Group D and in two cases
in Group LD. The difference in the degree of
demyelinization of the myelin sheaths between
Group D and Group L was statistically significant
(P 50.035) (Figs 5 and 6, respectively). In addition
to these results, we observed deep sedation in
Group D and Group LD.
r 2007 Copyright European Society of Anaesthesiology, European Journal of Anaesthesiology 25: 403–409
Discussion
Dexmedetomidine is a highly selective, short-acting
central a2-adrenoceptor agonist. Adrenergic agonists
acting at the a2-adrenoceptors produce antinocicep-
tion. These responses have been well documented in
animals and in human clinical studies [8]. It has been
demonstrated that dexmedetomidine produces anti-
nociception in systemic [9,10], intrathecal [11–14],
epidural administration [15,16] or into the locus
coeruleus administration [17].
In general, dexmedetomidine is used as an anti-
nociceptive agent, and it has been investigated with
regard to its antinociceptive effect or prevention of
postoperative pain. Its intraoperative use has been
under investigation recently. Memis and colleagues
[18] have shown that the addition of dexmedetomi-
dine to the local anaesthetic solution during i.v.
regional anaesthesia improved the quality of anaes-
thesia and perioperative analgesia. Another study by
Esmaoglu and colleagues [19] has demonstrated that
the addition of dexmedetomidine to local anaesthetic
solution in i.v. regional anaesthesia improved the
quality of anaesthesia and decreased analgesic require-
ments, but had no effect on the onset and regression
times of sensory and motor blocks.
Since epidural administration of dexmedetomi-
dine is approximately five times more effective than
systemic administration in producing an anti-
nociception effect [15], we chose the epidural route.
Our results were similar to that of the study of
Esmaoglu and colleagues [19], although the admi-
nistration route of dexmedetomidine was different
in our study. We were not able to show motor
 Dexmedetomidine neurotoxicity 407

Figure 3.
Evaluation of painful stimuli applied on the tail, lower extremities, and upper and lower abdomen. There were significant differences at 2, 3,
4, 5, 15, 30 and 45 min between Group D and the other two groups (P , 0.01).

Figure 4. Figure 5.
Mild diffuse parenchymatous swelling of the white matter (left Myelin loss of the oligodendrocytes in the white matter; Group D
side; H&E 3220). (myelin basic protein 3440).

blockade and antinociception from the epidural
administration of dexmedetomidine (10 mg dose) in
response to twisting with a surgical clamp. We are
aware that the dexmedetomidine doses (5 and
10 mg) that we used might not be enough to produce
adequate block. We did not create dose-response
curves for rabbits and there is no previous study for
evaluating a dose-response curve in rabbits. However,
similar drug doses had been used in rat studies [15].
Asano and colleagues [15] examined the dose-
dependent (0.5, 1, 5 and 10 mg epidurally) antinoci-
ceptive dexmedetomidine effect in rats. They showed
that dexmedetomidine produced dose-dependent
antinociceptive effect. Walker and colleagues [16]
also showed that dexmedetomidine produced a dose-
dependent (1, 2, 4, 10 and 20 mg kg21 epidurally)
antinociceptive effect. Although we observed adequate
sedation with these drug doses, even with these doses,
myelin sheath injury occurred. The onset and regres-
sion of motor block in Group L were similar to Group
LD. We did not observe any synergistic effect between
dexmedetomidine and lidocaine.
To the best of our knowledge, there has been no
study in the English medical literature about the
effect of the epidural administration of dexmede-
tomidine on neural injury. In contrast, dexmedeto-
midine provides neuroprotection in models of brain
ischaemia in animals [20,21]. A neuroprotective

r 2007 Copyright European Society of Anaesthesiology, European Journal of Anaesthesiology 25: 403–409
408 S. Konakci et al
Figure 6.
Group L cytoplasmic staining with myelin basic protein antibody
in oligodendrocytes (3 oil immersion field).
effect of dexmedetomidine is mediated by the
activation of the a2-adrenergic receptor subtype
[22]. As dexmedetomidine has neuroprotective
effects, it could be expected that dexmedetomidine
by epidural or intrathecal administration would not
be harmful. However, this study has shown that
dexmedetomidine (10 mg) produced the moderate
or severe demyelinization of myelin sheaths in
the white matter, when it was administered via the
epidural route. This effect could be related to
vasoconstriction of the medullary spinal vessels [23]
and pH of dexmedetomidine. Precedex (dexmede-
tomidine) is supplied as a clear, colourless, isotonic
solution with a pH of 4.5–7.0, and this pH may
cause demyelinization. Each 1 mL of Precedex con-
tains 118 mg of dexmedetomidine HCl (equivalent
to 100 mg dexmedetomidine base) and 9 mg of
NaCl in water. The solution is preservative-free and
contains no additives or chemical stabilizers. Thus,
we do not think that demyelination could be related
to additives or chemical stabilizers.
Furthermore, dexmedetomidine did not have an
antinociception effect against surgical stimulus or
twisted stimulus by surgical clamp. We observed
that dexmedetomidine (5 mg) with local anaesthetic
solution in epidural anaesthesia had sedative and
haemodynamic stabilization effects. In spite of
administering dexmedetomidine, which causes a
dose-dependent decrease in BP and HR, we did not
observe any haemodynamic side-effects such as
hypotension or bradycardia requiring intervention.
The reason for this might be the use of low-dose
dexmedetomidine.
A significant number of rabbits (seven rabbits)
were removed from the study due to the failure of
placement of the epidural catheter. One may spec-
ulate that demyelinization may be a result of trauma
r 2007 Copyright European Society of Anaesthesiology, European Journal of Anaesthesiology 25: 403–409
rather than a specific effect of dexmedetomidine.
However, all of the rabbits removed from the study
were the first seven animals (learning curve) and no
animal was excluded from the study for failure of
placement of the epidural catheter afterwards. It is
conceivable that the presence of an epidural catheter
alone could have produced the injury we found. A
control group that received only NaCl would have
allowed us to separate catheter injury from drug-
induced injury. However, previous studies on the
safety of epidural catheters found no neurotoxic
effect of these catheters. Canduz and colleagues [24]
showed that there was no histopathological sign of
neurotoxicity in the control group, which had only
an epidural catheter without receiving any drug. In
addition, Lim and colleagues [25] epidurally
administered hyaluronic acid to rabbits and the
subsequent electron microscopic findings showed
no neurotoxicity in the control group.
In summary, i.v. dexmedetomidine may be an
appropriate and safe adjuvant agent for local or general
anaesthesia. However, it caused significant neural
injury when it was applied via the epidural route in
rabbits. In order to administer dexmedetomidine via
the epidural route as a safe adjuvant agent, further
studies using lower doses of dexmedetomidine and
advanced pathologic investigations are required.
Acknowledgements
The authors are grateful to Mehmet Haciyanli for
his careful English review of the manuscript.
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