Download Dexmedetomidine Use in General Anaesthesia

Current Drug Targets, 2009, 10, 687-695
687
Dexmedetomidine Use in General Anaesthesia
A. Arcangeli*, C. D’Alò and R. Gaspari
Institute of Anesthesia and Intensive Care, Catholic University of Rome, Italy
Abstract: Dexmedetomidine is a potent and highly selective 2-adrenoreceptor agonist currently utilized for continuous
infusion for sedation/analgesia in the intensive care unit (ICU). Dexmedetomidine offers remarkable pharmacological
properties including sedation, anxiolysis, and analgesia with the unique characteristic to cause no respiratory depression.
In addition it posses sympatholytic and antinociceptive effects that allow hemodynamic stability during surgical
stimulation. Different from most of clinically used anesthetics, dexmedetomidine brings about not only a sedativehypnotic effect via an action on a single type of receptors, but also an analgesic effect and an autonomic blockade that is
beneficial in cardiac risk situations. Several studies have demonstrated its safety, although bradycardia and hypotension
are the most predictable and frequent side effects.
Dexmedetomidine has shown to consistently reduce opioids, propofol, and benzodiazepines requirements. In the last years
it has emerged as an affective therapeutic drug in a wide range of anesthetic management, promising large benefits in the
perioperative use. In particular this review focuses on dexmedetomidine utilization in premedication, general surgery,
neurosurgery, cardiac surgery, bariatric surgery, and for procedural sedation and awake fiberoptic intubation. In all these
fields dexmedetomidine has demonstrated to be an efficacious and safe adjuvant to other sedative and anesthetic
medications.
Keywords: 2-Adrenoreceptor agonists, dexmedetomidine, sedation, anesthesia, perioperative use.
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INTRODUCTION
Dexmedetomidine is a potent, highly selective and
specific 2-adrenoreceptor agonist that has both sedative and
analgesic effects. The prototype of 2-adrenoreceptor agonist
clonidine was initially developed in 1960s as a nasal
decongestant for its locally acting -adrenergic
vasoconstrictor action, but later in 1966 it was introduced
into the market as a potent antihypertensive drug [1].
Nowadays the therapeutic use of this class of drugs has
shifted to various other clinical indications including
anxiolysis, analgesia, sedation that render them suitable as
adjuncts in anesthesia. Dexmedetomidine was approved in
the USA in 1999 for sedation and analgesia in the intensive
care unit. Compared with clonidine, dexmedetomidine is
about eight times more specific for 2-adrenoreceptors with
an 2: 1 selectivity ratio of 1600 : 1 Fig. (1). These unique
properties of dexmedetomidine make it an 2-adrenoreceptor
full agonist agent with sedative and anxiolytic effects. The
elimination half-life of dexmedetomidine is approximately 2
hours with a rapid distribution half-life being approximately
6 min [2, 3]. It has a rapid onset of action. It undergoes
biotransformation in the liver, and the kidney excretes 95%
of its metabolites.
The short half-life of dexmedetomidine makes it
particularly suitable for intravenous infusion. Although
dexmedetomi-dine is approved for sedation/analgesia in an
intensive care setting, in the last years it has emerged as an
affective therapeutic drug in a wide range of anesthetic
management.
*Address correspondence to this author at the Institute of Anesthesia and
Intensive Care, Catholic University of the Sacred Heart, Largo F. Vito 1,
00013 Rome, Italy; E-mail: [email protected]
1389-4501/09 $55.00+.00
N
NH
N
H
Cl
Clonidine
CH3
H
CH3
CH3
C
N
N
H
Dexmedetomidine
Fig. (1). The chemical structure of 2-adrenoreceptor agonists
clonidine and dexmedetomidine.
PHARMACOLOGY
2-adrenoreceptor agonists act at pre- and postsynaptic
adrenoceptors and their pharmacology is complex. The
human 2-adrenoreceptors can be classified into 2A, 2B and
2C adrenoceptors subtypes. These receptor subtypes are
distributed ubiquitously and each may be responsible for a
specific action of 2 -agonists [4, 5]. The predominant 2 adrenoreceptor agonist subtype mediating sedative and
antinociceptive actions is the 2A-adrenoceptor. Whereas
stimulation of 2B-adrenoceptor mediates the vasoconstrictive cardiovascular effect, which causes the initial
hypertension observed after the administration of 2-adrenoreceptor agonists [6,7]. The 2C - adrenoceptors subtype has
© 2009 Bentham Science Publishers Ltd.
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been shown to modulate dopaminergic neurotransmission,
hypothermia and a variety of behavioral responses.
The hypnotic effect of dexmedetomidine is mediated by
the hyperpolarization of noradrenergic neurons located in the
locus ceruleus [8]. Dexmedetomidine acts through a Gcoupled protein receptor that produces an inhibition of
adenylcyclase and this results in decreased formation of
cyclic AMP (cAMP), that is an important regulator of many
cellular functions acting in various intracellular subsystem
like the control of phosphorilation state of regulatory
proteins. Other effects of 2-adrenoreceptor agonists include
activation of potassium ion channels causing efflux of
potassium and an inhibition of calcium entry into calcium
channels in neuronal cell [9]. These effects lead to change in
membrane ion conductance and produce 2-adrenoreceptor
agonist hyperpolarization of the membrane which suppresses
neuronal activity. The main effect is an inhibition of
noradrenalin release causing a reduction of excitation,
especially in locus coeruleus. The locus coeruleus is 2 adrenoreceptor agonist small neuronal nucleus located
bilaterally in the upper brainstem and is the 2 adrenoreceptor agonist major site of noradrenergic
innervations in the brain [10]. The locus coeruleus has also
been implicated as 2-adrenoreceptor agonist key modulator
for 2-adrenoreceptor agonist variety of important brain
functions, including arousal, sleep, anxiety and drug
withdrawal associated with CNS depressant, like opioids.
Cardiovascular Effects
The hemodynamic effects of dexmedetomidine result
from peripheral and central mechanism. Alpha2 adrenoreceptor agonists show a biphasic, dose-dependent,
blood pressure effect. At low doses the dominant action of
2-adrenoreceptor agonist activation is a reduction in
sympathetic tone, mediated by a reduction of norepinephrine
release at the neuroeffector junction, and a inhibition of
neurotransmission in sympathetic nerves [11]. The net effect
of dexmedetomidine action is a significant reduction in
circulating catecholamines with a slight decrease in blood
pressure and a modest reduction in heart rate [12]. When
dexmedetomidine is administered as a continuous infusion,
is associated with an expected and stable hemodynamic
response. Significant hypotension is usually only observed in
patients with preexisting hypovolemia or vasoconstriction.
The bradycardia frequently seen after the administration of
dexmedetomidine may be due to the central sympatholytic
action and partly by baroceptor reflex and enhanced vagal
activity. This effect is frequently observed in younger
patients with high levels of vagal tone.
Arcangeli et al.
even very high doses of dexmedetomidine did not
compromise respiratory function [13]. Absence of respiratory depression was also observed in patients sedated with
dexmedetomidine, which was administered at infusion rates
10 to 15 times higher than maximally recommended [14]. It
was also demonstrated that combination of 2-adrenoreceptor
agonist with opioids does not lead to further ventilator
depression.
Central Nervous System Effects
Dexmedetomidine, like other 2-adrenoreceptor agonists,
provides sedation, anxiolysis and analgesia. The sedation
produced by 2-adrenoreceptor agonists does not depend
primarily on activation of the -aminobutyric acid (GABA)
receptors like that produced by traditional sedatives, such as
propofol or benzodiazepines. The primary site of action of
2-adrenoreceptor agonist is the locus ceruleous and not the
cerebral cortex, as would be the case with GABA-mimetic
drugs [15]. This should be the reason why this class of drugs
produces a different type of sedation compared with
benzodiazepines and propofol.
Sedation induced by dexmedetomidine has unique
properties, it produces an unusually cooperative form of
sedation in which the patient is calmly and easily roused
from sleep to wakefulness to allow task performance and
excellent communication and cooperation while intubated
and ventilated and then quickly back to sleep when not
stimulated [16]. The unusual subcortical form of
dexmedetomidine induced sedation is characterized by an
easy and quick arousal, resembling natural sleep. With
increasing doses of dexmedetomidine, profound anesthetic
actions have been demonstrated, and this advocates that
dexmedetomidine could be used as total intravenous agent.
The neuroprotective properties of dexmedetomidine have
been demonstrated in various animal models of cerebral
ischemia [17]. There are recent experimental data suggesting
that in addition to 2-adrenoreceptor agonists, the
neuroprotective effect of dexmedetomidine may include
other pathways in the brain, independent of 2 adrenoreceptor agonists and most probably involve I1imidazoline receptors in the brainstem and hippocampus
[18].
Analgesia
At higher doses of dexmedetomidine produce an
hypertensive action caused by the activation of 2B
adrenoceptors located on vascular smooth muscle cells. This
effect proscribes the rapid intravenous injection of
dexmedetomidine.
Dexmedetomidine has been demonstrated to have
significant analgesic effects and consistently reduce opioid
requirements [19]. It is believed that the spinal cord is
probably the major site of analgesic action, where the
activation of 2c-adrenoreceptor agonist subtype seems to
increase the analgesic action of opioids in lowering the
transmission of nociceptive signals to brain centers [20].
Dexmedetomidine also inhibits the release of substance P
from the dorsal horn of the spinal cord, leading to primary
analgesic effects.
Respiratory System Effects
Renal System Effects
The 2-adrenoreceptor agonists have minimal effects on
ventilation. Although dexmedetomidine produces sedative,
analgesic and anxiolytic affects, unlike other sedatives, it
provides respiratory stability and does not cause ventilator
depression. This was shown in healthy volunteers in whom
Stimulation of 2-adrenoreceptors in the kidneys results
in diuresis and natriuresis possibly through an ability to
reduce efferent sympathetic outflow of the renal nerve. In
addition dexmedetomidine has shown to decrease the
secretion of vasopressin and to antagonize its effect on renal
Dexmedetomidine Use in General Anaesthesia
tubules. 2-adrenoreceptor agonists are also thought to
increase the release of atrial natriuretic peptide resulting in
natriuresis [21].
Endocrine System Effects
Action of 2-adrenoreceptor agonists on endocrine
system are mainly related to their action on sympathetic
outflow and the decrease of catecholamines, this can
attenuate the responses to stress by inhibiting the secretion of
adrenocorticotropic hormone (ACTH) and cortisol [21]. In
addition stimulation of 2-adrenoreceptor agonists located on
cells of the islet of Langerhans can temporally cause direct
inhibition of insulin release with concomitant detectable
clinical hyperglycemia [22].
CLINICAL APPLICATIONS IN ANESTHESIA
Premedication
The sedative and anxiolytic properties of dexmedetomidine as well as sympatholytic characteristics make this
drug of particular interest for premedication. Most of the
studies focusing at dexmedetomidine as premedicant have
found interesting benefits. Dexmedetomidine lower the
tachycardic response to endotracheal intubation and assures a
greater hemodynamic stability during the intraoperative
period. It has the ability to potentiate the anesthetic
requirements for opioids as well as volatile and regional
agents. Several studies have demonstrated the beneficial
effects of dexmedetomidine premedication in patients with
coronary artery disease because it allows a stable
perioperative hemodynamic. Jaakola [23] evaluates the
efficacy and safety of intravenous dexmedetomidine as a
premedication before regional anesthesia showing that
dexmedetomidine attenuated the increase in HR and BP
during extubation. Patients received either dexmedetomidine
i.v. or saline placebo i.v. 10 minutes before exsanguination
and inflation of a tourniquet. Regional blockade was induced
with 0.5% lidocaine 3 mg/kg. Dexmedetomidine preoperatively induced 16% to 20% decreases in blood pressure and
heart rate. The subjective intensity of pain during tourniquet
inflation was similar in both groups, but fewer intraoperative
opioids analgesics were needed in the dexmedetomidine
group. General effectiveness was graded superior in the
dexmedetomidine group. The author at the end accomplished
that dexmedetomidine is an effective premedication before
i.v. regional anesthesia because it reduces patient anxiety,
sympathoadrenal responses, and opioids analgesic requirements.
Unlugenc et al. [24] gave 1 g/kg dose of
dexmedetomidine within 10 minutes of induction and they
found a marked decrease in HR within 10 minutes, whereas
heart rate an mean arterial pressure were similar to values
seen in the other group during surgery. In a recent study
Basar et al. [25] utilized dexmedetomidine as a single
preanesthetic drug to investigate the hemodynamic,
cardiovascular and recovery effects in patients undergoing
elective cholecystectomy. 40 adult patients were randomly
assigned to receive 0,5 g/kg dexmedetomidine or saline
solution. Main cardiovascular parameters, times for
awakening, and postoperative Aldrete’s recovery score were
recorded. The authors observed that a single dose of
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dexmedetomidine given before induction of anesthesia
decreased thiopental requirements without serious
hemodynamic effects or any effect on recovery time.
Dexmedetomidine premedication has been evaluated in
children population too. Yuen et al. [26] evaluated whether
intranasal dexmedetomidine was as effective as oral
midazolam for premedication in children. 96 children
scheduled for elective minor surgery were randomly
assigned to receive oral midazolam 0,5 mg/kg, and intranasal
dexmedetomidine at 0.5 or 1 g/kg respectively. Patient’s
sedation status and cardiovascular parameters were recorded
until induction of anesthesia together with recovery
characteristics. They concluded that intranasal dexmedetomidine produces more sedation than oral midazolam, but
with similar and acceptable cooperation. Schmidt et al. [27]
assessed the effects of preanesthetic administration of
midazolam, clonidine or dexmedetomidine on postoperative
pain and anxiety in children. They found that children
receiving clonidine or dexmedetomidine have similar levels
of anxiety and sedation postoperatively as those receiving
midazolam. However children given 2-adrenoreceptor
agonists had less perioperative sympathetic stimulation and
less postoperative pain.
Perioperative Use
Dexmedetomidine may be a useful adjuvant during
general anesthesia to employ its sedative, hypnotic, analgesic
and sympatholytic properties for the benefit of surgical
patients by promoting hemodynamic stability and decreasing
the doses of anesthetics and analgesics. Aho et al. [28]
reported that the administration of an infusion of
dexmedetomidine in patients undergoing abdominal
hysterectomy was able to reduce isoflurane requirements by
90%. The heart rate response to endotracheal intubation was
significantly blunted.
Khan et al. [29] have investigated the pharmacokinetic
and pharmacodynamic interactions of dexmedetomidine and
isoflurane in human volunteers. Nine male subjects were
allocated randomly to receive isoflurane anesthesia preceded
by infusion of dexmedetomidine. They observed that
dexmedetomidine decreased isoflurane requirements in a
dose-dependent manner and reduced heart rate and arterial
pressure. Sedation and slight impairment of cognitive
function persisted for several hours after anesthesia.
Isoflurane did not appear to influence the pharmacokinetics
of dexmedetomidine. Since dexmedetomidine sedative
properties could possibly prolong recovery from anesthesia
Ohtani et al. [30] examined the effect of co-administration of
dexmedetomidine on the recovery profiles from sevoflurane
and propofol based anesthesia. Sixty patients were divided
into four groups according to the anesthetic to be
administered: sevoflurane, propofol, sevoflurane and
dexmedetomidine and propofol and dexmedetomidine as
maintenance general anesthetics. The main findings of this
study are that dexmedetomidine delays recovery from
propofol but not from sevoflurane and that postoperative
cognitive function is not affecting by co-administration of
dexmedetomidine in both groups. Dexmedetomidine was
also utilized as a total intravenous anesthetic; Ramsay et al.
[31] reported the administration of dexmedetomidine in this
fashion in three patients with potential airway management
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problems knowing the well-known profound sedative effect,
while avoiding respiratory depression. Dexmedetomidine
was administered until general anesthesia was achieved in
doses up to 10 g/kg per hour without hemodynamic
compromise, in addition no suppression of respiratory
activity was observed, only one patient needed airway
control by a chin lift maneuver. . Ebert and Maze [32] in an
editorial accompanying this paper were concerned with the
use of high concentration of dexmedetomidine when used as
the sole anesthetic for the potential for systemic and
pulmonary hypertension and direct or reflex bradycardia.
They conclude that “ although the possible monotherapeutic
application of 2-adrenoreceptor agonists to provide an
anesthetic state suitable for general anesthesia has been
described, it is much more likely that this class of compound
will be used in combination with other anesthetic adjuvants
in the perioperative period “.
Thoracic Surgery
In thoracic surgery the use of dexmedetomidine may
offer numerous physiologic benefits. It lowers the
perioperative oxygen consumption and the sympathetic
response to surgical stimulus that may assure
cardioprotective benefit. Wahlander et al. [33] have observed
that the use of dexmedetomidine in post-thoracotomy
patients as a supplementation to a low-dose thoracic epidural
bupivacaine (0.125%) reduce the requirement for opioids
and the potential for respiratory depression. In the same
study a post hoc analysis was conducted to test the
hypothesis that dexmedetomidine enhances urine flow rate
and perioperative renal function and it was found that
dexmedetomidine infusion induced diuresis in patients with
normal preoperative renal function and undergoing fluid
restriction.
Cardiac Surgery
The surgical stress response is important in the
pathogenesis of cardiovascular complications. The 2 adrenoreceptor agonists attenuate the stress response and
therefore potentially reduce cardiovascular complications.
There are a large number of studies that evaluated
dexmedetomidine as an adjunct to cardiac surgery.
Wiyeysundera et al. [34] investigated the effects of
2adrenoreceptor agonists, including dexmedetomidine,
clonidine, and mivazerol, on perioperative cardiovascular
complications and mortality in adults undergoing vascular
and cardiac surgery. Twenty-three trials comprising 3.395
patients were included. Overall, 2-adrenoreceptor agonists
reduced the incidence of myocardial infarction and mortality
significantly during vascular surgery. During cardiac
surgery, 2-adrenoreceptor agonists reduced the number of
ischemic episodes and were associated with a reduced risk of
myocardial infarction and trend toward decreased mortality.
The risk of hypotension during cardiac surgery was
highlighted in this analysis, but the authors did not find
statistically significant increases in the occurrence of
hypotension, bradycardia, or heart failure. Jalonen et al. [35]
evaluated eighty patients scheduled for elective coronary
artery bypass grafting receiving intravenous infusion of
dexmedetomidine. Dexmedetomidine decreased plasma
norepinephrine concentrations by 90%, attenuated the
increase of blood pressure, but increased slightly the need for
Arcangeli et al.
intravenous fluid challenge and induced more hypotension
during cardiopulmonary bypass. In addition it decreased the
incidence of intraoperative and postoperative tachycardia. In
another study But et al. [36] investigated the effects of preoperative dexmedetomidine infusion on hemodynamic in
patients with pulmonary hypertension undergoing mitral
valve replacement surgery. Patients received dexmedetomidine infusion until the surgical incision. They found that
dexmedetomidine decreases the fontanel requirement and
attenuates the increase in systemic vascular resistance index
(SVRI) and pulmonary vascular resistance index (PVRI) at
the post-sternotomy period relative to the baseline levels,
and decreases effectively mean arterial pressure (MAP),
mean pulmonary artery pressure (MPAP) and pulmonary
artery wedge pressure (PCWP) in comparison with the
values in the placebo group.
Few studies of the use of dexmedetomidine have been
performed during pediatric cardiac surgery. Muktar et al.
[37] evaluated the effects of dexmedetomidine on circulatory
dynamics and serum cortisol, glucose, epinephrine, and
norepinephrine concentrations in 30 children undergoing
cardiopulmonary bypass. Relative to baseline, arterial blood
pressure and heart rate decreased significantly after the
administration of dexmedetomidine through skin incision. In
the control group, heart rate and arterial blood pressure
increased after skin incision until the end of bypass. In both
groups, plasma cortisol, epinephrine, norepinephrine, and
blood glucose increased significantly relative to baseline,
after sternotomy, and after bypass. However, the values were
significantly higher in the control group compared with the
DEX group. They concluded that intraoperative
dexmedetomidine infusion can be a useful adjuvant in
pediatric cardiac anesthesia because it attenuates the
hemodynamic and neuroendocrinal response of surgical
trauma.
Dexmedetomidine has also been utilized as an
antiarrhytmic drug; Crysostomou et al. [38] examined the
possible effect of dexmedetomidine on atrial and junctional
tachyarrhythmia. Fourteen patients admitted to the cardiac
intensive care received dexmedetomidine for both
sedation/analgesia and for junctional ectopic tachycardia,
atrial ectopic tachycardia, reentry type supraventricular
tachycardia, atrial flutter and functional accelerated rhythm.
Dexmedetomidine was used as a primary drug or as a rescue
drug if other antiarrhythmics had been used. Ten patients
(71%) received an initial loading dose of 1.1 ± 0,5 g/kg. A
continuous infusion, 0.9 ± 0.3 g/kg/hr was administered in
12 patients. Adverse effect was seen in four patients
(28%).Three had hypotension and one had a possible brief
atrioventricular block. The primary outcome with rhythm
and/or heart rate control was achieved in 13 patients (93%).
The authors concluded that dexmedetomidine may have a
potential therapeutic role in the acute phase of perioperative
atrial and functional tachyarrhythmias for either control of
heart rate or conversion to normal sinus rhythm.
Neurosurgery
During intracranial surgical procedures the neurosurgeon
must often performs neurophysiological testing to evaluate
that the surgical target has been localized or to assess the
responses following deep brain stimulation for electrode
Dexmedetomidine Use in General Anaesthesia
implantation, surgical management of epilepsy and other
procedures. In this context an intraoperative active patient
participation is required. Drugs utilized in these procedures
should permit to modify rapidly the level of anesthesia from
a deep level during periods of intense stimulation to
consciousness during functional testing. In these
circumstances dexmedetomidine may be a useful adjunct to
the currently utilized anesthetic techniques. Low doses of
this drug, in fact, provide sedation that can be easily reversed
with verbal stimulation. Bekker et al. [39] reported the first
successful application of dexmedetomidine combined with
BIS monitoring in an awake craniotomy setting necessitating
an awake, cooperative patient. The pharmacology of
dexmedetomidine allowed achieving a level of sedation and
analgesia sufficient to complete the neuropsychiatric testing
required for the mapping of the cortical language area, as
well as to perform an awake tumor resection. The patients
remained hemodynamically stable and cooperative during
the “awake” portion of the procedure. In this case series
dexmedetomidine was selected also for its lack of respiratory
depression as well as its sedative and analgesic properties.
They concluded that dexmedetomidine appears to be a useful
sedative for awake craniotomy when sophisticated
neurologic testing is required. Souter et al. [40] utilized
dexmedetomidine in patients with refractory seizures that
underwent awake craniotomy for cortical resection of the
seizure area using intraoperative functional mapping and
electrocorticography (ECoG). In this situation the authors
found that dexmedetomidine does not suppress epileptiform
activity and then can be used in patients with seizures
disorders requiring brain mapping. Dexmedetomidine has
been also used during stereotactic implantation of deep brain
stimulators and has shown an improvement in patient
satisfaction without compromising target localization. Rozet
et al. [41] performed a retrospective chart review of
anesthesia records of patients who underwent deep brain
stimulator implantation. Demographic data, use of
antihypertensive medication, and duration of mapping were
compared between patients who received dexmedetomidine
and patients who did not receive any sedation.
Dexmedetomidine provided patient comfort and surgical
satisfaction with mapping in all cases, and significantly
reduced the use of antihypertensive medication. In deep
brain stimulator implantation, sedation with dexmedetomidine did not interfere with electrophysiologic mapping,
and provided hemodynamic stability and patient comfort.
Bekker et al. [42] have also been used Dexmedetomidine as
a primary sedative agent for sedating patients performing
awake carotid endoarteriectomy to allow intraoperative
neurological examination. Sixty-six patients were randomly
assigned to receive either dexmedetomidine (total dose of
97.5 +/- 54.7 cg) or normal saline (control). Supplemental
doses of midazolam, fentanyl, and/or propofol were
administered as deemed necessary by the anesthesiologist.
The use of dexmedetomidine in these patients resulted in
fewer fluctuations from the desired sedation level. In
addition patients receiving dexmedetomidine required less
antihypertensive therapy compared with the midazolam/
fentanyl/ propofol combination. Dexmedetomidine has found
useful also in patients undergoing craniotomy under general
anesthesia to obtain hemodynamic stability and modulation
of intraoperative sympathetic responses to attenuate
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cerebrovascular and myocardial risks and avoid intracranial
hemorrhage, in addition it allows immediate neurological
evaluation upon emergence. Tanskanen et al. [43] have used
dexmedetomidine as an anesthetic adjuvant to neurosurgical
anesthesia in patients scheduled for elective surgery of
supratentorial brain tumor. They were randomized to receive
a continuous dexmedetomidine infusion or placebo,
beginning 20 min before anesthesia and continuing until the
start of skin closure. Anesthesia was maintained with nitrous
oxide in oxygen and isoflurane. They found that dexmedetomidine significantly attenuated the hemodynamic responses
to intubation and the emergence from anesthesia. In addition,
it increased intraoperative cardiovascular stability. Most of
the effects were concentration dependent, and the higher
dose was more effective than the lower dose. Patients
receiving dexmedetomidine had their tracheal tubes removed
faster than those in the placebo group, indicating preserved
respiratory function. In a recent study Bekker et al. [44],
considering that the perioperative course of patients
undergoing intracranial surgery is frequently complicated by
hypertensive episodes, designed the study to assess the
efficacy of dexmedetomidine in controlling hypertensive
responses during the surgery. Patients were randomly
divided to receive either sevoflurane-opioids or sevofluraneopioids-dexmedetomidine. The dexmedetomidine group
required fewer opioids in the intraoperative period, but there
were no differences in the use of sevoflurane. In the
intensive care unit, patients in dexmedetomidine group had
fewer hypertensive episodes and were discharged earlier.
There were no differences in the requirement for postoperative opioids or antiemetics. They concluded that dexmedetomidine improved hemodynamic stability and was effective
for blunting the increase of systolic blood pressure
perioperatively. In addition the drug did not increase the
incidence of hypotension and bradycardia, common side
effect of this drug.
Procedural Sedation
There is a growing interest in utilization of this agent in
the pediatric population who require sedation for
radiographic procedures, in particular with radiologic
imaging (computed tomography and magnetic resonance
imaging - MRI). Koroglu et al. [45] randomized 80 children
(1-7 yrs of age) to dexmedetomidine or midazolam during
MRI. Dexmedetomidine was administered as a loading dose
of 1 g/kg over 10 min followed by an infusion of 0.5
g/kg/hr, whereas midazolam was administered as a loading
dose of 0.2 mg/kg followed by an infusion of 6 g/kg/hr.
The quality of sedation was better in the dexmedetomidine
group than in the midazolam group, as they achieve an
adequate lack of movement and sedation. In addition the
need for rescue sedation was less with dexmedetomidine
compared with midazolam. A second study by Koroglu et al.
[46] randomized 60 children to dexmedetomidine or
propofol during MRI. Although equally effective in
providing sedation, a faster onset of action, faster recovery
and discharge were noted in propofol group. Adverse effects
including hypotension and oxygen desaturation were more
common with propofol. Oxygen desaturation requiring
intervention (chin lift, discontinuation of the infusion, and
supplemental oxygen) occurred in four children receiving
propofol vs. none of those receiving dexmedetomidine. In
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Current Drug Targets, 2009, Vol. 10, No. 8
another study Heard et al. [47] compared the pharmacodynamic responses to dexmedetomidine –midazo-lam and
propofol in children anesthetized with sevoflurane
undergoing magnetic resonance imaging (MRI). Forty
children were randomized to receive either dexmedetomidine-midazolam or propofol for maintenance of anesthesia
for MRI after a sevoflurane induction. Dexmedetomidine
was administered at an initial loading dose of 1 g/kg
followed by a continuous infusion of 0.5 g/kg/hr.
Midazolam (0.1 mg/Kg) was administered when the infusion
started. Propofol was administered as a continuous infusion
(250-300 g/kg/hr). The authors found that dexmedetomidine-midazolam provides adequate anesthesia for MRI but
the times to fully recover and to discharge after
dexmedetomidine administration were significantly greater
than those after propofol. Heart rate and systolic blood
pressure was greater with dexmedetomidine compared with
propofol. Respiratory indices were similar for the two
treatments.
Dexmedetomidine was also used in pediatric population
for invasive procedures like gastrointestinal endoscopy, fiber
optic intubation and cardiac catheterization. Tosun et al. [48]
compared a dexmedetomidine-ketamine combination with a
propofol-ketamine combination in 44 children (4 months to
16 yrs) with acyanotic congenital heart disease undergoing
cardiac catheterization. Although sedation was managed
effectively with both regimens, patients sedated with
ketamine-dexmedetomidine required more ketamine and
more supplemental doses of ketamine and had longer
recovery times than patients sedated with a propofolketamine combination. The authors concluded that the
dexmedetomidine-ketamine combination was not superior to
a propofol-ketamine combination because of insufficient
sedation and analgesia and a longer recovery. For the same
purpose dexmedetomidine has also been used in adult
population, in fact in MRI setting where stereotactic frame
placement and accurate imaging in tremulous Parkinson’s
patients makes anesthetic management particularly complex.
In these circumstances dexmedetomidine utilization
represents a safe alternative with the classic deep propofol
sedation, assuring a sedation that reduces movement and
causes no respiratory depression [49].
Dexmedetomidine may also represents a good option
during sedation of adult patients requiring endoscopy,
Demiraran et al. investigate [50] and compare the safety and
efficacy of dexmedetomidine versus midazolam in providing
sedation for gastroscopy in 50 adult patients. After the
procedure, full recovery time, mean arterial pressure, heart
rate, respiratory rate and hemoglobin oxygen saturation
levels were similar in both groups. Dexmedetomidine
performed as effectively and safely as midazolam but it was
superior to it with regard to vomiting, rate of side effects and
endoscopist satisfaction. It was concluded that dexmedetomidine may be a good alternative to midazolam to sedate
patients for upper endoscopy. In another study dexmedetomidine showed negative effects, Jalowiecki et al. [51]
performed a study to evaluate the ability of dexmedetomidine to provide analgesia and sedation for outpatient
colonoscopy. Sixty-four patients were randomly assigned to
one of three treatment regimens. In group D, patients
received 1/g/kg dexmedetomidine over 15 min followed by
an infusion of 0.2 g/kg/h. Group P received meperidine (1
Arcangeli et al.
mg/kg) with midazolam (0.05 mg/kg), and group F received
fentanyl (0.1- 0.2 mg intravenous) on demand. The study
was terminated before the planned 90 patients had been
recruited because of adverse events in group D. In all groups,
negligible hemoglobin oxygen saturation and respiratory rate
variations were observed. In group D, there was a
significantly larger decrease in heart rate (to approximately
40 beats/min in 2 out of 19 cases) and blood pressure (to less
than 50% of the initial value in 4 of 19 patients).
Supplemental fentanyl was required in 47% of patients
receiving dexmedetomidine to achieve a satisfactory level of
analgesia (vs. 42.8% of patients in group P and 79.2% of
patients in group F). Vertigo (5 patients), nausea/vomiting (5
patients), and ventricular bigeminism (1 patient) were
observed only in group D. Time to home readiness was
longest in group D. The authors of this work concluded that
in patients undergoing colonoscopy, dexmedetomidine
provides a relatively satisfactory level of analgesia and
sedation without clinically notable adverse respiratory
effects. However, compared with commonly used sedation
regimens, dexmedetomidine was associated with the
frequent requirement for supplemental fentanyl, sometimes
profound hypotension and bradycardia, and prolonged
recovery time. At the end they affirmed that these side
effects may limit dexmedetomidine usefulness for this
indication.
Awake Intubation
Awake intubation in the patient with a potentially
difficult airway is a problematic procedure which may be
associated with wide hemodynamic changes. To attenuate
this response, blunting of airway reflexes is required without
losing the patient’s cooperation. Conventional agents such as
opioids, benzodiazepines, and propofol carry the risk of
respiratory depression, with possible inability to ventilate the
patient. Dexmedetomidine offers an ideal solution to this
problem because patients are maintained in spontaneous
breathing while attempts are made to secure their airway. In
addition thanks to its antisialagogue effect it maintains a dry
field for the anesthesiologist thus facilitating the procedure.
Bergese et al. [52] in a recent investigation reported on 4
patients with particularly difficult airways who underwent
successful awake fiberoptic intubation with dexmedetomidine. Dexmedetomidine was used to provide a moderate
level of conscious sedation without causing respiratory
distress or hemodynamic instability during fiberoptic
intubation. Abdelmalak et al. [53] reported a series of
successful awake fiberoptic intubations in patients with
critical (unstable and difficult) airways using dexmedetomidine. The authors affirmed that dexmedetomidine appears
to be a useful agent for sedation during awake fiberoptic
intubation in difficult airway patients. Recently [54] dexmedetomidine has been utilized for laryngeal mask insertion
comparing with fentanyl combined with propofol. The
authors in their conclusion stated that dexmedetomidine,
when used before propofol induction provides successful
laryngeal mask insertion comparable to fentanyl, while
preserving respiratory functions more than fentanyl.
Bariatric Surgery
Obesity is increasingly common, particularly in
developed countries, and represents a serious hazard to
Dexmedetomidine Use in General Anaesthesia
public health, with consequent repercussions on health care
expenditure. Bariatric surgery represents a great advance in
the treatment of obese patients. Applied when all other
measures have failed, this therapeutic option is achieving
very favorable outcomes and is therefore being carried out
with increasing frequency. Obese patients are at a
disadvantage during anesthesia, given that techniques are
more difficult to perform and risk increases. Obesity is often
associated with marked respiratory co-morbidities such as
obstructive sleep apnea and/or pulmonary hypertension that
may have a profound impact on anesthetic management of
these patients and may increase the risk of morbidity and
mortality due to inadequate postoperative ventilation.
Because of opioid ventilatory depressing effect,
dexmedetomidine has been used to diminish this threat and
thereby decrease the incidence of respiratory depression.
Feld et al. [55] evaluated whether dexmedetomidine infusion
could replace fentanyl for facilitation of open gastric bypass
surgery. In this context, they observed that dexmedetomidine
treatment during bariatric surgery decreased blood pressure,
heart rate, and desflurane anesthetic requirement and
attenuated pain level and morphine use in the PACU
compared with fentanyl. The decrease in morphine use in
dexmedetomidine-treated patients may be important for
attenuating the risk of narcotic-induced postoperative
respiratory depression and hypoxemia in patients after this
type of surgery. In one case report, Hofer et al. [56] describe
the anesthetic management of a patient with extreme obesity
undergoing bariatric surgery whose intraoperative narcotic
management was entirely substituted with dexmedetomidine,
because of the concern that the use of narcotics might cause
postoperative respiratory depression. They substituted the
intraoperative use of narcotics with dexmedetomidine;
Isoflurane was administered at an initial end-tidal
concentration of 0.9% and then reduced to an averaged
0.6%. After completion of the operation and after tracheal
extubation, the dexmedetomidine infusion was continued
uninterrupted throughout the end of the first postoperative
day. A significant reduction in the morphine dose
requirements was observed on the first postoperative day
when compared with the second postoperative day.
Dexmedetomidine has been also evaluated during
laparoscopic bariatric surgery to assess the effect on both
early and late recovery [57]. Dexmedetomidine infusion at
0.2, 0.4, and 0.8 g/kg/h rates reduced the average end tidal
desflurane concentration by 19, 20, and 22%, respectively.
However, it failed to facilitate a significantly faster
emergence from anesthesia. In addition it decreased fentanyl
use, antiemetic therapy, and the length of stay in the PACU.
However, it failed to facilitate late recovery (e.g., bowel
function) or improve the patients’ overall quality of
recovery. When used during bariatric surgery, the authors
recommend a dexmedetomidine infusion rate of 0.2 g/kg/h
to minimize the risk of adverse cardiovascular side effects.
From these studies it can be concluded that
dexmedetomidine may be a useful adjuvant in this type of
surgery for the minimal respiratory depression that it causes
while offering adequate pain relief.
Lithotripsy
The new generation lithotriptors are less painful, thus the
anesthetic techniques have shifted from general anesthesia to
Current Drug Targets, 2009, Vol. 10, No. 8
693
analgosedation. At present propofol is the most frequently
used sedative hypnotic agent for this purpose but it may have
some respiratory depression effect, especially when used in
conjunction with opioids. Dexmedetomidine in this context
may be a safe and attractive option for its analgesic and
sedative properties with little effect on ventilation. Kaygusuz
et al. [58] have thus evaluated the utility of dexmedetomidine compared with propofol during extracorporeal
shockwave lithotripsy (ESWL) procedure. Forty-six patients
were randomly allocated into two groups to receive either
dexmedetomidine or propofol for elective ESWL.
Dexmedetomidine was started at 6 g/kg/h infusion rate for
10 min, followed by a 0.2 g/kg/h rate. Propofol was infused
at 6 mg/kg/h for 10 min, followed by an infusion of 2.4
mg/kg/h. Fentanyl, 1 g/kg, was given i.v. to all patients 10
min before ESWL. Pain intensity was evaluated with a visual
analog scale at 5-min intervals during ESWL. Sedation
scores and hemodynamic and respiratory variables were
recorded regularly during ESWL (35 min) and up to 85 min
after. The authors observed that analgesic and respiratory
variables were better with dexmedetomidine than propofol.
Therefore, they concluded that dexmedetomidine in
combination with a small dose of fentanyl can be useful
during ESWL and it may be a valuable alternative to
propofol. In another study Alhashemi et al. [59] compared
the analgesic effects of dexmedetomidine/morphine with
those of tramadol/midazolam in patients undergoing
extracorporeal shockwave lithotripsy (ESWL). Sixty patients
were randomized to receive either dexmedetomidine 1 Bg/kg
iv followed by 0,5 Bg/kg/h infusion together with morphine
patient-controlled analgesia, or tramadol 1.5 mg/kg premixed with midazolam 30 Bg/kg iv followed by tramadol
patient-controlled analgesia. Pain was assessed at baseline
and every 15 min thereafter. Patients’ and urologist’s
satisfaction with analgesia and sedation were determined on
a seven-point scale ranging from 1 (extremely dissatisfied) to
7 (extremely satisfied). Patient’s discharge time was also
documented. Results showed that visual analogue scale
scores over time were consistently lower in the group treated
with dexmedetomidine compared with the group treated with
tramadol. Patients’ satisfaction with analgesia and with
sedation and urologist’s satisfaction were all higher amongst
treated with dexmedetomidine. They concluded that
dexmedetomidine in combination with morphine PCA
provided better analgesia for ESWL and was associated with
higher patients’ and urologist’s satisfaction when compared
with tramadol/midazolam PCA combination.
Ambulatory Anesthesia
In ambulatory anesthesia the choice of a safe and
effective anesthetic is of paramount importance due to the
need to have quick recovery and minimal complication and
to assure an excellent level of safety in patients that have to
came back home. Dexmedetomidine appears to be a good
option because of its analgesia and short-lived sedation
properties that improves safety and efficacy by maintaining
hemodynamic stability. Thaghinia et al. [60] conducted a
retrospective study to evaluate the safety and efficacy of
dexmedetomidine in rhytidectomy surgery. Records were
reviewed for 155 consecutive face lifts performed under
sedation by the same surgeon over 3.5 years. Intraoperative
and postoperative parameters and outcomes were compared
694
Current Drug Targets, 2009, Vol. 10, No. 8
for 78 patients sedated with dexmedetomidine (dexmedetomidine group) and 77 sedated without dexmedetomidine
(propofol, ketamine, fentanyl, and midazolam). Intraoperatively, the dexmedetomidine group had significantly lower
mean systolic and diastolic blood pressures and heart rate.
Fewer dexmedetomidine group patients had oxygen
desaturation below 92% and fewer required antihypertensives, although more required vasopressors. The dexmedetomidine patients needed less midazolam and fentanyl.
Postoperatively, the dexmedetomidine group again had
lower mean systolic and diastolic blood pressures and heart
rate. In addition, fewer patients in this group needed
postoperative antiemetics. The results of this study suggest
that when compared with conventional sedation,
dexmedetomidine appears to improve anesthetic safety and
efficacy for rhytidectomy patients. Ustün et al. [61]
performed a study in dental surgery setting comparing the
use of dexmedetomidine with the use of midazolam during
intravenous conscious sedation in third molar surgery.
Twenty healthy patients with symmetrically impacted
mandibular third molars were included in this double-blind,
crossover, randomized study. Either dexmedetomidine
(group D) (4 Og/kg/h) or midazolam (group M) (0.4
mg.kg/h) was administered intravenously for 15 minutes
before the first operation. At the second operation, the other
agent was applied. The intraoperative sedation level, patient
cooperation, and postoperative performance were scored and
any pain reaction during the local anesthetic injection was
recorded. Visual analog scales were additionally used for the
subjective assessment of pain and patient satisfaction.
Amnesia was evaluated by the patients' ability to recall the
objects shown during the operations and the local anesthetic
injection. Patients' preferences were recorded during the
interview at the end of the second operations. The results
showed that the mean heart rate and blood pressure
measurements were significantly lower in group D. There
was no significant difference in the respiratory findings. A
significantly higher number of patients showed pain
reactions in group M. Sedation level, postoperative
performance, and VAS pain scores were not statistically
significant, whereas the differences in cooperation score and
VAS for patient satisfaction were significant. Adequate
amnesia was obtained in group M, however, no amnesia was
demonstrated in group D. Sixty-five percent of the patients
indicated a preference for dexmedetomidine sedation. The
authors concluded that dexmedetomidine may be a
remarkable alternative to midazolam for intravenous
sedation because it seems to be a reliable and safe method,
with additional analgesic effect providing a satisfactory
sedation level without any serious side effects during
impacted third molar surgery.
Arcangeli et al.
sedation in the ICU but also for anesthetic management.
Data regarding the perioperative utilization “ off label ” are
promising bur are limited in number and further studies are
required to establish a definitive role of this drug in the
anesthetic field.
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Accepted: April 09, 2009