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-Adrenergic Agonists: Dexmedetomidine

Sejarah

The 2-adrenergic agonists provide sedation, anxiolysis, hypnosis, analgesia, and


sympatholysis. The initial impetus for the use of 2 agonists in anesthesia resulted from
observations made in patients during anesthesia who were receiving clonidine therapy. [466] [467]
This was soon followed by a description of the minimum alveolar concentration (MAC)
reduction of halothane by clonidine.[468] Dexmedetomidine is a more selective 2 agonist with
a 1600 greater selectivity for the 2 receptor compared with the 1 receptor. It was introduced
in clinical practice in the United States in 1999 and approved by the FDA only as a short-term
(<24 hours) sedative for mechanically ventilated adult ICU patients. Dexmedetomidine is
now being used off-label outside of the ICU in various settings, including sedation and
adjunct analgesia in the operating room, sedation in diagnostic and procedure units, and for
other applications such as withdrawal/detoxification amelioration in adult and pediatric
patients. [469] [470]
Physicochemical characteristic

Dexmedetomidine is the d-enantiomer of medetomidine, a substance that has been used for
sedation and analgesia in veterinary medicine for many years.[471] It shows a high ratio of
specificity for the 2 receptor (2/1 1600:1) compared with clonidine (2/1 200:1), making
it a complete 2 agonist.[472] Dexmedetomidine belongs to the imidazole subclass of 2
receptor agonists, similar to clonidine, and its structure is illustrated in Figure 26-19 . It is
freely soluble in water.

Metabolisme dan farmakokinetik


Dexmedetomidine is rapidly distributed and extensively metabolized in the liver and excreted
in urine and feces. It undergoes conjugation (41%), n-methylation (21%), or hydroxylation
followed by conjugation. Dexmedetomidine is 94% protein bound, and its concentration ratio
between whole blood and plasma is 0.66. Dexmedetomidine has profound effects on
cardiovascular variables and may alter its own pharmacokinetics. With large doses, there is

marked vasoconstriction, which probably reduces the drug's volumes of distribution. In


essence, dexmedetomidine displays nonlinear pharmacokinetics.[473] Dyck and coworkers[474]
found that its pharmacokinetics in volunteers is best described by a three-compartment model
(see Table 26-1 ). These pharmacokinetic parameters apparently are unaltered by age or
weight or renal failure, but clearance is a function of height. [473] [475] The elimination half-life
of dexmedetomidine is 2 to 3 hours, with a context-sensitive half-time ranging from 4
minutes after a 10-minute infusion to 250 minutes after an 8-hour infusion. Postoperative
patients sedated with dexmedetomidine display similar pharmacokinetics to the
pharmacokinetics seen in volunteers.[476]
Farmakologi
Dexmedetomidine is a nonselective 2 agonist. Alpha2 adrenoreceptors are membranespanning G proteins. Intracellular pathways include inhibition of adenylate cyclase and
modulation of ion channels Three subtypes of 2 adrenoreceptors have been described in
humans: 2A, 2B, and 2C ( Fig. 26-20 ).[477] The 2A adrenoreceptors are primarily distributed
in the periphery, whereas 2B and 2C are in the brain and spinal cord. Postsynaptic located 2
adrenoreceptors in peripheral blood vessels produce vasoconstriction, whereas presynaptic 2
adrenoreceptors inhibit the release of norepinephrine, potentially attenuating the
vasoconstriction. The overall response to 2 adrenoreceptors agonists is related to the
stimulation of 2 adrenoreceptors located in the CNS and spinal cord. These receptors are
involved in the sympatholysis, sedation, and antinociception effects of 2 adrenoreceptors.[478]

Efek ke Sistem Saraf Pusat


Sedasi
The 2 agonists produce their sedative-hypnotic effect by an action on 2 receptors in the
locus caeruleus and an analgesic action at 2 receptors within the locus caeruleus and within
the spinal cord.[479] The quality of sedation produced by dexmedetomidine seems different
compared with that produced by other sedatives acting through the GABA systems. Patients
receiving dexmedetomidine infusions as part of their sedation regimen in the postoperative
ICU setting have been described as being very easy to wake up and having the ability to
follow commands and cooperate while being tracheally intubated. Undisturbed, patients were
noted to fall asleep right away.[480] Despite sound levels of sedation with dexmedetomidine,
there is limited respiratory depression, providing wide safety margins.[481] This characteristic
allows for daily wake up tests to be done in a safe fashion. This critical testwhen
ventilated ICU patients are taken off all sedatives to assess their mental status and titrate
sedationshortens their ventilated and ICU length of stay.[482]
The 2 agonists act through the endogenous sleep-promoting pathways to exert their sedative
effect ( Fig. 26-21 ). Dexmedetomidine produces a decrease in activity of the projections of

the locus caeruleus to the ventrolateral preoptic nucleus. This increases GABAergic and
galanin release in the tuberomammillary nucleus, producing a decrease in histamine release
in cortical and subcortical projections.[483] The 2 agonists seem to inhibit ion conductance
through L-type or P-type calcium channels and facilitate conductance through voltage-gated
calcium-activated potassium channels.[484] The similarity between natural sleep (nonrapid
eye movement) and dexmedetomidine-induced hypnosis has been speculated to maintain
cognitive and immunologic function in the sleep-deprived states (as in the ICU).[485]
Dexmedetomidine can produce profound sedation, and it has been used as a total IV
anesthetic when given at 10 times the normal sedation concentration range.[486]

The 2 agonists have the advantage that their effects are readily reversible by 2-adrenergic
antagonists (e.g., atipamezole).[487] Atipamezole is not currently approved for human use.
Similar to other adrenergic receptors, the 2 agonists also show tolerance after prolonged
administration.[488] Because dexmedetomidine is approved by the FDA only for short-term
sedation (24 hours), tolerance, dependence, or addiction does not seem to be a problem.
Dexmedetomidine can be employed for addiction treatment; dexmedetomidine has been
described for use in rapid opioid detoxification, cocaine withdrawal, and iatrogenic induced
benzodiazepine and opioid tolerance after prolonged sedation.[489] In animals,
dexmedetomidine, in contrast to opioids, does not result in hyperalgesia or allodynia after its
withdrawal.[490] Rats rendered tolerant to morphine also show a decrease in efficacy of
hypnotic and analgesic effects of dexmedetomidine. As tolerance to opioids recovers, there is
a more rapid recovery of the hypnotic effect of dexmedetomidine than its analgesic efficacy.
[491]
These data would tend to indicate a possible cross-tolerance between receptors.

Analgesia

The analgesic effects of dexmedetomidine are complex. Alpha2 agonists do have an analgesic
effect when injected via the intrathecal or epidural route.[492] Clonidine injected in the neural
axis helps with short-term pain, cancer pain, and neuropathic pain. [493] [494] Intrathecally
injected dexmedetomidine in sheep reduces blood pressure in 1 minute. When
dexmedetomidine is injected into the epidural space, it rapidly diffuses into the CSF (in one
study,[495] 22% of the injected dose was identified in the CSF). The effects on blood pressure
are slower in onset with an epidural injection than with an intrathecal administration.
Epidural effects are seen in 5 to 20 minutes. The primary site of analgesic action is thought to
be the spinal cord.[495] Systemic use of dexmedetomidine shows narcotic sparing. In the
postoperative ICU setting, narcotic requirements were reduced by 50% when patients were
receiving a dexmedetomidine drip compared with placebo.[480]
Some of the systemic analgesic effects have been attributed to the confounding sedative
effects.[496] In human pain studies, the results of systemically administered dexmedetomidine
are inconsistent. Modest reductions in pain were observed in cold pressor tests when patients
were receiving dexmedetomidine.[497] More recently, in a model of heat and electrical pain in
human volunteers, dexmedetomidine was not capable of attenuating the pain response in the
clinical dose range when subjects were conscious.[485] The analgesic effect of
dexmedetomidine has been compared with remifentanil. In a noxious heat versus pain
intensity plot obtained in a group of volunteers, dexmedetomidine was less effective in
reducing pain (less of a right shift of the curve) than remifentanil. Also, the slope was
different, suggesting a different mechanism of action and an effect from sedation.[498] In the
clinical setting, when pain is likely to occur, if dexmedetomidine is to be used, the addition of
a narcotic seems warranted.

Proteksi SSP dan efek lain ke SSP

The CNS protective effects are not well defined. Dexmedetomidine in animal models of
incomplete cerebral ischemia and reperfusion reduces cerebral necrosis and improves
neurologic outcome. In a model of focal ischemia in rabbits, dexmedetomidine, administered
at doses that reduced the MAC of halothane by 50%, resulted in less cortical neuronal
damage than when halothane was administered alone at equieffective MAC concentrations.
[499]
In a rat model of unilateral carotid ligation accompanied by systemic hypotension, the
administration of dexmedetomidine provided for lower plasma catecholamines with less
neurologic and histopathologic damage.[500] The prevalent idea was that dexmedetomidine
reduced the intracerebral catecholamine outflow during injury and resulted in less neural
tissue damage with better neurologic outcome.[501] Others have found no reduction in cerebral
catecholamines after receiving dexmedetomidine during injury.[502] The neuroprotection may
be attributed to modulation of proapoptotic and antiapoptotic proteins.[341] Also, the reduction

of the excitatory neurotransmitter glutamate during injury may explain some of the protective
effects.[503]
The neuroprotective properties of dexmedetomidine in humans have not been investigated.
Little is known of the effects of dexmedetomidine alone on ICP and CBF. In patients after
pituitary surgery, a target concentration of 600 ng/mL of dexmedetomidine resulted in no
increase in lumbar CSF pressure.[504] In dogs, in the presence of volatile anesthetics and
dexmedetomidine, CBF was decreased, and oxygen consumption was maintained. [505] [506]
CBF velocity, as measured by transcranial Doppler, decreased with increasing concentrations
of dexmedetomidine in parallel with decreasing MAP and increasing PaCO2.[507] These
decreases in CBF are not accompanied by a reduction in CRMO2. Despite the significant
reduction in CBF with dexmedetomidine, there was no evidence of cerebral ischemia in a dog
model.[551] In a preliminary study in patients undergoing cerebrovascular surgery using
dexmedetomidine, there was no evidence of a detrimental effect on local brain tissue
oxygenation.[508] More recently, in a study in six normal volunteers, the administration of
dexmedetomidine to achieve serum levels of 0.6 ng/mL and 1.2 ng/mL (with and without
hyperventilation) produced the predicted reduction of CBF with a concomitant reduction in
CRMO2.[509] This finding suggests the maintenance of the cerebral oxygen supply-to-demand
relationship; however, further work in injured brains needs to be done.
In a rat seizure model, dexmedetomidine showed significant proconvulsant action, which is
consistent with previous findings that inhibition of central noradrenergic transmission
facilitates seizure expression.[510] This finding is in contrast to an anticonvulsant effect shown
in rats after kainic acidinduced seizures.[511] As yet, there have been no reports of seizures in
humans. Dexmedetomidine has been used in neurosurgical procedures involving
neurophysiologic monitoring. Cortical evoked potentials amplitudes and latencies were
minimally affected when using dexmedetomidine intraoperatively when patients underwent
craniotomies.[508] Dexmedetomidine also is able to reduce muscle rigidity after high-dose
opioid administration.[512] In resting volunteers, dexmedetomidine increased growth hormone
secretion in a dose-dependent manner, but it had no effect on other pituitary hormones. [513] [514]
Dexmedetomidine ablates memory in a dose-dependent manner. In concentrations used for
clinical sedation (i.e., 0.7 ng/mL), recall of picture cards is preserved. Increasing the
concentration of dexmedetomidine to 2 ng/mL largely ablates recall and recognition of a
picture card.[515]

Efek ke Respirasi

In volunteers, dexmedetomidine at concentrations producing significant sedation reduces


minute ventilation, but retains the slope of the ventilatory response to increasing carbon
dioxide.[516] The changes in ventilation appeared similar to those observed during natural
sleep. Ebert and colleagues,[515] infusing dexmedetomidine to concentrations of 15 ng/mL in
spontaneously breathing volunteers, showed no change in arterial oxygenation or pH. At the
highest concentrations, PaCO2 increased by 20%. Respiratory rate increased with increasing
concentration from 14 breaths/min to 25 breaths/min.[515] When dexmedetomidine and
propofol were titrated to equal sedative end points (BIS of 85), both resulted in no change in
respiratory rate.[517] In a study comparing the effects of remifentanil and dexmedetomidine on
respiratory parameters in normal volunteers,[518] the hypercapnic ventilatory response was
unaffected even at doses that produced unresponsiveness to vigorous stimulation. PaCO2
increased mildly with dexmedetomidine, but it reached a plateau after the first increment.
Dexmedetomidine also exhibited a hypercarbic arousal phenomenon, which has been
described during normal sleep and is a safety feature. IV or inhaled dexmedetomidine has
been implicated in blocking histamine-induced bronchoconstriction in dogs.[519]

Efek ke Kardiovaskular
The basic effects of 2 agonists on the cardiovascular system are decreased heart rate;
decreased systemic vascular resistance; and indirectly decreased myocardial contractility,
cardiac output, and systemic blood pressure. By developing highly selective agonists, it has
been hoped to decrease some of these adverse cardiovascular effects and to maximize the
desirable hypnotic-analgesic properties. The hemodynamic effects of a bolus of
dexmedetomidine in humans have shown a biphasic response. An acute IV injection of
2 g/kg resulted in an initial increase in blood pressure (22%) and decrease in heart rate
(27%) from baseline that occurred at 5 minutes after injection. This initial increase in blood
pressure is probably due to the vasoconstrictive effects of dexmedetomidine when stimulating
peripheral 2 receptors. Heart rate returned to baseline by 15 minutes, and blood pressure
gradually declined to approximately 15% below baseline by 1 hour. After an IM injection of
the same dose, the initial increase in blood pressure was not seen, and heart rate and blood
pressure remained within 10% of baseline.[473]
Ebert and colleagues[515] performed an elegant study in volunteers using a target-controlled
infusion system to provide increasing concentrations (0.7 to 15 ng/mL) of dexmedetomidine (
Fig. 26-22 ). The lowest two concentrations produced a decrease in MAP (13%) followed by
progressive increase (12%). Increasing concentrations of dexmedetomidine also produce
progressive decreases in heart rate (maximum 29%) and cardiac output (35%).[515] Infusion of
dexmedetomidine in volunteers also has been shown to result in a compensated reduction in
systemic sympathetic tone without changes in baroreflex sensitivity. It also blunts the heart
rate and systemic sympathetic activation owing to sweating, but is less effective in blunting
cardiac sympathetic response to shivering.[520]

The incidence of hypotension and bradycardia may be related to the administration of a


loading dose. Omitting the loading dose or not giving more than 0.4 g/kg reduces the
incidence of hypotension, or makes it less pronounced. Giving the loading dose over 20
minutes also minimizes the transient hypertension.[521] In several studies after IM and IV
administration, dexmedetomidine caused, in a small percentage of patients, profound
bradycardia (<40 beats/min) and occasionally sinus arrest/pause. Generally, these episodes
resolved spontaneously or were readily treated without adverse outcome by anticholinergics.
It would be expected from its profile that dexmedetomidine would be beneficial to the
ischemic myocardium. In animal models, dexmedetomidine showed some beneficial effects
on the ischemic heart through decreased oxygen consumption and redistribution of coronary
flow from nonischemic zones to ischemic zones after acute brief occlusion.[522]
Dexmedetomidine also decreases serum lactate in a dog model of coronary ischemia with an
associated decrease in heart rate and measured catecholamines. It also produced an increase
in the endocardial/epicardial blood flow ratio by 35%.[523]
The perioperative use of 2 agonists reduces the incidence of perioperative myocardial
ischemia.[524] More recently, Wallace and associates[525] showed that the administration of
clonidine in the preoperative period reduces the incidence of perioperative cardiac ischemia
from 31% to 14%, and reduces the mortality for 2 years from 29% to 15% compared with
placebo. The only data on potential benefits in perioperative ischemia prevention with
dexmedetomidine are provided in an underpowered study in vascular surgery patients who
received the drug in the perioperative period. Blood pressure and heart rate were lower in the
dexmedetomidine group, but these patients also needed the use of more drugs
intraoperatively to sustain blood pressure and heart rate. No reductions of ischemic events
were noted.[189] No rebound effects have been found when discontinuing dexmedetomidine
drips, even when it is given for more than 24 hours.[526]
A frequently reported side effect of dexmedetomidine has been a dry mouth. Dry mouth is
due to a decrease in saliva production.[527]

Penggunaan
Dexmedetomidine has been approved as a short-term sedative for adult intubated patients in
the ICU. Given its well-documented beneficial effects of anxiolysis, sedation, analgesia, and
sympatholysis with minimal respiratory depression, it also has been used in various other
clinical scenarios.

ICU
Dexmedetomidine has advantages over propofol for sedation in mechanically ventilated
postoperative patients. When both drugs were titrated to equal sedation as assessed by the

BIS (approximately 50) and Ramsay sedation score (5), dexmedetomidine patients required
significantly less narcotics (alfentanil 2.5 mg/hr versus 0.8 mg/hr). Heart rate was slower in
the dexmedetomidine group, whereas MAP was similar. The PaO2/FIO2 ratio was significantly
higher in the dexmedetomidine group. Time to extubation after discontinuation of the
infusion was similar at 28 minutes. Patients receiving dexmedetomidine seemed to have
greater recall of their stay in the ICU, but all described this as pleasant overall.[528]
Several other studies have confirmed the decreased requirement for opioids (>50%) when
dexmedetomidine is used for sedation compared with propofol or benzodiazepines. Most
studies also describe more stable hemodynamics during weaning when dexmedetomidine is
used for sedation.[529] This is of obvious benefit in patients with high risk for myocardial
ischemia. For sedation in the ICU, loading doses of 0.5 to 1 g/kg have been used. Omitting
the bolus or giving the lower dose has been associated with fewer episodes of severe
bradycardia and other hemodynamic perturbations. Infusion rates of 0.1 to 1 g/kg/hr are
generally needed to maintain adequate sedation. Delirium in the ICU is a risk factor for
increased length of stay and increased mortality.[530] In a double-blind, randomized controlled
trial of sedation in ventilated patients with dexmedetomidine versus lorazepam, it was found
that using dexmedetomidine infusions provided more days alive without delirium or coma
and a greater amount of time spent at the appropriate sedation level compared with
lorazepam.[531]
2-adrenoreceptor agonists have been used in the treatment of alcohol and drug withdrawal.
In a comparison between clonidine and chlordiazepoxide in the treatment of patients with
alcohol withdrawal, clonidine proved to give better anxiolysis with better hemodynamics.[532]
Dexmedetomidine has been successfully used in the treatment of withdrawal of narcotics,
benzodiazepines, alcohol, and recreational drugs. Maccioli[489] reported the successful use of
dexmedetomidine in two adult patients, one with cocaine and alcohol withdrawal symptoms,
and another with withdrawal from prolonged use of benzodiazepines and narcotics in the
ICU. Dexmedetomidine controlled withdrawal behavior and allowed for successful
detoxification of young cardiothoracic patients (spanning the ages of days to 17 years) who
developed drug withdrawal from prolonged use of benzodiazepines and narcotics in the ICU.
[533]

The unique characteristics of dexmedetomidineproviding adequate sedation with minimal


respiratory depressioncan be used when weaning patients from the ventilator. Siobal and
colleagues[534] reported the successful weaning of five ventilated patients who had failed
weaning secondary to agitation. Infusions of dexmedetomidine of 0.5 to 0.7 g/kg/hr were
used (no loading) and permitted the discontinuation of propofol in four of five patients. All
patients were extubated while still on the dexmedetomidine infusion. One patient required
reintubation for upper airway obstruction. The use of dexmedetomidine to facilitate daily
wake up tests in mechanically ventilated patients seems attractive, but few data have been
published.[535]

The FDA approved the use of dexmedetomidine infusions for 24 hours or less. Multiple
studies have shown the safety of using this drug for longer periods, however. In data collected
from prescribing patterns in 10 institutions, it was shown that dexmedetomidine was used
longer than 24 hours in 33.8% of cases. It also was noted that 33% of patients received a
loading dose, 27% of patients received a dose higher than the recommended maximum, and
60% of patients remained on the infusion after extubation.[
Anesthesia
As a premedicant, dexmedetomidine, at IV doses of 0.33 to 0.67 g/kg given 15 minutes
before surgery, seems efficacious, while minimizing the cardiovascular side effects of
hypotension and bradycardia.[537] Within this dosage range, dexmedetomidine reduces
thiopental requirements (by 30%) for short procedures,[537] reduces the requirements of
volatile anesthetics (by 25%), and more effectively attenuates the hemodynamic response to
endotracheal intubation compared with 2 g/kg of fentanyl.[538] Dexmedetomidine also has
been evaluated as an IM injection (2.5 g/kg) with or without fentanyl administered 45 to 90
minutes before surgery. This regimen was compared with IM midazolam plus fentanyl and
was found to provide equal anxiolysis, reduced response to intubation, smaller volatile
anesthetic requirements, and a decreased incidence of postoperative shivering but a higher
incidence of bradycardia. Atipamezole, a selective 2 antagonist, at 50 g/kg was effective in
reversing the sedation of dexmedetomidine (2 g/kg intramuscularly), when used to provide
sedation for brief operative procedures.[487] This reversal of effects resulted in a more rapid
recovery than occurred after equisedative doses of midazolam.
Dexmedetomidine has been used for sedation for monitored anesthesia care. In a study
comparing the efficacy of dexmedetomidine or propofol as a sedative agent in a group of 40
patients receiving local anesthesia or regional blocks, dexmedetomidine (1 g/kg given over
10 minutes) when used for intraoperative sedation resulted in a slower onset than propofol
(75 g/kg/min for 10 minutes), but similar cardiorespiratory effects when titrated to equal
sedation. The average infusion rate of dexmedetomidine intraoperatively to maintain a BIS
value of 70 to 80 was 0.7 g/kg/min. Sedation was more prolonged after termination of the
infusion, as was recovery of blood pressure. Smaller doses of opioid were needed in the first
hour, however.[517]
Dexmedetomidine sedation has been done successfully in pediatric patients. Two studies,
comprising 140 children 1 to 7 years old, reported successful sedation for MRI scans
compared with midazolam or propofol. [539] [540]
When dexmedetomidine is used as a premedication 10 minutes before general surgery for
cataract removal, intraocular pressure is decreased (33%), catecholamine secretion is
reduced, perioperative analgesic requirements are less, and recovery is more rapid. [541] [542]
For maintenance of anesthesia, dexmedetomidine has been used in patients undergoing
multiple types of surgery. In patients given an infusion regimen to achieve a plasma

concentration of slightly less than 1 ng/mL, combined with 70% nitrous oxide,
dexmedetomidine reduced isoflurane requirements by 90% compared with a control group.
[543]
One retrospective study and two prospective, randomized controlled trials in bariatric
surgical patients have found that a balanced anesthetic with desflurane or propofol plus
dexmedetomidine (0.5 to 0.8 g/kg bolus plus 0.4 g/kg/hr infusion) reduces postoperative
pain scores and morphine consumption, and improves hemodynamics compared with
desflurane-fentanyl or propofol-fentanyl anesthetics. [544] [545] [546]
In patients presenting for vascular surgery, three infusion rates of dexmedetomidine were
compared with a placebo infusion starting 1 hour before surgery and administered until 48
hours after surgery. In the groups receiving dexmedetomidine, more vasoactive agents were
required to maintain hemodynamics intraoperatively, but less tachycardia was noted
postoperatively. No other significant differences were noted between the groups.[547]
Grant and colleagues[548] described the use of dexmedetomidine when securing the airway
with a fiberoptic intubation in three patients undergoing cervical spine surgery. The procedure
was well tolerated with no hemodynamic compromise or respiratory depression. Because this
drug provides good sedation with minimal respiratory depression, it has been used in patients
undergoing awake craniotomies with functional testing and electrocorticography[549] or awake
carotid endarterectomies with fewer fluctuations from the desired sedation level and more
stable hemodynamics.[550]
Another use of dexmedetomidine has been as an anesthetic adjunct or sedative agent for
patients who are susceptible to narcotic-induced respiratory depression or sleep apnea. In a
morbidly obese patient, the narcotic-sparing effects of dexmedetomidine were evident
intraoperatively and postoperatively after bariatric surgery.[551] The addition of
dexmedetomidine infusions to assist on transesophageal echocardiography examination has
been described, with better hemodynamic profile and improved patient satisfaction than with
benzodiazepine and narcotics alone, with no added respiratory depression.
The use of dexmedetomidine has dramatically increased. This highly selective 2 agonist has
a set of unique effects that include titratable sedation, sympatholysis, and analgesia without
significant respiratory depression. Originally approved as a sedative in the ICU, it has found
many off-label applications in the ICU, the operating room, and perioperative environment.
The off-label use of dexmedetomidine in infants and children is rapidly increasing. More than
800 reports have been published regarding its use in this population.[470]

Daftar Pustaka
1. Millers Anesthesia ed 7

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