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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.
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.
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
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]
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 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