dexmedetomidina en neuroanesteia

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Anesthesia for functional neurosurgery:
the role of dexmedetomidine
Irene Rozet
Introduction
‘Functional neurosurgery’ is a broad term applied to a
variety of neurosurgical procedures in which monitoring
of brain function during the procedure is crucial for
localization of the area of surgical interest and successful
outcome. Anesthetic management for these procedures is
challenging because intraoperative monitoring requires
fully preserved brain function. This is a direct contra-
diction of the essential goal of anesthesiology, which is
to provide the patient with sedation, analgesia, and
anesthesia.
Dexmedetomidine, an a-2-adrenergic agonist, acting at
the subcortical areas of the brain and not involving the
g-amino-butyric acid (GABA) receptors, provides a seda-
tion, which resembles natural sleep, without respiratory
depression. These unique properties of dexmedetomi-
dine make it a potentially advantageous sedative agent
for functional neurosurgery.
The review discusses the challenges and current
approaches of anesthetic management, including clinical
applications of dexmedetomidine, for the two most pop-
ular functional neurosurgical procedures requiring an
awake cooperative patient and fully preserved cerebral
electrophysiology: ‘awake’ craniotomy requiring brain
mapping, and implantation of deep brain stimulators
for movement disorders.
General principles of anesthetic management
of functional neurosurgery
Ideal perioperative management for functional neurosur-
gery should satisfy multiple anesthetic and surgical goals
simultaneously. These objectives include patient com-
fort and analgesia, patient immobility throughout the
procedure (often for a long duration), adequate oxygen-
ation and ventilation, hemodynamic stability, optimal
brain conditions, prevention of brain swelling, and full
Department of Anesthesiology, Harborview Medical
Center, Seattle, Washington, USA
Correspondence to Irene Rozet, MD, Department of
Anesthesiology, Harborview Medical Center, 325 Ninth
Avenue, Box 359724, Seattle, WA 98104, USA
Tel: +1 206 744 3059; fax: +1 206 744 8090;
e-mail: irozet@u.washington.edu
Current Opinion in Anaesthesiology 2008,
21:537–543
Purpose of review
The purpose of this review is to summarize current approaches to the anesthetic
management of functional neurosurgery and to describe the application of an
a-2-adrenergic agonist dexmedetomidine in the anesthetic management of functional
neurosurgical procedures.
Recent findings
Dexmedetomidine, an a-2-adrenergic agonist, causes a unique kind of sedation, acting
on the subcortical areas, which resembles natural sleep without respiratory depression.
Experimental data demonstrate both cerebral vasoconstriction and vasodilatation,
depending on the model and dose studied. At the clinically relevant doses,
dexmedetomidine decreases cerebral blood flow and cerebral metabolic rate of oxygen
in healthy volunteers. Clinical experience of dexmedetomidine use in functional
neurosurgery is limited to small case-series. Nevertheless, these reports indicate that
use of dexmedetomidine does not interfere with electrophysiologic monitoring, thus
allowing brain mapping during awake craniotomy and microelectrode recording during
implantation of deep-brain stimulators.
Summary
Dexmedetomidine has been demonstrated to provide a successful sedation without
impairment of electrophysiologic monitoring in functional neurosurgery. Prospective
randomized studies are warranted to delineate an optimal regimen of dexmedetomidine
sedation and any dose-related influence on neurophysiologic function.
Keywords
awake craniotomy, dexmedetomidine, implantation of deep brain stimulator
Curr Opin Anaesthesiol 21:537–543
ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins
0952-7907
0952-7907 ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI:10.1097/ACO.0b013e32830edafd

2. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
patient cooperation with intact electrophysiologic moni-
toring. Obviously, the above-mentioned conditions often
contradict each other, making ‘anesthetic’ management
for awake neurosurgical procedures one of the most
challenging in anesthesia practice.
The kind of neurologic monitoring required for func-
tional neurosurgery depends on the procedure and the
area of interest in the brain. An assessment of cognitive
function, speech, vision, and motor function is required in
surgery for resection of brain tumors or epileptic focus
located close to the eloquent cortex (Broca’s and
Wernicke’s speech areas in the dominant frontal and
temporal lobe, motor strip, and visual cortex). During
implantation of a deep brain stimulator (DBS) for a patient
with movement disorder, an assessment of changes in
tremor or spasticity/rigidity in a fully awake patient is
mandatory. Intraoperative electrophysiologic testing for
tumor and epilepsy surgery includes electroencephalo-
graphy (EEG) and electrocorticography (ECocG) for
cortical brain mapping. The microelectrode recording
(MER) of impulses of subcortical areas, including sub-
thalamic nucleus, is used during DBS implantation.
Patient positioning for functional neurosurgery makes
access to the patient’s airway difficult, further complicat-
ing anesthesia management (Fig. 1).
Intraoperative ‘anesthetic’ management of awake craniot-
omy has changed during the last two decades. Anesthesia
medications with rapid onset of action and short half-lives
such as propofol andremifentanil replaced previously used
neuroleptanalgesia with fentanyl and droperidol. Multiple
anesthestic techniques are used for awake craniotomies:
monitored anesthesia care, conscious sedation, the
‘asleep–awake’ and ‘asleep–awake–asleep’ techniques
[1
]. The ‘asleep–awake–asleep’ technique is currently
considered as the most popular one [1
]. The first ‘asleep’
stage is provided with heavy sedation or even general
anesthesia in the beginning of the surgery during a
patient’s positioning, fixation of the head with pins, cra-
niotomy or burr holes, and final exposure of the brain. Skin
infiltration with local anesthetic at pin insertion sites and
the skin incision, or performance of a scalp nerve block,
are essential for pain relief and reducing opiates-related
complications [2]. A variety of different medications
and combinations of medications has been reported to
be successfully used: propofol, remifentanil, fentanyl,
midzolam [1
,3,4]. For airway management, oral or naso-
pharyngeal airways, oral and nasal endotracheal tubes,
laryngeal mask (LMA) as well as unprotected airway have
all been used with different degrees of success [1
]. For the
next awake stage, the patient must be brought to full
consciousness. In this awake phase, mapping of the brain
with electrocorticography during cognitive testing is per-
formed to delineate the area to be resected. The transition
from the ‘asleep’ to the ‘awake’ phase is the most challen-
ging task in the anesthetic management because of poten-
tial complications during the awakening and manipulation
of the airway, while the brain is exposed. Coughing,
Valsalva maneuver, vomiting and movement during extu-
bation of the airway may lead to disastrous complications
such as bleeding, brain swelling, venous air embolism, and
potentially death. Consequently, many anesthesiologists
538 Neuroanaesthesia
Figure 1 Positioning of patient for functional neurosurgery
Positioning
Head fixation
Pins
Mayfield
frame
Head position
Neutral
Flexion
Extension
Lateral flexion
Pins
Stereotactic
frame
Hoarshoe
gelpad
Supine SittingLateral
Body positioning
OR Table
90˚ 180˚
OR, operating room.

3. Copyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.
try to avoid airway instrumentation. When mapping is
completed, either sedation or analgesia or both may be
provided again for the ‘asleep’ phase. Airway instrumenta-
tion when the patient’s head is in pins and covered by the
surgical drapes may be difficult, especially if emergency
intubation of the trachea is required.
In implantations of DBS, the first ‘asleep’ phase usually
requires less time than the first ‘asleep’ phase in awake
craniotomy. DBS implantation does not require wide
exposure of the brain. Only burr holes are needed, which
can be performed under local infiltration of the scalp.
Although the use of various sedative techniques, includ-
ing propofol infusion, fentanyl, remifentanil, and inhala-
tional anesthetics have been reported [5,6
], many
surgeons prefer to avoid any sedation because of the
extreme sensitivity of subcortical areas to the GABA-
ergic medications, which may completely abolish MER
recording and tremor. When localization of the DBS
electrode is finalized, the patient’s head is disengaged
from the frame, and the patient may then be anesthe-
tized for the implantation of the generator into the
chest wall.
Potential risks involved in anesthetic management
for awake neurosurgical procedures are summarized in
Table 1. Unfortunately, the actual incidence of compli-
cations and therefore the optimal anesthetic management
are largely unknown due to the lack of prospective
randomized studies. Currently available data are incon-
clusive because the studies differ in: anesthetic manage-
ment, criteria applied for definitions of complications,
and study design. The largest retrospective chart review
of awake craniotomy by Skucas and Artru [3] reported
that airway problems occurred in 2% out of 332 cases of
asleep–awake–asleep technique using only propofol
infusion in patients with unsecured airway undergoing
epilepsy surgery. Manninen et al. [4] prospectively
randomized 50 patients undergoing tumor surgery with
brain mapping to receive sedation with propofol and
remifentanil infusion, or propofol and fentanyl, and
observed an incidence of respiratory complications as
high as 18% in this cohort, without any difference
between the two groups. Respiratory complications were
defined as any of following: a decrease in respiratory
rate, oxygen desaturation, or airway obstruction. Because
the majority of surgeons request the avoidance of any
sedation, the most significant challenge in DBS implan-
tations is the maintainance of hemodynamic stability and
the prevention/treatment of intraoperative hypertension,
a known risk factor for developing intracerebral hemor-
rhage. In the prospective study involving 128 patients
receiving DBS implantations for Parkinson’s disease with
intermittent infusion of propofol, about 60% of patients
developed intraoperative hypertension [7]. Intracerebral
hemorrhage is considered to be the most severe compli-
cation, with an incidence of 3.3–6% reported in the
prospective studies [8–10]. The incidence of respiratory
complications in DBS implantations is unknown.
Benzodiazepines, barbiturates, and opioids may deliver
patient comfort and hemodynamic stability, but they
may also depress electyrophysiologic activity of the brain,
interfere with mapping, and cause respiratory depression
and airway compromise. To achieve a balance between
uneventful awakening and avoidance of respiratory com-
plications, the pharmacokinetic-guided titration of propo-
folandremifentanilusingthetargetcontrolinfusiondevice
has been advocated in patients with Parkinson’s disease
[11]andforawakecraniotomies[12].Thesedevicesarenot
yet approved for use in the United States.
In addition to obesity [3] and age [6
], which were
suggested by the retrospective chart reviews as risk factors,
other patient-related risk factors are less clear. Previously,
obstructive sleep apnea was considered as a potential risk
factor for perioperative respiratory complications [1
].
However, there are no data to support this. There is also
a paucity of data to predict who would be an ideal candi-
date for awake functional neurosurgery. According to the
Anesthesia for functional neurosurgery Rozet 539
Table 1 Potential risks and complications expected in awake
functional neurosurgery
Undersedation Oversedation
General General
Pain Drowsiness
Discomfort Restlessness
Restlessness Impaired cognition, lack of
cooperation, inability to
perform mapping
Anxiety
Inability to stay still Respiratory
Voluntary movements Airway obstruction
Respiratory depression
Hypoventilation
Respiratory Hypercarbia
Inability to clear secretions (PD) Oxygen desaturation
Coughing Apnea
Dyspnea–hyperventilation Need for airway manipulations
and for providing an
emergency airway
Coughing and Valsalva during
transition from ‘asleep’ to
‘awake’ stage
Neurological
Seizures Neurological
Brain swelling Brain swelling
Bleeding Seizures
Bleeding
Hemodynamic
Arterial hypertension Hemodynamic
Tachycardia, arrhythmia Arterial hypotension
Gastrointestinal Gastrointestinal
Nausea, vomiting Nausea, vomiting
Aspiration of gastric contents
Involuntary movements
Shivering
Sedative-induced dyskinesias
Arterial hypotension
PD, Parkinson’s disease.

4. Copyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.
current data, in most instances, only the lack of patient
cooperation will preclude awake neurosurgery. However,
factors including abnormal anatomy of the airway, pre-
sence of gastroesophageal reflux and obesity should be
considered as potential risk factors.
Dexmedetomidine: a unique sedative agent
Dexmedetomidine is a selective agonist of a2-adrenergic
receptors (a2-ARs) with high affinity to a2-ARs (a2:a1
effectratio of1620:1),whichiseighttimeshigher thanwith
clonidine. Dexmedetomidine has a rapid onset of action. It
undergoes biotransformation in the liver, and the kidneys
excrete about 95% of its metabolites. Its distribution half-
life is 6 min, and a clearance half-life is 2 h.
Presynaptic and postsynaptic a2-ARs are distributed over
vital organs (heart, pancreas, kidneys), blood vessels and
the central and the peripheral nervous system. Stimulation
of postsynaptic a2-ARs leads to hyperpolarization of
neuronal membrane, whereas stimulation of presynaptic
a2-ARs reduces the release of norepinephrine. In the
spinal cord, a2-ARs are predominantly postsynaptic, and
located in the dorsal horn. Activation of spinal a2-ARs
inhibits nociception, which most likely explains the
analgetic properties of dexmedetomidine. Both presyn-
aptic and postsynaptic a2-ARs are widely distributed in
the brain, particularly in the pons and medulla. The major
site of noradrenergic innervation in the brain with the
highest concentration of presynaptic a2-ARs is the locus
ceruleus, which is responsible for arousal, sleep, anxiety,
and withdrawal symptoms from drug addiction. As a result,
the central effect of dexmedetomidine, which is mani-
fested by anxiolysis and sedation, is noncortical and sub-
cortical in origin. It does not involve the GABA system and
consequently does not cause cognitive impairment or
disinhibition, differentiating dexmedetomidine from all
GABA-mimetic sedatives and anesthetics.
The mechanisms of anesthetic-induced effects on uncon-
sciousness and amnesia are not clear. Recently, both
cortex [13] and thalamus [14] have been suggested to
be primarily responsible for the anesthetic-induced
unconsciousness. The unusual subcortical form of dex-
medetomidine-induced sedation is characterized by an
easy and quick arousal, resembling natural sleep.
The neuroprotective properties of dexmedetomidine
have been demonstrated in various animal models of
cerebral ischemia [15–17]. There are recent experi-
mental data suggesting that in addition to a2-ARs, the
neuroprotective effect of dexmedetomidine may include
other pathways in the brain, independent of a2-ARs,
and most probably involve I1-imidazoline receptors in
the brainstem and hippocampus [18]. Further in-vivo
studies are required to support this suggestion and to
elucidate mechanisms of dexmedetomidine-induced
neuroprotection.
Postsynaptic a2-ARs are widely presented in smooth
muscles of conductance and resistance vessels. Both vaso-
dilatating [19–21] and vasoconstricting [21–24] effects of
dexmedetomidine on cerebral and spinal arteries and
venules have been reported in animal studies. These
contradictory results may be explained by the differences
between models, animal species, and the dose of dexme-
detomidine, as well as experimental conditions and back-
ground anesthesia, all of which can potentially modify
vascular reactivity to the drug. Current data suggest that
dexmedetomidine-induced cerebral vasoconstriction has a
direct nonendothelium-dependent mechanism, whereas
dexmedetomidine-induced vasodilatation may be endo-
thelium dependent and involve nitric oxide pathways.
However, the exact mechanisms of dexmedetomidine’s
effect on the cerebral vasculature have not been comple-
tely elucidated yet.
Regardless of the mechanisms involved, current human
studies on healthy volunteers clearly demonstrate that
dexmedetomidine decreases cerebral blood flow (CBF)
[25,26
]. Using a PET-scan in awake healthy volunteers,
Prielipp et al. [25] demonstrated a decrease in global CBF
by about 30% with intravenous infusion of dexmedetomi-
dine of only 0.2mg/kg/hour for 30min. Prielipp et al. [25]
suggested cerebral vasoconstriction as an underlying
mechanism of decreased CBF, which is in agreement with
the previous in-vitro data and one in-vivo study in dogs
[27]; however, a recent study by Drummond et al. [26
]
demonstrated a simultaneous decrease of CBF and
CMRO2 with dexmedetomidine in healthy volunteers.
In this study [26
] CBF was estimated by measuring
blood flow velocity in the middle cerebral arteries (Vmca)
using Transcranial Doppler Ultrasonography (TCD) and
CMRO2 was calculated by measuring oxygen saturation in
the jugular bulb. In healthy volunteers, dexmedetomidine
also preserves cerebral autoregulation but slightly
decreases carbon dioxide reactivity (A.M. Lam, personal
communication).
Although both anticonvulsant and proconvulsant effects
of dexmedetomidine have been shown in animal studies
[28–31], there are no data supporting proconvulsant
effects of dexmedetomidine in humans; however, a-2
agonists may produce epileptiform activity in some
patients with epilepsy. The underlying mechanism of
this phenomenon was suggested to resemble the epilepti-
form activity during sleep deprivation, as a-2 agonists
modulate pathways of natural sleep [32].
The effect of dexmedetomidine on ventilation is minimal.
Initially, administration of dexmedetomidine increases
arterial carbon dioxide (PaCO2), but it also leads to
540 Neuroanaesthesia

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an increase in respiratory rate, a process described as
‘hypercapnic arousal phenomenon’. Hypercapnic arousal
phenomenon is a specific respiratory response to dexme-
detomidine and is associated with partial awakening and
hyperventilation in response to an increase in PaCO2,
without significant respiratory depression even at the deep
level of sedation [33]. This phenomenon makes dexme-
detomidine a unique sedative agent lacking respiratory
depressive properties of central origin, and, in contrast, it
causes a natural sleep-like sedation without respiratory
depression and with an easy arousal.
Bradycardia and decrease in blood pressure (BP) are the
most common hemodynamic effects of dexmedetomi-
dine. However, a biphasic effect on BP, contingent on the
dose and the rate of infusion, may also be observed, with a
decrease in BP at low doses but an increase in BP at high
doses.
Clinical application of dexmedetomidine to
functional neurosurgery
The first successful use of dexmedetomidine in functional
neurosurgery was published in 2001 by Bekker et al. [34],
who reported sedation with dexmedetomidine in a patient
requiring language mapping for tumor resection. It was
followed by the discouraging report of the inability to
perform neurocognitive testing with dexmedetomidine
by Bustillo et al. [35]. This most probably occurred because
of concomitant use of fentanyl and midazolam. A number
of recent case series clearly demonstrate that dexmedeto-
midine may be successfully used in functional neurosur-
gery [6
,36,37
,38,39
].
Souter et al. [37
] were the first to report the use of
dexmedetomidine not just for sedation at the first ‘asleep’
phase in awake craniotomy but during language mapping
and electrocorticography (ECoG) recording. It was suc-
cessfully used in six patients with seizure disorders, with
three of them receiving dexmedetomidine only. All three
patients received continuous infusion of dexmedetomi-
dine at 0.3–0.7 mg/kg/hour, which was titrated to main-
tain sedation, guided by modified OAA/S score. One
patient developed a subclinical seizure detected by
EEG while being sedated with dexmedetomidine, thus
allowing the investigators to conclude that dexmedeto-
midine does not supress epileptiform activity and can be
used in patients with seizure disorders requiring brain
mapping [37
]. To prove this, Talke et al. [39
] prospec-
tively observed EEGs in five patients with intractable
seizures who received 0.5 mg/kg/hour of dexmedetomi-
dine, followed by a bolus of 0.5 mg/kg, and found that
there was no decrease in epileptiform activity. Moreover,
in some foci an increase in epileptiform activity was
observed. Oda et al. [40
] evaluated the influence of
dexmedetomidine on the ECoG recording in 11 patients
with temporal lobe epilepsy, anesthetized with 2.5% of
sevoflurane and hyperventilated to PaCO2 of 30 mmHg,
and demonstrated that the median frequency of ECoG
recording did not change at a plasma level of dexmede-
tomidine of 0.5 ng/ml, but decreased at 1.5 ng/ml. How-
ever, there was no change in spike activity. It is possible
that concomitant use of sevoflurane and hyperventilation
could potentially affect anticonvulsant or proconvulsant
activity of dexmedetomidine. To verify the dose-depen-
dent anticonvulsant versus proconvulsant effect of dex-
medetomidine, and its effect on the seizure activity when
other anesthetics are used concomitantly, prospective
randomized trials are required.
As mentioned above, most neurosurgeons are reluctant to
use any kind of sedation for DBS implantations when
MERs are utilized for thepositioningof theDBS electrode
because of the profound suppressive effect of GABA-ergic
medications on the basal ganglia. At first, dexmedetomi-
dine had been reported to provide adequate sedation
without impairment of MER recordings in a series of 11
patients undergoing DBS implantations for Parkinson’s
disease [38], when dexmedetomidine was titrated to main-
tain sedation and guided by the modified OAA/S score.
When this cohort of patients was compared with the
historical control cases, dexmedetomidine provided better
hemodynamic stability and patient satisfaction [38].
Recently, Elias et al. [41
] demonstrated the depression
of MER recording with moderate/heavy sedation with
dexmedetomidine, defined as sleepy and unarousable
state, with a bispectral index less than 80. On the contrary,
in lightly sedated patients with a bispectral index higher
than 80, no depression of MER recording has been
observed. This was associated with the dexmedetomidine
infusion of 0.1–0.4mg/kg/hour [41
]. Although dexmede-
tomidine has theoretical advantages over GABA-ergic
medications such as lack of respiratory depression, hemo-
dynamic stability, and possible ability to suppress GABA-
ergic drugs-induced dyskinesias [42], the optimal sedative
dose of dexmedetomidine, the incidence of complications
as well as benefits of dexmedetomidine use in DBS
implantationsremainunknown andshould beinvestigated
prospectively.
Conclusion
Current data on the anesthetic techniques for functional
neurosurgery is provided by the retrospective chart
reviews and small prospective case series. With conven-
tional sedation for the awake craniotomy and implanation
of DBS, the patient is potentially at risk for respiratory
depression, discomfort and arterial hypertension.
Dexmedetomidine is a unique sedative agent, which
does not cause respiratory depression. It has been shown
to be safe in both awake craniotomy and DBS implan-
Anesthesia for functional neurosurgery Rozet 541

6. Copyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.
tations in small retrospective case series. The optimal
dose regimen of dexmedetomidine for functional neuro-
surgery is unknown.
Prospective randomized trials are necessary to elucidate:
an optimal anesthetic technique for awake craniotomy
and DBS implantation; incidence of complications,
including respiratory complications and hemodynamic
stability; safety and usefulness of combinations of differ-
ent anesthetics; dose–response of dexmedetomidine on
the electrocorticography and MER recording.
Acknowledgement
The author is grateful to Professor AM Lam for providing his data on the
influence of dexmedetomidine on the cerebral autoregulation and carbon
dioxide reactivity in healthy volunteers, and to Professor CM Bernards for
providing his data and input on the influence of sedation and opioids on
the respiratory depression in patients with sleep apnea syndrome.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:
of special interest
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World Literature section in this issue (p. 684).
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