Journal of Clinical Neuroscience (2005) 12(4), 375–378

0967-5868/$ - see front matter ª 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.jocn.2004.06.008

Review

The role of a2-agonists in neurosurgery

JR Cormack1 MBBS FANZCA, RM Orme2, TG Costello1
1
Department of Anaesthetics, St. Vincent’s Hospital, Melbourne, Vic., Australia, 2Department of Anaesthetics, The Royal Melbourne Hospital, Melbourne, Vic.,
Australia

Summary a2-agonists have been extensively used and studied in anaesthesia and intensive care medicine. A list of benefits includes
anxiolysis, blood pressure stabilization, analgesia, anaesthetic sparing effects and sedation without respiratory depression or significant
cognitive impairment. Fear of inadvertent hypotension, bradycardia or post-operative sedation, and the variability of the haemodynamic
response to different doses or rates of administration, have meant that universal acceptance in clinical practice has not yet been seen.
Recently, the actions of these agents on the a2-adrenoreceptor and the imidazoline receptor have been more accurately identified, helping to
explain the differences between the actions of various agents. The two readily available agents, clonidine and dexmedetomidine have already
been used in many different anaesthetic situations, for a wide variety of surgical procedures. We believe that both of these a2-agonists are
useful adjuncts for the management of the neurosurgical patient during surgery, and in the intensive care unit.
ª 2004 Elsevier Ltd. All rights reserved.

Keywords: a2-agonists, clonidine, dexmedetomidine, neurosurgery, anaesthesia

PHARMACOLOGY OF a2-AGONISTS
a2-agonists act at the a2-adrenoreceptor and the imidazoline
receptor.1–3 a2-receptors are located in the brain, spinal cord
and periphery and have been sub-classified to a-2a, a-2b, and
a-2c4 and more recently according to subtype genes.5 They act
pre- or post-synaptically via G-protein coupled mechanisms.2 In
the brain, a2-agonists mediate sedation via the a2a receptor in
the locus coeruleus.6 This occurs as a result of membrane hyper-
polarisation by a G-protein coupled increase in potassium conduc-
tance, and decreased release of the mediator noradrenaline.
a2-receptors in the substantia gelatinosa of the spinal cord mediate
analgesia, again by G-protein coupled increases in potassium con-
ductance and inhibition of calcium conductance at N-type calcium
channels. The action of a2-agonists in the periphery results in di-
rect smooth muscle vasoconstriction,7 inhibition of insulin from
islet cells in the pancreas,8 inhibition of lipolysis and platelet
aggregation.9 When considering the use of a2-agonists for neuro-
anaesthesia it is important to note that the potential deleterious ef-
fects of hyperglycaemia10 and platelet aggregation11 are largely
negated by the decreased stress response to surgery. Other effects
of xerostomia and decreased gut motility, renal inhibition of renin
release, increased sodium and water excretion and increased glo-
merular filtration2 are of no clinical importance in the routine per-
ioperative setting.
Clonidine has long been available as an antihypertensive but has
been superseded by newer agents without any sedative actions. On
the other hand, the mild sedative, anxiolytic and anaesthetic-
sparing effects of clonidine make it a suitable adjunct to anaes-
thesia for many neurosurgical operations. Medetomidine and
dexmedetomidine have long been available in veterinary practice
and dexmedetomidine has recently been introduced into intensive
care practice for sedation, offering a unique mode of sedation in
Received 20 April 2004
Accepted 1 June 2004
Correspondence to: J.R. Cormack, Unit 7/13, Brunswick Street, Fitzroy, Vic.,
3065, Australia. Tel.: +61 3 94173600; Fax: +61 3 94171295;
E-mail: analg@ozemail.com.au
that setting, particularly for ventilated patients where neurological
assessment is required.12–14 Dexmedetomidine has the advantage of
having six times the selectivity for the a2-receptor compared with
clonidine,15 with more rapid onset and shorter duration of action.
Early hopes that reversal of a2-agonists with atipamazole would
add increased utility have thus far been unrealised due to an unac-
ceptable side effect profile.16 Clonidine also acts at imidazoline
receptors but has a lower a2a to imidazoline receptor selectivity
than dexmedetomidine. Imidazoline agonists produce hypotension
via I-1 receptors in the rostral ventrolateral medulla, and analgesia
via I-2 receptors in the spinal cord. The imidazoline receptors have
no role in sedation or anaesthetic action.
PRE-OPERATIVE USE
With close to 100% oral bioavailability, peak plasma concentra-
tion in 1–2 h and duration of action of 6–12 h, oral clonidine pro-
vides sedation and anxiolysis in a dose of 2–3 lg/kg.17
Dexmedetomidine has also been used anecdotally as a premedi-
cant given by intramuscular injection in doses of 0.5–1.5 lg/
kg.18 This a2 mediated sedation differs from benzodiazepines or
opioids by allowing the patient to be roused easily with minimal
respiratory depression if appropriate doses are used.12,14,19,20
These qualities are of particular advantage for patients facing
intracranial surgery.
INTRAOPERATIVE USE
Intracranial surgery
By virtue of the reduction in sympathetic tone and inhibition of
peripheral noradrenaline release, a2-agonists reduce the hyperten-
sive responses to certain critical phases of many neurosurgical pro-
cedures. Tracheal intubation,21–24 head pin holder application25 and
extubation26,27 have been shown to have less associated hyperten-
sion in the presence of a2-gonists. Overall, intraoperative haemody-
namic stability may be improved with the use of clonidine28,29 but
this effect is not noticed in all groups, for example patients undergo-
ing carotid artery surgery.30 Interestingly in these vascular patients,
reduced perioperative myocardial ischaemia occurs with clonidine
despite the absence of improved haemodynamics.31 In anaesthesia

375
376 Cormack et al.

Dexmed = dexmedetomidine, HR = heart rate, MAP = mean arterial pressure, CBF = cerebral blood flow, CPP = cerebral perfusion pressure, ICP = intracranial pressure, CVR = cerebrovascular resistance, AVDO2 = arteriovenous
for craniotomy, haemodynamic stability and avoidance of perioper-

No change
ative hypertension are essential, particularly for tumour surgery,

Elevated
glucose
Serum
cerebral aneurysm and arteriovenous malformation surgery. Care
must be exercised with intravenous clonidine, as rapid injection will
result in a1-receptor activation with consequent increase in systemic

ischaemia
vascular resistance and brief hypertension.

Cerebral
The anaesthetic-sparing properties of a2-agonists are well
recognised with both volatile and intravenous anaesthesia32–35

No
and while some may argue that it is preferable to give more of
the primary anaesthetic agents such as propofol or remifentanil,

protection
Cerebral
we prefer to add an a2-agonist in order to smooth induction and
extubation, to avoid sudden emergence pain,36,37 tachycardia,28

Yes

Yes
hypertension26 and agitation,38 and to save considerably on the
overall cost of the anaesthetic.

No change
No change
While a2-agonists have little effect on intracranial pressure,39,40

AVDO2
direct activation of cerebral a2b-receptors may result in cerebral
vasoconstriction (and perhaps more importantly venoconstriction),
which combined with reduction in mean arterial pressure (MAP)

Reduced
Reduced
may reduce cerebral perfusion. The reduction of cerebral perfusion

CVR
pressure (CPP) with clonidine seems to closely follow MAP, and
MAP reduction is dependent on route of administration (oral ver-
sus intravenous) and dose, with 2–3 lg/kg orally causing the least

Transient rise
No change
No change
No change

No change
disturbance. The clinical advantage of this is in theoretically better
operating conditions but conversely a reduction of CPP may be

ICP
critical in patients with raised ICP, for example, those with severe
head injury.41 A non-randomised study incorporating clonidine to
reduce intracerebral blood volume and favouring the ‘‘Lund Prin-

No change
Reduced

Reduced
ciple” of normovolaemic vasoconstriction improving microcircu- CPP
lation, in patients with raised ICP, showed that there may be
some outcome advantages in using clonidine under certain, highly
controlled circumstances.42 Our recommendation is to use a2-
CO2 reactivity

agonists with great caution in patients with raised ICP. a2-agonists

No change

No change

No change
have been implicated in the uncoupling of cerebral blood flow and
cerebral metabolic requirement for oxygen, however other studies
have shown that a2-agonists have no effect on cerebral metabolic
requirement for oxygen.41,43 Therefore, the clinical relevance of
No change
No change

these findings is still unclear when reasonable blood pressure is

Reduced

Reduced

Reduced
Reduced
maintained. Our application of this information has led to the safe
CBF

and successful use of these agents for intracranial surgery over the
last decade, with the caveats of particular care to maintain an ade-
No change
No change

quate MAP with preoperative volume replacement and avoidance

Increased
Reduced
Reduced

Reduced

in patients with suspected acute raised ICP.

MAP

With clonidine there is a suggestion that cerebral autoregula-

tion, even in the head injured patient, is not abolished and that
No change

the cerebral vasculature may dilate to compensate for a reduction

Reduced

Reduced
Reduced
Reduced

in MAP.43 Fale et al.44 further demonstrated in dogs, that dex-

medetomidine limits the vasodilatory effect of raised PaCO2.
HR

No human studies have been performed to examine cerebral pro-

tection or ischaemia, however in rabbits and rats, dexmedetomi-
Clonidine 2.5 lg/kg
Dexmed 600 pg/ml

Dexmed 10 lg/kg

Dexmed 10 lg/kg
Dexmed 10 lg/kg
Dexmed 30 lg/kg
Clonidine 1 lg/kg

Clonidine 1 lg/kg

Dexmed 4 ng/ml

dine conveys dose related cerebral protection from

Table 1 Summary of reported effects of a2-agonists

ischaemia,45,46 and in dogs there was no evidence of cerebral

Drug used

ischaemia despite reductions of cerebral blood flow. Reports of

Dexmed

the effects of a2-agonists relevant to neurosurgical anaesthesia

are summarised in Table 1.
Route

iv
iv
iv
iv
iv
iv
iv
iv
iv
iv

Awake craniotomy
difference in oxygen content.

Because dexmedetomidine induces a state of sedation with clear

Sample

Human

Human
Human
Human
Rabbit

Rabbit

sensorium, analgesia and minimal respiratory depression, it has

Dog

Dog
Dog
Rat

been used as a sedative for awake procedures in neurosurgical pa-

tients. It is a more titratable agent than clonidine for intraoperative
Asgeirsson43

use; however, oral clonidine is a good premedicant in this often anx-

Minassian41

Hoffman45

ious group of patients.47 Lower dosage ranges are suggested for this
Karlson69
Zornow67

Zornow70
Mirzai71

Maier46
Talke68
Study

Fale44

procedure (0.01–0.2 lg/kg/min) during cognitive testing and corti-

cal mapping48,49 as higher doses can impair patient responses.50

Journal of Clinical Neuroscience (2005) 12(4), 375–378 ª 2004 Elsevier Ltd. All rights reserved.

Spinal surgery
The use of a2-agonists has not been extensively studied in spinal
surgery, however we believe that they do have a role to play in the
treatment of intraoperative hypertension in selected patients. De-
creased intraoperative blood loss has been shown in middle ear
surgery51 and the decrease in intraocular pressure seen with cloni-
dine52,53 may well offer unrecognised advantages over other anti-
hypertensive agents, as impaired ocular perfusion pressure is
thought to be a major contributor in visual loss following pro-
longed spinal surgery in the prone position.54
Carotid endarterectomy
Dexmedetomidine intraoperatively,55 or clonidine preoperatively,
can be used in awake carotid endarterectomy surgery, as in awake
craniotomy, to provide conscious sedation. Alternatively, these
agents can be used as an anaesthetic sparing adjunct to general
anaesthesia with the added benefit of reducing perioperative myo-
cardial ischaemia.31 The theoretical disadvantage of reduced cere-
bral perfusion pressure during the carotid cross-clamp period, and
the theoretical advantage of decreased post-operative cerebral
hyperperfusion have yet to be investigated.
POST-OPERATIVE USE
In the recovery room, a2-agonists such as clonidine are useful to
treat hypertension26 and shivering.56–58 Emergence hypertension
post-craniotomy is common and has been implicated in post-
operative intracranial haemorrhage.59 Post-operative haemody-
namics are improved with clonidine used pre- or intraoperatively
with heart rate reduction60 and blood pressure reduction26 being
consistent findings.27
Post-operative pain may be reduced by clonidine. There is a
large volume of work with experimental models showing antino-
ciceptive effects,61,62 and some, but not all, clinical studies have
shown a marked morphine sparing effect in clonidine37 or dex-
medetomidine63 treated subjects. It remains to be seen whether
these effects are as evident in intracranial surgery, where the
advantages of opioid reduction are greatest. Nausea and vomiting
may also be decreased in some post-operative settings following
breast surgery64 and laparoscopic cholecystectomy65 but not in
paediatric strabismus surgery.66 Again, further studies in the neu-
rosurgical population are needed to prove effectiveness in this
group.
SUMMARY
a2-agonists such as clonidine and dexmedetomidine, have a mul-
tifactorial role as an adjunct to care for the neurosurgical patient.
Haemodynamic control peri-operatively, less respiratory depres-
sion, anxiolysis with no hangover effects and reduction of post-
operative shivering are potentially beneficial to improve outcome.
Disadvantages such as hypotension and bradycardia are dose-
related and easily treatable. Dexmedetomidine is now proving to
have a role in awake procedures or for sedation in the intubated
patient, where a clear sensorium for neurological testing is
important.
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ª 2004 Elsevier Ltd. All rights reserved.