Alpha-2-agonists in day case anaesthesia

Ian Smith
University Hospital of North Staffordshire, Stoke-on-
Trent, Staffordshire, UK
Correspondence to Dr Ian Smith, BSc, MD, FRCA,
Directorate of Anaesthesia, University Hospital of
North Staffordshire, Newcastle Road, Stoke-on-Trent,
Staffordshire ST4 6QG, UK
Tel: +44 1782 553054;
e-mail: damsmith@btinternet.com
Current Opinion in Anesthesiology 2011,
24:644–648
Purpose of review
Alpha-2-agonists have long been known to have anaesthetic-sparing, sedative and
analgesic properties which are desirable in day case anaesthesia. Their routine use was
hampered by a high incidence of undesirable effects, however. In recent years, there
have been many attempts to define a role for these unique agents in which their benefits
would outweigh their apparent disadvantages.
Recent findings
Many recent studies have confirmed the usefulness of alpha-2-agonists in providing
sedation and analgesia, although the results have been far from consistent. Some, but
by no means all studies have shown advantages over alternative agents, but concerns
also remain over acute and possible long-term adverse effects.
Summary
Alpha-2-agonists still have no clearly defined routine role in day surgery. Their most
promising application is in limiting recovery agitation in children, but even here, there
remain concerns about their routine use.

Keywords
ambulatory anaesthesia, analgesia, clonidine, dexmedetomidine, sedation

Curr Opin Anesthesiol 24:644–648

ß 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins
0952-7907

[2]; however, remifentanil was associated with faster

Introduction
Since the early 1990s, alpha-2-agonists, such as clonidine
and the more selective dexmedetomidine, have been
known to have anaesthetic-sparing, sedative and analge-
sic properties, suggesting they would be useful in day
case anaesthesia. However, many early studies found
these useful properties to be accompanied by equally
undesirable effects, such as hypotension, bradycardia and
prolonged recovery, which limited their routine use.
Subsequent research has tried to refine the appropriate
dose and find suitable applications in which benefits can
be achieved without adverse effects. How successful has
this work been?
Adult applications
The earliest applications of alpha-2-agonists were as an
anaesthetic and analgesia adjuvant and for procedural
sedation. More recently, they have also been evaluated as
adjuvants to regional anaesthesia.
Supplementing general anaesthesia
One early study found that giving dexmedetomidine
15 min before anaesthesia reduced the induction dose
of thiopental by 37%, although this was associated with
sedation and a modest delay in awakening [1]. A more
recent study showed dexmedetomidine to be comparable
to remifentanil as an adjuvant to desflurane anaesthesia
0952-7907 ß 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins
recovery, whereas dexmedetomidine reduced postopera-
tive nausea, vomiting and analgesic requirements.
Another study found that premedication with oral
clonidine increased the proportion of patients who were
completely free from nausea and vomiting after ear
surgery from 33 to 67% [3]. This level of response is
typical of that achieved with single-agent prophylaxis and
it is unfortunate that no comparison was made with any of
the established antiemetics.
The analgesic properties of alpha-2 agonists are alluring,
but difficult to exploit without accompanying adverse
effects. Used after laparoscopic sterilization, 0.4 mg/kg
dexmedetomidine reduced postoperative pain to a com-
parable degree to oxycodone, 60 mg/kg [4]. However,
dexmedetomidine was slower acting, requiring three
bolus doses compared to one with oxycodone, produced
more sedation and resulted in bradycardia for which
a third of the patients required atropine.
Sedative applications
The sedative and analgesic properties of alpha-2-agonists
have resulted in extensive evaluation of their use during
local anaesthetic procedures, either as premedication or
for intraprocedural sedation.
Given intramuscularly before cataract extraction, both
dexmedetomidine, 1 mg/kg, and midazolam, 20 mg/kg,
DOI:10.1097/ACO.0b013e328349d0da

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produced comparable sedation, but only dexmedetomi-
dine produced a useful reduction in intraocular pressure
[5]. Only minor haemodynamic effects were observed at
this dose in these elderly patients. In a more recent study,
moderate sedation and reduction in intraocular pressure
were also observed after premedication with 100 mg/kg
of clonidine, although an unacceptable degree of hypo-
tension was observed with a higher dose of 200 mg/kg [6].
Oral premedication with morphine or midazolam before
facial surgery under local anaesthesia reduced pain
and anxiety, respectively, whereas 1.5 mg/kg of clonidine
reduced both pain and anxiety with minimal haemody-
namic disturbance and without the nausea associated
with morphine [7].
Used as an infusion during cataract surgery, dexmedeto-
midine produced comparable sedation to midazolam,
lower postoperative pain scores and minimal haemody-
namic disturbance [8]. During third molar extraction
under local anaesthesia, 4 mg/kg/h of dexmedetomidine
produced comparable sedation and superior pain relief to
midazolam [9]. This dose of dexmedetomidine produced
no serious adverse effect and was preferred to midazolam
by 65% of the participants in this crossover study [9].
In contrast, dexmedetomidine was ineffective as the sole
sedative for colonoscopy when compared to midazolam–
pethidine or fentanyl. A bolus of 1 mg/kg dexmedetomi-
dine followed by an infusion of 0.2 mg/kg/h produced
inadequate analgesia in 47% of cases, yet was associated
with delayed recovery and an unacceptable incidence
of severe hypotension and bradycardia, which led to early
termination of the study [10]. A similar dexmedetomi-
dine regimen was also less effective than midazolam–
fentanyl for sedation and analgesia during extracorporeal
shockwave lithotripsy and again prolonged recovery
[11]. Similarly, prolonged recovery times were observed
in a noncomparative evaluation of dexmedetomidine
in office-based oral and maxillofacial surgery [12]. The
authors concluded that dexmedetomidine was unsuitable
for routine use in the busy office setting, but might be
of value in patients at higher risk of respiratory compli-
cations, such as the obese and those with sleep apnoea.
Supplementing local and regional anaesthesia
Whereas the analgesic effects of systemic alpha-2-ago-
nists are associated with adverse effects [4], they may
be more promising when used to supplement local
anaesthesia. The addition of clonidine to preincisionally
infiltrated ropivacaine provided additional analgesia
which outlasted the local anaesthetic effect and
decreased pain, opioid use and the time to return to
normal activity after tonsillectomy [13]. For intravenous
regional anaesthesia (IVRA), dexmedetomidine, either
administered as a premedicant bolus or added to the
intravenous lidocaine, improved the quality of periopera-
tive anaesthesia and analgesia [14]. Similarly, clonidine
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Alpha-2-agonists in day case anaesthesia Smith 645
Key points
 The potential beneficial effects of alpha-2-agonists
must be balanced against a high incidence of
adverse effects, especially cardiovascular.
 Alpha-2-agonists still have no routine role in day
surgery anaesthesia.
 In children, alpha-2-agonists can improve analgesia
and emergence delirium, but with concerns over the
balance of risks and benefits.
 Alpha-2-agonists may have a useful role in specific
patients, such as those with sleep apnoea or specific
sensitivities to common anaesthetic or sedative
supplements.
also improved the quality of IVRA, but this effect was no
better than that of either tramadol or sufentanil [15].
Spinal anaesthesia can extend the range of patients and
procedures suitable for day surgery, but the technique
needs to be modified such that the duration of block does
not compromise discharge. When added to a low-dose
(8 mg) ropivacaine subarachnoid block, 15 mg of clonidine
improved the quality of analgesia without prolongation of
the block or adverse systemic effects, although higher
doses were associated with prolonged motor block, seda-
tion and hypotension [16]. In combination with 5 mg of
bupivacaine, 15 mg of clonidine also improved the quality
of analgesia, but was associated with a modest increase in
the duration of motor block and also delayed the time to
spontaneous voiding [17]. The same dose of clonidine
combined with 5 mg of bupivacaine achieved comparable
unilateral analgesia and similar discharge times to 6 mg of
bupivacaine alone, but the addition of clonidine resulted
in a greater degree of hypotension and requirement for
vasopressors, despite the reduced bupivacaine dose [18].
Paediatric applications
The two main applications of alpha-2-agonists in children
have been for premedication to facilitate the induction
of anaesthesia and to reduce postoperative agitation while
supplementing postoperative analgesia.
Premedication
One recent meta-analysis [19] claims ‘superior effect
on sedation at induction’ with clonidine compared to
midazolam, the commonest sedative premedicant in chil-
dren. However, it is difficult to understand this claim given
that this aspect of the meta-analysis included only two
studies, in one of which [20], clonidine resulted in good
quality induction in only 50% (2 mg/kg) or 30% (4 mg/kg) of
children compared with 70% with midazolam (0.5 mg/kg).
In addition, this meta-analysis failed to consider anxiety at
induction, which is at least as important as sedation. In at
least one study [21], clonidine premedication resulted in
 646 Ambulatory anesthesia
more intense anxiety at separation from the parents at
induction of anaesthesia compared with midazolam.
The child’s perspective of clonidine premedication
does not appear to have been sought, although in adults
only a third would be happy to receive clonidine pre-
medication again in contrast to midazolam which was a
more effective sedative and anxiolytic, with fewer
adverse events and was considered a welcome addition
in most cases [22].
Postoperative agitation in children
Postoperative agitation is a common phenomenon in
children, especially those below school age and receiving
short-acting anaesthetic agents. Although self-limiting,
many strategies have been evaluated to try to minimize
this distressing complication. Alpha-2-agonists are one
of the several therapies which are effective in reducing
or preventing postoperative agitation [23], an effect
observed with both clonidine and dexmedetomidine,
although the former has been more widely studied.
Clonidine resulted in significantly less emergence
agitation than midazolam [19] and has been shown to
be effective in the prevention of emergence agitation
when administered by a wide variety of routes [24].
Because pain is an obvious cause of postoperative distress
in children, clonidine may be especially beneficial
because it prolongs the effect of regional anaesthesia
as well as reduces postoperative agitation. Caudal analge-
sia is commonly used in many paediatric day surgery
procedures and the addition of caudal clonidine can
significantly prolong the duration of analgesia, typically
by more than 2 h [25]. Doubts have been raised, however,
about the wisdom of routinely using clonidine as a
supplement to day surgery anaesthesia [25]. This is based
on the lack of clear evidence of improved patient out-
come, as well as concerns over sedative and cardiovas-
cular side-effects and the theoretical risk of neurotoxicity.
Some of these adverse effects are known to be dependent
on the dose of clonidine used. At a dose of 3 mg/kg,
caudal clonidine was completely effective in preventing
agitation after sevoflurane anaesthesia, but resulted in
significantly lower mean arterial blood pressure [26].
Caudal clonidine at a dose of 2 mg/kg failed to increase
the time to first oral analgesia or the total requirement for
supplemental analgesia in children undergoing lower body
day surgery procedures [27], although all these children
also received epinephrine in the analgesic mixture, which
may have negated the advantage of clonidine. When given
before surgery, 2 mg/kg of clonidine reduced postoperative
agitation by 57% and also significantly reduced pain and
discomfort scores [28]. In a recent study, 1 mg/kg of caudal
clonidine was reported to result in significantly less
agitation after sevoflurane anaesthesia compared to even
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
lower doses of clonidine or bupivacaine analgesia alone
[29]. Haemodynamic and respiratory adverse effects were
not observed at this low dose. This finding is in contrast to
an earlier, but smaller, study which failed to show any
reduction of postoperative agitation from 1 mg/kg of caudal
clonidine [26]. Interestingly, the addition of 1 mg/kg of
clonidine to an ilioinguinal–iliohypogastric block with
bupivacaine also offered no apparent benefit after day
case herniorrhaphy or orchidopexy in children aged
1–12 years [30]. In particular, clonidine did not reduce
the requirement for supplemental oral analgesia, either in
hospital or following discharge home.
A number of studies have shown a reduction in post-
operative agitation in children with dexmedetomidine,
with relatively few of these reporting significant adverse
events from intravenous doses ranging from 0.3 to 0.5 mg/
kg [31,32–35] or 2.5 mg/kg orally [36]. One recent
study found particular benefits in children with obstruc-
tive sleep apnoea undergoing tonsillectomy [37]. Sleep
apnoea is now an important indication for tonsillectomy
and these children can be challenging to manage on a day
case basis. As well as reducing postoperative agitation,
a perioperative infusion of dexmedetomidine improved
postoperative pain scores, reduced the requirement
for postoperative opioid analgesia and resulted in signifi-
cantly fewer episodes of postoperative haemoglobin oxy-
gen desaturation [37], all apparently without adverse
events. Although not the sole cause, postoperative
agitation is obviously more likely in small children who
are in pain and it is therefore not surprising that agents
such as alpha-2-agonists which enhance analgesia are
also effective at reducing agitation. However, 1 mg/kg
of dexmedetomidine reduced agitation from 47.6 to 4.8%
after sevoflurane anaesthesia for diagnostic MRI [38], an
investigation which would not be expected to cause pain
or discomfort after its completion. Dexmedetomidine
did slightly prolong the time to awakening, but did not
delay discharge from the recovery room or to home.
Caudal dexmedetomidine (1 mg/kg) added to bupivacaine
has also been shown to prolong analgesia and reduce
postoperative agitation [39]. Although the benefits of
dexmedetomidine seem promising, one recent study
concluded that there was insufficient evidence about
the safety of dexamethasone to recommend its routine
use in preference to fentanyl [31].
Conclusion
After more than 20 years, alpha-2-agonists have still not
found a routine place in day case anaesthesia, despite
several favourable properties. Used as a sedative or to
supplement general anaesthesia, the results are highly
variable and often associated with adverse effects. As
supplements to local anaesthesia, they appear effective,

although not necessarily superior to other, better estab-
lished alternatives.
In paediatric day cases, they represent an alternative
sedative premedication, but evidence of superior effect,
especially with respect to reduction of anxiety, is limited.
Their most effective role seems to be in the reduction
of postoperative agitation in children, where there is
considerable evidence of their efficacy. However, even
in this use, haemodynamic disturbances remain a valid
concern and there is still doubt about their long-term
safety, especially when administered perineurally. Alpha-
2-agonists may have the most to offer in select groups of
patients, such as those with sleep apnoea, in which the
sedative and respiratory depressant effects of conven-
tional supplements would be especially undesirable.
Acknowledgements
Conflicts of interest
There are no conflicts of interest.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:
 of special interest
 of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (pp. 708–709).
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 648 Ambulatory anesthesia
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received 1 mg/kg of clonidine compared with eight (27%) receiving 0.75 mg/kg
and 12 (40%) without clonidine. No haemodynamic or respiratory compromise
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degrees, with similar haemodynamic effects. Despite slight prolongation of
awakening with fentanyl, the authors concluded that further studies of the safety
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One hundred and twenty-two patients, aged 2–10 years, with obstructive sleep
apnea syndrome undergoing tonsillectomy and adenoidectomy were randomly
allocated to receive intravenous dexmedetomidine 2 mg/kg over 10 min followed
by 0.7 mg/kg/h or a 1 mg/kg bolus of fentanyl. Anaesthesia was induced and
maintained with sevoflurane. Dexmedetomidine resulted in lower requirements for
anaesthetic agents and supplemental fentanyl, but also lower heart rates and blood
pressure, although not to a detrimental degree. After surgery, dexmedetomidine
reduced the incidence of severe agitation from 46 to 18% and also shortened the
duration of agitation. Postoperative pain scores were also lower following dex-
amethasone, consequently the proportion of children requiring morphine was
reduced from 47.5 to 16.3% and postoperative desaturation (to below 95%)
was reduced from 41 to 18%.
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Compared to bupivacaine alone, the additional of 1 mg/kg of caudal dexmedeto-
midine reduced intraoperative sevoflurane requirements, decreased postoperative
agitation, prolonged the duration of analgesia and reduced the total consumption
of rescue analgesia without apparent adverse haemodynamic effects.