Acta Anaesthesiol Scand 2006; 50: 135143

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Copyright # Acta Anaesthesiol Scand 2006

ACTA ANAESTHESIOLOGICA SCANDINAVICA

doi: 10.1111/j.1399-6576.2005.00940.x

Review Article: Experts Opinion

Clonidine in paediatric anaesthesia: review of the

literature and comparison with benzodiazepines for
premedication
H. BERGENDAHL1, P-A. LONNQVIST2 and S. EKSBORG3
1

Department of Anaesthesia, Intensive, and Pain Care, Karolinska University Hospital, Huddinge, Department of Paediatric Anaesthesia and
Intensive Care, 2Astrid Lindgrens Childrens Hospital and 3Karolinska Pharmacy, and Department of Woman and Child Health, Childhood Cancer
Research Unit, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

Background: Children undergoing anaesthesia and surgery can

experience significant anxiety and distress during the perioperative period, but whether routine premedication is necessary is currently debated.
Benzodiazepines are the most frequently used drugs as premedication in paediatric anaesthesia. In the US, 50% of young
children undergoing surgery receive premedication and midazolam is the most frequently used drug in this context (1).
Nishina and coworkers (2) concluded in a review article in
1999 that clonidine, administered via an oral, rectal, or caudal
route, is a promising adjunct to anaesthetics and analgesics to
enhance quality of peri-operative management in infants and
children. Later publications also support the use of clonidine for
premedication (36).
The aim of this communication is to review the use of clonidine in paediatric anaesthesia and to propose clonidine as a
promising alternative to midazolam.
Clonidine is associated with a number of beneficial effects in
the context ofanaesthesia both in adults and children. Why

clonidine is not routinely use in clinical practice despite the

massive publication list is to a large extent due to the lack of
marketing efforts from the pharmaceutical industry since multiplegeneric preparations are now readily available on most markets.
Midazolam is also associated with a number of beneficial
effects, but is far from an ideal premedicant in children, especially
with regards to the amnesia, confusion and long term behavioural
disturbances. Clonidine has contrary to midazolam no effect on
respiration. We believe that clonidine is a good alternative to
midazolam as premedication in infants and children.

Clonidine in paediatric anaesthesia

maximum plasma concentration is approximately

50 min (8).

In 1993, Mikawa and coworkers published their first

report on the use of oral premedication with clonidine
in children (7). A brief summary of the currently
known effects of clonidine in paediatric anaesthesia
is outlined below.

Pharmacokinetics of clonidine in children

After rectal administration, the elimination halflife is similar to that described in adults (12.5 h)
(8). After epidural administration of clonidine, the
pharmacokinetic profile in children is similar to
that described in adults (9). Rectal administration
of clonidine is associated with high bio availability (95%) and the median time to obtain a

Accepted for publication 1 October 2005

Key words: analgesia; anaesthesia; clonidine; midazolam;

premedication; apha-2 agonists; children; post-operative;
pediatric.
#

Acta Anaesthesiologica Scandinavica 50 (2006)

Haemodynamic effects of clonidine in children

During isoflurane anaesthesia in children aged
110 years, we have documented a significant
reduction in mean arterial blood pressure (MABP)
(26.3%, SD 13.6) after intravenous clonidine
2.5 mg/kg. A minor and brief reduction in heart
rate was also observed despite rectal premedication
with atropine 40 mg/kg (10) and, thus, pretreatment
with an anticholinergic is recommended when
clonidine is used. Increased post-operative blood
pressure stability is observed when a continuous
post-operative epidural infusion of clonidine is
used in children (11).

135

H. Bergendahl et al.

Peri-operative sedation, axiolysis and analgesia

In their initial study, Mikawa et al. reported that
oral clonidine 4 mg/kg administered 105 min prior
to anaesthetic induction provided improved
sedation, better quality of separation from parents,
and a higher acceptance rate of mask application
compared with clonidine 2 mg/kg or diazepam
0.4 mg/kg (7). These beneficial effects of clonidine
premedication were later supported by Ramesh
and colleagues who showed that oral clonidine
3 mg/kg produced comparable sedation to diazepam 0.2 mg/kg, but was also able to attenuate the
haemodynamic response to endotracheal intubation
without any prolongation of the recovery time from
anaesthesia (12). In neither of these studies were any
adverse effects, such as bradycardia, hypotension or
respiratory depression, noted. In paediatric surgical
patients, the sedative and anxiolytic effect of oral
clonidine (45 mg/kg) has been found to produce
similar degrees of sedation and anxiolysis as oral
midazolam (0.10.5 mg/kg) (13, 14). As demonstrated
by Sumiya in 2003 (15), plasma clonidine concentrations of 0.30.8 ng/ml produce satisfactory sedation
without changes in haemodynamic parameters.
Mikawa et al. suggests that oral clonidine premedication (4 mg/kg) facilitates post-operative analgesia in
children undergoing minor surgery (16). In children
undergoing ophthalmological surgery, the same
group has also shown that oral clonidine premedication augmented post-operative pain relief using a
diclofenac suppository or intravenous flurbiprofen
(17). Despite these data showing an analgesic potential of clonidine in children, contradictory data with
regards to analgesia has been reported when clonidine
is used in the context of adeno-tonsillectomy. In this
subgroup of paediatric patients, Reimer et al. found
that oral premedication with clonidine (4 mg/kg)
resulted in similar analgesia as compared with intravenous fentanyl (3 mg/kg) (18), whereas results from a
similar study by Fazi et al. (clonidine 4 mg/kg as oral
premedication) showed an increased post-operative
demand for analgesia when compared with children
treated with oral midazolam (0.5 mg/kg) (19). Local
infiltration of ropivacaine combined with clonidine in
the tonsillar fossae prior to tonsillectomy has recently
been reported to produce long-lasting improvement
of post-operative pain in paediatric patients (20).
In a recent study, we have shown that rectal premedication with clonidine 5 mg/kg is associated
with a significant reduction in pain scores during
the early post-operative period after adeno-tonsillectomy when compared with midazolam 300 mg/kg.

136

The use of clonidine was also associated with slightly

increased sedation ratings during the first 24 postoperative hours. However, this sedative effect is in
agreement with an unequivocal parental preference
of a calm and sedated child during the early postoperative period (4).

Effects on shivering, post-operative nausea and

vomiting and post-operative agitation-confusion
Both oral and caudal clonidine has been reported to
reduce the incidence of post-operative vomiting in
children (2123). After paediatric strabismus surgery, Handa et al. have shown that pretreatment
with oral clonidine 4 mg/kg enhances the antiemetic effect of propofol when compared with
midazolam 0.4 mg/kg (24), but Gulhas et al. could
not corroborate these results in a similar study
comparing oral clonidine 4 mg/kg with placebo (25).
In adults, clonidine decreases the incidence of
post-operative shivering (26) and is an effective
alternative in the treatment of already established
shivering (27). In our recent publication (4), we
reported a possible preventive action of clonidine
on post-operative shivering as none of the patients
in the clonidine group shivered whereas 11%
of patients in the midazolam group were found
to shiver during the recovery room stay. For treatment of shivering, adult data indicates that less than
two patients need to receive clonidine 1.5 mg/kg for
one to stop shivering in 5 min after drug administration (28).
The use of sevoflurane in children, especially in
preschool boys, has been associated with an
increased incidence of early post-operative confusion and delirium (29). After both caudal and intravenous administration of clonidine in children, Bock
et al. have demonstrated a dose-dependent prevention of agitation after sevoflurane anaesthesia (5). In
keeping with the results presented by Kulka et al.
(30), we recently showed that clonidine reduces the
incidence of post-operative confusion in the
children less than 5 years of age compared with
midazolam (4).

Effects on the stress response secondary to

endotracheal intubation and surgery
In line with previous adult findings, several paediatric studies have shown that oral administration of
clonidine is capable of blunting both the catecholamine release and the haemodynamic response secondary to endotracheal intubation in otherwise
healthy children 717 years (7, 12, 21). However, as

Clonidine in paediatric anaesthesia

the adrenergic stress response to routine tracheal

intubation in children 19 year is short lived and
of limited magnitude, as indicated by the lack
of neuropeptide Y release (31), routine attempts to
attenuate the stress response after tracheal intubation in otherwise healthy children might be
debatable.
In a recent study by Nishina et al., oral clonidine
premedication was found to attenuate the hyperglycaemic response to surgical stress (32). These
authors suggested that a 2% glucose infusion
would to be optimal in order to maintain blood
glucose concentrations within the physiologic
range when using this approach.

Anaesthetic sparing effect

Oral clonidine premedication (24 mg/kg) in children aged 712 years successfully decreases the dose
of intravenous barbiturate required for induction of
anesthesia (33). Compared with placebo, oral clonidine treatment with 4 mg/kg in children undergoing
minor surgery has been demonstrated to both
reduce the halothane requirements for maintenance
of anaesthesia (34) as well as the MACTI of sevoflurane for endotracheal intubation (35).

Supplement to regional anaesthesia and

post-operative analgesia
After caudal blockade in children, the administration of clonidine (15 mg/kg) as an adjunct to local
anaesthetics has repeatedly been found to prolong
and improve post-operative pain relief (22, 3642).
The addition of clonidine (> 0.1 mg/kg/h) to a continuous epidural infusion of ropivacaine has also
been found to improve the quality of post-operative
pain relief in children (42, 43). Kaabachi in 2002
and Rochette et al. in 2004 have suggested that
intrathecal clonidine 2 mg/kg in a combination
with bupivacaine is associated with extending the
duration of postoperative analgesia with moderate
side-effects (44, 45).
Oral administration has been shown to be less
potent than epidural clonidine regarding the
enhancement of epidural blockade in adults (46).
However, the administration of oral clonidine
5 mg/kg has been reported to cause an increased
duration of bupivacaine-induced caudal anesthesia
in children (47). Furthermore, in a recent study,
Hansen et al. have demonstrated that the analgesic
effect of clonidine 2 mg/kg as an adjunct to caudal
block with bupivacaine 0.25%, 0.5 ml/kg is similar
whether administered intravenously or caudally.

The popularity of the use of adjunct clonidine has

recently been illustrated by a survey of regional paediatric anaesthesia from the UK (48) where 26% of
respondents used clonidine as adjuvants to local
anaesthetics for caudal blockade. Two recent reviews
have also been published regarding the use of adjuvants to local anaesthetics in children (49, 50).

Adverse effects and contraindications

In general, clonidine has not been shown to cause
any interference with ventilation and does not
potentiate opioid-induced respiratory depression
(51). However, respiratory depression has been
reported after a massive clonidine overdose (52,
53). Two paediatric case reports have been published suggesting that clonidine administration
potentially contributed to the development of
post-operative apnoea in preterm infants treated
with a caudal technique including clonidine
administration (54, 55). Although no conclusive
argument to attribute this adverse effect to clonidine
could be given in these reports, caudal clonidine
should be used sparingly in preterm infants.
Further support for the benign effect of clonidine
on ventilation is given in a case report where a
1000-fold unintentional overdose of clonidine
was not found to cause any signs of respiratory
depression (56).
Although clonidine can induce hypotension and
bradycardia, no serious adverse effects such as pronounced hypotension and bradycardia have been
reported in children when using doses of clonidine
< 10 mg/kg (2). We have demonstrated a minor
short-acting reduction in heart rate after intravenous clonidine 2.5 mg/kg despite rectal atropine
premedication 40 mg/kg (10). In the beginning of
routine clonidine premedication practice with rectal
clonidine without atropine, we observed two cases
of bradycardia that responded promptly to atropine
administration. Based on these observations, we
recommend atropine administration in combination
with clonidine. We now use a mixture of clonidine
4 mg/kg and atropine 20 mg/kg for oral and rectal
administration. Late onset haemodynamic reactions
are not reported in the literature or observed in our
clinical practice of clonidine premedication in more
than 500 patients.
The pharmacological treatment of bradycardia
and hypotension caused by clonidine overdose
include administration of atropine, volume expansion and dopamine infusion (57).
Clonidine attenuates the hyperglycaemic response
to surgical stress (32). However, early or late onset

137

H. Bergendahl et al.

hypoglycaemia has not been reported but Nishina

et al. suggests that a 2% glucose infusion should
be administrated until oral intake is adequate (33).
This is usually not a clinical problem as glucosecontaining infusions are frequently used in paediatric anaesthesia.
Although strict contraindications to the use of
clonidine are few, clonidine should also be avoided
in paediatric patients with hypovolaemia, A-V
block, prolonged P-R intervals and spontaneous
bradycardia (58).

General aspects of premedication

in children
Children undergoing anaesthesia and surgery can
experience significant anxiety and distress during
the peri-operative period. In a study by Loewenthal
et al., approximately 60% of the children experienced
anxiety and distress (59), but whether routine premedication is necessary is currently debated. Hatava
and Olsson have demonstrated that pre-operative
psychological preparation and parental presence is
beneficial and may reduce the need for pharmacological premedication (60). However, sedative premedication with midazolam has been reported to be
more effective than either parental presence or no
intervention at all in managing child/parent anxiety
during the pre-operative period (61). The level of
anxiety is individual, with children who have previous negative experiences from operations or painful procedures showing more anxiety (62) and, thus,
the need for premedication should be individualized
according to the specific needs of the child.
Premedication may not only be advantageous in conjunction with surgery but can also be desirable before
other painful and/or stressful invasive procedures.
A major objective in out-patient surgery in adults is
rapid recovery and early ambulation in order to facilitate discharge from the hospital. This is important in
order to increase turnover and thereby improve the
cost-effectiveness of ambulatory surgery. Thus, a key
factor in adult out-patients is the ability to cope without assistance from hospital staff or relatives and residual sedation using the premedicant drug is in this
setting clearly unwanted both by the patient and the
hospital staff. However, this is not the situation after
paediatric ambulatory surgery as the child is always
accompanied by the parents or other caregivers.
It has even been suggested by Lerman that a certain degree of residual sedation in the early postoperative phase might represent a desired effect by
the parents (63) and in a recent study we could

138

corroborate this statement (4). A slight degree of

residual post-operative sedation in children is,
thus, in the authors opinion not to be seen as an
unwanted side-effect but more as a positive spin-off
effect of the premedicant drug.

Clonidine vs. midazolam as

premedication in children
Midazolam
In the US, 50% of young children undergoing surgery
receive premedication and midazolam is the most
frequently used drug in this context (64). Oral or rectal
doses of 0.51.0 mg/kg are regularly used worldwide
but in Scandinavia slightly lower oral or rectal doses
(0.30.4 mg/kg) are more common (65). Midazolam
has a number of beneficial effects when used as
premedication in children, i.e. sedation, reduction of
vomiting, amnesia, fast onset and short action (6669).
Rectal midazolam improves sedation and is more
effective with a dose of 1 mg/kg compared with
0.5 mg/kg but inadequate sedation still frequently
occurs (> 25%) and prolonged agitation can occur if
higher doses are given (70). Even if the respiratory
effects of midazolam itself are minor in nature, postoperative oxygen supplementation is not infrequently
needed when midazolam has been used as premedication (19).
The reason for the popularity of midazolam is
somewhat obscure as the published scientific documentation is far from conclusive regarding its superiority compared with other alternatives in children.
The present popularity can in the authors opinion to
a large extent be attributed to aggressive and successful marketing of the drug. Midazolam does clearly
posses certain merits in the context of premedication
but its cost and the risk of prolonged post-operative
behavioural problems (71) and requirement for postoperative oxygen supplementation in children (19)
should be taken into consideration.

Clonidine
Oral premedication with clonidine in children produces similar or even better sedation compared with
diazepam (7, 12). Furthermore, clonidine premedication reduces the need for an induction agent (33)
and decreases the stress response associated with
endotracheal intubation (21). Improved postoperative pain relief (16), reduced incidences of
shivering and PONV (6, 22) as well as attenuation
of post-operative delirium frequently seen in the
immediate post-operative period after sevoflurane

Clonidine in paediatric anaesthesia

anaesthesia (29), are also associated with the use of

clonidine premedication in children (30).
The effect on circulation is mild but routine atropine administration is recommended. There is no
effect on respiration and opioid-induced respiratory
depression is not potentiated (19, 51, 56). Prolonged
sedation may in older children be considered a
potential disadvantage.
A comparison of commonly used premedicants,
including clonidine, is listed in Table 1.

Amnesia and effects on cognition: midazolam vs.

clonidine
Midazolam causes anterograd and retrograde amnesia in children (68) and is frequently put forward as a
specific advantage of midazolam (69). However, the
ability to produce amnesia is dubious as the amnesic
effect is perhaps not something that is readably
appreciated by the patient. A period of loss of memory or blurred memory is frequently experienced as
quite distressful in adults and there is no data indicating that this would be different in the paediatric
population. It can be argued that even if the memory
of a procedure is unpleasant it could nevertheless be
preferable to a period of black-out. The amnesic
effect of midazolam effects explicit memory but not
implicit memory explaining the mechanism of conditioned anxiety in children associated with aversive
medical procedures (72) and this mechanism has
previously also been documented in adults (73).
Clonidine lacks the psychotropic quality of bensodiazepines and will cause a state of sedation more
similar to normal tiredness-sleepiness where the
patient can easily be awoken to perform various
tests (3). A further difference compared with bensodiazepines is that clonidine is frequently described
as in fact enhancing memory, especially in the early

stages of Alzheimers disease (74), whereas bensodiazepines impair memory function and even produce amnesia (75, 76). In the authors opinion,
further investigations regarding amnesia and premedication are clearly warranted.
Early post-procedure agitation occurs in 17% of
paediatric patients premedicated with midazolam
(0.5 mg/kg: 6%, 1 mg/kg: 27%) (70), and has
also been shown to increase the occurrence of early
post-operative sevoflurane delirium (70). In 1998,
McGraw identified negative post-operative behaviour changes in children such as nightmares,
night terrors, food rejection, anxiety and negativism
after oral midazolam premedication at a 1 week
follow-up (71), findings that in the authors opinion
potentially could be a result of the amnesia caused
by midazolam as mentioned above.
Clonidine not only reduces agitation associated
with induction of sevoflurane anaesthesia compared
with midazolam (77) but has also repeatedly been
shown to reduce the incidence of early postoperative sevoflurane agitation (5, 30, 78) and similar results are seen after premedication with the
more selective alpha-2 agonist dexmedetomidine
(79). Prolonged negative behavioural effects of clonidine, similar to those associated with midazolam
premedication, have so far to our knowledge not
been reported in the literature.
An over-all comparison of the advantages and
disadvantages of clonidine and midazolam as premedication drugs in children are listed in Tables 24.

Conclusions
As has been outlined above, clonidine is associated
with a number of beneficial effects in the context
of anaesthesia both in adults and children. Why

Table 1
A comparison of commonly used premedicants and clonidine.
Effect

Pre-anaesthetic

Effect of clonidine

Anxiolysis
Sedation
Amnesia
Analgesia
Reduced salivation
Vagolysis
Reduced gastric secretion
Reduced acidity
Sympathicolytic effects
Reduced PONV

Benzodiazepines
Benzodiazepines
Benzodiazepines, especially midazolam
Morphine, NSAID, paracetamol
Atropine, scopolamine, glycopyrrat

Cimetidin, ranitidin, omeprazol, sucralfat

b-adrenoceptor antagonists
Droperidol, ondansetron

Yes (80)
Yes (81)
No
Yes (82)
Yes (83)
No (84)
Yes (85)
No
Yes (85)
Yes (86)

Halldin-Lindahl, Anestesi, Liber AB, modified with permission.

139

H. Bergendahl et al.
Table 2
Paediatric use of clonidine: advantages and disadvantages.
Advantages

Possible advantages

Pre-operative sedation (12)

Reduction of anaesthetic requirements (33, 34)
Attenuation of haemodynamic response to tracheal
intubation and surgical stimuli (21)
Reduction of PONV (6, 22, 24)
Prolonged effect, if operation is delayed (4)
Reduced post-operative confusion after sevoflurane anaesthesia (4, 5, 30)
Post-operative analgesia (4, 1618)
No effect on respiration, do not potentiate opioid-induced respiratory depression (19, 51,
Multiple route of administration possible (4, 7, 10, 12, 16, 87)
Tasteless solution

Post-operative sedation (4)

Action of sleep-like sedation (3)
Satisfied parents (4)
Decreased incidence of shivering (4, 28)

56)

Disadvantages
Attenuation of HR response to atropine (67)
Slow onset of action after oral and rectal route (7, 8, 19)
Prolonged post-operative sedation (4)
Contraindications: Hypovolemia, A-V block, prolonged P-R interval and spontaneous bradycardia (58)
Attenuation of hyperglycaemic response to surgical stress (32)

Table 3
Paediatric use of midazolam: advantages and disadvantages.
Advantages

Possible advantages

Sedation and anxiolysis (66)

Reduction in vomiting (67)
Better mask acceptance (66)
Fast onset and short time of action (66, 69)
Multiple route of administration possible (66)

Amnesia (68, 69)

Disadvantages:
Amnesia (68, 69)
No analgesic effect (4, 87)
Hiccups (88)
Dose-dependent post-operative agitation (70)
Increased requirement of post-operative oxygen supplementation (19)
Long-term behavioural disturbances (weeks) (71)
Disturbed memory/cognition (73)
Potentiates opioid-induced respiratory depression (19, 89, 90)
Bitter taste (91)
Nasal sting (91)

Table 4
Clonidine vs. midazolam: effects on respiration.
Clonidine

Midazolam

No effect on respiration, do not potentiate opioid-induced

respiratory depression (19, 51, 56)

Increased requirement of post-operative oxygen supplementation (4)

Potentiates opioid-induced respiratory depression (19, 89, 90)

clonidine is not routinely use in clinical practice

despite the massive publication list is to a large
extent due to the lack of marketing efforts from the
pharmaceutical industry as multiple generic preparations are now readily available on most
markets.

140

Midazolam is also associated with a number of

beneficial effects, but is far from an ideal premedicant in children, especially with regards to the
amnesia, confusion and long-term behavioural disturbances. Clonidine has contrary to midazolam no
effect on respiration. We believe that clonidine may

Clonidine in paediatric anaesthesia

be a potential promising alternative to midazolam

as premedication in infants and children.

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Address:
Bergendahl Henrik
Department of Anaesthesia, Intensive, and Pain Care
Karolinska University Hospital
Huddinge
141 86 Huddinge
Sweden
e-mail: henrik.bergendahl@karolinska.se

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