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Keywords:

  • analgesia;
  • anaesthesia;
  • clonidine;
  • midazolam;
  • premedication;
  • apha-2 agonists;
  • children;
  • post-operative;
  • pediatric

Abstract

  1. Top of page
  2. Abstract
  3. Clonidine in paediatric anaesthesia
  4. General aspects of premedication in children
  5. Clonidine vs. midazolam as premedication in children
  6. Conclusions
  7. References

Background:  Children undergoing anaesthesia and surgery can experience significant anxiety and distress during the peri-operative 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 (3–6).

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

  1. Top of page
  2. Abstract
  3. Clonidine in paediatric anaesthesia
  4. General aspects of premedication in children
  5. Clonidine vs. midazolam as premedication in children
  6. Conclusions
  7. References

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 half-life 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 maximum plasma concentration is approximately 50 min (8).

Haemodynamic effects of clonidine in children

During isoflurane anaesthesia in children aged 1–10 years, we have documented a significant reduction in mean arterial blood pressure (MABP) (26.3%, SD 13.6) after intravenous clonidine 2.5 µg/kg. A minor and brief reduction in heart rate was also observed despite rectal premedication with atropine 40 µg/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).

Peri-operative sedation, axiolysis and analgesia

In their initial study, Mikawa et al. reported that oral clonidine 4 µg/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 µg/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 µg/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 (4–5 µg/kg) has been found to produce similar degrees of sedation and anxiolysis as oral midazolam (0.1–0.5 mg/kg) (13, 14). As demonstrated by Sumiya in 2003 (15), plasma clonidine concentrations of 0.3–0.8 ng/ml produce satisfactory sedation without changes in haemodynamic parameters.

Mikawa et al. suggests that oral clonidine premedication (4 µg/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 µg/kg) resulted in similar analgesia as compared with intravenous fentanyl (3 µg/kg) (18), whereas results from a similar study by Fazi et al. (clonidine 4 µg/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 µg/kg is associated with a significant reduction in pain scores during the early post-operative period after adeno-tonsillectomy when compared with midazolam 300 µg/kg. The use of clonidine was also associated with slightly increased sedation ratings during the first 24 post-operative hours. However, this sedative effect is in agreement with an unequivocal parental preference of a calm and sedated child during the early post-operative 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 (21–23). After paediatric strabismus surgery, Handa et al. have shown that pretreatment with oral clonidine 4 µg/kg enhances the anti-emetic 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 µg/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 µg/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 7–17 years (7, 12, 21). However, as the adrenergic stress response to routine tracheal intubation in children 1–9 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 (2–4 µg/kg) in children aged 7–12 years successfully decreases the dose of intravenous barbiturate required for induction of anesthesia (33). Compared with placebo, oral clonidine treatment with 4 µg/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 (1–5 µg/kg) as an adjunct to local anaesthetics has repeatedly been found to prolong and improve post-operative pain relief (22, 36–42). The addition of clonidine (> 0.1 µg/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 µg/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 µg/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 µg/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 µg/kg (2). We have demonstrated a minor short-acting reduction in heart rate after intravenous clonidine 2.5 µg/kg despite rectal atropine premedication 40 µg/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 µg/kg and atropine 20 µg/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 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 glucose-containing 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

  1. Top of page
  2. Abstract
  3. Clonidine in paediatric anaesthesia
  4. General aspects of premedication in children
  5. Clonidine vs. midazolam as premedication in children
  6. Conclusions
  7. References

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 post-operative phase might represent a desired effect by the parents (63) and in a recent study we could 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

  1. Top of page
  2. Abstract
  3. Clonidine in paediatric anaesthesia
  4. General aspects of premedication in children
  5. Clonidine vs. midazolam as premedication in children
  6. Conclusions
  7. References

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 0.5–1.0 mg/kg are regularly used worldwide but in Scandinavia slightly lower oral or rectal doses (0.3–0.4 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 (66–69). 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, post-operative 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 author's 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 post-operative 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 post-operative 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 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.

Table 1.  A comparison of commonly used premedicants and clonidine.
EffectPre-anaestheticEffect of clonidine
  1. Halldin-Lindahl, Anestesi, Liber AB, modified with permission.

AnxiolysisBenzodiazepinesYes (80)
SedationBenzodiazepinesYes (81)
AmnesiaBenzodiazepines, especially midazolamNo
AnalgesiaMorphine, NSAID, paracetamolYes (82)
Reduced salivationAtropine, scopolamine, glycopyrratYes (83)
VagolysisNo (84)
Reduced gastric secretionCimetidin, ranitidin, omeprazol, sucralfatYes (85)
Reduced acidityNo
Sympathicolytic effectsβ-adrenoceptor antagonistsYes (85)
Reduced PONVDroperidol, ondansetronYes (86)

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 Alzheimer's 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 beha-viour 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 post-operative 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 2–4.

Table 2.  Paediatric use of clonidine: advantages and disadvantages.
AdvantagesPossible advantages
Pre-operative sedation (12)Post-operative sedation (4)
Reduction of anaesthetic requirements (33, 34)Action of sleep-like sedation (3)
Attenuation of haemodynamic response to trachealSatisfied parents (4)
intubation and surgical stimuli (21)Decreased incidence of shivering (4, 28)
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, 16–18)
No effect on respiration, do not potentiate opioid-induced respiratory depression (19, 51, 56)
Multiple route of administration possible (4, 7, 10, 12, 16, 87)
Tasteless solution
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.
AdvantagesPossible advantages
Sedation and anxiolysis (66)Amnesia (68, 69)
Reduction in vomiting (67)
Better mask acceptance (66)
Fast onset and short time of action (66, 69)
Multiple route of administration possible (66)
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.
ClonidineMidazolam
No effect on respiration, do not potentiate opioid-inducedIncreased requirement of post-operative oxygen supplementation (4)
respiratory depression (19, 51, 56)Potentiates opioid-induced respiratory depression (19, 89, 90)

Conclusions

  1. Top of page
  2. Abstract
  3. Clonidine in paediatric anaesthesia
  4. General aspects of premedication in children
  5. Clonidine vs. midazolam as premedication in children
  6. Conclusions
  7. References

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 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.

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 be a potential promising alternative to midazolam as premedication in infants and children.

References

  1. Top of page
  2. Abstract
  3. Clonidine in paediatric anaesthesia
  4. General aspects of premedication in children
  5. Clonidine vs. midazolam as premedication in children
  6. Conclusions
  7. References