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August 1998
Plasma levels of clonidine following epidural bolus injection in children.
CO2 tension effects of clonidine in paediatric caudal analgesia.
Ivani G, Bergendahl HGT, Lampugnani E, Eksborg S, Jasonni V, Palm C, Mattioli G, Podesta E, Famularo A, Lonnqvist PA. Acta Anaesthesiol.Scand. 1998;42:306-311.
[ see abstract below ]
Transcutaneous CO2 tension effects of clonidine in paediatric caudal analgesia.
Dupeyrat A, Goujard E, Muret J, Ecoffey C. Transcutaneous Paediat. Anaesth. 1998;8:145-148.
[ see abstract below ]
The use of alpha2 adrenoceptor
agonists in anesthesiology has been addressed on AnesthesiaWeb in the April
1997 and December 1996 editions. Recently, two papers extending the available
information about the use of clonidine in infants and children have been published.
[1,2]
Discussion about the first of these, from the Gaslini Hospital in Genua, Italy and the Karolinska Hospital in Stockholm, Sweden, must begin with a warning: The dose of clonidine listed in the abstract and in the body of the paper is 2 mg/kg. Since all other pediatric papers report the use of 1-2 µg/kg, and the highest dose reported for adults is 900 µg, this must be a misprint.
The authors measured plasma clonidine levels, postoperative analgesia and sedation in pediatric patients (1-9 yr) undergoing ureteral reimplantation. In 6 of 8 patients, venous plasma pharmacokinetics followed a pattern quite similar to that seen in adults. The other two patients, both 1 year of age, had a slower absorption pattern. The authors hypothesize that this may be due to binding of lipophilic clonidine to the known greater amount of epidural fat in infants. The authors also report the presence of residual sedation at plasma concentrations as low as half of those associated with sedation in adults. This finding is relevant, since sedation is thought likely to reflect systemic absorption and vascular redistribution to higher centers. They confirm that, as in adults, epidural clonidine was associated with only minor hemodynamic effects (thought to be due to actions in the brain and in the periphery) and correlation between plasma clonidine levels and pain scores is poor. The latter finding is not surprising, in light of the hypothesized spinal, and not systemic, analgesic action of epidurally administered clonidine. (For additional mechanistic information, see: Eisenach JC; De Kock M; Klimscha W. Alpha(2)-adrenergic agonists for regional anesthesia. A clinical review of clonidine (1984-1995). Anesthesiology. 1996 Sep;85(3):655-74.)
The effects of epidural administration of clonidine on ventilation is reported by Dupeyrat and her colleagues at l'Univiersiti Paris-Sud. The addition of clonidine to epidural bupivacaine in adults results in measurable respiratory depression only in the case of a CO2 challenge. These authors performed a randomized, double-blind comparison of bupivacaine-clonidine to bupivacaine alone in 24 pediatric patients (9 mo - 7 yr), and measured the effects on ventilation (respiratory rate, oxygen saturation (SpO2) and transcutaneous CO2), analgesia and sedation. They found no differences between the groups except that patients in the clonidine group were significantly more sedated. No patient had a respiratory rate less than 16/min or an SpO2 <97%. Clearly, anxiety and/or pain often increase alveolar ventilation, and any drug which relieves these is likely to blunt this increase and may thereby unmask respiratory depressant effects of concurrently administered medications.
Since the addition of clonidine to epidural bupivacaine enhances the quality and duration of postoperative analgesia, children and adults should be able to take advantage of these benefits. Preservative-free clonidine for epidural use (Duraclon) was FDA approved in October 1996 and is marketed through Roxane Laboratories (800-962-8364 for more information). [3] Data about the ways that children and adults differ and are similar in their responses to clonidine are central to maximizing the risk-benefit ratio in infants and children. It is hoped that the addition of the above papers to the available knowledge about epidural clonidine will take us another step toward approval for pediatric use.
Table. Some Recent Publications On Epidural Clonidine In Pediatric Patients.
| Author |
Procedure |
Dose |
Concomitant
Medication |
Hr. Analgesia: Control/ clonidine |
| Ivani [1] |
Ureteral reimplantation |
2/mg/kg* |
0.25% bupivacaine, 2mg/kg |
|
| Dupevrat [2] |
Urologic |
1 µg/kg |
0.25% bupivacaine, 2mg/kg |
|
| Lee [4] |
Orthopedic surgery |
2 µg/kg |
0.25% bupivacaine, 2mg/kg |
5.2/9.8 |
| Jamali [5] |
Hernias, urologic |
1 µg/kg |
0.25% bupivacaine, 2mg/kg |
7.8/16.5 |
| Cook [6] |
orchidopexy |
2 µg/kg |
0.25% bupivacaine, 2mg/kg |
3.2/5.8 |
*Presumably 2 mg/kg.g/kg.
References
1. Plasma levels of clonidine following epidural bolus injection in children. Ivani G; Bergendahl HT; Lampugnani E; Eksborg S; Jasonni V; Palm C; Mattioli G; Podesta E; Famularo A; Lonnqvist PA. Acta Anaesthesiol Scand. 1998 Mar;42(3):306-11.
2. Transcutaneous CO2 tension effects of clonidine in paediatric caudal analgesia. Dupeyrat A; Goujard E; Muret J; Ecoffey C. Paediatr Anaesth. 1998;8(2):145-8.
3. Duraclon (clonidine) package insert.
4. Comparison of a bupivacaine-clonidine mixture with plain bupivacaine for caudal analgesia in children [see comments]. Lee JJ; Rubin AP. Br J Anaesth. 1994 Mar;72(3):258-262.
5. Clonidine in pediatric caudal anesthesia. Jamali S; Monin S; Begon C; Dubousset AM; Ecoffey C. Anesth Analg. 1994 Apr;78(4):663-666.
6. Comparison of the effects of adrenaline, clonidine and ketamine on the duration of caudal analgesia produced by bupivacaine in children. Cook B; Grubb DJ; Aldridge LA; Doyle E. Br J Anaesth. 1995 Dec;75(6):698-701.
Return to the Current Literature Review Front Page, or read the abstract:
ABSTRACT
1. Plasma levels of clonidine following epidural bolus injection in children. Ivani G; Bergendahl HT; Lampugnani E; Eksborg S; Jasonni V; Palm C; Mattioli G; Podesta E; Famularo A; Lonnqvist PA. Acta Anaesthesiol Scand. 1998 Mar;42(3):306-11.
BACKGROUND: The use of clonidine as an adjunct to epidural administration of local anesthetics in children has been reported to substantially improve the duration and quality of postoperative analgesia. The aims of the present study were to determine the pharmacokinetic profile and to investigate the interaction between postoperative sedation and analgesia after epidurally administered clonidine in children.
METHODS: Plasma levels of clonidine (0-10 h postop) and assessment of postoperative analgesia and sedation (0-24 h postop) were performed at predetermined intervals following lumbar epidural administration of bupivacaine 2.0 mg/kg and clonidine 2 mg/kg in 8 children undergoing ureteral re-implantation surgery using general anesthesia (age range: 1-9 yr, weight range: 9-41 kg). Plasma levels of clonidine were analyzed by radioimmunoassay, and sedation and analgesia were assessed by previously described scoring systems.
RESULTS: The venous plasma pharmacokinetics of clonidine following epidural administration showed a considerable interindividual variation. Cmax and Tmax values of clonidine were found to be within the 0.45-0.77 ng/mL and 48-193 min range, respectively. The time to absorb 95% of the clonidine dose from the epidural space into plasma varied between 36 min and 7.6 h. In 6 of the 8 patients postoperative analgesia substantially outlasted the duration of sedation (> or = 2 h). Sedation could not be detected in any patients at plasma concentrations below 0.3 ng/mL.
CONCLUSIONS: The pharmacokinetic profile associated with epidural clonidine administration in children (1-9 y) was similar to that previously reported in adults. The postoperative analgesia seen after administration of epidural bupivacaine-clonidine during general anesthesia in children cannot only be explained by residual postoperative sedation.
2. Transcutaneous CO2 tension effects of clonidine in paediatric caudal analgesia. Dupeyrat A; Goujard E; Muret J; Ecoffey C. Paediatr Anaesth. 1998;8(2):145-8.
In adults, clonidine when added to bupivacaine, results in no detectable respiratory depressant effect except when carbon dioxide challenge is performed. However, to date no investigations have quantified this in children. Twenty-four children (nine months to seven years) were randomized in a double-blind study into two groups. After induction, a caudal block was performed with 1 ml.kg-1 0.25% bupivacaine. Clonidine 1 microgram.kg-1 was added in the clonidine group, and 1 ml normal saline in the placebo group. Patients were monitored in the recovery room for three h from arrival to discharge with continuous pulse oximetry, respiratory rate, a transcutaneous CO2 tension (tcPCO2) every 15 min, and a four point sedation score every 30 min. Mean tcPCO2 and respiratory rate values were not different between the two groups. Apnoea and desaturation less than 97% were not observed. The sedation score decreased with time in both groups, and the score time interval was significantly higher in the clonidine group (P < 0.05). All the patients left the recovery room with a sedation score of 1, excepting four in the clonidine group with a sedation score of 2. Clonidine 1 microgram.kg-1 with 0.25% bupivacaine mixture in caudal analgesia in children did not induce an increase in tcPCO2 despite prolonged sedation
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