Clonidine vs. midazolam as premedication in children undergoing adeno-tonsillectomy: a prospective, randomized, controlled clinical trial.

BACKGROUND: Clonidine administration in the setting of paediatric anaesthesia is associated with a number of desirable effects, e.g. preoperative sedation, analgesia and reduced anaesthetic requirements. The aim of the current study was to compare postoperative outcome variables using a prospective, randomized, double-blind design after premedication with clonidine or midazolam. METHODS: One hundred paediatric ASA physical status 1 patients (age 1-11 year) scheduled for adeno-tonsillectomy were assigned to receive rectal premedication with midazolam (300 microg kg(-1) and atropine 40 microg kg(-1); group M, n = 52) or clonidine (5 microg kg(-1 and) atropine 40 microg kg(-1); group C, n = 48) prior to a standardized sevoflurane anaesthetic. The incidence of immediate postoperative pain (0-2 h), as assessed by repeated Objective Pain Scale (OPS) scores, was chosen as the primary end-point of the study. Degree of sedation (modified Vancouver sedation scale 0-3), occurrence of postoperative vomiting (POV), and incidence of shivering and immediate postoperative confusion were registered as secondary end-points. After hospital discharge parents were instructed to continue the evaluation of pain, sedation, POV and sleep pattern during a 24-h period. Parents were also asked for their preference concerning the postoperative behaviour of their child (calm, sedated vs. alert, active). RESULTS: In the early postoperative period patients in the clonidine group had a significantly lower sum of 5 OPS scores (median = 8.0) compared to group M (median = 11.5) (P = 0.011). Administration of clonidine was also associated with a slightly higher sum of sedation scores (median = 13) in the early postoperative period compared to children receiving midazolam (median = 12) (P < 0.001). No episode of shivering was observed in the clonidine group but was present in five of the patients in the midazolam group (P = 0.057). In younger children (< 5 years) the incidence of postoperative confusion was lower in the clonidine group (P = 0.001). No difference in the frequencies of POV incidences, degree of postoperative pain, need for analgesics, or sleep pattern during the first 24 postoperative hours could be observed between the groups according to the parental evaluation. Children premedicated with clonidine were more calm and sedated compared to children in the midazolam group (P = 0.024) as judged by their parents. A significant majority of parents (75%; P < 0.001) preferred a calm and sedated child during the first postoperative 24-h period. CONCLUSION: Rectal premedication with clonidine was associated with a significant reduction of pain in the early postoperative period compared to midazolam and was also associated with moderately increased sedation during the first 24 postoperative hours. The sedative effect of clonidine is in agreement with the unambiguous finding of a parental preference for a calm and sedated child during the first 24 postoperative hours.

Neuropeptide Y response to tracheal intubation in anaesthetized children: effects of clonidine vs midazolam as premedication.

We have determined if tracheal intubation causes an increase in neuropeptide Y (NPY), a marker of major adrenergic activation, and investigated if rectal premedication with clonidine 2.5 micrograms kg-1 might be capable of attenuating the stress response to tracheal intubation compared with midazolam 300 micrograms kg-1, in 20 paediatric patients (1-9 yr). Prospective randomization was performed in a double-blind manner. After induction of anaesthesia with 1% isoflurane, tracheal intubation was performed, and norepinephrine, NPY concentrations and haemodynamic variables were recorded. Tracheal intubation did not increase NPY plasma concentrations, despite transient increases in norepinephrine concentrations, heart rate and arterial pressure. There was no significant difference between the two groups. We conclude that the adrenergic stress reaction in response to tracheal intubation in children was short-lived and of limited magnitude, as indicated by the lack of NPY release.

Plasma levels of clonidine following epidural bolus injection in children.

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.

Low-dose intravenous clonidine in children: plasma concentrations and haemodynamic response.

The beneficial perioperative effects of the alpha-2 agonist clonidine have recently been verified in paediatric patients, and the pharmacokinetics have been found to be similar to what has been reported in adults. In a previous study we found that 2.5 micrograms/kg of clonidine causes a significant reduction in blood pressure. The aim of the present study was to evaluate if even lower doses of clonidine are associated with dose dependent or plasma-dependent haemodynamic changes. In a prospective, single, blind, controlled clinical trial, 24 paediatric patients (age range: 13-78 months) were randomised into three groups: control, intravenous clonidine 0.625 microgram/kg and intravenous clonidine 1.25 micrograms/kg respectively. Non-invasive blood pressure and heart rate were recorded at 3-min intervals for 30 min. Plasma concentrations of clonidine were analysed at 15 and 30 min post-injection. A decrease in MABP compared to baseline values was observed in all groups. A significantly greater reduction in blood pressure was seen in all groups receiving clonidine compared to control. In conclusion, low doses of clonidine (0.625 and 1.25 micrograms/kg) were found capable of causing a blood pressure reduction compared to control. We could not establish a plasma concentration dependent blood pressure effect. The observed blood pressure reductions caused by clonidine were of moderate magnitude. No effect on heart rate was observed, a finding which most likely is explained by the inclusion of atropine in the premedication.

Pharmacokinetics of clonidine after rectal administration in children.

BACKGROUND: alpha 2 Agonists have been shown to produce desirable effects when used as premedication or as an adjunct to general anesthesia in adult patients. Several of these beneficial effects (e.g., reduced anesthetic requirements and analgesia without respiratory depression) would be of great benefit in pediatric anesthesia. Information regarding the use of alpha 2 agonists in children is largely lacking. The aim of this study was to investigate the pharmacokinetics of clonidine after rectal administration in children. METHODS: Ten ASA physical status 1 pediatric patients (age 14-48 months, weight 10-20 kg) received 2.5 micrograms.kg-1 of clonidine by the rectal route. Blood samples were taken during a 24-h period after the administration. Plasma levels of clonidine were analyzed by radioimmunoassay and subjected to a computer-aided curve-fitting program (PC Nonlin). To estimate the bioavailability of clonidine the results from the current study were compared with data from a previous study in which the same dose of clonidine was given to a similar patient population by the intravenous route. RESULTS: Maximum plasma concentration was 0.77 ng.ml-1 (0.62-0.88), time to maximum plasma concentration 51 min (29-70), terminal half-life 12.5 h (8.7-19.5), and bioavailability 95% (73-119) (medians [95% confidence interval]). Plasma concentrations within the adult clinically effective range (0.2-2.0 ng.ml-1) were obtained within 10 min of administration. CONCLUSIONS: Rectal administration of 2.5 micrograms.kg-1 of clonidine in children, approximately 20 min before induction of anesthesia, achieves plasma concentrations within the range known to be clinically effective in adults.