Clonidine in paediatric anaesthesia: : Pharmacokinetic and pharmacodynamic aspects

Sammanfattning: Clonidine is a mixed alpha-2/alpha-1 adrenoceptor agonist. It reduces sympathetic and increases parasympathetic tone which results in a lowering of the baseline blood pressure and heart rate. Descending posjunctional noradrenergic antinociceptive pathways originating in the brainstem are believed to contribute to pain control of both nociceptive and neuropathic origin after clonidine challenge. The sedative effect of clonidine is due to alpha-2 adrenoceptor stimulation in the locus coeruleus. In adults, oral clonidine provides preoperative sedation, increases perioperative haemodynamic stability, reduces the requirements of volatile anaesthetic requirements, and attenuates the stress response secondary to intubation. A pure analgesic effect is seen after both systemic and neuraxial administration. In paediatric anaesthesia similar beneficial effects have been observed. To provide safe and effective use of clonidine in children further studies delineating its specific pharmacokinetic and haemodynamic characteristics are needed, despite its recently increased clinical use. Randomised controlled trials comparing the clinical use of clonidine as a premedicant drug to the currently widely used premedicant gold standard represented by midazolam are warranted. The primary aims of this dissertation were to describe the pharmacokinetics after different routes of administrations and delineate the intraoperative haemodynamic profile. The magnitude of the stress-response caused by endotracheal intubation with special emphasis on the Neuropeptide Y response was compared after premedication with low-dose clonidine and rnidazolam. The postoperative analgesic and sedative effects of clonidine after epidural co-administration together with bupivacaine has also been evaluated. The influence of epidural co-infusion of clonidine and ropivacaine on postoperative blood pressure variability was furthermore investigated. Effects on postoperative analgesia, sedation, delirium shivering and postoperative vomiting after premedication with clonidine and midazolam were compared. Clonidine analysis was made by radioimmunoassay. NPY was analysed with a competitive radioimmunoassay. Postoperative analgesia was assessed by Objective Pain Scale and sedation was assessed by the Vancouver Sedative Recovery Scale. A new statistical procedure for calculations of bioavailability from two independent populations was introduced. Parental preferences were assessed using a written questionnaire. In total 238 children, age 1-10 years, were included in seven different studies. The haemodynamic response after clonidine administration was moderate and should be well tolerated in otherwise healthy children. Epidural clonidine improves blood pressure stability by reducing blood pressure variability. The pharmacokinetic profile after intravenous, rectal, and epidural administration were similar to that reported in adults. We therefore conclude that there are no pharmacokinetic or haemodynamic aspects contraindicating further use of clonidine in paediatric anaesthesia. The stress response after endotracheal intubation is of only moderate magnitude, as indicated by the lack of NPY release, and is not attenuated by low dose of clonidine. Rectal administration of clonidine was associated with a significant reduction of pain scores in the early postoperative period following adeno-tonsillectomy when compared to rectal midazolam. The analgesic effect seen after epidural and rectal clonidine cannot be explained by residual sedation alone. The use of clonidine is also associated with slightly increased sedation ratings during the first 24 postoperative hours compared to midazolam. However, this observation is in agreement unequivocal parental preference of a calm and sedated child during the early post- operative time period. Based on our own results, as well as data published by other research groups, we conclude that clonidine represents a useful pharmacological alternative in paediatric anaesthesia.