Intravenous induction of anaesthesia in children : aspects on propofol and etomidate

University dissertation from Stockholm : Karolinska Institutet, Dept of Physiology and Pharmacology

Abstract: Propofol is today the most commonly used drug for induction of anaesthesia and for short-term sedation. However, one specific problem is that intravenous injection of propofol often results in quite severe injection pain, which in the paediatric population is a serious clinical dilemma. Different methods have been tried in order to reduce injection pain, adding the local anaesthetic lidocaine being the most common, but the incidence of injection pain still remains 20-40%. Thus, there is an urgent need to find new alternatives to propofol that adequately will reduce injection pain during intravenous induction of anaesthesia. Furthermore, there is on-going debate whether exposure to general anaesthesia in early life may be harmful since a large number of animal studies have shown various signs of neurotoxicity after anaesthesia exposure at an early age. New induction agents aimed for use also in neonates and infants must therefore be investigated with regards to potential neurotoxicity. In Study I the incidence and intensity of injection pain was compared between two different formulae of propofol; the former standard propofol solution (Diprivan®) with added lidocaine vs. a more novel plain formulation- Propofol-®Lipuro. Contrary to previous published adult results, the new formula was associated with a higher incidence of injection pain compared to Diprivan®+ lidocaine (66.7 % vs 39.0 %) (P = 0.016). In Study II we compared Diprivan®+ lidocaine with an alternative hypnotic induction agent-etomidate- that now is available as a lipid preparation (Etomidate-®Lipuro). At an interim analysis demanded by the Ethics Committee, data showed that the pain incidence in the etomidate-group was significantly reduced compared to the propofol group (5.0 % vs 47.5 %; p < 0.001), and the study was subsequently stopped. One of few side effects considering etomidate is a high incidence of myoclonic movements (MM) following induction of anaesthesia. In adults the incidence and intensity of MM is reduced if a small, non-sedative priming dose of etomidate is administered immediately before the main induction dose. The aim of Study III was to investigate if this therapeutic modification was valid also in children. However, no evidence for a reduced incidence of MM was found following the use of a small priming dose in children (incidence of MM: priming dose: 75.0 % vs. placebo: 72.5 %). A post hoc analysis did identify children in the age group 5-10 years to display a higher incidence of MM compared to other ages groups (P=0.0021). In study I-III the incidence and severity of injection pain as well as the incidence and severity of MM were measured using 4-point assessment scores, which is in line with previously published paediatric studies. In Study IV the effects on apoptosis and later behavioural alterations of varying doses of etomidate (0.3, 3, and 10 mg/kg) and two other commonly used anaesthetics (propofol 60 mg/kg and ketamine 50 mg/kg) were studied in infant mice (postnatal day 10). No evidence of enhanced apoptosis was found in any of the treatment groups when compared to placebo. In contrast to the other groups, ketamine exposed mice expressed altered motor behaviour when tested at an age corresponding to young human adults (P< 0.01). Enhanced apoptosis was measured by activated caspase-3 (ELISA) and behavioural alterations were assessed by measuring spontaneous activity in a new environment. Conclusions Etomidate-®Lipuro is associated with significantly less injection pain compared to traditional propofol (Diprivan®) with added lidocaine. Etomidate exposure in infant mice does not induce enhanced apoptosis or changes in long-term motor behaviour in an animal model.

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