1 Department of Paediatric Anaesthesia and Intensive Care, Astrid Lindgrens Children's Hospital, 2 Karolinska Pharmacy, Karolinska University Hospital and Childhood Cancer Research Unit and 3 Department of Woman and Child Health, Karolinska Institutet, Stockholm, Sweden
* Corresponding author. Department of Anaesthesia and Intensive Care, Astrid Lindgrens Childrens Hospital/Karolinska University Hospital, SE-171 76 Stockholm, Sweden. E-mail: yvonne.nyman{at}karolinska.se
Accepted for publication March 24, 2005.
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Abstract |
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Methods. Eighty-three children (age range 218 yr) were randomized to receive 3 mg kg1 of either Propofol-Lipuro® (propofol dissolved in a mixture of medium- and long-chain triglycerides [MCTLCT]; group pL, n=42) or Diprivan® (propofol dissolved in long-chain triglycerides [LCT]) with added lidocaine (0.3 mg kg1) (group pD, n=41). A specially trained nurse anaesthetist assessed the occurrence of injection pain using a four-graded pain scale.
Results. Significantly fewer patients had an entirely pain-free propofol injection in group pL (33.3%) than in group pD (61.0%) (P=0.016).
Conclusions. A new MCTLCT propofol formulation as a plain solution was associated with a higher incidence of injection pain than LCT propofol with added lidocaine when used for induction of anaesthesia in children.
Keywords: anaesthesia ; anaesthetics i.v., propofol ; anaesthetics local, lidocaine ; children ; pain, injection
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Introduction |
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Recently a new propofol formulation, using a different lipid solvent, has been registered. In this formulation propofol is dissolved in a lipid mixture of medium- and long-chain triglycerides (MCTLCT) that differs from other propofol emulsions where only long-chain triglycerides (LCT) are used. This new formulation has been shown to reduce injection pain in adults,1012 but paediatric data are limited.13
The aim of the current prospective randomized double-blind study was to compare the incidence of injection pain between this new propofol formulation and our current standard (LCT propofol+lidocaine) in a mixed paediatric outpatient population.
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Methods |
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Following the application of EMLA cream, all patients had an intravenous cannula (Optiva 0.9 mm, Johnson & Johnson, New Brunswick, NJ, USA) inserted on the dorsum of the hand. This procedure was performed in the day-care unit before arrival in the operating room. All patients were given intravenous midazolam 0.05 mg kg1 and rectal acetaminophen 40 mg kg1 as premedication before transfer to the operating room where standard monitoring was applied. Propofol was then injected according to the previous randomization. Coded propofol syringes were prepared by the hospital pharmacy in order to ensure blinding. Lidocaine (1 ml of a 10 mg ml1 solution) was added to each 10 ml of LCT propofol whereas MCTLCT propofol was used as a plain solution. However, all syringes were delivered filled to a total amount of 11 ml and no differences between syringes could be detected visually. The speed of the propofol injection was similar for both study drugs (approximately 0.4 ml s1) and patients were given a total dose of 3 mg kg1. All patients had a parent present during the induction process.
A specially trained nurse anaesthetist (KvH) assessed injection pain according to a four-point scale: 1=no pain (no reaction to injection), 2=slight pain (minor verbal/facial response or motor reaction to injection), 3=moderate pain (clear verbal/facial response or motor reaction to injection) and 4=severe pain (the patient both complained of pain and withdrew the arm). The assessment was made from the start of the injection to the point when the patient lost consciousness. Following the induction of anaesthesia the study was terminated, and the anaesthetic was continued as necessary in relation to the planned surgical intervention.
Before the patient was discharged from the outpatient clinic the injection site was inspected for signs of residual irritation, and the parents and patient were asked if there were any problems with pain from the injection site. All patients received a follow-up telephone call the day after surgery and were asked if there had been any problems from the injection site following discharge from the hospital.
A prospective randomized double-blind controlled study design was used. The randomization process was performed using a computer-generated random list (GraphPAD StateMate, version1.01) and was carried out by the hospital pharmacy. The primary endpoint of the study was the number of patients in each group without injection pain. Based on our initial clinical experience and the opportunity to detect a 25% difference in the primary endpoint between groups with an value <0.05 and a ß value of 80%, a sample size of 40 patients was generated for each group. The difference in primary outcome between the treatment groups and the distribution of gender in the treatment groups as well as in groups of patients with/without pain was evaluated by the Fisher exact test.
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Results |
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A significantly higher number of patients in group pD were pain free (pain score=0) during the injection compared with group pL (61.0% vs 33.3%) (P=0.016) (Fig. 1). No correlation between the occurrence of injection pain and patient characteristics (e.g. age, weight) could be identified. None of the patients reported any pain or discomfort from the injection site either at the control before discharge or at the telephone follow-up the day after surgery.
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As a result of this study, a further randomized double-blind pilot study was performed in 20 patients comparing the incidence of injection pain, in the same manner as described above, between MCTLCT propofol with lidocaine and LCT propofol with lidocaine. The results of this pilot study are given in the Appendix.
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Discussion |
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The incidence of pain on injection of propofol in children has been reported to range from 30% to 90%.9 1315 In order to improve this situation a number of different strategies, including addition of local anaesthetics and cooling of the propofol solution, have been attempted in paediatric patients, but the incidence still remains at 1030%.9 1416
In adult studies, the use of propofol dissolved in a new lipid emulsion (MCTLCT) has been found to result in significantly less injection pain compared with propofol solutions dissolved in LCT lipid emulsion.11 12 A recent paediatric study reported a reduced incidence of injection pain when using this new propofol drug formulation compared with plain propofol (10% vs 25%).13 Since the addition of 0.2 mg kg1 of lidocaine to propofol solutions has been shown to reduce the risk of injection pain in children,9 15 we decided that a more clinically relevant comparison would be to compare this new formulation with propofol with added lidocaine.
In contrast with the adult data,1012 the new propofol formulation was associated with fewer patients having a pain-free injection when compared with propofol with added lidocaine. However, this discrepancy can be explained by the fact that previous comparisons of MCTLCT propofol with LCT propofol have been performed in a context where either both were in a plain solution or both were mixed with lidocaine.
More recent adult data, which were published after the design of the present study, comparing MCTLCT propofol with propofol and lidocaine are in agreement with our present paediatric study.17 18 Thus the reduced incidence of injection pain associated with the new lipid emulsion appears to be less than that obtained with the addition of lidocaine. For further studies and also to assess whether addition of lidocaine does affect injection pain associated with the new propofol formulation in children we conducted a second pilot study, using the same study design (see Appendix). No firm conclusions can be drawn from a pilot study, but the addition of lidocaine does appear to be effective with the new propofol preparation and thus is advocated regardless of which propofol preparation is used.
Unfortunately, the randomization process resulted in a significant difference in gender distribution between the two study groups. However, when the primary outcome parameter was correlated with gender, no gender-associated effect could be identified. In addition, we believe that it is unlikely that boys and girls would have a significantly different pain reaction in response to propofol injection. However, this unusual outcome of gender distribution caused by the computer-generated randomization must be kept in mind when interpreting the results of the study.
In conclusion, the use of a new MCTLCT propofol formulation as a plain solution was associated with a higher incidence of injection pain compared with LCT propofol with added lidocaine when used for induction of anaesthesia in children.
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Appendix |
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Acknowledgments |
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References |
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