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British Journal of Anaesthesia 95 (2): 222–5 (2005)

doi:10.1093/bja/aei156 Advance Access publication May 13, 2005

PAEDIATRIC ANAESTHESIA
Propofol injection pain in children: a prospective randomized
double-blind trial of a new propofol formulation versus propofol
with added lidocaine
Y. Nyman1*, K. von Hofsten1, A. Georgiadi2, S. Eksborg2 3 and P. A. Lönnqvist1
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@karolinska.se
Background. The incidence of pain on injection of propofol remains unacceptably high in
children, despite various strategies to reduce it. A new drug formulation of propofol has, in
adult studies, been reported to cause less injection pain compared with other propofol solutions.
The aim of the present prospective randomized double-blind clinical trial was to compare the
incidence of pain-free injection following the use of this new formulation with that following the
use of propofol with added lidocaine in children undergoing day case surgery.
Methods. Eighty-three children (age range 2–18 yr) were randomized to receive 3 mg kg 1 of
either Propofol-Lipuro (propofol dissolved in a mixture of medium- and long-chain triglycerides
[MCT–LCT]; group pL, n=42) or Diprivan (propofol dissolved in long-chain triglycerides [LCT])
with added lidocaine (0.3 mg kg 1) (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 MCT–LCT 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.
Br J Anaesth 2005; 95: 222–5
Keywords: anaesthesia; anaesthetics i.v., propofol; anaesthetics local, lidocaine; children;
pain, injection
Accepted for publication: March 24, 2005

Although propofol should not be used for long-term paedi- and also introduces the risks associated with drug mixing
atric intensive care sedation,1–4 it has become a popular (e.g. bacterial contamination, drug mixing errors).
choice for anaesthesia induction and short-term sedation Recently a new propofol formulation, using a different
for various procedures in children. However, despite using lipid solvent, has been registered. In this formulation
various strategies to reduce propofol injection pain, this propofol is dissolved in a lipid mixture of medium- and
still represents a clinical problem in both adults and children, long-chain triglycerides (MCT–LCT) that differs from other
with reported incidences of injection pain of 30–90%.5–7 propofol emulsions where only long-chain triglycerides
One of the most common practices adopted to reduce the (LCT) are used. This new formulation has been shown to
incidence of injection pain is to add lidocaine to the pro- reduce injection pain in adults,10–12 but paediatric data are
pofol solution.6–8 Although the addition of >0.2 mg kg 1 limited.13
of lidocaine is able to reduce the incidence of injection The aim of the current prospective randomized double-
pain by 70–80%,5 7 9 this practice involves extra work blind study was to compare the incidence of injection pain

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Propofol injection pain in children

between this new propofol formulation and our current using a computer-generated random list (GraphPAD
standard (LCT propofol+lidocaine) in a mixed paediatric StateMate, version1.01) and was carried out by the hospital
outpatient population. 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
Methods to detect a 25% difference in the primary endpoint between
Following ethical committee approval and parental informed groups with an a value <0.05 and a b value of 80%, a
consent, paediatric outpatients (age range 2–18 yr) were sample size of 40 patients was generated for each group.
prospectively randomized to receive either the new MCT– The difference in primary outcome between the treatment
LCT propofol formulation (Propofol-Lipuro 10 mg ml 1, groups and the distribution of gender in the treatment groups
B. Braun, Melsungen, Germany) or LCT propofol as well as in groups of patients with/without pain was evalu-
(Diprivan 10 mg ml 1, AstraZeneca, Södertälje, Sweden) ated by the Fisher exact test.
with added lidocaine (Xylocain , AstraZeneca, Södertälje,
Sweden) for induction of anaesthesia. Exclusion criteria
were ASA >3 or known contraindications to propofol or Results
lipid emulsions. A total of 83 patients were included in the study; 42 patients
Following the application of EMLA cream, all patients were assigned to the MCT–LCT propofol group (group pL)
had an intravenous cannula (Optiva 0.9 mm, Johnson & and 41 patients were assigned to the LCT propofol plus
Johnson, New Brunswick, NJ, USA) inserted on the dorsum lidocaine group (group pD). All patients completed the
of the hand. This procedure was performed in the day-care study. The median age was 10.2 (2.2–14.0) yr in group pL
unit before arrival in the operating room. All patients were and 9.0 (3.0–18.0) yr in group pD. The gender distribution
given intravenous midazolam 0.05 mg kg 1 and rectal acet- was 11 girls and 31 boys in group pL, and 22 girls and
aminophen 40 mg kg 1 as premedication before transfer 19 boys in group pD (P=0.013).
to the operating room where standard monitoring was A significantly higher number of patients in group pD
applied. Propofol was then injected according to the previ- were pain free (pain score=0) during the injection compared
ous randomization. Coded propofol syringes were prepared with group pL (61.0% vs 33.3%) (P=0.016) (Fig. 1). No
by the hospital pharmacy in order to ensure blinding. Lido- correlation between the occurrence of injection pain and
caine (1 ml of a 10 mg ml 1 solution) was added to each 10 patient characteristics (e.g. age, weight) could be identified.
ml of LCT propofol whereas MCT–LCT propofol was used None of the patients reported any pain or discomfort from
as a plain solution. However, all syringes were delivered the injection site either at the control before discharge or at
filled to a total amount of 11 ml and no differences between the telephone follow-up the day after surgery.
syringes could be detected visually. The speed of the propo- There were no differences in treatment outcome between
fol injection was similar for both study drugs (approximately females and males (P-values of 0.46 and 0.76 for groups pL
0.4 ml s–1) and patients were given a total dose of 3 mg kg 1. and pD, respectively; P=0.18 all patients taken together).
All patients had a parent present during the induction As a result of this study, a further randomized double-
process. blind pilot study was performed in 20 patients comparing the
A specially trained nurse anaesthetist (KvH) assessed incidence of injection pain, in the same manner as described
injection pain according to a four-point scale: 1=no pain
(no reaction to injection), 2=slight pain (minor verbal/facial
80
response or motor reaction to injection), 3=moderate pain P = 0.0157
(clear verbal/facial response or motor reaction to injection)
Fraction of pain-free patients (%)

and 4=severe pain (the patient both complained of pain and


60
withdrew the arm). The assessment was made from the start
of the injection to the point when the patient lost conscious-
ness. Following the induction of anaesthesia the study was
terminated, and the anaesthetic was continued as necessary 40
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 20
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 0
surgery and were asked if there had been any problems from MCT–LCT LCT propofol
the injection site following discharge from the hospital. propofol + lidocaine
A prospective randomized double-blind controlled study Fig 1 Children with pain-free injection of propofol (error bars indicate 95%
design was used. The randomization process was performed confidence interval).

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Nyman et al.

above, between MCT–LCT propofol with lidocaine and two study groups. However, when the primary outcome
LCT propofol with lidocaine. The results of this pilot parameter was correlated with gender, no gender-
study are given in the Appendix. associated effect could be identified. In addition, we believe
that it is unlikely that boys and girls would have a signifi-
cantly different pain reaction in response to propofol
Discussion injection. However, this unusual outcome of gender
The main finding of the present study was that the use of the distribution caused by the computer-generated randomiza-
new MCT–LCT propofol formulation as a plain solution was tion must be kept in mind when interpreting the results of
associated with a higher incidence of injection pain than the study.
experienced with LCT propofol with added lidocaine. In conclusion, the use of a new MCT–LCT propofol
Thus, the addition of lidocaine appears to be necessary in formulation as a plain solution was associated with a higher
order to minimize the risk for propofol injection pain in incidence of injection pain compared with LCT propofol
children regardless of the propofol solution used. with added lidocaine when used for induction of anaesthesia
The incidence of pain on injection of propofol in children in children.
has been reported to range from 30% to 90%.9 13–15 In order
to improve this situation a number of different strategies,
including addition of local anaesthetics and cooling of Appendix
the propofol solution, have been attempted in paediatric
To assess whether addition of lidocaine is useful with the
patients, but the incidence still remains at 10–30%.9 14–16
new MCT–LCT propofol preparation, we performed a
In adult studies, the use of propofol dissolved in a new
second prospective randomized double-blind pilot study.
lipid emulsion (MCT–LCT) has been found to result in
Twenty patients were randomly assigned to be induced
significantly less injection pain compared with propofol
with either MCT–LCT propofol with lidocaine (group pLl,
solutions dissolved in LCT lipid emulsion.11 12 A recent
n=10) or LCT propofol with lidocaine (group pDl, n=10)
paediatric study reported a reduced incidence of injection
using the same methodology as in the main study. Nine
pain when using this new propofol drug formulation
patients in group pLl and seven patients in group pDl had
compared with plain propofol (10% vs 25%).13 Since the
entirely pain-free injections.
addition of >0.2 mg kg 1 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 Acknowledgements
with propofol with added lidocaine. The authors would like to thank sincerely the staff at the Day Surgery Unit
for excellent cooperation and support throughout the study.
In contrast with the adult data,10–12 the new propofol
formulation was associated with fewer patients having a
pain-free injection when compared with propofol with added References
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