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A combination of lidocaine and nitrous oxide in oxygen is more effective in preventing pain on propofol injection than either treatment alone

Niazi, A.*; Galvin, E.*; Elsaigh, I.*; Wahid, Z.*; Harmon, D.; Leonard, I.*

European Journal of Anaesthesiology: April 2005 - Volume 22 - Issue 4 - p 299–302
doi: 10.1017/S0265021505000505
Original Article
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SDC

Background and objective: Propofol is an intravenous (i.v.) anaesthetic agent that possesses many of the qualities of an ideal anaesthetic agent. The most significant side-effect associated with propofol is pain on injection. Despite optimal therapy, the incidence of pain on propofol injection remains a problem. This prospective, randomized, double blinded study evaluated the effect of three different treatment strategies in decreasing pain on propofol injection.

Methods: We studied 102 adult, ASA I-II patients, scheduled for elective surgical procedures. Combination of i.v. lidocaine and nitrous oxide (N2O) in oxygen (O2) inhalation pre-treatment was compared with either treatment alone in the prevention of pain on propofol injection. A standard propofol injection technique and scoring system, to measure the pain on injection was used.

Results: Demographic variables were similar between the groups. The incidence of no pain on propofol injection was similar in the lidocaine and N2O groups (63.6% vs. 57.5%) (95% confidence interval (CI): 0.17-0.29, P = 0.61). Combination therapy was associated with a greater incidence of no pain on injection (84% vs. 63.6%) (95% CI: 0.06-0.48, P = 0.04).

Conclusion: Combination of i.v. lidocaine and N2O in O2 inhalation pre-treatment is more effective than either treatment alone in decreasing pain on propofol injection.

*Beaumont Hospital, Department of Anaesthesia and Intensive Care Medicine, Dublin, Ireland

Cork University Hospital, Department of Anaesthesia and Intensive Care Medicine, Cork, Ireland

Correspondence to: Ahtsham Niazi, Toronto Western Hospital, 399 Bathurst Street, EC 2-046 Toronto, ON, M5T 2S8 Canada. E-mail: ahtshamniazi@hotmail.com; Tel: 1 416 3410439

Accepted for publication January 2004

Propofol is given intravenously (i.v.) for the induction and maintenance of anaesthesia, and possesses many characteristics of an ideal anaesthetic agent [1-3]. One of the most significant side-effects that limit the use of propofol is pain experienced on injection. The incidence of pain is reported to vary between 30% and 90% when veins on the dorsum of the hand are utilized for injection [4,5].

Several methods have been used in an attempt to decrease the incidence of pain [6-11]. Inhalation of nitrous oxide (N2O) in oxygen (O2) has been reported to decrease pain on injection with similar efficacy to the admixture of 20 mg lidocaine to propofol [12]. Lidocaine pre-treatment with a rubber tourniquet on the forearm has been proposed as the ideal method of decreasing pain on propofol injection [13]. Despite this treatment 40% of patients will still complain of pain [13]. Combination therapy has thus been suggested [14]. In this prospective, double-blinded, randomized study we compared the combination of i.v. lidocaine and N2O in O2 inhalation pre-treatment with either treatment alone in the prevention of pain on propofol injection.

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Methods

With institutional ethics approval, written informed consent was obtained from participating patients. A prospective, randomized double-blinded study was designed. An incidence of no pain on injection of propofol of 60% has been reported [13]. Based on α = 0.05 and α = 0.8, a minimum sample size of 34 patients/group was calculated to detect a 25% decrease in the incidence of no pain on propofol injection between the groups. Adult ASA I-II patients with no anticipated difficult airway (Mallampati Class I-II) aged between 18 and 55 yr of age, undergoing elective surgery were included. Exclusion criteria included: patients of ASA grades III-V, airway Mallampati Class III-IV, history of cardiac conduction defects, anti-dysrhythmic medications, allergies to local anaesthetics and propofol, abnormalities of lipid metabolism, epilepsy, pregnancy and analgesic drug use in the previous 24 h.

A member of the anaesthesia team took responsibility for anaesthesia and another to record pain on propofol injection. Patients were randomly allocated to one of three groups by a computer-conducted randomisation with the code sealed until arrival of the patient in the operating room. The investigator measuring pain scores was blinded to the drugs given as all drug syringes were labelled as ‘study drug’. The investigator was blinded to the gas mixture administered to the patient by applying a cardboard cover over the gas flowmetres. Premedication was not given. On arrival in the operating theatre, standard monitoring which included pulse oximetry, non-invasive blood pressure and electrocardiogram (ECG) was instituted. In all patients a 20-G i.v. cannula was inserted on the dorsum of the non-dominant hand and was flushed with 2 mL 0.9% normal saline. No drugs or continuous i.v. fluids were administered prior to propofol injection.

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Group assignment

  • A: i.v. lidocaine 0.5 mg kg−1, 50% O2 in air mixture.
  • B: 0.9% normal saline, 50% N2O in O2 mixture.
  • C: i.v. lidocaine 0.5 mg kg−1, 50% N2O in O2 mixture.

All patients inhaled the delivered gas mixture for 120 s prior to propofol injection. All patients had a rubber tourniquet applied to the forearm with the sited i.v. cannula. Patients in Groups A and C were given 0.5 mg kg−1 of lidocaine i.v. Patients in Group B were given 1-3 mL 0.9% normal saline i.v. Lidocaine or normal saline was administered at the same time as the gas mixture, 120 s prior to propofol injection.

In all groups 120 s after the injection the tourniquet was released and propofol 50 mg was injected i.v. at a rate of 10 mg s−1. The speed of injection was carefully controlled by hand. The injection was stopped at 5 s and the degree of pain experienced by the patient was scored by any verbal response and the observation of any behavioural signs, such as facial grimacing or arm withdrawal. At 10 s if there was no verbal or observed pain response, the patient was asked a standard question about comfort at the injection site (Table 1). Patients were designated as having pain or no pain on injection as above. Pain on injection was further delineated by a scoring system described by McCrirrick and Hunter [7]. Following recording of the intensity of pain on injection, induction of anaesthesia proceeded according to the attending anaesthetist. Anaesthesia was subsequently maintained with an inhalation technique using oxygen in air. Following emergence from anaesthesia, recovery room nurses assessed explicit recall by asking patients whether they remembered any pain on injection.

Table 1

Table 1

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Statistical analysis

As the physical characteristics of the three groups were not normally distributed, differences were assessed using the Kruskal-Wallis analysis of variance (ANOVA). The incidence of no pain on propofol injection was normally distributed and compared using repeated measures ANOVA and post hoc χ2-test as appropriate. P < 0.05 was considered significant. Data is presented as number (SD, range or percentage).

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Results

A total of 102 patients were recruited; three of whom were excluded due to difficulty with venous cannulation. The three groups were comparable with regard to patients' age, weight, ASA status and gender ratio (Table 2).

Table 2

Table 2

The incidence of no pain on injection of propofol was similar in Groups A and B. In Group A, 21 (63.6%) patients compared with 19 (57.5%) patients in Group B did not complain of pain on injection (95% confidence interval (CI): 0.17-0.29, P = 0.61). The incidence of no pain on injection of propofol was greater in the combination group, 28 (84%) compared to either Group A (95% CI: 0.007-0.41, P = 0.01) or Group B (95% CI: 0.06-0.48, P = 0.04). Distribution of pain scores in the study groups is shown in Table 3.

Table 3

Table 3

There was no difference in the incidence of recall of pain on injection in the treatment groups. In Groups A and B, eight of 33 (24%) patients had recall of pain on injection. In Group C, three of 33 (9%) patients had recall of pain on injection. One patient in Group A and three in Group B had recall of pain on injection in the recovery room but did not complain of pain on injection of propofol at assessment.

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Discussion

The results of this study have demonstrated that the combination of lidocaine 0.5 mg kg−1 i.v. and inhaled 50% N2O in O2 mixture was more effective in decreasing the incidence of pain on injection of propofol than either treatment alone.

Pain on injection of propofol remains a disadvantage with its use. When clinical importance and frequency are considered, propofol induced pain has been ranked seventh of 33 clinical outcomes [15]. Factors known to influence pain on propofol injection are site of i.v. cannula, speed of injection, temperature of propofol and pre-treatment with sedatives and opioids [6-11]. Our study was designed to control for all of these variables.

The mechanism of pain on propofol injection remains unclear, although a number of mechanisms have been proposed [10,16]. Pain may be immediate or may be delayed within 10-20 s of injection [17]. Local irritation can probably explain immediate pain effect whereas delayed pain may result from an indirect effect via the kinin cascade [16]. Lidocaine has been commonly used and may act by stabilizing the kinin cascade [16]. N2O due to its opioid nature and ability to stimulate inhibitory pathways [18,19] may prevent the local irritant effect of propofol. A quantitative systematic review by Picard and Tramer [13] has shown that i.v. lidocaine (0.5 mg kg−1) given with a rubber tourniquet on the forearm, 30-120 s prior to propofol injection reduced pain in approximately 60% of patients. Harmon and colleagues [12] showed that inhaling 50% N2O in O2 mixture for 2 min prior to injection of propofol was as effective as the admixture of lidocaine 20 mg to propofol in decreasing the incidence of pain. Inhalation of N2O in O2 mixture has also been shown to be effective in decreasing pain of propofol injection in children [20]. In our study, the use of lidocaine pre-treatment with a rubber tourniquet prevented pain in approximately 64% of patients. This was similar to that observed by Mangar and Holak [21]. Pre-treatment with N2O in O2 mixture prevented pain in 57.5% of patients [12].

We also found that the combination of N2O in O2 mixture and lidocaine pre-treatment prevented pain in 84% of patients. This was greater than either treatment when used on its own. The likely mechanism of the observed efficacy of the combination of lidocaine and N2O may be the prevention of the local irritant effect of propofol by the opioid effect of N2O and the stabilization of the kinin cascade by lidocaine [16,18]. Due to the presence of the tourniquet, lidocaine is allowed more time in close association to this mediator. Due to its established analgesia efficacy [22] addition of N2O to lidocaine further reduced pain in this study.

Four patients, one in Group A and three in Group B recalled pain in the recovery room but did not complain of pain on propofol injection. This may be due to the delayed pain these patients experienced due to possible stimulation of the kinin cascade [16]. Three patients in Group C recalled pain in the recovery room after complaining of mild to moderate pain on injection of propofol. We find this hard to explain and may be due to variability in the perception of pain by different patients. Neither lidocaine nor N2O in O2 produced amnesia, since the percentage of patients amnesic for pain in the recovery room was not different among the three groups studied. This finding is similar to previous studies [12,23].

Considering the incidence of pain with propofol after optimal treatment remains 40%, it was considered unethical to include a placebo group. A potential concern in the use of N2O during induction would be the unanticipated difficult airway and compromised pre-oxygenation, we excluded all patients from our study that had anticipated difficult airways, however, previous studies [12,24] have shown that the use of N2O during induction did not impair oxygenation.

In conclusion, we found that the combination of lidocaine 0.5 mg kg−1 i.v. and inhaled 50% N2O in O2 mixture was more effective in decreasing the incidence of pain on injection of propofol than either treatment alone.

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Keywords:

ANAESTHETICS; intravenous; propofol; lidocaine; NITROUS OXIDE; COMPLICATIONS; pain

© 2005 European Society of Anaesthesiology