Cisatracurium pretreatment with tourniquet reduces propofol injection pain: A double-blind randomized controlled trial

Abstract

Objectives

To investigate the efficacy of pretreatment with cisatracurium for prevention of pain associated with propofol injection, and compare its efficacy with that of lidocaine.

Methods

Patients undergoing general anaesthesia were randomized to receive normal saline (control group), lidocaine (0.5 mg/kg), 0.03 mg/kg cisatracurium or 0.15 mg/kg cisatracurium. All drugs were administered into the largest dorsal vein of the hand with venous occlusion for 30 s, followed by propofol (0.5 mg/kg). Pain was evaluated using a four-point scale.

Results

The incidence and severity of pain was significantly lower in the lidocaine and 0.15 mg/kg cisatracurium groups than the control and 0.03 mg/kg cisatracurium groups (n = 50/group). There was no significant difference between the lidocaine and 0.15 mg/kg cisatracurium groups in the incidence and severity of pain.

Conclusions

0.15 mg/kg cisatracurium effectively decreases the incidence and severity of pain induced by propofol injection without any significant complications.

Keywords

Cisatracurium general anaesthesia propofol injection pain

Introduction

Propofol (2, 6-di-isopropylphenol) is widely used for sedation and general anaesthesia because of its rapid onset and short duration of action (allowing prompt emergence), and low incidence of postoperative nausea and vomiting.^1,2 Pain is a common adverse event associated with propofol injection, however, and is ranked seventh of the 33 low- morbidity clinical outcomes, as determined by expert anaesthetists (taking into account both clinical importance and frequency).³ Pharmacological and nonpharmacological interventions to reduce propofol injection pain have been attempted with varying success. These include co-injection with lidocaine,^4,5 injection of propofol into a large vein,⁶ and pretreatment with lidocaine,^7,8 ketamine,⁹ thiopental,¹⁰ ondansetron,¹¹ dexamethasone,¹² opioids,^13,14 paracetamol¹⁵ or dexmedetomidine¹⁶ (with or without tourniquet). Lidocaine pretreatment in conjunction with venous occlusion is recommended as the most effective method to reduce the incidence and severity of propofol injection pain when the site of injection is the back of the hand.^17,18 This procedure has a failure rate of 13–48%, however,^17,18 indicating the need for alternative methods or agents for reducing propofol-associated pain.

Intravenous regional anaesthesia (IVRA) is used in extremity surgery and produces analgesia via intravenous injection of local anaesthetic and application of a tourniquet. The addition of cisatracurium (a nondepolarizing neuromuscular blocking drug) to lidocaine has been shown to improve the quality of analgesia during IVRA.¹⁹ We therefore hypothesized that tourniquet-controlled pretreatment with cisatracurium could reduce propofol injection pain. To our knowledge, there are no studies that report the characteristics of propofol injection pain following cisatracurium pretreatment.

The aim of the present study was to investigate the efficacy of pretreatment with 0.03 mg/kg or 0.15 mg/kg cisatracurium in the prevention of propofol-associated pain, injected 30 s before propofol injection with venous occlusion at the forearm. The efficacy of cisatracurium was compared with that of lidocaine.

Patients and methods

Study population

This double-blind, prospective, randomized, controlled study recruited patients scheduled to undergo elective noncardiac surgery under general anaesthesia at Korea University Anam Hospital, between October 2010 and June 2012. Patients were required to be American Society of Anesthesiologists physical status I or II²⁰ and aged 18–65 years. Exclusion criteria were: study refusal; allergy to propofol or egg; Mallampati class III–IV;²¹ limited neck mobility; history of difficult intubation; history of cardiovascular, respiratory, neurological, neuromuscular or psychiatric disease.

The trial was registered with the Clinical Research Information Service, Republic of Korea (no. KCT0000451) and performed according to the Declaration of Helsinki. Ethical approval was provided by the Institutional Review Board of Korea University Medical Centre, Anam Hospital. All patients provided written informed consent.

Study design

Patients were randomly assigned to one of four groups, using a computer generated randomization table: control group, pretreatment with normal saline; lidocaine group, pretreatment with 0.5 mg/kg preservative-free lidocaine; cisatracurium 0.03 mg/kg group, pretreatment with 0.03 mg/kg cisatracurium; cisatracurium 0.15 mg/kg group, pretreatment with 0.15 mg/kg cisatracurium. A summary of the experimental procedure is given in Figure 1. All pretreatment drugs were stored at room temperature (20–23℃), diluted to identical volume with saline, and presented in identical 10 ml syringes. To ensure double blinding, an anaesthetist who was not involved in the study prepared all pretreatment drugs.

Figure 1.

Experimental protocol for a randomized, double-blind study investigating the efficacy of pretreatment with lidocaine or cisatracurium in the prevention of propofol injection-associated pain.

Treatment

Patients were taken into the operating room and electrocardiogram, pulse oximetry, noninvasive arterial pressure and bispectral index score monitoring were established. A 20-G cannula was inserted into the largest visible vein on the radial side of the non-dominant forearm, attached to a three-way tap, and flushed with Ringer’s lactate solution.

A venous tourniquet was applied just above the elbow and the pretreatment drug was administered in a double-blind manner. The tourniquet was released after 30 s, then 0.5 mg/kg propofol was delivered via the intravenous cannula. In order to evaluate pain and determine the possibility of muscle paralysis, patients were asked “does it hurt?” by the anaesthetist (J. N.) at 10 s after the initial propofol dose, and at 20 s intervals thereafter until unresponsive. Any spontaneous movement of the wrist, elbow or shoulder was noted. Pain scores were evaluated by an anaesthetist who was blinded to group assignment, and expressed using a four-point scale: 0, no pain; 1, mild pain (pain reported only in response to questioning and without behavioural signs); 2, moderate pain (pain reported in response to questioning and with behavioural signs, or pain reported without questioning); 3, severe pain (strong vocal or behavioural response). Each patient’s highest pain score was documented. Adverse effects (including airway obstruction and diplopia) were noted. Induction of anaesthesia was completed with the remaining 1.5 mg/kg propofol.

Tracheal intubation was facilitated with additional cisatracurium to a total dose of 0.15 mg/kg per patient. Anaesthesia was maintained with desflurane in 50% nitrous oxide–oxygen.

Adverse effects at the injection site (pain, oedema, weal, inflammation) were assessed by the study investigator for 24 h after surgery, using spontaneous reporting and patient interview.

Statistical analyses

A pilot study of 20 patients indicated a required sample size of 44 patients per group with a two-sided α-error of 0.05 and power >80%. To compensate for potential dropouts, 200 participants (50 per group) were considered necessary.

Continuous variables were expressed as mean ± SD or median (range). Categorical variables were described as n (%). Demographic data were analysed with one-way analysis of variance and Scheffé’s post hoc test, or χ²-test. Between-group variation in the incidence of pain was analysed using χ²-test. Differences in mean pain intensity score were analysed using linear trend analysis with χ²-test. Statistical significance was defined as P < 0.05. Statistical analyses were performed with SPSS® version 12.0 (SPSS Inc., Chicago, IL, USA) for Windows®.

Results

A total of 216 subjects were referred from the anaesthetist for initial screening. Of these, seven refused to participate in the study and nine were excluded (Mallampati class III–IV, n = 3; limited neck mobility n = 1; cardiovascular disease, n = 2; respiratory disease, n = 3). The study therefore included 200 patients (n = 50/group). A flow chart indicating patient flow through the study is shown in Figure 2. Demographic and clinical characteristics of the patients are presented in Table 1. There were no significant between-group differences in age, sex, ASA status or weight.

Figure 2.

Flow of participants through a randomized, double-blind study investigating the efficacy of pretreatment with lidocaine or cisatracurium in the prevention of propofol injection-associated pain.

Table 1.

Demographic and clinical characteristics of patients undergoing general anaesthesia, included in a study investigating the efficacy of pretreatment with lidocaine or cisatracurium in the prevention of propofol injection-associated pain.

Characteristic	Control group n = 50	Lidocaine group n = 50	Cisatracurium 0.03 mg/kg group n = 50	Cisatracurium 0.15 mg/kg group n = 50
Age, years	43.3 ± 10.9	43.9 ± 13.1	45.5 ± 10.1	46.9 ± 11.4
Male/female	26/24	24/26	25/25	24/26
ASA grade, I/II	34/16	35/15	35/15	31/19
Weight, kg	64.4 ± 10.4	64.0 ± 11.9	67.5 ± 11.6	66.0 ± 13.4

Data presented as mean ± SD or n.

No statistically significant between-group differences (P ≥ 0.05; one-way analysis of variance and Scheffé’s post hoc test or χ²-test).

Data regarding pain scores are shown in Table 2. The incidence of pain was significantly lower in the lidocaine and 0.15 mg/kg cisatracurium groups than the control and 0.03 mg/kg cisatracurium groups (P < 0.05 for each comparison). There were no significant differences in the incidence of pain between the control and 0.03 mg/kg cisatracurium groups, or between the lidocaine and 0.15 mg/kg cisatracurium groups (Table 2). Significantly fewer patients reported moderate or severe pain in the lidocaine and 0.15 mg/kg cisatracurium groups than in the control and 0.03 mg/kg cisatracurium groups (P < 0.05 for each comparison). The incidence of severe pain was significantly lower in the 0.03 mg/kg cisatracurium group than the control group (P < 0.05). There were no significant between-group differences in the incidence of mild pain.

Table 2.

Propofol injection-associated pain in patients undergoing general anaesthesia, stratified by pretreatment medication.

Pain score	Control group n = 50	Lidocaine group n = 50	Cisatracurium 0.03 mg/kg group n = 50	Cisatracurium 0.15 mg/kg group n = 50
Median score	2 (0–3)	1 (0–3)	1 (0–3)	0 (0–3)
Any pain	42 (84.0)	26 (52.0)^a,b	37 (74.0)	23 (46.0)^a,b
Pain grade
0, none	8 (16.0)	24 (48.0)^a,b	13 (26.0)	27 (54.0)^a,b
1, mild	10 (20.0)	17 (34.0)	18 (36.0)	13 (26.0)
2, moderate	18 (36.0)	8 (16.0)^a,b	14 (28.0)	7 (14.0)^a,b
3, severe	14 (28.0)	1 (2.0)^a,b	5 (10.0)^a	3 (6.0)^a,b

Data presented as median (range) or n (%).

P < 0.05 versus control group; ^bP < 0.05 versus cisatracurium 0.03 mg/kg group; χ²-test or χ²-test for trend.

No patient experienced airway obstruction, diplopia, erythema, itching, bradycardia or arrhythmia. No complications (pain, oedema, weal or inflammation) were observed at the injection site within the first 24 h after surgery.

Discussion

Data from the present study indicate that pretreatment with 0.15 mg/kg cisatracurium was as effective as 0.5 mg/kg lidocaine in attenuating pain during intravenous injection of propofol. Pretreatment with 0.03 mg/kg cisatracurium decreased the intensity but not the frequency of pain. These findings indicate that cisatracurium has a primary analgesic effect.

The aetiology of propofol-associated pain is not fully understood, but the pain can be immediate or delayed by 10–20 s. Propofol is a phenol compound that can directly stimulate pain receptors in the skin, mucous membrane and venous intima, causing immediate pain.¹¹ In addition, propofol may activate the kallikrein–kinin system and release kinins, including bradykinin,²² which cause delayed pain via venous dilatation and hyperpermeability.²³

Lidocaine alleviates propofol injection pain via changes in pH²⁴ or the reversible blockade of peripheral nerve pathways.²⁵ Pretreatment with either 0.15 mg/kg cisatracurium or 0.5 mg/kg lidocaine was equally effective in attenuating pain in the present study. The pH of lidocaine is 6.5 (5.0–7.0), while the pH of cisatracurium is adjusted to 3.25–3.65. Therefore, the mechanism by which cisatracurium reduced propofol injection pain does not seem to be via changes in pH. Cisatracurium is a nondepolarizing skeletal muscle relaxant, and it is known that neuromuscular blocking agents affect sensory nerve endings, nerve trunks and muscle spindles.^26,27 The addition of a small dose of neuromuscular blocking agent to the local anaesthetic during IVRA has been shown to decrease the pain experienced by the patient, both during and after the procedure.^19,27–29 Cisatracurium may therefore reduce propofol injection pain via blockade of peripheral nerve endings by direct diffusion of the local anaesthetic from the vessels into the nearby nerves, followed by blockade of nerve trunks at a proximal site.³⁰

The findings of the present study indicate a possible pharmacological method to prevent pain from propofol injection, and show that cisatracurium is an acceptable alternative to lidocaine, opioids, ketamine, NSAIDs or other drugs used for this purpose. A major advantage of cisatracurium over other drugs is that cisatracurium is required for muscle relaxation in general anaesthesia, thus avoiding side-effects from additional drugs used for reducing propofol-associated pain. Importantly, no signs of muscular weakness or evidence of respiratory difficulty were noted by the observer or reported by the patients in the present study. Cisatracurium-associated muscle weakness was not a concern in the design of the present study, since the onset of cisatracurium is 3–5 min after administration and propofol was injected within 30 s following tourniquet release.

The present study was limited by the use of a narrow dose range of cisatracurium. We used only the recommended intubation or maintenance dose, and further studies are therefore required to establish the optimal dose of cisatracurium for prevention of propofol injection pain.

In conclusion, 0.15 mg/kg cisatracurium retained in tourniquet-occluded veins effectively decreases the incidence and severity of pain induced by propofol injection without any significant complications in general anaesthesia.

Footnotes

Declaration of conflicting interest

The authors declare that there are no conflicts of interest.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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