The Effect of a Eutectic Mixture of Local Anesthetic Cream on Wrist Pain during Transradial Coronary Procedures

There has been growing interest in transradial coronary procedures due to the rare incidence of complications at this puncture site, elimination of the need to limit the patient’s activity and the possibility of early patient discharge.^1,2 Furthermore, use of the radial artery as a vascular access route is expected to expand due to the miniaturization and improvement of the devices, improvement of the techniques and increasing experience by operators with transradial coronary procedures. However, unlike the femoral approach, patients who undergo transradial coronary procedures complain primarily of wrist pain at the puncture site. A eutectic mixture of local anesthetic (EMLA) cream, composed of lidocaine 2.5% and prilocaine 2.5%, is known to be an effective topical anesthetic agent. It is used for a variety of painful cutaneous procedures on intact skin, including phlebotomy, intravenous catheterization, arterial cannulation and lumbar puncture.^3–5 Despite the usefulness of EMLA cream, it is not widely used in standard clinical practice because the optimal preprocedure application time frame is unknown, and differing results are reported in terms of efficacy depending on the procedure for which it is used. We hypothesized that applying EMLA cream would effectively reduce wrist pain without adverse drug reactions during transradial coronary procedures and evaluated the optimal time range for preprocedure application of EMLA cream. Patients and Methods Patients. From October 2003 to March 2004, 400 consecutive patients scheduled for elective coronary angiography or percutaneous coronary intervention via the radial artery were included. Patients were excluded if they presented with a negative Allen’s test on both wrists, chronic renal failure requiring current dialysis, chronic renal failure that would require dialysis in the future and any known allergy to contrast medium or local anesthetics. Written, informed consent was obtained from the patient or family member(s) before the procedure. Methods. The study period was divided into two phases. The Phase I study was the initial trial of 147 patients from October to December 2003 to evaluate the efficacy and safety of EMLA cream during transradial coronary procedures. The Phase II study was designed to evaluate the optimal time range for EMLA cream application before the start of a procedure for adequate reduction of wrist pain in 400 cases from October 2003 to March 2004. The sequences of EMLA or placebo application, right or left hand application and the sequences of radial artery puncture were randomized by a simple randomization table. The subjects and the physician performing the radial artery cannulation were blinded as to which wrist was treated with placebo and which received the EMLA cream. The EMLA or placebo cream was applied on the wrist from 2 to 4 hours before the procedure in the Phase I study. In the Phase II study, patients were randomized to 5 time groups according to the preprocedure application time range. The experiment investigators provided blinded tubes containing either EMLA cream or placebo, which was an odorless white cream that resembled the EMLA cream. All EMLA and placebo creams were applied to both wrists 2 cm above the styloid process of the radius and then covered with a transparent 5-cm dressing (Figure 1). The amount of EMLA or placebo cream used was 2.5 g, the standard adult dose. The patient was not premedicated, and local anesthesia with 0.6 mL of lidocaine using a 24-gauge needle was performed at the time of the procedure. Radial artery puncture was tried using 20 G-catheter needle (Sindonbang Company, S. Korea), and a 5, 6 or 7 Fr arterial sheath (Terumo Company, Japan) was inserted depending on the type of procedure. Each patient was asked to identify the pain score that best described the pain he/she experienced on the cream application site immediately after radial cannulation. The pain was evaluated when it was felt at the time of the initial puncture and at arterial sheath insertion. The pain score was assessed by the visual analogue scale (VAS) and a 4-category verbal rating scale (VRS-4).⁶ On the VAS, the patients indicated their pain intensity by making a mark on a 10-cm long line that included descriptors labeled at each end of the line of pain intensity (e.g., from “no pain” to “pain as bad as it could be”). The patient was instructed to regard the VAS as a continuum and to make a mark at the point along the line corresponding to his/her current level of pain. The score was determined by measuring the distance from the left end of the line to the patient’s mark. Scoring of VRS-4 consists of a finite list of intensity descriptors: 1 point = “no pain”; 2 points = “a little pain”; 3 points = “painful, but tolerable”; 4 points = “most pain possible”. In the event the patient underwent a repeat coronary procedure (n = 42), we also asked about the patient’s perception of the change in his/her pain from the previous study by percentage change of pain perception. We evaluated the safety profiles, local reactions (erythema, contact dermatitis) and systemic reactions (central nervous system side effect of local anesthetics, urticaria, angioedema and bronchospasm), as noted on the EMLA label. The primary endpoint was the patient’s pain experienced during radial cannulation and sheath insertion as assessed by VAS and VRS-4. The secondary endpoint was the optimal time frame for EMLA cream application prior to the procedure for relief of pain without the occurrence of adverse drug reactions. Statistics. In this study, the minimum clinically significant difference in VAS scores used was 13 mm, as determined by Todd et al.⁶ Using the difference of 13 mm and a standard deviation of 27 mm, as determined by our preliminary data in this study, we calculated the sample size to be 70 subjects in each group to achieve a power of at least 80% at the 5% significance level for the primary endpoint.Continuous variables are expressed as mean and standard deviations. A two-tailed Student’s t-test and ANOVA (post hoc analysis: Scheffe) were used to determine the differences between clinically significant changes in pain among the groups. A Likert score analysis for VRS-4 scoring was performed and expressed mean and standard deviations. A p-value (SPSS, Inc., Chicago, Illinois). Results Four hundred consecutive patients were enrolled in this study. Five patients were excluded from the analysis because of incomplete study data. Phase I study of efficacy and safety of EMLA cream. The clinical characteristics of 147 cases in the control and EMLA groups are listed in Table 1. There were no differences in age, gender, procedure time or clinical diagnosis between the two groups. Wrist pain during lidocaine infiltration and sheath introduction was reduced significantly in the EMLA group compared to the placebo group as assessed by VAS (control: 49 ± 24, EMLA: 19 ± 22; p = 0.001) and VRS-4 (control: 2.3 ± 0.5, EMLA: 1.5 ± 0.6; p = 0.001). There was a significant negative correlation between VAS and the time frame of drug application (r = -0.476; p = 0.001). The application of EMLA cream markedly reduced wrist pain as expressed by the percentage of change compared to the previous procedure (control: 135 ± 45, EMLA: 60 ± 41%; p = 0.01) in cases of repeat transradial coronary procedures (n = 42) for follow-up angiography. Multivariate regression for age, sex, EMLA application and puncture site as independent variables and the VAS score as the dependent variable demonstrated that EMLA application (beta: -0.517; p Phase II study to determine the optimal duration of EMLA efficacy. The baseline clinical characteristics of 395 cases in the control and EMLA groups according to the preprocedure application time frame are listed in Table 2. There were no statistical differences in age, sex, procedure site or clinical diagnosis among the groups. There was a reduction in both VAS (control: 49 ± 29, EMLA 0–1 hour: 39 ± 27) and VRS-4 (control: 2.4 ± 0.6, EMLA 0–1 hour: 2.0 ± 0.6) at the time point of EMLA 0–1 hour compared to the control group, but this was not statistically significant. However, there was a significant difference in the pain score between the control and EMLA 1–2 hours groups as determined by VAS (control: 49 ± 29, EMLA 1–2 hours: 32 ± 24) and VRS-4 (control: 2.4 ± 0.5, EMLA 1–2 hours: 1.9 ± 0.6). There was a significant difference in the VAS between the EMLA 1–2 hours and EMLA > 4 hours groups (EMLA 1–2 hours: 32 ± 24, EMLA > 4 hours: 14 ± 18), but there was no statistical difference in the VRS-4 (EMLA 1–2 hours: 1.9 ± 0.6, EMLA > 4 hours: 1.5 ± 0.5). There were no major adverse drug reactions. Minor local erythema occurred in 12 cases (3.5%), and was particularly frequent in the EMLA 3–4 hours (6.6%) and EMLA > 4 hours (11.9%) groups. Discussion Radial artery cannulation for transradial coronary procedures is a painful procedure. The standard method of providing analgesia involves infiltration of the skin and subcutaneous tissue with lidocaine or prilocaine using a small-gauge needle.⁷ In our study, we demonstrated that the application of EMLA cream was effective in reducing wrist pain during transradial coronary procedures, and that the skin analgesic effect was time-dependent. The EMLA cream is an oil-water emulsion of lidocaine and prilocaine. Eutectic means that the crystalline bases are mixed to lower the melting point, thus making it possible to create an ideal preparation for skin penetration.⁸ Topical EMLA cream allows the anesthetics to hinder initiation and conduction of nerve impulses, thus it is widely used for a variety of painful cutaneous procedures.^3–5 Several studies have reported EMLA cream to be superior to lidocaine infiltration in providing analgesia for radial artery cannulation in pressure monitoring procedures.⁵ We also documented that EMLA cream is an effective topical anesthesia for reducing wrist pain in transradial coronary procedures and that the skin analgesic effect was time-dependent in reducing wrist pain in the initial phase of the procedure. The wrist pain-reducing effect was confirmed in cases of repeat angiographic follow up in the Phase II study (control: 135 ± 45, EMLA: 60 ± 41%; p = 0.01). These data suggest that pain was greater in patients who underwent repeat procedures because patient anxiety likely increases as they are reminded of the pain experienced in the previous procedure.⁹ In these cases, EMLA cream was effective in controlling the pain. Despite these findings, EMLA cream is not widely used in daily practice because the optimal preprocedure application time is undetermined. It is therefore essential to determine the optimal preprocedure application time frame for EMLA for the different types of procedures. Joly et al reported that EMLA cream was superior to lidocaine local infiltration in a study of 500 patients on whom the cream was applied 2 hours prior to cannulation.⁵ In that report, EMLA was applied at a fixed time (2 hours) before the procedure, thus the optimal preprocedure time frame for cream application was not determined. The early studies from the 1980s and manufacturers have suggested that applying EMLA cream 60 minutes prior to a procedure is necessary to provide sufficient analgesia.^3,4 Bjerring et al showed that a 60-minute preprocedure application time frame is insufficient to produce effective anesthesia because the depth of dermal anesthesia is approximately 5 mm after 90 minutes.¹⁰ Thus, a 2-hour preprocedure time frame was suggested to optimize anesthesia effectiveness. Russell et al randomized 60 patients to receive either EMLA cream or 2% lidocaine infiltration 60 or 90 minutes before radial artery cannulation for pressure monitoring. Most of the patients in the 90-minute EMLA group experienced no pain or mild pain, and the difference was statistically significant compared with the other two groups.¹¹ This study suggested that a 90-minute application time prior to radial cannulation is better than 60 minutes. However, these data were inconclusive due to the small number of patients in the study and the different procedure types that were performed. It is therefore difficult to extrapolate these data to transradial coronary procedures. In real practice, it is impossible to apply EMLA cream at a fixed time prior to a procedure for various reasons including time delays in prior procedures, ad hoc procedures or emergency procedures. Thus, it is necessary to determine an appropriate preprocedure time range for cream application that will sufficiently reduce wrist pain. In this study, we documented that 3 hours prior to a procedure was associated with an increase in erythematous complications at the application site. Therefore, this study shows that EMLA cream was able to reduce cannulation pain during transradial procedures, and that the analgesia continued to increase in a time-dependent fashion. The optimal balance of EMLA cream reduces wrist pain without complications when the application time is between 1 to 3 hours before the start of a procedure.

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