In this randomized, double-blinded, placebo-controlled study, we evaluated the safety and efficacy of lidocaine iontophoresis for the prevention of pain associated with venipuncture in 59 children aged 6–17 yr. Children received either lidocaine HCl 2% with epinephrine 1:100,000 (Active) or the same formulation without lidocaine (Placebo) via a 20 mA/min iontophoretic treatment. Pain during venipuncture was assessed by the subject, parent, and nurse using a 100-mm visual analog scale. Median (interquartile range) visual analog scale scores were significantly lower in the Active versus Placebo groups: subject, 7.0 (2.0–20.8) versus 31.0 (12.0–48.0), P < 0.001; nurse, 5.0 (2.2–10.8) versus 24.0 (9.0–47.0), P < 0.001; and parent, 3.0 (0.8–7.2) versus 20.0 (4.5–43.0), P < 0.002, respectively. Similarly, higher median satisfaction scores were given to the Active versus Placebo group by the three evaluators. Of the 59 subjects completing the study, 10 subjects experienced a total of 12 adverse events that were all graded as mild. In conclusion, lidocaine iontophoresis is safe in children, reduces discomfort associated with venipuncture, and increases satisfaction when compared with the placebo.
Department of Anesthesiology and Critical Care Medicine, Children’s Hospital of Philadelphia, University of Pennsylvania, School of Medicine, Philadelphia
Supported, in part, by a grant from Empi Inc, St Paul, MN.
November 21, 2001.
Address correspondence and reprint requests to John B. Rose, MD, Department of Anesthesiology and Critical Care Medicine, Children’s Hospital of Philadelphia, 34th St. and Civic Center Blvd., Philadelphia, PA 19104. Address e-mail to firstname.lastname@example.org.
An effective method for reducing pain during venipuncture in pediatric patients can alleviate the distress caused by this procedure and is therefore desirable. Rapid dermal anesthesia can be achieved by local anesthetic infiltration, but it may evoke anxiety in children frightened by needles or distort the skin, making vascular access more difficult and increasing the risk of needle exposure to health care workers. Dermal anesthesia can also be achieved without needles by the topical application of local anesthetics (e.g., EMLA®, ASTRA Pharmaceutical, Sodertalje, Sweden) or by lidocaine iontophoresis (1–3). EMLA requires an application time of 60–90 min to provide dermal anesthesia (4). By contrast, noninvasive dermal anesthesia can be established in 5–15 min without distorting underlying tissues by lidocaine iontophoresis, where a direct electrical current facilitates dermal penetration of positively charged lidocaine molecules when placed under the positive electrode. The amount of drug delivered via iontophoresis is dependent on the current and the duration of delivery. The iontophoretic dose is computed by multiplying the duration of delivery with the current used to deliver the drug. It is expressed as mA/min.
Limited information is available concerning safety, effectiveness, and satisfaction with iontophoresis in children. We performed this investigation to determine if the administration of lidocaine HCl 2% with 1:100,000 epinephrine via iontophoresis for 20 mA/min is safe and effective in reducing pain associated with venipuncture in 6- to 17-yr-old children. A secondary objective was to determine overall satisfaction with iontophoresis for venipuncture.
The protocol was approved by our institutional review board. Written informed parental consent and subject assent were obtained for all study participants. Children coming to the Children’s Hospital of Philadelphia on a nonemergency basis who required blood sampling and analysis were eligible for enrollment if they were between 6 and 17 yr old. Children were not eligible to participate in this trial if: (a) they had pain from any source, (b) they had taken prescription analgesics within the last 3 days, (c) they were currently taking monoamine oxidase inhibitors, tricyclic antidepressants, phenothiazines, butyrophenones, or vasopressor drugs, (d) they had broken, abraded, inflamed, or infected skin at the treatment site, (e) they were pregnant or nursing, (f) they had known sensitivities or allergies to epinephrine, lidocaine, or sulfites, (g) they had metallic implants at or near the treatment site, (h) they had a known adverse reaction to the application of electrical current, (i) they had cardiac pacemakers or other implanted electronic devices, or (j) they had any significant health problem.
Demographic data including age, race, and sex were recorded for all subjects, a medical history (including medications) was obtained, and weight and baseline heart rate, respiratory rate, systolic blood pressure, and diastolic blood pressure were measured and recorded. Children were then randomly placed in a 2:1 ratio to Active or Placebo groups to receive either lidocaine HCl 2% with epinephrine 1:100,000 (Active) or the same preparation without lidocaine (Placebo). The patient and all evaluators were blinded to the study group assignment. Both the active and placebo solutions were supplied in cartridges manufactured by Novocol Pharmaceutical of Canada Inc (Cambridge, Ontario, Canada). The iontophoretic treatments were delivered with the Dupel® Iontophoresis System (Empi Co, St Paul, MN). The use of this device in pediatric patients is investigational.
The right or left antecubital fossa was used as the positively charged delivery electrode site depending on which arm had the best vein, which was determined by the phlebotomist. The electrode sites were washed with a soft cloth and water. The delivery electrode reservoir was saturated with 2 mL of the study medication by a research assistant and centered over the venipuncture site. The negatively charged grounding electrode was moistened with tap water and placed over the belly of the triceps muscle at least 4 in. from the delivery electrode. The initial current was set at 1.0 mA and increased by the research nurse gradually to a maximum of 4.0 mA, as tolerated by the subject. The iontophoretic treatment was discontinued after a dose of 20 mA/min was delivered. Upon completing the iontophoretic treatment, vital sign measurements were repeated, and the skin at both electrode sites was graded for blanching (yes or no) and erythema (0 = none, 1 = barely perceptible, 2 = mild, 3 = moderate, and 4 = marked) by the research nurse. Within 10 min of completing the iontophoresis, venipuncture was performed by the phlebotomist. Immediately after venipuncture, pain assessments were performed by the patient, parent, and research nurse using a 100-mm visual analog scale (VAS). These three evaluators also rated their overall satisfaction using an 11 point scale (0 = not at all satisfied and 10 = completely satisfied). Follow-up was obtained by telephone 48–72 h after venipuncture. All adverse events were recorded and graded as mild, moderate, or severe (5).
The primary end point of this investigation was the VAS pain score. We calculated that a sample size of 20 Active and 10 Placebo subjects was sufficient to detect an effect size of 1.0 (mean difference/common standard deviation) for pain scores between groups at a significance level of 0.05 (two sided) with 80% power. We asked to enroll 60 children because of the potential for children to withdraw from the study after enrollment for a variety of reasons, and also because of the potential to lose children at the follow-up telephone contact. Data were entered into a Microsoft Excel worksheet and transferred into SPSS for statistical analysis. Data were analyzed on an intention-to-treat basis and subjected to the Student’s t-test, Mann-Whitney U-test, and analysis of variance where appropriate with P < 0.05 considered significant.
Sixty subjects were enrolled. One subject (Placebo) fainted before electrode application and was removed from the study. The remaining 59 subjects completed all study evaluations. Venipuncture was successful on the first attempt in all subjects. One subject (Active) underwent venipuncture outside the delivery electrode site. Two subjects (Placebo group) did not complete the iontophoretic treatment because of discomfort.
Study groups were similar with regard to age, weight, and sex (Table 1). Vital signs did not change in either group (Table 1). Although the maximum current tolerated was greater in the Active versus the Placebo group (3.3 ± 0.8 mA versus 2.7 ± 0.8 mA, respectively, P = 0.013), the time required to deliver the 20 mA/min treatment was not different (8.8 ± 2.1 min versus 9.2 ± 1.9 min, respectively, P = 0.663).
The majority of subjects in both the Active and Placebo groups experienced blanching at the delivery electrode (36 of 40 versus 17 of 19, respectively, P = 0.95). Blanching did not occur in either group at the return electrode. There were no cases of moderate or marked erythema. Erythema graded as barely perceptible or mild occurred with similar frequency in both the Active and Placebo groups at the delivery electrode (18 of 40 versus 8 of 19, respectively, P = 0.83) and the return electrode (22 of 40 versus 13 of 19, respectively, P = 0.33).
VAS pain scores by each evaluator were less in the Active versus Placebo groups (Table 2). Similarly, greater satisfaction scores were given in the Active versus Placebo groups (Table 3). Parents of 7 subjects in the Placebo group and 14 subjects in the Active group preferred to be absent during venipuncture and did not provide VAS pain scores. Only two of these parents (one in the Active group and one in the Placebo group) provided satisfaction scores.
At follow-up, the return electrode was normal in all 59 subjects, and the delivery electrode site was normal in 56 subjects. Two subjects (Active) reported petechiae and one subject (Active) reported a bruise at the venipuncture site. Of the 59 subjects that completed the study, 10 subjects reported 12 adverse events that were all graded as mild (Table 4).
We have demonstrated that lidocaine iontophoresis in children is safe, significantly reduced discomfort associated with venipuncture, and increased satisfaction when compared with the placebo. On average, dermal anesthesia was achieved in <10 minutes by iontophoresis of lidocaine HCl 2% with epinephrine 1:100,000 for 20 mA/min.
These findings are in keeping with published studies of lidocaine iontophoresis in both adult and pediatric subjects (1–3,6–14). In a pediatric study comparing dermal anesthesia with lidocaine 4% with 1:50,000 epinephrine by either iontophoresis (30 mA/min) or subcutaneous injection, all evaluators rated subcutaneous injection as more painful than iontophoresis yet more effective in reducing pain associated with dialysis catheter insertion (1). In 2 reports involving 89 children more than 7 years old, lidocaine HCl 2% with epinephrine 1:100,000 administered iontophoretically for 30 or 40 mA/min resulted in lower pain scores associated with venipuncture in the emergency room when compared with the placebo (2,3). Kim et al. (3) reported that 95% of subjects treated with lidocaine and 100% of their parents would choose to have iontophoresis in the future.
Side effects of lidocaine iontophoresis in children are frequent, usually mild, and include temporary blanching at the delivery electrode site, transient erythema at either electrode, petechiae, and a tingling or itching sensation under either electrode (1–3). Serious complications have also been reported in children including cutaneous burns, papular lesions, urticarial lesions, and erythematous streaks at the electrode sites but were not observed in our study (1–3). Discomfort caused by tingling or itching sensations at either electrode site has been reported in other studies in 50%–70% of children, and some subjects were unable to complete iontophoresis because of intolerable pain (2,3). Two subjects in our Placebo group could not complete iontophoresis because of a painful scratchy or itchy sensation. Both of these subjects complained of discomfort immediately after starting iontophoresis and asked for it to be discontinued after one and four minutes, respectively. Additionally, three subjects in our Active group reported mild discomfort during iontophoresis, but all were able to complete the therapy.
Our study differed from other pediatric investigations in that we used a smaller iontophoretic dose (20 mA/min versus to 30–40 mA/min). This may explain the infrequent incidence of discomfort reported in our patients, as well as the absence of burns, papular or urticarial lesions, and erythematous streaks. In the study reporting that 70% of subjects experienced some discomfort during iontophoresis, the treatment was initiated with a current of 3.0 mA and increased to 4 mA as tolerated (3). This is in contrast to the method used in our study, and by others, where the initial current was set between 0.0–1.0 mA and gradually increased as tolerated by the patient to a maximum of 4.0 mA (2,3). Using this technique, all of the patients in our Active group completed the treatment.
Dermal anesthesia with EMLA has been compared with intradermal lidocaine infiltration for preoperative phlebotomy in children (15). Pain was reduced comparably in both groups. We did not include study groups treated with EMLA or intradermal lidocaine because this would have compromised our double-blinded study design. However, we note that the average time of 8.8 ± 2.1 minutes to achieve dermal anesthesia with lidocaine iontophoresis is a major advantage over EMLA application. Even with the newer, more rapidly acting topical anesthetic cream containing lidocaine 4% (ELA-Max®, Ferndale Laboratories Inc, Ferndale, MI), maximum dermal anesthesia was achieved by only 70% of adult subjects in 20 minutes (16).
Aside from the complications mentioned previously, other potential limitations of lidocaine iontophoresis exist. Vasoconstriction at the delivery electrode site from epinephrine could make venipuncture more difficult. However, in our study this was not a problem because venipuncture was successful on the first attempt in all subjects. Vasoconstriction and blanching have also been noted after EMLA application (4,15). Another problem is that iontophoresis targets one site, and if venipuncture fails at that site, additional time is required to provide dermal anesthesia at a second site. At our institution, the cost of lidocaine iontophoresis (between $6.00 and $7.00 per disposable electrode set) is slightly more than that of EMLA ($4.26 per application). Finally, tolerability of lidocaine iontophoresis has not been assessed in children less than six years old and therefore we cannot recommend its use in this patient population.
In conclusion, we found that the iontophoretic administration of lidocaine HCl 2% and epinephrine 1:100,000 for 20 mA/min was safe and effective in providing dermal anesthesia for venipuncture in children 6–17 years old. Although patient, research nurse, and parent satisfaction was high with lidocaine iontophoresis, two subjects in our Placebo group stopped iontophoresis shortly after initiation because of discomfort. Thus, this technique may not be applicable to all children. Future studies may provide information on the minimum effective iontophoretic dose for dermal anesthesia in children and the comparison of the anesthetic efficacy and satisfaction of lidocaine iontophoresis with topical anesthetic creams and subcutaneous infiltration.
The authors thank Mehernoor F. Watcha, MD, Department of Anesthesiology and Critical Medicine, Children’s Hospital of Philadelphia, for his assistance in preparing this manuscript.
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