EMLA for painful procedures in infants

Pediatric Pharmacology

www.jpedhc.org

Clinical Report

Section Editor Rosalie Sagraves, PharmD, FAPhA, FCCP Professor and Dean, College of Pharmacy The University of Illinois at Chicago Chicago, Illinois

EMLA for Painful Procedures in Infants Karen L. Weise, PharmD, & Milap C. Nahata, PharmD

OBJECTIVES Based on the content of the article, you will be able to: 1. Identify the two drugs in EMLA and the youngest pediatric age for its approved use. 2. List the procedures for which EMLA has been used to control pain in infants. 3. Describe the efficacy of EMLA vs. other agents in treating pain. 4. Discuss the potential adverse effects of EMLA in infants. See page 48 for instructions.

Karen L. Weise currently is a Pharmacy Practice Resident at the University of California, San Francisco. At the time of writing, Weise was a PharmD student at the College of Pharmacy, Ohio State University and Children’s Hospital, Columbus, Ohio. Milap C. Nahata is Professor and Chair, Division of Pharmacy Practice and Administration, College of Pharmacy, and Professor of Internal Medicine and Pediatrics, College of Medicine and Public Health, Ohio State University and Children’s Hospital, Columbus, Ohio. Reprint requests: Dr. Milap C. Nahata, Division of Pharmacy Practice and Administration, College of Pharmacy, Ohio State University, Columbus, OH 43210-1214; e-mail: [email protected]. J Pediatr Health Care. (2005). 19, 42-47. 0891-5245/$30.00 Copyright © 2005 by the National Association of Pediatric Nurse Practitioners. doi:10.1016/j.pedhc.2004.09.002

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INTRODUCTION Neonates and infants in the neonatal intensive care unit (NICU) frequently undergo painful procedures such as heel lancing, venipuncture, arterial sticks, lumbar puncture, intramuscular immunizations, and circumcision throughout the course of their treatment. There are reports of individual infants receiving over 400 procedures during a given stay in a NICU (Stevens, 1996). Recent studies indicate that untreated pain in neonates may have long-term sequelae such as sleep disturbances, decreased mother-infant bonding, and hypersensitivity to pain, in addition to short-term discomfort (Halimaa, 2003; Larsson, 1999; Stevens, 1996). In 2001, the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) recognized the importance of pain management, making it the fifth vital sign. EMLA (Eutectic Mixture of Local

Anesthetics, AstraZeneca) 5%® is a 1:1 mixture of lidocaine 2.5% and prilocaine 2.5% in a cream base (EMLA® Cream and Anesthetic Disk Package Insert, 2003) that is approved for use in infants 3 months and older. However, there is considerable interest in its use for younger patients. Unfortunately, studies in this patient population have suffered from small sample size, failure to include patient gestational age and baseline characteristics, lack of repeated dosing, and vague reports of the doses used and the extent of surface area covered. Efficacy outcome endpoints also have varied among studies from using composite scales (eg, Premature Infant Pain Scale) to individual values (eg, heart rate). This makes data extrapolation to specific patient populations difficult. The purpose of this article is to review several double-blind, randomized, placebo-controlled studies, as well as other randomized and Journal of Pediatric Health Care

TABLE. Summary of trials using EMLA in infants for painful procedures Study

Procedure

Study design

Age

Number of patients

Dosage used

Outcome measures

McIntosh, van Veen, & Brameyer (1994)

Heel lancing

Placebocontrolled

26-34 weeks gestation

35

Dosage not given

Stevens et al. (1999)

Heel lancing

Two-phase, randomized, controlled trial

30-36 weeks gestation

120

Larsson, Jylli, Lagercrantz, & Olsson (1995)

Heel lancing

Double-blind, randomized, placebocontrolled

36.8-42.6 weeks gestation

112 (7 per group)

Acharya et al. (1998)

Venipuncture

26-33 weeks gestation

19

Lindh, Wiklund, & Hakansson (2000)

Venipuncture

37-42 weeks gestation

60

Gradin et al. (2002)

Venipuncture

Randomized, double-blind, placebocontrolled, cross-over Randomized, double-blind, placebocontrolled Randomized, controlled, double-blind

Phase I: 0.5 g with occlusion × 30 minutes. Phase II: 0.5 g with occlusion × 60 minutes 0.5 g with occlusion for 10, 20, 30, 40, 50, 60, 90, and 120 minutes 0.5 mL with occlusion x 60 minutes

201

Lindh, Wiklund, Blomquist, & Hakansson (2003)

Immunization -DPT

Randomized, double-blind, placebo-controlled +/– oral glucose

>36 weeks gestation with postnatal age >24 hours and <30 days 3 months old

Uhari (1993)

Immunization -DPT (majority)

Randomized, double-blind

3-28 months (mean: 9 months)

155

Lander et al. (1997)

Circumcision

≥37 weeks gestation

52

Taddio et al. (1997)

Circumcision

Randomized, placebocontrolled Double-blind, randomized, placebocontrolled

≥37 weeks gestation

68

Benini, Johnston, Faucher, & Aranda (1993)

Circumcision

Randomized, controlled

37-42 weeks gestation

28

0.05 mL with occlusion x 45-60 minutes

Kaur, Gupta, & Kumar (2003)

Lumbar puncture

Randomized, double-blind, placebocontrolled

≥34 weeks gestation

60

1 g with occlusion x 60-90 minutes

Journal of Pediatric Health Care

90

1 mL applied to a 4 cm2 area with occlusion x 60 minutes 0.5 g with occlusion x 60 minutes

1 g with occlusion x 60 minutes +/–1 mL gluose to the tongue 2 minutes prior Dose not given, applied for duration of at least 1 hour prior 2 g with occlusion x 90 minutes 1 g with occlusion x 60-80 minutes

Heart rate, respiratory rate, transcutaneous oxygen tension, carbon dioxide tension PIPP, MetHb levels

Occurance of pain cry, flexor reflex response

Heart rate, oxygen saturation, blood pressure, facial action, cry, local changes, MetHb concentrations Incidence of crying, heart rate, and spectral analysis of heart rate PIPP, duration of crying after skin puncture, local changes

ECG, VAS by nurse and parents, pre- and postheart rate and variability, MBPS, latency to first cry and duration of first cry VAS by nurses and parents, local changes

Heart rate, cry, methemoglobin level Heart rate, duration of cry, facial activity using Neonatal Facial Coding System (NFCS), blood pressure Heart rate, trancutaneous oxygen saturation, NFCS, duration of cry and special features using CSPEECH software program Heart rate, trancutaneous oxygen saturation, NFCS

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blinded (but uncontrolled) studies concerning the use of EMLA for pain associated with various procedures performed in infants. HEEL LANCING A total of three published, controlled studies have been undertaken to evaluate EMLA use in the alleviation of pain associated with heel lancing. The Table summarizes the pertinent data from the trials. Patient ages varied from 26 weeks gestational age to full-term. EMLA doses were reported in 2 of the 3 studies with a standard dose of 0.5 g used in all studies. Duration of exposure prior to a procedure varied from 10 to 120 minutes. No differences in pain were reported with EMLA versus placebo at any time in any of these studies (Larsson, Jylli, Lagercrantez, & Olsson, 1995; McIntosh, van Veen, & Brameyer, 1994; Stevens et al., 1999). Thus, EMLA may not be recommended for pain associated with heel lancing. VENIPUNCTURE Four studies have been undertaken to evaluate EMLA use for the alleviation of pain associated with venipuncture in infants. Two studies compared EMLA with a placebo and reported mixed results. Acharya et al. (1998) assessed 19 infants in a double-blind, placebo-controlled crossover study in which the median gestational age was 31 weeks (range 26-33 weeks) and median birthweight was 1564 g (916-2246 g) using physiological and behavioral endpoints to determine efficacy. The median age at study time was 21 (3-65) days. An EMLA dose of 0.5 mL (~0.5 g) in cream was applied in a thick layer over a prominent vein on the dorsum of the hand or foot and was occluded for 60 minutes. At the end of this time period, the cream was removed and a blood pressure cuff and pulse oximeter were connected to the child who was then given 10 minutes to relax. Results showed no statistically significant differences in any outcome measures between the placebo 44

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cream and the EMLA cream. Lindh, Wiklund, & Hakansson (2000) conducted a double-blind, randomized, placebo-controlled study of 60 3-day-old healthy newborns. All patients were full-term (gestational ages 37 to 42 weeks), vaginally delivered, APGAR score at 5 minutes of >7, and normal birth weight. One gram (~1 mL) of cream was applied to a 4 cm2 area on the dorsal side of the hand and was occluded for 60 minutes. Ten minutes after cream removal, the hand was warmed and venipuncture performed. Results showed a significantly higher and variable heart rate in the placebo group. There was no difference between the groups in incidence of crying. Finally, Gradin et al. (2002) assessed oral glucose (30%) versus EMLA cream in a randomized, double-blind controlled study of 201 newborns. Newborns (gestational age ≥ 36 weeks, postnatal age of >24 hours but <30 days) received a 0.5 g EMLA dose on the dorsal side of the hand, which was occluded for 60 minutes. The cream was then removed and a 15-minute time period was allowed for the infant to relax and to reduce any vein constriction. Outcomes were compared using the Premature Infant Pain Scale (PIPP). The PIPP scores were significantly lower in the glucose group versus the EMLA group. The duration of crying was also significantly lower in the glucose group. Heart rate was not different. Studies have not shown a significant decrease in pain associated with venipuncture in preterm or term infants who received EMLA versus placebo. The only study that compared oral glucose to EMLA in infants showed better efficacy with glucose. Because of more difficult administration and potential adverse effects, EMLA is not recommended for venipuncture in neonates and infants. INTRAMUSCULAR IMMUNIZATIONS EMLA cream in combination with oral glucose was assessed in 3-

month-old infants who were undergoing diptheria-pertussis-tetanus (DPT) immunization (Lindh, Wiklund, Blomquist, & Hakansson, 2003). The infants were born at term, of normal birth weight, and otherwise healthy. Gestational age of the infants was not given. All infants were seen in an outpatient clinic where they received EMLA 1 g applied to the lateral region of the right thigh. The cream was then occluded for 60 minutes. There was a 3-minute period after cream removal before immunization occurred, in which the baby was given 1 mL of 30% glucose solution or placebo orally. Immediately after immunization, parents were asked to rate the infant’s pain experience on a Visual Analog Scale (VAS) of 110 with 0 representing “no pain” and 10 representing “worst possible pain.” The investigator also rated the pain experience on the VAS scale independently without prior viewing of parents’ assessments. All infants were monitored via electrocardiogram throughout the procedure. The procedure was also videotaped for further evaluation by the Modified Behavioral Pain Scale (MBPS) by two independently working, experienced pediatric nurses. The procedure was rated in three sequences: at baseline, 0-10 seconds after injection, and 11-20 seconds after injection. The infants’ responses to immunization were measured as the difference in MBPS scorings pre- and postinjection, and were significantly lower in the EMLA-glucose group than in the placebo group (difference between baseline and 0-10 seconds after injection, P<.001, difference between baseline and 11-20 seconds, P=.004). The infants in the placebo group cried earlier than those in the treatment group, and for a longer duration. Infants in the placebo group also showed increased heart rates and heart rate variability as compared with those in the treatment group. Finally, the VAS scores performed by parents and the investigator were lower in the EMLA-glucose group than in the placebo Journal of Pediatric Health Care

group. The authors concluded that the combination of oral glucose and EMLA cream decreased pain in 3month-old infants. Uhari (1993) conducted a study of 155 infants with a median age of 5.2 months (range 2.8-28.3 months) who received intramuscular immunizations, of which the most were DPT (98%). An unspecified amount of cream was applied to the immunization site and occluded for a minimum of 60 minutes. Immediately following immunization, both the nurse and parents evaluated the child using a VAS to evaluate the amount of pain, crying, and fear the infant exhibited. Both nurses and parents rated the pain and crying as significantly less in children who received EMLA. These studies suggested that EMLA cream (1 g applied for a minimum of 60 minutes) may be effective in alleviating pain associated with intramuscular injections in patients 3 months and older. For enhanced pain relief, oral glucose may be administered in addition to EMLA for a synergistic effect. CIRCUMCISION EMLA has been studied numerous times for pain associated with neonatal circumcision. Lander et al. (1997) reported success with EMLA versus placebo using efficacy outcome measures of heart rate and crying. This randomized and controlled trial enrolled 52 healthy fullterm neonates (1 to 3 days of age). Fifteen patients received EMLA, 11 received placebo, 12 received ring block, and 14 received nerve block. In the EMLA arm, a dosage of 2 g was applied to the penis and then occluded for 90 minutes. Each newborn was evaluated every 10 minutes and additional cream was applied if the cream leaked or the infant urinated. Results showed that EMLA was more effective than placebo, but less effective than ring block and dorsal penile nerve block. The authors suggested that EMLA may not have penetrated to the depth required for circumcision and therefore may not be a prudent choice. Journal of Pediatric Health Care

Taddio et al. (1997) conducted a double-blind, randomized, controlled trial of 68 full-term neonates, of which 38 received EMLA 5% cream. A 1 g dose of the cream was applied to the penis with an occlusive dressing applied for 6080 minutes prior to circumcision. Behavioral (crying and facial expression) and physiological (heart rate and blood pressure) outcomes were recorded. Results showed that neonates treated with EMLA had less facial activity during the procedure (P<.001), cried less than half as much as those in the placebo arm (P<.001), and had smaller increases in heart rate (P=.007). Thus, EMLA was determined to be efficacious for the prevention of pain resulting from neonatal circumcision. Benini, Johnston, Faucher, & Aranda (1993) showed benefit of EMLA versus placebo in a randomized controlled trial involving 28 newborn infants (gestational ages 37 to 42 weeks), who had uncomplicated deliveries, 5 minute Apgar scores >7, and birthweights >2500 grams. A 0.5 mL (~0.5 g) dose of EMLA was applied on the outside of the prepuce and occluded for 45-60 minutes. Outcome variables included heart rate, transcutaneous oxygenation, facial expression, and crying. Overall, EMLA was found to be significantly better at decreasing pain as measured by the outcome variables. Thus, EMLA can be a viable alternative to penile nerve block or ring block in neonates at doses as high as 2 grams. LUMBAR PUNCTURE (LP) Kaur, Gupta, & Kumar (2003) studied 60 consecutive newborns undergoing diagnostic lumbar puncture. Inclusion criteria was an uncomplicated vaginal or cesarean delivery, gestational age of ≥ 34 weeks, postnatal age <4 weeks, 5minute Apgar score of ≥ 7, no history of maternal medication use, absence of structural neurodevelopmental anomalies, and rectal temperature of 37ºC ± 0.5ºC. The neonates could not have received sedatives or

analgesics. The newborns were randomized to receive EMLA or placebo in a double-blind fashion. A 1 mL dose of cream (EMLA or placebo) was uniformly applied to an area that was 1 in2 at the site of the procedure and was then covered with an occlusive dressing for 60-90 minutes before the scheduled time of the lumbar puncture. The newborn was then placed in a servomechanism-controlled open care system. The dressing was removed immediately prior to the procedure and any local reactions were noted. The procedure was composed of 8 events: baseline (preprocedural 60 to 90 minutes prior to EMLA application), preparation, positioning, needle insertion, needle in place, needle withdrawal, 5-minute postprocedural period (5 minutes after needle withdrawal), and 1 hour postprocedural period. The same person carried out all lumbar punctures. Physiological responses including heart rate and oxygen saturation were measured using a compact vital signs monitor. The mean value for each event was used for comparisons between groups. Facial expressions were recorded by video camera mounted on a tripod at the newborn’s bedside. One person then coded the videotapes according to the Neonatal Facial Coding System in a blinded manner. Four items of facial action (brow bulge, eye squeeze, nasolabial furrow, and open mouth) and the presence of crying were used as measures of behavioral response to pain. Each response was given a score of 1 if present and 0 if absent, for a possible total ranging from 0 to 5. Infants were monitored closely for 24 hours for the presence of any local or systemic adverse effects linked to EMLA application. Heart rate was significantly different between groups (P=.04) and between events (P<.001). The difference from baseline value was significantly lower for the EMLAgroup compared with the placebo January/February 2005

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group at insertion and withdrawal of the needle (P<.001). Oxygen saturation was significantly different between events (P<.001) but similar between groups (P=.35). The percentage change from the initial baseline value was found to be smaller in the EMLA group compared with the placebo group during positioning, needle insertion, and needle withdrawal, although the differences were not statistically significant. This study established that EMLA is an efficacious agent for reducing pain associated with needle insertion and withdrawal during lumbar puncture in neonates; however, additional studies are needed to assess the efficacy of EMLA for LP versus other current therapies (eg, 40% lidocaine hydrochloride or 20% benzocaine). SAFETY Many theoretical concerns exist about the possibility of increased methemoglobin concentrations following lidocaine-prilocaine administration. However, there has been only one case report of toxic methemoglobin levels after the administration of a one-time dose of 1 gram or less applied for 60-90 minutes. This report described a dose of 0.5 g applied 1.25 hours preoperatively to the lower backs of premature infants up to a corrected age of 3 months who were undergoing herniotomy. The infants also received peridural prilocaine for the procedure. They experienced mottled skin, paleness, cyanosis, and poor peripheral perfusion, with some requiring medical intervention. The authors speculated that the EMLA cream probably contributed little in comparison to the peridural prilocaine (Frey, & Kehrer, 1999). In various studies (Acharya et al., 1998; Brisman et al., 1998; Lander et al., 1997; Law et al., 1996; Stevens et al., 1999; Taddio et al., 1997) methemoglobin concentrations have been monitored at regular intervals for up to 24 hours after single EMLA dose. Although meth46

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emoglobin concentrations have been higher than those in the placebo groups, these have been well below the upper limit of 5%6%. A study by Essink-Tebbes, Wuis, Liem, van Dongen, & Hekster (1999) assessed EMLA safety in 12 neonates ages 30.1-36.3 weeks gestation with birthweights of 1100-2910 g. The study evaluated applications of 0.5 g of EMLA over a surface area of 5 cm2 four times daily and showed them to be safe with maximum lidocaine and prilocaine concentrations of 0.230 mg/L and 0.223 mg/L, respectively. Plasma concentrations of o-toludine, a metabolite of prilocaine, were also measured and remained below the detectable limit of 0.025 mg/L. However, EMLA was only applied for 30 minutes compared with the usual 60 minutes and the study was done over only 24 hours of continuous dosing. This does not reflect practice in NICUs where a neonate or infant may be undergoing painful procedures multiple times daily for weeks or even months. Thus, it is recommended that if EMLA is to be used on an ongoing basis with multiple daily doses, methemoglobin concentrations should be monitored periodically to establish safety. SUMMARY I nfants in NICUs are exposed repeatedly on a daily basis to painful procedures. There is a scarcity of data evaluating the role of EMLA for routine use in the NICU setting. Several small studies have reported pain relief from venipuncture, immunization, lumbar puncture, and circumcision with a one-time EMLA dose. Efficacy of EMLA for heel lancing remains unproven. Only one study has assessed the safety of repeated daily applications of EMLA. This study reported modest increases in methemoglobin concentrations after a four-times-daily schedule. Thus, it is recommended that for patients receiving multiple daily doses of EMLA, methemoglobin concentrations should be meas-

ured periodically. EMLA application re-quires increased nursing time and planning because of the need for a 60-minute occluded application. REFERENCES Acharya, A. B., Bustani, P. C., Phillips, J. D., Taub, N. A., & Beattie, R. M. (1998). Randomised controlled trial of eutectic mixture of local anaesthetics cream for venepuncture in healthy preterm infants. Archives of Disease in Childhood. Fetal and Neonatal Edition, 78, F138-F142. Brisman, M., Ljung, B. M. L., Otterbom, I., Larsson, L. E., & Andreasson, S. E. (1998). Methaemoglobin formation after the use of EMLA cream in term neonates. Acta Paediatrics, 87,11911194. Benini, F., Johnston, C. C., Faucher, D., & Aranda, J. V. (1993). Topical anesthesia during circumcision in newborn infants. Journal of the American Medical Association, 270, 850-853. Essink-Tebbes, C. M., Wuis, E. W., Liem, K. D., van Dongen, R. T. M., & Hekster, Y. A. (1999). Safety of lidocaine-prilocaine cream application four times a day in premature neonates: a pilot study. European Journal of Pediatrics, 158, 421423. Frey, B., & Kehrer, B. (1999). Toxic methaemoglobin concentrations in premature infants after application of a prilocaine-containing cream and peridural prilocaine. European Journal of Pediatrics, 158, 785-788. Gradin, M., Eriksson, M., Holmqvist, G., Holstein, A., & Schollin, J. (2002). Pain reduction at venipuncture in newborns: Oral glucose compared with local anesthetic cream. Pediatrics, 110, 1053-1063. Halimaa, S.-L. (2003). Pain management in nursing procedures on premature babies. Journal of Advanced Nursing, 42, 587-597. Kumar, A. R., Dunn, N., & Naqvi, M. (1997). Methemoglobinemia associated with a prilocaine-lidocaine cream. Clinical Pediatrics, 36, 239-240. Kaur, G., Gupta, P., & Kumar, A. (2003). A randomized trial of eutectic mixture of local anesthetics during lumbar puncture in newborns. Archives of Pediatric Adolescent Medicine, 157, 1065-1070. Lander, J., Brady-Fryer, B., Metcalfe, J. B., Nazaralli, S., & Muttitt, S. (1997). Comparision of ring block, dorsal penile nerve block, and topical anesthesia for neonatal circumcision. Journal of the American Medical Association, 278, 2157-2162. Larsson, B. A. (1999). Pain management in neonates. Acta Paediatrics, 88, 13011310. Larsson, B. A., Jylli, L., Lagercrantz, H., &

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Olsson, G. L. (1995). Does a local anaesthetic cream (EMLA) alleviate pain from heel lancing in neonates? Acta Anaesthesiologica Scandinavica, 39, 1028-1031. Law, R., Halpern, S., Martinsn, R. F., Reich, H., Innanen, V., & Ohlsson, A. (1996). Measurement of methemoglobin after EMLA analgesia for newborn circumcision. Biology of the Neonate, 70, 213217. Lindh, V., Wiklund, U., Blomquist, H. K., & Hakansson, S. (2003). EMLA cream and oral glucose for immunization pain in 3-month-old infants. Pain, 104, 381388. Lindh, V., Wiklund, U., & Hakansson, S. (2000). Assessment of the effect of

EMLA during venipuncture in the newborn by analysis of heart rate variability. Pain, 86, 247-254. Mcintosh, N., van Veen, L., & Brameyer, H. (1994). Alleviation of the pain of heel prick in preterm infants. Archives of Disease in Childhood. Fetal and Neonatal Edition, 70, F177-F181. Package Insert. EMLA Cream and Anasthetic Disk. AstraZeneca, 2003. Stevens, B. (1996). Management of painful procedures in the newborn. Current Opinion in Pediatrics, 8, 102-107. Stevens, B., Johnston, C., Taddio, A., Jack, A., Narciso, J., Stremler, R., et al. (1999). Management of pain from heel lance with lidocaine-prilocaine (EMLA) cream: Is it safe and efficacious in

preterm infants? Journal of Developmental and Behavioral Pediatrics, 20, 216-221. Taddio, A., Ohlsson, A., Einarson, T. R., Stevens, B., & Koren, G. (1998). A systematic review of lidocaine-prilocaine cream (EMLA) in the treatment of acute pain in neonates. Pediatrics, 101, E1. Taddio, A., Stevens, B., Craig, K., Rastogi, P., Ben-David, S., Shennan, A., et al. (1997). Efficacy and safety of lidocaineprilocaine cream for pain during circumcision. New England Journal of Medicine, 336, 1197-1201. Uhari, M. (1993). A eutectic mixture of lidocaine and prilocaine for alleviating vaccination pain in infants. Pediatrics, 92, 917-921

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