PEDIATRIC ANESTHESIA

SECTION EDITOR WILLIAM J. GREELEY

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PEDIATRIC ANESTHESIA

EMLA Versus Nitrous Oxide for Venous Cannulation in Children

Olivier Paut, MD*, Claire Calme jane, Jean Camboulives, MD*
MD*,

Jean Delorme,

PhD,

Fre de ric Lacroix,

MD*,

and

*Departments of Pediatric Anesthesia and Intensive Care and Pharmacy, La Timone University Hospital, Marseilles, France

We compared EMLA cream with nitrous oxide (N2O) for providing pain relief during venous cannulation in children. In a prospective, double-blinded, randomized study, 40 children, 6 11 yr, ASA status I or II, undergoing scheduled surgery received either EMLA cream and inhaled air and oxygen (Group EMLA) or a placebo cream and inhaled 70% N2O in oxygen (Group N2O) before venous cannulation. Pain was evaluated with a visual analog scale and the Objective Pain Scale. The ease of venous cannulation and the observers assessment of its efficacy for preventing pain were assessed. Heart rate, blood pressure, respiratory rate, and oxygen saturation were compared before and after venous cannulation. Visual analog

scale scores (4.4 7.5 vs 3.9 9.3 mm, P 0.85), Objective Pain Scale scores (median 0 [0 6] vs 0 [0 1], P 0.61), efficacy (median 0 [0 1] vs 0 [0 1], P 0.59), and ease of venous cannulation (0 [0 2] vs 0 [0 1], P 0.84) were not different between EMLA and N2O groups, respectively. There was no statistical difference between the groups for the physiologic variables. Minor side effects were significantly more common in the N2O group (11 of 20) than in the EMLA group (7 of 20) (P 0.0248). We conclude that both techniques provided adequate pain relief during venous cannulation, as demonstrated by the low pain scores. (Anesth Analg 2001;93:590 3)

enous cannulation can be a painful and stressful experience for children and a difficult challenge for anesthesiologists. Although venous cannulation is most often performed on anesthetized children after an inhaled induction by mask, some children sometimes prefer an IV induction, often because they have some fear of the mask. Furthermore, interest in total venous anesthesia or computer-assisted continuous infusion anesthesia has grown considerably during the past decade, and both techniques require a first-class IV access before the induction of IV anesthesia (1). Currently, for those children sustaining an IV induction, several means for reducing the pain of venous cannulation are available. Local anesthesia administered intradermally (2), nitrous oxide (N2O) (3), and EMLA cream (AstraZeneca Pharma, Westborough, MA) (4) are effective. Few studies have dealt with the direct comparison of EMLA and N2O in children. The results of these studies were conflicting, and they had methodologic bias (57).

This study was conducted to compare the efficacy of EMLA cream and inhaled N2O for pain relief during venous cannulation in pediatric anesthesia, and we started with the hypothesis that N2O would be more effective than EMLA for that purpose.

Methods
This study was a prospective, double-blinded, randomized trial and was approved by our ethics committee. After obtaining written, informed consent from the parents, we studied 40 unpremedicated children aged between 6 and 11 yr, ASA I or II, undergoing elective surgery. Exclusion criteria were a history of allergy to any amide local anesthetic, a congenital methemoglobinemia, recent use of sulfonamide, and any dermatologic disorder. All children who participated in the study were trained in the use of the visual analogic scale (VAS) at the time of enrollment. The children were randomly allocated to one of two groups: in the EMLA group, children received 2.5 g of EMLA cream at least 1 h before IV catheter insertion in the operating room (OR), and in the N2O group, children received a placebo cream under the same conditions. The cream was applied by a pain nurse in a selected area, preferably on the dorsum of the hands,
2001 by the International Anesthesia Research Society 0003-2999/01

Supported, in part, by a grant from Assistance PubliqueHo pitaux de Marseille (AP-HM promoteur, 1997). Accepted for publication April 10, 2001. Address correspondence and reprint requests to Olivier Paut, MD, Department of Pediatric Anesthesia and Intensive Care, La Timone University Hospital, Bd Jean Moulin, 13385 Marseilles Cedex 5, France. Address e-mail to opaut@ap-hm.fr.

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at two sites. The tube was coated with an opaque adhesive so that the child was blinded to the nature of the cream applied. The cutaneous area with the cream was covered with an occlusive dressing (Tegaderm, 3M, St. Paul, MN) that was removed while the cream was wiped off, at least 15 min before venous puncture. Before entering the OR, the childs anxiety was assessed with the Yale Preoperative Anxiety Scale (Yale PAS) (8). In the OR, standard monitoring was placed. Before venous cannulation, all children breathed a gas mixture administered by the anesthesia machine via a face mask for 3 min before and during venous cannulation. EMLA patients breathed air in oxygen (30%), whereas N2O patients breathed N2O in oxygen (70%/ 30%). The skin was then cleansed with an isopropyl alcohol wipe, and a 22-gauge catheter was placed by one investigator in the selected area. The sole investigator who was aware of the nature of the gas mixture inhaled by the child was the anesthesiologist or nurse anesthetist responsible for maintaining the face mask and administering gas. The anesthesia machine screen and rotameters were hidden from the child and the investigators. The following variables were recorded by two blinded investigators: ease of venous cannulation was assessed by the anesthetist nurse or the anesthetist who inserted the venous catheter with a fourpoint scale (very easy, easy, intermediate, or difficult); the observers assessment of the efficacy of the technique for preventing pain during venous access was assessed with a four-point scale (very good, good, intermediate, and poor efficacy); and the patients pain was assessed with the Objective Pain Scale (OPS) of Hannallah et al. (9) and recorded by another blinded observer. After 2 min of breathing 100% oxygen, the patient was asked to rate his or her pain experienced during venous cannulation by using a 0 100-mm VAS. Every side effect was noted in the protocol chart. Physiologic variables heart rate, respiratory rate, mean blood pressure, and Spo2were recorded twice: before mask application and 1 min after catheter insertion. The duration of cream application and the time from cream removal to venous cannulation were recorded. Sample size was determined before commencing the study. In a former group of 10 patients having venous cannulation with either EMLA or N2O, we found that the sd for the VAS score was at 9.75 mm. Power analysis indicated that 20 subjects in each group would allow us to detect a 10-mm difference in VAS score, a difference we considered clinically significant (1- 90%, risk at 5%). Patient demographics were compared with analysis of variance (ANOVA) (age, weight) or the Mann-Whitney U-test (Yale PAS score). Physiologic variables before and after puncture were compared by using ANOVA. VAS scores from the EMLA and N2O groups were compared with ANOVA, whereas OPS scores, efficacy

assessment, and ease of venous puncture were compared between groups by the Mann-Whitney U-test. The incidence of side effects was compared with Fishers exact test. P 0.05 was considered statistically significant.

Results
Twenty children were included in each group. There was no difference between the two groups in weight, age, Yale PAS, duration of cream application, or time from cream removal to venous cannulation (Table 1). Venous cannulation was successful on the first attempt for 38 children and on the second attempt for 2 children, both from the EMLA group. One of these two children was considered to have a difficult venous access. The results of pain assessments with VAS and OPS, overall efficacy, and ease of venous cannulation are reported in Table 2. There was no statistical difference between the EMLA and N2O groups for these principal assessment criteria. The two techniques provided very good pain relief as assessed by the zero median VAS and OPS scores in each group (Table 2). The distribution of the various pain scores among children is shown in Table 2. Thirty-seven children had an OPS score of 0 or 1. Three children (two in the N2O group and one in the EMLA group) rated their pain during venous cannulation at 30 mm with VAS, the highest value in this series of patients. The concomitant OPS scores in these children were low, 0 for one child and 1 for two children. One child (group EMLA) had an OPS score of 6, although he rated his pain with VAS at 0 mm. In fact, this child said that he was afraid of the venipuncture, and his behavior influenced the OPS score, but he did not sustain pain. The two groups did not differ in physiologic variables before or after venous catheterization. Furthermore, in each group, heart rate, respiratory rate, mean blood pressure, and Spo2 values were not different before or after venous access. There was no episode of coughing, laryngospasm, bronchospasm, hypotension, bradycardia, allergy, or nightmare. Only minor side effects were encountered. There were 22 side effects in 18 children (Table 3). The overall number of children sustaining at least one side effect was significantly more in the N2O group (11 of 20) than in the EMLA group (7 of 20) (P 0.0248). The most frequent side effects were movements and restlessness.

Discussion
This study shows that the use of EMLA cream or 70% N2O in oxygen are two effective means of providing pain relief during venous cannulation in children. There was no difference between the two methods as determined by VAS or OPS. Median pain assessment ratings were as low as 0 in both groups. Side effects

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Table 1. Demographic Data Variable Age (yr) Weight (kg) Patch application duration (min) Time from patch removal to venous cannulation (min) Anxiety (Yale Pediatric Anxiety Scale) EMLA group (n 20) 8.45 1.5 32.3 7.3 87.2 24 46.9 36 6 (518) N2O group (n 20) 8.8 1.5 31.9 9.1 82.4 20 29.8 19 5 (512) P value 0.46 0.88 0.5 0.07 0.32

Age, weight, and duration are expressed as mean sd. Anxiety is expressed as median (range). N2O nitrous oxide.

Table 2. Pain Scores and Ease of Venous Cannulation Assessment Variable EMLA group N2O group 3.9 9.3 14 6 0 0 0 0 0 0 0 (01) 16 4 0 0 0 (01) 17 3 0 0 0 (01) P value 0.85

Table 3. Description of Side Effects During the Whole Procedure (3 min Gas Inhalation and Venous Cannulation) Variable Restlessness, movements Nausea, vomiting Dysphoria Scared by the face mask or refused it temporarily Miscellaneous Total
N2O nitrous oxide. * P 0.0248.

Group EMLA 3 0 0 3 1 7

Group N2O 8 1 3 1 2 15*

VAS score (mm) 4.4 7.5 OPS score 0 13 1 4 2 0 3 0 4 0 5 0 6 1 6 0 Median (range) 0 (06) Observors assessment 0 14 1 6 2 0 3 0 Median (range) 0 (01) Ease of venous cannulation 0 15 1 4 2 1 3 0 Median (range) 0 (02)

0.61

0.84

0.59

Visual analog scale (VAS) is expressed as mean sd. Objective Pain Scale (OPS), observors assessment of efficacy of the technique to provide pain relief, and ease of venous cannulation are expressed as median (range). N2O nitrous oxide.

were minor in each group, and their incidence was significantly increased in the N2O group compared with the EMLA group. EMLA is effective for providing pain relief during venepuncture at the IV induction of anesthesia with small needles (10,11). EMLA cream is also effective for reducing the pain associated with insertion of a venous cannula in children: in two randomized, controlled studies, EMLA provided significantly more pain-free cannula insertions than placebo cream (12,13). The main disadvantage of EMLA cream is the long application timeat least 1 h before venous puncture, which means that application of the cream should be anticipated and included in the premedication protocol of a given institution (12). EMLA use is logistically feasible in clinical practice in most institutions (11).

N2O is still widely used in pediatric anesthesia. Henderson et al. (3) evaluated the effects of N2O in oxygen for providing analgesia for venous cannulation in children in a prospective, randomized study. They showed that N2O, 50% or 70% in oxygen, was effective in decreasing the pain associated with venous cannulation when compared with control groups of patients breathing oxygen or room air. The Childrens Hospital of Eastern Ontario Pain Scale (CHEOPS) score (14) was 7 in 15% of children breathing room air, in 16% of children breathing oxygen, in 56% of children breathing 50% N2O, and in 77% of children breathing 70% N2O (3). The incidence of side effects was significantly more with 70% N2O than in all other groups (3). These side effects were minormainly restlessness and movements (3), as we have seen in this study. From our point of view, this increase in the incidence of minor side effects associated with the use of 70% N2O does not represent a major argument for selecting one technique over the other. Although both EMLA cream and N2O are effective at decreasing the pain associated with venous cannulation, few studies have directly compared these two techniques. In a prospective randomized trial, N2O (70% in oxygen) was compared with EMLA cream in 50 children aged 6 to 12 years (5). The pain scores generated by both the investigator and the children (by using VAS) were significantly lower in the N2O group than in the EMLA group. The authors concluded that N2O provided superior analgesia for pediatric venous cannulation compared with EMLA (5). However, there are some methodologic concerns with that study. First, neither the child nor the investigators were blinded, which could have

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introduced bias. Second, although the mean VAS scores in the N2O group were very low (mean 3.2 mm, maximal value 25 mm), in agreement with the VAS scores we found in this study, those in the EMLA group were much higher (mean 23 mm, maximal value 100 mm). These latter values are very different from those we observed in the EMLA group (mean 4.4 mm, maximal value 30 mm), suggesting that a technical problem during EMLA application could have occurred (5). In another prospective, randomized, double-blinded study, three groups of young children aged three months to five years received either EMLA cream, N2O (50% in oxygen), or both EMLA and N2O (6). Although EMLA and N2O provided better CHEOPS scores during venous cannulation than with the two other techniques, no difference in pain scores was found between the EMLA and the N2O groups. Behavioral issues (e.g., anxiety) could have interacted with pain assessment and could explain the high median CHEOPS scores seen in both groups (6). Pain is difficult to assess in this young age group. In the past decade, several methods for measuring pain have been developed for the youngest children, but unfortunately, none is completely accepted as an objective measure (15). Furthermore, the youngest children show some anxiety with needles, leading to difficulties for pain assessment. This is why, in our study, we focused on those older children who are able to rate their pain with a VAS. Recently, EMLA has been compared with N2O (50% in oxygen) for routine preoperative laboratory testing. Both EMLA and N2O were found to be effective in reducing CHEOPS scale rates during venipuncture when compared with a parallel control group, but no difference was shown between these two analgesia techniques except in children one to four years old, for whom EMLA cream was more effective than 50% N2O (7). However, the experimental design of this latter study unblinded and without randomizationlimited considerably the extent of the conclusions (7). Although both techniques are equally efficient for reducing pain at venous cannulation, which technique to choose will depend on several other variables: the childs choice, the anesthesiologists preference, the existence of a contraindication for one medication, the concern for room pollution, an unanticipated time for surgery that makes it impossible to wait one hour for cream application, and the cost. Although EMLA cream is not by itself expensive, its cost is considerably more than that of N2O. In summary, we conclude that the administration of EMLA cream or of N2O (70% in oxygen) are two effective tools for providing pain relief for venous cannulation in pediatric anesthesia. Although there is no significant difference between the two analgesia techniques

(except an increased incidence of minor side effects associated with N2O, but these are considered clinically negligible), other variables, such the child or anesthetists preference, should dictate the choice between EMLA and N2O.
The authors thank Wanda Paredero, pain service nurse, and Sydney Melka, nurse anesthetist, for their contribution to this study. Special thanks to Bernard Giusiano, MD, for his help in statistical analysis.

References
1. Morton N. Total intravenous anesthesia (TIVA) in paediatrics: advantages and disadvantages. Paediatr Anaesth 1998;8:189 94. 2. Brislin RP, Stayer SA, Schwartz RE, Pasquariello CA. Analgesia for venepuncture in a paediatric surgery centre. J Paediatr Child Health 1995;31:542 4. 3. Henderson JM, Spence DG, Komocar LM, et al. Administration of nitrous oxide to pediatric patients provides analgesia for venous cannulation. Anesthesiology 1990;72:269 71. 4. Chang P, Goresky G, OConnor G, et al. A multicentre randomized study of single-unit dose package of EMLA patch vs EMLA 5% cream for venepuncture in children. Can J Anaesth 1994;41: 59 63. 5. Vetter TR. A comparison of EMLA cream versus nitrous oxide for pediatric venous cannulation. J Clin Anesth 1995;7:486 90. 6. Mjahed K, Sadraoui A, Benslama A, et al. Association cre ` me EMLA et protoxyde dazote pour labord veineux chez lenfant. Ann Fr Anesth Re anim 1997;16:488 91. 7. Gall O, Annequin D, Ravault N, Murat I. Relative effectiveness of lignocaine-prilocaine emulsion and nitrous oxide inhalation for routine preoperative laboratory testing. Paediatr Anaesth 1999;9:30510. 8. Kain Z, Mayes L, Cicchetti D, et al. The Yale Preoperative Anxiety Scale: how does it compare with a gold standard? Anesth Analg 1997;85:783 8. 9. Hannallah RS, Broadman LM, Belman AB, et al. Comparison of caudal and ilioinguinal/iliohypogastric nerve blocks for control of post-orchiopexy pain in pediatric ambulatory surgery. Anesthesiology 1987;66:832 4. 10. Hopkins C, Buckley C, Bush G. Pain-free injection in infants. Use of a lignocaine-prilocaine cream to prevent pain at intravenous induction of general anesthesia in 15-year-old children. Anaesthesia 1988;43:198 201. 11. Cooper C, Gerrish S, Hardwick M, Kay R. EMLA cream reduces the pain of venepuncture in children. Eur J Anaesthesiol 1987; 4:441 8. 12. Hallen B, Uppfeldt A. Does lidocaine-prilocaine cream permit painfree insertion of IV catheters in children? Anesthesiology 1982;57:340 2. 13. Manner T, Kanto J, Lisalo E, et al. Reduction of pain at venous cannulation in children with a eutectic mixture of lidocaine and prilocaine (EMLA cream): comparison with placebo cream and no local premedication. Acta Anaesthesiol Scand 1987;31:7359. 14. Beyer JE, McGrath PJ, Berde CB. Discordance between selfreport and behavioral pain measures in children aged 37 years after surgery. J Pain Symptom Manage 1990;5:350 6. 15. Mitchell P. Understanding a young childs pain. Lancet 1999; 354:1708.