Published online May 5, 2008
PEDIATRICS (doi:10.1542/peds.2007-3104)
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ARTICLE

EMLA Cream and Nitrous Oxide to Alleviate Pain Induced by Palivizumab (Synagis) Intramuscular Injections in Infants and Young Children

Ricardo Carbajal, MD, PhDa, Valérie Biran, •••b, Richard Lenclen, •••c, Ralph Epaud, •••d, Patricia Cimerman, •••a, Pascale Thibault, •••a, Daniel Annequin, •••a, Francis Gold, •••b and Brigitte Fauroux, •••d

a Centre National de Resources de Lutte Contre la Douleur
b Hôpital Service de Néonatologie, Armand Trousseau, Assistance Publique-Hôpitaux de Paris, Paris, France
c Centre Hospitalier Poissy Saint-Germain, Service de Médecine Néonatale, Poissy, France
d Pediatric Pulmonary Department, Hôpital Armand Trousseau, Assistance Publique-Hôpitaux de Paris, and Research Unit INSERM UMR-S 719, Université Pierre et Marie Curie-Paris 6, Paris, France


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. Palivizumab (Synagis [•••, •••, •••) is recommended for the prevention of severe lower respiratory tract infections caused by respiratory syncytial virus in infants at high risk. These injections are very painful, and currently the use of analgesics is not systematic. The objective of this study was to compare the efficacy of EMLA with premixed 50% nitrous oxide/oxygen, used alone or combined with EMLA, for pain alleviation during palivizumab injections.

METHODS. This randomized, double-blind, multicenter study included children who were younger than 24 months. Each child randomly received during the first 3 monthly injections 3 different analgesic interventions: (1) EMLA: application of EMLA plus air inhalation; (2) nitrous oxide/oxygen: inhalation of 50/50 nitrous oxide/oxygen plus application of a placebo cream; and (3) nitrous oxide/oxygen plus EMLA: inhalation of 50/50 nitrous oxide/oxygen plus application of EMLA. Each child was his or her own control. Procedural pain was assessed through videotapes with the Modified Behavioral Pain Scale. The procedure itself was subdivided in 2 periods: (1) injection and (2) recovery (first 30 seconds after the removal of the needle). Modified Behavioral Pain Scale scores over time (injection and recovery periods) and among treatments were compared by repeated-measures analysis of variance.

RESULTS. Fifty-five children were included. Mean ± SD Modified Behavioral Pain Scale pain scores for EMLA, nitrous oxide/oxygen, and nitrous oxide/oxygen plus EMLA were, respectively, 9.3 ± 1.0, 8.8 ± 1.2, and 8.2 ± 1.8 during the injection and 7.8 ± 1.7, 7.4 ± 1.9, and 6.9 ± 2.4 during the recovery period. A significant time and treatment effect in favor of the combined nitrous oxide/oxygen plus EMLA was observed.

CONCLUSIONS. The administration of 50/50 nitrous oxide/oxygen to infants and young children is effective in decreasing the pain associated with palivizumab intramuscular injections. The combined nitrous oxide/oxygen plus EMLA cream was more effective than either EMLA cream or nitrous oxide/oxygen alone.

Key Words: palivizumab • pain • EMLA • nitrous oxide • infants • children • analgesia • procedures • intramuscular • injections • immunizations

Abbreviations: RSV—respiratory syncytial virus • N2O—nitrous oxide • O2—oxygen • VAS—visual analog scale • MBPS—Modified Behavioral Pain Scale


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Palivizumab (Synagis [•••, •••]) is recommended for the prevention of severe lower respiratory tract infections caused by respiratory syncytial virus (RSV) in infants at high risk (eg, certain preterm infants, children who are younger than 24 months and have chronic lung disease or hemodynamically significant congenital heart disease).1 Palivizumab is administered intramuscularly once per month beginning just before the onset of the RSV season. In general, a total of 5 doses are sufficient to provide protection during the entire RSV season.

Palivizumab injections are empirically considered to be very painful, and currently they are performed without a systematic use of analgesics. In 1999, some authors expressed their concern about the insufficient use of analgesia in this context.2 The pain associated with these injections and with immunizations in general may be a source of great anxiety and distress. Indeed, recent research suggested that not only the children themselves but also their families and health care providers have concerns about the pain associated with multiple and frequent injections.3 Parental concern about painful injections may even reduce their compliance with medical care.4 Moreover, children, even at young ages, seem to have a pain memory.5 This growing body of evidence and the widespread acceptance of the ethical imperative to treat pain and anxiety in children make it necessary to find effective ways to alleviate the pain that is induced by these injections.

To our knowledge, no study has focused on pain induced by palivizumab injections. In a more general context, EMLA cream, notwithstanding its limited depth of penetration, has been shown to decrease effectively the pain that is associated with both subcutaneous and intramuscular immunizations.6–9 Inhaled nitrous oxide (N2O) has also been shown to be safe and efficacious to provide anxiolysis, analgesia, and some sedation in children during painful procedures such as venous cannulation,10–12 laceration repair,13 lumbar puncture,14 bone marrow aspiration,14 and fiber-optic bronchoscopy.15 This gas mixture is well tolerated and effective in the outpatient setting.16–18 It is commonly dispensed at concentrations between 50% and 70% with oxygen (O2) composing the remainder of the mixture to alleviate procedural pain. In some countries, a premixed of 50% N2O and O2 in a single tank is available. The objective of this study was to compare the efficacy of EMLA cream with premixed 50% N2O/O2, used alone or combined to EMLA cream, for pain alleviation in infants and young children who underwent repeated intramuscular injections of palivizumab.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Protocol
This randomized, double-blind study took place in the outpatient facilities of 2 neonatal and 1 pediatric pulmonary departments of 2 hospitals. The study protocol was approved by the local ethics committee for the protection of human subjects in medical research. Written informed consent was obtained from parents of each included child. The study patients were medically stable children who required palivizumab intramuscular injections, as part of their medical care, to receive passive immunization against RSV.1 Included children were younger than 2 years. Pretreatment fasting was not required. Exclusion criteria were known allergy to local anesthetics; fever; clinical instability; methemoglobinemia; administration of sulfonamides, metoclopramide, or an analgesic or sedative drug during the preceding 12 hours; and parents who did not understand the study protocol.

Procedures and Masking
During the first 3 consecutive monthly palivizumab injections, each child randomly received 3 different analgesic protocols:

  1. EMLA: application of EMLA cream plus air inhalation;
  2. N2O/O2: inhalation of a 50/50 N2O/O2 mixture plus application of a placebo cream; and
  3. N2O/O2 plus EMLA: inhalation of a 50/50 N2O/O2 mixture plus application of EMLA cream.

Thus, during the study period, each child received 3 injections, 1 per month. For each child, a different intervention was used for each injection, and the order in which the child received the 3 interventions was random. Identical-appearing placebos were available for both EMLA and N2O/O2; placebo cream had the same aspect as EMLA cream, and air and N2O/O2 containers were covered in exactly the same way and labeled with a code. Air and N2O/O2 were administered via a disposable, cushioned facial mask covering the child's nose and mouth. Each child was his or her own control. At inclusion, the research assistants opened a consecutively numbered opaque envelope, which contained the treatment assigned to each infant. According to the indication in the envelopes, they prepared the corresponding gas container and inhalation system and also applied ~1.0 g of the cream on the child's left thigh. The cream application site was covered with a dressing. After 1 hour, the dressing was removed and the cream was wiped away by 1 of the research assistants. Participating children were taken to a quiet room for injections, and their parents were encouraged to be present during the procedure. Children's legs and feet were uncovered to allow observation of movements. They laid supine on an examination table during the procedures. No specific comfort measures were provided. All the injections were videotaped with a color digital camera by 2 research assistants. A mirror was mounted on the wall behind the examination table so that facial expressions could be captured on the video both face on and from the mirror image. The assigned gas was administered with a continuous flow for 3 minutes before the injection was performed; the inhalation continued throughout the injection and ended at the needle removal. The gas flow meter was initially set to provide 6 L/minute and was then adapted to the child's breathing.19 All injections were performed on the anterolateral thigh of the child by 4 experienced health care providers (operators): 1 nurse in 1 neonatology department, 2 nurses in the pulmonary department, and 1 staff neonatologist in the other neonatology department. Needles for injections were 25 mm (1 in) and 24 G in all centers. The maximum volume injected on a thigh was 1 mL; when the total required dosage of palivizumab (15 mg/kg [0.15 mL/kg]) exceeded this volume, the rest of the dose was injected on the other thigh. All injections started on the left thigh. For the purpose of the study, only the first injection (left thigh) was videotaped and analyzed. After the end of the procedure, the patient remained for observation in the outpatient facility for at least 15 minutes and was then discharged from the hospital.

Pain Assessment
At the end of the procedure, parents and operators were asked to rate on a visual analog scale (VAS; 0–100 mm, where 0 indicates no pain and 100 indicates maximum pain) the pain induced by the injection. Whenever mothers were present, they conducted parents' assessments; fathers did so only when mothers were absent. We decided to use VAS because we believed that it was easy to use by parents. When all inclusions were completed, 2 specially trained observers assessed together the procedure-related pain from the video recordings using the Modified Behavioral Pain Scale (MBPS) for infants. This is a behavioral scale developed to rate acute pain in infants.20 Scores range from 0 (no pain) to 10 (maximum pain). It evaluates 3 items: facial expressions, cry, and movements (Table 1).


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  		TABLE 1 Modified Behavioral Pain Scale20

 
For the video assessment, observers first established a baseline MBPS score for the 30-second period that preceded the start of gas inhalation. The procedure itself was subdivided in 2 observation periods: (1) the injection (skin puncture, injection of palivizumab, and removal of the needle) and (2) the recovery (the first 30 seconds after the removal of the needle). Observers could stop and restart the videotape as many times as they needed to establish a score. These observers were unaware of treatment assignment. The MBPS score during the procedure was the primary outcome measure. Secondary outcomes were the VAS pain scores as assessed by the parent and the operator.

Assessment of Adverse Effects
Adverse effects were evaluated for all children. Local skin reactions, such as blanching and local erythema, were assessed by visual examination at time of dressing removal and 5 and 10 minutes later. Level of consciousness, vomiting, and agitation were also monitored during inhalation and until 15 minutes after the removal of the inhalation device.

Assignment
Each child was randomly assigned to receive the 3 different analgesic interventions in a random order during the first 3 consecutive monthly palivizumab injections. An assistant not involved in the study performed the randomization in advance using a random-number table. A randomization list was prepared for each center. Treatment allocations were placed in opaque sealed envelopes numbered consecutively; each of these principal envelopes contained 3 secondary envelopes marked first, second, and third injection that contained indications for the type of intervention for each injection. The randomization assignment was stored in a secure location that could not be accessed by the study investigators, who were blind to these allocations. Codes of allocation were kept secret by the assistant who performed randomization, and they were uncovered only after all videotape assessments were accomplished.

Sample Calculation
Calculations were conducted with the NCSS (•••, •••, •••) and PASS 2002 (•••, •••, •••) statistical software using the module designed for 1-sample t test power analysis to approximate the sample needed for a repeated-measure analysis. We calculated that a sample of 45 infants would achieve 90% power to detect a difference of 1 point in the primary outcome measure, the MBPS scores, with a SD of 2.0 and with a significance level ({alpha}) of .05 using a 2-sided test. We decided to randomly assign 59 infants to cover potential problems with video recordings and dropouts after the first injection.

Statistical Analysis
Pain scores over time and among treatments were compared by repeated-measures analysis of variance. Before this analysis, we verified whether baseline MBPS scores (ie, before gas inhalation) were similar among the 3 analgesic interventions. Because the 3 analgesic interventions were made on the same patients, 2 within-subjects factors analysis were included in the model. The first factor was time, which included 2 levels: injection and recovery periods. The second factor was treatment, which included 3 levels corresponding to each analgesic intervention. To have another approach to pain assessment, MBPS scores observed during the injection period were dichotomized in >6 and ≤6 for the 3 interventions. Their equality of proportions across the 3 interventions was compared with a nonparametric test for related groups, the Cochran's Q Test. Regression analysis was used to determine whether demographic characteristics predicted MBPS scores. Parent VAS and operator VAS rating across the 3 interventions were compared by repeated-measures analysis of variance; the models included 1 within-subject factor, the treatment. Because vomiting, local skin reactions, and operators' satisfaction were dichotomous variables, their proportions across the interventions were compared with the Cochran's Q Test. In all analyses, P < .05 was considered statistically significant. The statistical analysis was conducted by using SPSS 14 for Windows software (SPSS Inc, Chicago, IL).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Between October 2004 and March 2006, a total of 59 children were randomly assigned; of these, 55 completed the 3 injections and were retained in the analyses. Two parents withdrew consent, and parents of 2 infants abandoned the study after the first injection. Figure 1 shows the flow of study participants. Table 2 shows the demographic characteristics of the participating children. Mean (SD) noncorrected postnatal age at time of EMLA, N2O/O2, and N2O/O2 plus EMLA treatments were, respectively, 8.7 (5.7), 8.8 (5.6), and 8.7 (5.5) months (P = .8).


Figure 1
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  		FIGURE 1 Flow diagram of the trial profile.

 

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  		TABLE 2 Demographic Characteristics of the Study Population

 
MBPS Scores
The application of the facial mask did not interfere with the ability to perform MBPS scores. Mean MBPS scores are summarized in Fig 2. Baseline mean (SD) MBPS scores were similar for the 3 interventions: EMLA 2.7 (1.8), N2O/O2 3.0 (2.0), and N2O/O2 plus EMLA 2.5 (1.5; P = .31). Mean (SD) MBPS pain scores for EMLA, N2O/O2, and N2O/O2 plus EMLA treatments were, respectively, 9.3 (1.0), 8.8 (1.2), and 8.2 (1.8) during the injection period and 7.8 (1.7), 7.4 (1.9), and 6.9 (2.4) during the recovery period. Analysis of scores from serial measurements showed a significant time (P < .001), and treatment (P < .001) effect in favor of the combined N2O/O2 plus EMLA treatment. All pairwise comparisons of MBPS scores among the 3 analgesic treatments were statistically significant: EMLA versus N2O/O2 (P = .024), N2O/O2 versus N2O/O2 plus EMLA (P = .013), and EMLA versus N2O/O2 plus EMLA (P < .001). During the injection period, the number of MBPS scores ≤6 were, respectively, 1, 3, and 8 for EMLA, N2O/O2, and N2O/O2 plus EMLA treatments (P = .008). A regression analysis did not show any predictive value of gender, birth weight, gestational age at birth, or corrected age at injection on MBPS scores. A repeated-measures analysis including 3 groups of gestational age at birth (25–28 weeks [n = 29], 29–36 weeks [n = 16], and 37–41 weeks [n = 10]) as a between-subjects factor did not show an effect of gestational age on MBPS scores during the inhalation and recovery periods (P = .396).


Figure 2
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  		FIGURE 2 Mean MBPS scores before gas inhalation and during the injection and recovery periods as assessed from videotape recordings. MBPS scores before inhalation were similar among the 3 interventions (P = .31). A repeated-measures analysis including the injection and recovery periods showed significant time (P < .001) and treatment (P < .001) effects. All pairwise comparisons of MBPS scores among the 3 analgesic treatments were statistically significant: EMLA versus N2O/O2 (P = .024), N2O/O2 versus N2O/O2 plus EMLA (P = .013), and EMLA versus N2O/O2 plus EMLA (P < .001).

 
Operators' and Parents' Pain Assessment
Pain assessments by the operator and parents are shown in Fig 3. For operator assessments, the means (SDs) of VAS scores were 45.9 (22.1), 40.4 (22.6), and 37.4 (23.4) for EMLA, N2O/O2, and N2O/O2 plus EMLA treatments, respectively. A within-subjects factor analysis showed a treatment effect (P = .019); pairwise comparisons are shown in Fig 3. With regard to parent assessment, data were not obtained on 7 occasions (EMLA: n = 2; N2O/O2: n = 3; and N2O/O2 plus EMLA: n = 2) because parents, although present, preferred not to look at the injection procedure. Mothers were present and assessed the injection pain on 44, 44, and 46 occasions for EMLA, N2O/O2, and N2O/O2 plus EMLA treatments, respectively; the other assessments were completed by fathers. Hence, the repeated-measures analysis was conducted only for the 50 children for whom parent assessments were complete for the 3 interventions. Means (SD) for parent VAS scores were 36.1 (24.4), 34.9 (24.9), and 26.0 (23.7) for EMLA, N2O/O2, and N2O/O2 plus EMLA treatments, respectively. A within-subjects factor analysis showed a treatment effect (P = .015); pairwise comparisons are described in Fig 3. Operators were satisfied or very satisfied with the analgesic efficacy of the interventions in 23 (41%) of 55 cases during EMLA, in 32 (58%) of 55 during N2O/O2, and in 33 (60%) of 55 during N2O/O2 plus EMLA (P = .019).


Figure 3
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  		FIGURE 3 Mean pain scores during palivizumab injections as assessed by operators and parents on a 0- to 100-mm VAS. A within-subjects factor analysis showed a treatment effect (operators' assessments: P = .019; parents' assessments: P = .015). Pairwise comparisons of operator VAS scores show EMLA versus N2O/O2 (P = .071), N2O/O2 versus N2O/O2 plus EMLA (P = .314), and EMLA versus N2O/O2 plus EMLA (P = .008). Pairwise comparisons of parental VAS scores showed EMLA versus N2O/O2 (P = .77), N2O/O2 versus N2O/O2 plus EMLA (P = .019), and EMLA versus N2O/O2 plus EMLA (P = .005).

 
Adverse Effects
All adverse effects encountered in this study were minor and self-limiting. Vomiting and consciousness levels were monitored as potential adverse effects of N2O inhalation. One episode of vomiting was observed for only 1 patient during N2O/O2 plus EMLA treatment (P = .36). No drowsiness was observed, and all children remained awake during the 3 interventions. With regard to localized cutaneous reactions, a mild blanching was observed in 4 (7.3%) of 55, 4 (7.3%) of 55, and 5 (9.1%) of 55f EMLA, N2O/O2, and N2O/O2 plus EMLA treatments, respectively (P = .92). A transient mild erythema at the site of cream application was observed in 1 of 55, 0 of 55, and 1 of 55 EMLA, N2O/O2, and N2O/O2 plus EMLA treatments, respectively (P = .60).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
To our knowledge, this is the first study to evaluate the relative effectiveness of EMLA cream and inhaled N2O for infants and young children who were undergoing palivizumab injections. We found that the combination of EMLA cream and fixed 50% N2O/O2 was more effective than either EMLA cream alone or fixed 50% N2O/O2 alone in reducing the pain that is induced by these injections as judged by MBPS scores that were obtained by 2 trained observers from videotape recordings and by VAS rated by parents. Analysis of operators' assessments showed that the combination of EMLA cream and fixed 50% N2O/O2 was superior to only EMLA cream. With regard to the other pairwise comparison (N2O/O2 versus EMLA), only the analysis of the main outcome, MBPS scores, showed that fixed 50% N2O/O2 was more effective than EMLA cream. These assessment differences highlight the difficulties of pain assessment of infants and young children and underline the need for the use of validated tools to measure pain in this population. It is important to note the higher pain intensity observed with the MBPS scale as compared with VAS assessments conducted by parents and operators. One possible explanation is that baseline MBPS scores already approached 3 before inhalation; thus, the final score may have summed up the reactions induced by the injection and the baseline anxiety. Parents and operators, however, may have assessed only the pain that was induced by the injection. Other authors have compared EMLA cream and N2O/O2 during other painful procedures in older children. Hee et al10 found in children aged 8 to 18 years no difference between EMLA and 50% N2O/O2 to reduce pain during venous cannulation. They did find, however, in agreement with our results, that the combination of both techniques was superior to either 1 alone with significant reduction of pain and provision of greater satisfaction with the procedure experience.10

Most infants at high risk who require palivizumab have a history of hospitalization during their first days or weeks of life and have usually undergone many painful procedures. Recent data suggest that early injury can permanently alter pain processing21 and that the plasticity of the developing nervous system may allow for the greatest impact of pain to occur in the least maturely born infants.22 Thus, the potential pain sensitization developed by infants who have experienced repetitive pain together with the increased awareness that the treatment and prevention of pain are human rights regardless of age make the alleviation of repeated, painful, intramuscular palivizumab injections an important issue. One possible explanation for the important pain that is induced by palivizumab injections is the acidic pH of the injected material; the reconstituted palivizumab solution has a pH of 6.0 (Abbot Laboratories Ltd, package insert). Higher pain for acidic vaccines has already been reported.23

Our study has also shown that 50% N2O in O2 may be effective for children who are younger than 2 years; however, other studies have suggested that N2O is less effective for children who are younger than 2 or 3 years. Bar-Meir et al24 found that children who were younger than 3 years benefited less from 50% N2O in O2 compared with older children during repair of facial lacerations. This observation is in agreement with results reported by Annequin et al14 indicating that more pain behavioral reactions were observed in children who were younger than 3 years. Similarly, Fauroux et al15 found that the rate of failure during fiberoptic bronchoscopy in children with premixed 50% N2O/O2 was greater in patients who were ≤2 years compared with older children. This reduced efficacy may be attributed to the distress that is induced by the application of the mask to the face and the difficulty in explaining the procedure to the younger children.24 Nonetheless, in all of these studies, an analgesic effect of N2O/O2 was observed in children who were younger than 3 years; and even if it seemed to be inferior to that observed in older children, pain scores were lower compared with their counterparts in the control groups.15,24 Therefore, we believe that 50% N2O in O2 combined to EMLA cream is an effective analgesic strategy during palivizumab injections, which are empirically considered by parents and health care providers to be very painful. It has been suggested that higher N2O concentrations are more effective. Henderson et al11 compared 70% N2O with 50% N2O during venous cannulation in children aged 3 weeks to 18 years. They found the former concentration to be more effective in reducing cannulation-induced pain; however, the adverse effects were higher in the 70% N2O group; 28% of patients in 70% N2O group presented adverse effects that included excitement, dysphoria, nausea, restlessness, and opisthotonic movements versus none in the 50% N2O group. Of note, 75% of these adverse effects occurred in children who were ≥5 years of age.

With regard to adverse effects attributable to N2O/O2 in our study, vomiting was observed in only 1 child, and none of the children lost consciousness while breathing the fixed 50% N2O/O2 mixture. Indeed, many studies have shown that 50% N2O/O2 is very safe.14,25,26 The incidence of vomiting during 50% N2O/O2 inhalations in children was, respectively, 6% and 3.7% in 2 studies reported by Luhmann et al13 and Annequin et al.14 Although vomiting is a possible event, preprocedure fasting is not required because the aspiration risk seems not to be significant. Two experimental studies showed that pharyngeal and laryngeal reflexes are not compromised by brief N2O exposure at concentrations of <65%.27,28 To our knowledge, no study has reported aspiration during the clinical use of 50% N2O/O2 for procedural pain. The safety of N2O inhalation is reinforced by the use of a fixed 50% mixture in O2 because at this concentration, patients remain awake in a state of mild sedation. In fact, N2O is a relatively weak inhalation anesthetic agent that has effective analgesic properties at concentrations below those required for anesthesia.29 The minimum alveolar concentration of N2O, defined as the alveolar concentration of the gas required to prevent movement in 50% of patients who are given a noxious stimulus, has been studied in adult volunteers by using hyperbaric pressures and was found to be 1.04 atm absolute.30,31 Minimum alveolar concentration values increase with decreasing age31; therefore, at atmospheric pressure, N2O cannot achieve anesthesia. Collado et al32 conducted a literature review on the safety of 50% N2O/O2 in children and adults and concluded that this gas mixture is extremely safe in a wide range of disciplines and clinical contexts whether administered by physicians other than anesthetists, dentists, or paramedical personnel. In 2002, the American Society of Anesthesiologists stated that 50% N2O in O2 with no additional analgesia or sedation by any route elicits minimal sedation with minimal risks and thus can be safely used by practitioners who are not specialists in anesthesiology.33

Although no study has been reported on the efficacy of EMLA cream to alleviate the pain related to palivizumab injections, this cream is used in some centers for this indication probably because some studies suggested that it is effective to reduce immunization pain. Halperin et al6 reported the efficacy of EMLA cream to reduce the pain related to diphtheria, tetanus, acellular pertussis, inactivated poliovirus, Haemophilus influenzae type b conjugate, and hepatitis B vaccines in 165 infants from birth to 6 months of age. Likewise, Taddio et al8 found that EMLA cream decreased pain that is associated with diphtheria-pertussis-tetanus vaccination in infants. Despite the limited depth of penetration of EMLA cream, its efficacy in reducing injection pain is likely attributable to a decrease in pain as the needle penetrates the skin, as well as a reduction in the underlying muscle spasm that is associated with this pain.3 Although the delayed onset of action of EMLA cream (60 minutes) may limit its applicability for immunization in the office setting, this may not be an issue during palivizumab injections in the outpatient hospital facilities, because a careful coordination will allow this potential problem to be overcome either by establishing a protocol for application of the cream by nurses on arrival or by home application by parents, instructed on the application site, before leaving for the hospital. Furthermore, the reconstituted palivizumab should stand undisturbed at room temperature for at least 20 minutes before injection.

Interpretations of these results should acknowledge 3 limitations. First, we did not include a placebo group that would have allowed us to determine the absolute efficacy of each analgesic intervention. We chose not to randomly assign children to a placebo group because there was some evidence of the effectiveness of EMLA cream for intramuscular immunizations and because many centers already use EMLA cream for palivizumab injections. We believed that it would be not ethical to deny children analgesia for the purposes of our study. Second, the use of 50% N2O/O2 requires that children receive palivizumab injections in a hospital setting because this gas mixture is not available outside the hospital. It should be noted, nonetheless, that in many French centers, palivizumab injections are administered in the outpatient facilities of neonatal and pulmonary hospital departments. Finally, it should be noted that MBPS is a measure of distress that includes pain and anxiety and that it is almost impossible to differentiate 1 from the other in infants. Also, because we did not determine MBPS scores during the 3 minutes of gas application preceding the injection, we cannot exclude that the application of the gas mask induced a certain anxiety during that phase. The distress that is induced by the application of the mask to young children has been previously described.15,24


   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
The administration of 50% N2O in O2 to infants and young children is effective in decreasing the pain that is associated with palivizumab intramuscular injections. We found that the combined N2O/O2 plus EMLA cream was more effective than either EMLA cream or N2O/O2 alone and that N2O/O2 may be more effective than EMLA cream alone. The use of these analgesic strategies will contribute to the improvement of pain management during palivizumab injections. Nevertheless, that even with the use of these analgesic interventions pain scores were still high supports the need to pursue the search for other effective ways to reduce further the pain that is induced by these intramuscular injections. Future investigations might explore the efficacy of these strategies combined to nonpharmacologic approaches such as distraction, music, parental comforting, or sweet solutions in infants who are younger than 6 months.


   ACKNOWLEDGMENTS
 
This study was funded by the Association Pour le Développement du Centre National de Ressources de Lutte Contre la Douleur (Paris, France). Air Liquide covered the cost of the insurance paid for this study ({euro}3061). Air Liquide did not participate in any phase of the study, nor did they did have access to any data or report of the study.

We thank the nursing staff of the participating units of the Trousseau Hospital and Poissy Saint Germain Hospital. We are indebted to the parents for allowing their infants to participate in the study. We also thank Florence Reiter and Elisabeth Sohet for technical assistance during the different phases of this study.


   FOOTNOTES
 
Accepted Nov 30, 2007.

Address correspondence to Ricardo Carbajal, MD, PhD, Centre National de Ressources de Lutte Contre la Douleur, Hôpital d'Enfants Armand Trousseau, 26, av du Dr Netter, 75012 Paris, France. E-mail: ricardo.carbajal{at}trs.aphp.fr

Dr Carbajal conceived and designed the study, supervised data collection, performed the statistical analysis, analyzed the results, wrote the final article, and is guarantor; Drs Epaud, Biran, and Lenclen participated in the design of the study, enrolled patients, analyzed the results, and participated in writing the article; Dr Fauroux participated in design of the study and in writing the article; Drs Cimerman and Thibault participated in the design of the study, and writing the article, and Drs Annequin and Gold participated in the design of the study and in writing the article.

This study was presented at the annual meeting of the Pediatric Academic Societies (May 5–7, 2007; Toronto, Ontario, Canada).

This trial has been registered at the Agence Française de Sécurité Sanitaire de Produits de santé (AFSSAPS; identifier 040852).

The authors have indicated they have no financial relationships relevant to this article to disclose.


What's Known on This Subject

Palivizumab injections are very painful, and currently the use of analgesics is not systematic. N2O has been shown to be safe and efficacious in providing anxiolysis, analgesia, and some sedation during painful procedures.

 

What This Study Adds

N2O (50%) in oxygen effectively decreased pain associated with palivizumab injections. The combination of N2O plus EMLA was more effective than either EMLA or N2O alone. These analgesic strategies will improve pain management during palivizumab injections.

 


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics




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