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Topical Lidocaine to Improve Oral Intake in Children With Painful Infectious Mouth Ulcers: A Blinded, Randomized, Placebo-Controlled Trial
PEDIATRICS/ORIGINAL RESEARCH
Topical Lidocaine to Improve Oral Intake in Children With Painful Infectious Mouth Ulcers: A Blinded, Randomized, Placebo-Controlled Trial Sandy M. Hopper, FRACP, FACEM; Michelle McCarthy, MN; Chasari Tancharoen, MBBS; Katherine J. Lee, PhD; Andrew Davidson, MD; Franz E. Babl, MD, MPH
Study objective: We establish the efficacy of 2% viscous lidocaine in increasing oral intake in children with painful infectious mouth conditions compared with placebo. Methods: This was a randomized placebo-controlled trial of viscous lidocaine versus placebo at a single pediatric emergency department. Study staff, clinicians, nurses, caregivers, and participants were blinded to the group assignment. Children with acute infectious ulcerative mouth conditions (gingivostomatitis, ulcerative pharyngitis, or hand, foot, and mouth disease) and poor oral fluid intake were randomized to receive 0.15 mL/kg of either 2% viscous lidocaine or placebo with identical appearance and flavor. The primary outcome was the amount of fluid ingested in the 60 minutes after administration of the intervention, with a difference in intake of 4 mL/kg considered clinically important. Secondary outcomes were specific milliliter per kilogram fluid targets and incidence of adverse events. Results: One hundred participants were recruited (50 per treatment group), all of whom completed the 60-minute fluid trial period. Oral intake 1 hour after drug administration was similar in both groups: lidocaine median 8.49 mL/kg (interquartile range 4.07, 13.84 mL/kg) versus placebo 9.31 mL/kg (interquartile range 3.06, 15.18 mL/kg); difference in medians 0.82 mL/kg (95% confidence interval –2.52 to 3.26); Mann-Whitney P¼.90. Likewise, short-term secondary outcomes were similar between the groups and there were no adverse events in either group. Conclusion: Viscous lidocaine is not superior to a flavored gel placebo in improving oral intake in children with painful infectious mouth ulcers. [Ann Emerg Med. 2014;63:292-299.] Please see page 293 for the Editor’s Capsule Summary of this article. A feedback survey is available with each research article published on the Web at www.annemergmed.com. A podcast for this article is available at www.annemergmed.com. 0196-0644/$-see front matter Copyright © 2013 by the American College of Emergency Physicians. http://dx.doi.org/10.1016/j.annemergmed.2013.08.022
INTRODUCTION Background Painful ulcerative infectious mouth conditions in children are a common presentation to emergency departments (EDs). These are predominantly viral conditions such as gingivostomatitis (herpetic and nonherpetic), ulcerative pharyngitis, herpangina, and hand, foot, and mouth disease. Of these, primary herpetic gingivostomatitis is the most studied.1-3 Presentation to the ED is often due to decreased oral intake or pain. The diagnosis of infectious mouth conditions is clinical,4 and treatment primarily involves pain relief and the provision of sufficient oral fluid intake to prevent dehydration.4,5 Randomized trials of acyclovir for primary herpetic gingivostomatitis provide weak evidence in support of its use.1-3,6 However, even if antiviral medications are used, their onset of action limits their effectiveness in resolving the acute issue of fluid refusal. Many topical agents have been described for specific painful
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ulcerative mouth conditions in adults and children, such as cancerrelated mucositis, oral candidiasis, and aphthous ulcers.7 These include viscous lidocaine,8-10 benzocaine preparations, diphenhydramine elixir,11 coating agents (such as sucralfate,12 Maalox,3 milk of magnesia and Kaopectate),13 antibiotics14 (particularly chlorhexidine15 and tetracycline), and combinations of these agents.11,16-19 The few trials that assess the efficacy of treatments for ulcerative mouth conditions focus on pain rather than oral intake and have been in adults with aphthous ulceration8,20 or patients with neoplasia-associated mucositis.12,16,18,21 Importance Although several authorities4,5,22,23 support viscous lidocaine as treatment for acute infectious ulcerative mouth conditions in children, to date there have been no randomized controlled trials to support the use of topical agents for painful ulcerative conditions of the mouth in otherwise healthy children.
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Editor’s Capsule Summary
What is already known on this topic Children with painful mouth ulcers drink less and may become dehydrated. What question this study addressed Does fluid intake improve when 2% viscous lidocaine is applied to oral ulcers? What this study adds to our knowledge In this randomized, placebo-controlled trial of 100 children with mouth ulcers and decreased oral intake, the volume of fluid subsequently ingested was similar between groups. How this is relevant to clinical practice The application of viscous lidocaine to painful oral ulcers does not enhance the willingness of young children to drink.
Goal of This Investigation In this placebo-controlled randomized trial we set out to assess whether topical 2% viscous lidocaine is better than placebo at increasing oral intake in children with infectious mouth conditions. A difference in fluid intake of 4 mL/kg was considered clinically important. The secondary goals were to determine whether there was a difference in the proportions of children ingesting 5, 10, or 20 mL/kg of fluid within 0 to 30 and 0 to 60 minutes from the time of administration of the study drug, the proportion deemed to have an adequate fluid intake according to the treating clinician, the proportion requiring additional treatments (analgesia, intravenous, or nasogastric fluid), the incidence of adverse events, the admission rate, and the duration of stay in the ED between the intervention and placebo group.
MATERIALS AND METHODS We present brief details of the study protocol below. A more detailed version of the trial protocol has been published elsewhere.24 Study Design and Setting This study was a randomized, blinded, placebo-controlled trial conducted at the ED of the Royal Children’s Hospital, a tertiary referral center in Melbourne, Australia, with an annual census of 70,000 patients. Ethics approval was obtained from the Royal Children’s Hospital Human Research and Ethics Committee, approval number 29070C. Parents or guardians gave written informed consent for their child to take part in this study. The trial was registered with the Australian and New Zealand Clinical Trials Registry: ACTRN12609000566235. Volume 63, no. 3 : March 2014
Selection of Participants The study participants were a convenience sample. When research assistants or investigators were present in the department (approximately 50 hours per week), potential participants were screened consecutively by triage or research staff on presentation to the ED and were approached by research staff if potentially eligible. Once consent was obtained, participants were assessed for eligibility. Participants were randomized once eligibility had been confirmed. Eligible participants were patients (1) aged 6 months to 8 years; (2) who presented with gingivostomatitis (herpetic or nonherpetic), ulcerative pharyngitis, herpangina, or hand, foot, and mouth disease as clinically diagnosed by the treating clinician; and (3) had a history of poor oral fluid intake (defined as parent or guardian report of “not drinking well,” as well as a parent-reported oral fluid intake less than 10 mL/kg of fluid in the preceding 2 hours). Exclusion criteria included hypersensitivity to any of the components of lidocaine or other amide local anesthetics, and patients with diseases in which elevated plasma levels of lidocaine may be dangerous (such as epilepsy, impaired cardiac conduction, bradycardia, or impaired hepatic or renal function). We also excluded patients who were severely dehydrated or toxic, requiring immediate resuscitation; patients with more than 2 episodes of vomiting before the ED presentation; dental disease, mouth trauma, or malignancy; patients receiving cardiac or other drugs with possible interactions with lidocaine; patients who had previously received more than 1 dose of oral topical anesthetic for the same illness; patients with preexisting upper airway obstruction or swallowing difficulties; patients who had received analgesia within 1 hour preceding enrollment to the study; and patients with non–English speaking parents/guardians. Interventions After consent, participants were randomized, using block randomization with block sizes of 2 and 4, to receive lidocaine or placebo. Sequentially numbered bottles of study drug were prepared by a pharmacist who was otherwise independent of the study. The randomization allocation sequence was prepared by the Clinical Epidemiology and Biostatistics Unit at the Royal Children’s Hospital. At randomization, participants were given the next available study number, which equated to an allocation of study drug dispensed in 2 bottles (labeled A and B). After randomization, patients received a weight-based dose from bottle A, which contained the allocated study drug (either lidocaine or placebo). Bottle B contained the alternative mixture, ie, lidocaine if randomized to placebo and placebo if randomized to lidocaine. Sixty minutes after the application of the dose from bottle A, the treating clinician was able to administer the contents of this second bottle if clinically warranted, which ensured that all participants in the study had access to the active treatment while maintaining the blinding of the study. All study drugs were packaged in blinded containers stored in a locked cupboard labeled only with the study details, the study number, and bottle A or B. Only the pharmacist and the Annals of Emergency Medicine 293
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Topical Lidocaine for Children With Mouth Ulcers independent person who generated the randomization list were aware of the treatment allocation and could unblind group assignment in an emergency. The participants, caregivers, treating staff, and research staff were blinded to the treatment allocation. Lidocaine was administered as a commercially available viscous mixture of 2% lidocaine hydrochloride (Xylocaine Viscous; AstraZeneca, North Ryde, New South Wales, Australia), made up with methyl hydroxybenzoate, propyl hydroxybenzoate, sodium hydroxide, saccharin sodium, cherry extract (water, flavor, citric acid, and amaranth), carmellose sodium, and water. Dosing of oral 2% viscous lidocaine was as set out according to the Royal Children’s Hospital Pediatric Pharmacopoeia at 0.15 mL/kg.25 The placebo was made up by the Royal Children’s Hospital Pharmacy from stock ingredients of methylcellulose and cherry flavoring and was identical to the study drug in terms of appearance, flavor, and smell. The single dose of 0.15 mL/kg of study drug was administered as soon as possible after randomization. Administration was by the treating nurse by a measured syringe to the oral cavity of the participant, aiming to cover the inflamed mucosa and ulcerative lesions (study flow chart; Figure 1). If the participant was mature enough, he or she was instructed to gargle and spit out the study drug. Younger participants simply swallowed or spat out the study drug. For the 60 minutes after application (the fluid trial period), subjects were actively encouraged to drink a range of fluids. The amount of fluid ingested within 0 to 30 and 30 to 60 minutes after administration was recorded on a hospital fluid balance chart. With the exception of the bottles of study drug, 2% viscous lidocaine was not prescribed by the treating clinician during the 90-minute study period or for the subsequent 90 minutes because of risk of lidocaine toxicity. Sixty minutes after study drug administration, the treating clinician reassessed the participant’s fluid intake and clinical status and then could decide to administer the second bottle of study drug allocated to that participant (bottle B) or administer other oral analgesia, eg, acetaminophen, ibuprofen, The study was terminated 90 minutes after study drug administration (ie, 30 minutes after the end of the 60-minute fluid trial period) (Figure 1), after assessment for adverse events; in particular, a review for signs of aspiration (new cough, decreased oxygen saturation, focal chest signs). A completed participant was defined as a participant who had the solution administered and had their fluid intake monitored for a minimum of 60 minutes from the time of study drug administration. After study termination, the treating physician was free to decide disposition care and further medications, including the prescription of viscous lidocaine. Methods of Measurement and Outcome Measures The primary outcome was the amount of fluid ingested within 60 minutes of administration of the study drug, expressed in milliliters per kilogram. 294 Annals of Emergency Medicine
Potential patient presents at ED Triage
Eligibility assessed and informed consent obtained
Double-blinded randomization
2% viscous lidocaine (bottle A)
Time = 0 minutes
Placebo Gel (bottle A)
60 min trial of fluids
Time = 60 minutes
Treating doctor reviews fluid intake with option to give bottle B and/or oral analgesia
Time = 90 minutes
Clinical review for signs of aspiration
Usual ED care
Description: the study schedule during the 60-minute fluid trial period and the subsequent 30-minute observation period.
Figure 1. Study flow chart.
Secondary outcomes included both short-term outcomes (those within 60 minutes of drug administration) and longer-term outcomes (those more than 60 minutes after drug administration). Longer-term outcomes were not part of the randomized comparison because after 60 minutes both groups had access to lidocaine and nonrandomized interventions (such as provision of additional oral analgesia). Short-term outcome measures included (1) whether the participant ingested more than 5, 10, or 20 mL/kg of fluid within 0 to 30 and 0 to 60 minutes from the time of administration of the study drug; (2) whether oral intake was deemed adequate at 60 minutes (as determined by the treating clinician); and (3) whether additional treatment for mouth ulcers was used at the end of the 60-minute fluid trial period, including bottle B and other oral analgesic agents. Longer-term outcome measures included (1) incidence of adverse events (allergic reactions, seizures, cardiac arrhythmia, and clinical episodes of aspiration) within the 90-minute study period; (2) whether the patient required fluid administration by intravenous line or nasogastric tube (oral hydration failures) within the 90-minute study period; (3) whether the participant required hospital admission; and (4) duration of stay in the ED. Volume 63, no. 3 : March 2014
Hopper et al Fluid amounts ingested were measured by research staff according to calculated measurements of cups, other containers, and syringes in use in the ED or packaged frozen rehydration solution. All adverse experiences observed by the investigator or one of the clinical staff, or reported by the patient’s parents/ guardians spontaneously or in response to a direct question that occurred during the 60-minute study period and the 30-minute observation period, were recorded. To our knowledge, before this study there was no published literature on the effectiveness of 2% viscous lidocaine for improving oral fluid intake in painful infectious mouth conditions in children; hence, we carried out a planned interim analysis after the first 20 patients to estimate the average fluid intake and spread of the data in our 2 treatment groups. The data from the interim analysis were reasonably normal; hence, we compared the mean fluid intake in the 2 groups. We found a mean difference of 4.3 mL/kg (SD¼7 mL/kg) ingested during the 60-minute fluid trial period between the 2 treatment groups. This difference was considered clinically important in a review of expert clinical opinion (10 pediatric emergency attending physicians in Melbourne, Australia). Assuming a slightly conservative estimate of the treatment effect of 4 mL/kg and an SD of 7 mL/kg, we estimated that a sample size of 50 children per group (100 children in total) would be required to find a difference between the 2 groups according to 80% power and 5% significance. No allowance was made for loss to followup because of the short timeframe of this study. Primary Data Analysis Analysis was by intention-to-treat, in which outcome data were available, although as a sensitivity analysis we also present data from a per-protocol analysis. Data were analyzed with Stata (version 12.0; StataCorp, College Station, TX). The planned analysis for the primary outcome according to the interim data was to report the mean intake in each group and its SD, with the comparison between the groups presented as a difference in means and its 95% confidence interval (CI), obtained by using an unadjusted linear regression, and the hypothesis of no difference between the groups tested with a t test. The observed data were reasonably skewed, so instead we summarize the data as the median and interquartile range within each group, present an estimate of the difference in medians and its 95% CI (estimated with the cendif command in Stata), and compare the 2 groups with a Wilcoxon rank sum test. We also present the results from the planned analysis for consistency. Secondary short-term outcomes were compared between the groups with linear regression for continuous data and differences in proportions for categorical data, with results presented as estimates of the difference between the groups and 95% CIs. Longer-term outcomes are reported descriptively only.
RESULTS Characteristics of Study Subjects Between November 2009 and November 2012, Royal Children’s Hospital ED diagnosed infectious mouth ulcers in Volume 63, no. 3 : March 2014
Topical Lidocaine for Children With Mouth Ulcers 710 children, of whom 221 were assessed for inclusion (Figure 2). In total, 101 patients were randomized; however, 1 participant left the ED before completion of the 60-minute fluid trial period. This participant left the ED 40 minutes after administration of the study drug; therefore, there were no outcome data and the participant was excluded from all analyses. Thus, 100 participants were available for analysis. Two participants in the lidocaine group received acetaminophen during the 60-minute fluid trial period, one from a parent and the other from a staff member. Both of these participants are included in the analysis. In addition, 1 family in the lidocaine group and 2 families in the placebo group left during the 30-minute observation period after the 60-minute fluid trial period. These participants had complete data for the 60-minute fluid trial period; hence, they were included in the analysis of the primary and short-term secondary outcomes but are not included in the summaries of the longer-term outcomes. Baseline characteristics of the groups are presented in Table 1. Most participants (73%) were mildly dehydrated and herpetic gingivostomatitis was the most frequent clinical diagnosis (42%). The amount of fluid ingested at 60 minutes was similar in both groups (Figure 3). The median amount of fluid ingested in the lidocaine group was 8.49 mL/kg (interquartile range 4.07, 13.84); in the placebo group, 9.31 mL/kg (interquartile range 3.06, 15.18) (difference in medians 0.82 mL/kg; 95% CI –2.52 to 3.26; Mann-Whitney P¼.9). In keeping with the original analysis plan, the mean amount of fluid ingested in the lidocaine group was 9.48 mL/kg (SD 7.02 mL/kg); in the placebo group, 9.32 mL/kg (SD 7.39 mL/kg). The mean difference between groups was 0.15 mL/kg (95% CI –2.7 to 3.0 mL/kg; t test P¼.9). Likewise, short-term secondary outcomes were similar between the groups (Table 2). Overall, 10 (10%) patients required nasogastric or intravenous fluids and were admitted for fluid administration, 7 (14%) in the lidocaine group and 3 (6%) in the placebo group.
LIMITATIONS This study has a number of limitations. First, the population included in the study was a convenience sample based on availability of research staff to enroll families. In addition, the methodology focused on short-term oral intake and we did not collect pain scores when a difference between groups might have been found. There might also have been more of a difference between the groups if patients had been more dehydrated before enrollment. Longer-term outcome data (intravenous/nasogastric administration and admission) cannot be compared in this study because both groups of participants had potentially received lidocaine at 60 minutes so that we did not have a randomized comparison for outcomes after this point. Although the study was blinded, it is possible that participants would have noticed if their mouth had become numb from lidocaine. However, research staff, parents/carers, treating clinicians, and nurses remained blinded throughout the study. Last, the diagnoses of Annals of Emergency Medicine 295
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Figure 2. Study flow chart in Consolidated Standards of Reporting Trials format.
the patients enrolled in this study were based on clinical diagnosis rather than laboratory testing. This, however, reflects a realistic clinical situation.
DISCUSSION This blinded, randomized, placebo-controlled trial did not find evidence that viscous lidocaine improved oral intake during the first hour after administration compared with placebo. The 296 Annals of Emergency Medicine
estimate of the difference in median fluid intake of 0.82 mL/kg was small, and the 95% CI around the difference of –2.5 to 3.3 mL/kg was within the 4-mL/kg difference that was considered clinically important according to a poll of 10 ED specialists. Children in both the lidocaine and placebo groups drank a surprisingly large amount of just over 9 mL/kg in 1 hour compared with a scant average parent estimate of around 15 mL/kg during the 24 hours before enrollment, although parents’ estimation of previous oral intake may be unreliable. It is unknown what was Volume 63, no. 3 : March 2014
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Table 1. Baseline characteristics of participants, presented separately by treatment group. Characteristic
Lidocaine, n[50
Age, median (IQR), y Male sex, No. (%) Oral intake past 24 h, median (IQR) mL/kg Analgesia in past 24 h, No. (%) Oral Topical Lidocaine viscous Degree of dehydration, No. (%)* Nil Mild Moderate Missing Oral ulcers, No. (%) >50 50 Number of ulcers, mean (SD) Clinical diagnosis, No. (%) Herpetic gingivostomatitis Non herpetic gingivostomatitis Hand foot and mouth disease Herpangina Ulcerative stomatitis/pharyngitis
2 (1.2–2.8) 29 (58) 13 (5.6–25)
Placebo, n[50 1.8 (1.3–2.9) 30 (60) 18.7 (8.4–24)
39 (78) 39 (100) 1 (3) 0
38 34 7 1
9 (19) 35 (73) 4 (8) 2
12 (24) 37 (74) 1 (2) 0
6 (12) 44 (88) 11.7 (8.5)
6 (12) 44 (88) 11.9 (8.5)
24 9 14 1 2
(48) (18) (28) (2) (4)
18 9 15 4 4
(76) (89.5) (18.4) (2.6)
(36) (18) (30) (8) (8)
IQR, Interquartile range. *Percentages of those with data available.
responsible in both placebo and active drug groups for the greater intake compared with that observed at home. It cannot be attributed to the numbing effect of lidocaine despite lidocaine’s providing profound and sustained anesthesia of the oral cavity after an initial bitter taste. We suspect that ED staff providing instructions about how to administer fluid and what fluid to administer, as well as giving encouragement to patients and caregivers, played a major role. Nonetheless, it is unlikely that coaching would have biased the results of this trial because presumably the amount and quality of coaching would have been equivalent in the 2 groups because this was a blinded study. Another possible explanation is that the methylcellulose in both the viscous lidocaine and placebo provided some coating effect on the ulcers, which led to increased oral intake; however, the methylcellulose base in the preparations is washed
Figure 3. Two percent viscous lidocaine versus placebo. Dot plot of amount of fluid ingested (mL/kg) during 60 minutes by the group with 10 mL/kg dichotomous cutoff (horizontal line).
from the mouth after a few swallows. From this study, it would appear that these factors are more important than the pharmacologic action of lidocaine. An alternative study may have been to consider the use of diphenhydramine/antacid mixtures (“magic mouthwash”) for improving oral intake rather than lidocaine because these treatments are frequently used preparations in North America,3 with no good evidence for efficacy. We chose to test lidocaine as an isolated agent in this study because it is widely accepted for use in our department and currently recommended by local guidelines.23 When designing the study, we considered incorporating the use of oral analgesics into the protocol; however, this would have been complex because of heterogeneity of previous dosing and trial dosing. Additionally, these medications are often refused, and the effect of oral analgesics would occur within the lidocaine trial of fluids period and hence would have obscured the treatment comparison. This posed a major confounding limitation of a not dissimilar trial involving topical analgesia for immediate pain relief in otitis media.26,27 A protocol that first tested oral painkillers or used the results of an oral fluid challenge would have led to unacceptably long
Table 2. Secondary outcomes. Oral Intake Able to ingest >5 mL/kg in 30 min Able to ingest >5 mL/kg in 60 min Able to ingest >10 mL/kg in 30 min Able to ingest >10 mL/kg in 60 min Able to ingest >20 mL/kg in 30 min Able to ingest >20 mL/kg in 60 min Adequate oral intake at 60 min Rescue medication at 60 min Given any additional analgesia Given acetaminophen Given ibuprofen Given acetaminophen and codeine Given bottle B
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Lidocaine (n[50), No. (%)
Placebo (n[50), No. (%)
Difference in Proportions (95% CI)
27 35 16 21 1 4 30
(54) (70) (32) (42) (2) (8) (60)
21 30 13 21 1 6 28
(42) (60) (26) (42) (2) (12) (56)
0.12 0.1 0.06 0 0 –0.04 0.04
(–0.07 to 0.31) (–0.09 to 0.29) (–0.12 to 0.24) (–0.19 to 0.19) (–0.05 to 0.05) (–0.16 to 0.08) (–0.15 to 0.23)
25 18 8 4 20
(50) (36) (16) (8) (40)
22 13 4 8 20
(44) (26) (8) (16) (40)
0.06 0.17 0.15 –0.17 0
(–0.14 to 0.26) (–0.09 to 0.44) (–0.08 to 0.38) (–0.4 to 0.06) (–0.19 to 0.19)
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Topical Lidocaine for Children With Mouth Ulcers ED stays and excessive delays in receipt of trial or adjunctive medication. Ethics approval would have been problematic because lidocaine was a widely accepted and used treatment option in this institution. A protocol comparing viscous lidocaine to either oral analgesics or magic mouthwash was also considered; however, this would not have answered the question of whether lidocaine (or any other preparation for that matter) is effective. In the absence of any evidence about the efficacy of medications in this group of diseases, a placebo-controlled trial was considered most appropriate. Instead we chose to compare the effects of lidocaine alone with a viscous placebo, which was more feasible but created the limitation that half of the participants had some delay in treatment. To mitigate, we minimized the trial period to the duration of effect of lidocaine, a relatively short 60 minutes, and also made bottle B available immediately after the study period and excluded patients who needed immediate analgesia. The results of the current study refute the putative value of lidocaine in treatment of painful infectious mouth ulcers.4,5,23 Clinicians should be very cautious in attributing success in increasing oral intake to any specific agent or combination of agents rather than the supportive encouragement of medical and nursing staff or possibly the coating effect of orally administered agents. Without evidence to support their use, if topical agents are deployed, it might be prudent to avoid agents with uncommon but severe adverse effects28-32 in favor of simple coating agents.13,16 Further studies assessing interventions for the treatment of mouth ulcers could be designed to examine the differential effects of combination preparations, that is, pharmacologic versus physical properties, by using multiple treatment arms. The effect of staff encouragement should also be considered because this might eclipse study drug effects. Other helpful data for future studies in this area are that 10% of children with this group of conditions required intravenous/nasogastric fluids and are admitted to the hospital, supplementing results of previous reports.2,3 In conclusion, this study found that viscous lidocaine is not superior to a flavored gel placebo in improving oral intake in otherwise healthy children with painful infectious mouth ulcers. It appears that staff coaching and possibly the coating effect of oral topical agents alone can increase oral intake. The authors acknowledge the participating families and the ED staff at Royal Children’s Hospital for their support in conducting this study; Amanda Fry, B Nurs, research coordinator, ED; Christine Plover, BPharm (Hons), MClinPharm, study pharmacist, Pharmacy Department, Royal Children’s Hospital, Melbourne, Australia; and Francesca Orsini, BSc, MSC, biostatistician, Murdoch Children’s Research Institute, Melbourne, Australia. Supervising editor: Steven M. Green, MD Author affiliations: From the Department of Emergency Medicine (Hopper, McCarthy, Babl) and Department of Anaesthesia and Pain Management (Davidson), Royal Children’s Hospital, Parkville,
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Victoria, Australia; the Murdoch Children’s Research Institute, Parkville, Victoria, Australia (Hopper, Lee, Davidson, Babl); the Department of Paediatrics, Faculty of Medicine, Dentistry, and Health Sciences, University of Melbourne, Victoria, Australia (Tancharoen, Lee, Davidson, Babl); and the Junior Medical Staff Department, St Vincent’s Hospital, Fitzroy, Victoria, Australia (Tancharoen). Author contributions: SMH and FEB were responsible for identifying the research question, for study design and research protocol, and for drafting the article. MM, CT, KJL, and AD contributed to the study design and the development of the protocol. SMH, MM, CT, and FEB collected the data. KJL was responsible for the statistical analysis. All authors provided comments on the drafts and have read and approved the final version of the article. All authors had full access to all of the data (including statistical reports and tables) at the conclusion of the study and take responsibility for the integrity of the data and the accuracy of the data analysis. SMH takes responsibility for the paper as a whole. Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The authors have stated that no such relationships exist or have arisen since submission of the article. Supported by the Murdoch Children’s Research Institute, Melbourne, Australia, and the Victorian Government’s Operational Infrastructure Support Program. Publication dates: Received for publication May 12, 2013. Revisions received July 29, 2013, and August 18, 2013. Accepted for publication August 23, 2013. Available online November 7, 2013. Address for correspondence: Sandy M. Hopper, FRACP, FACEM, E-mail [email protected].
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randomized, double-blind clinical trial. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997;84:356-361. Carnel SB, Blakeslee DB, Oswald SG, et al. Treatment of radiation- and chemotherapy-induced stomatitis. Otolaryngol Head Neck Surg. 1990;102:326-330. Mell HK. Management of oral and genital herpes in the emergency department. Emerg Med Clin North Am. 2008;26:457-473. Royal Children’s Hospital Melbourne Australia. Clinical Practice Guideline on HSV Gingivostomatitis. Melbourne, Australia: Royal Children’s Hospital; 2012; Available at: http://www.rch.org.au/ clinicalguide/guideline_index/HSV_Gingivostomatitis/; Accessed January 2, 2013. Hopper S, Babl F, McCarthy M, et al. A double blind, randomised placebo controlled trial of topical 2% viscous lidocaine in improving oral intake in children with painful infectious mouth conditions. BMC Pediatr. 2011;11:106. Kemp C, McDowell J, eds. Paediatric Pharmacopoeia. 13th ed. Melbourne, Australia: Royal Children’s Hospital; 2002. Bharti B, Bharti S. Is topical lignocaine for pain relief in acute otitis media really effective? Arch Dis Child. 2008;93:714. Bolt P, Barnett P, Babl FE, et al. Topical lignocaine for pain relief in acute otitis media: results of a double-blind placebo-controlled randomised trial. Arch Dis Child. 2008;93:40-44. Bernhardt DT. Topical diphenhydramine toxicity. Wisconsin Med J. 1991;90:469-471. Balit CR, Lynch A-M, Gilmore SP, et al. Lignocaine and chlorhexidine toxicity in children resulting from mouth paint ingestion: a bottling problem. J Paediatr Child Health. 2006;42:350-353. Giard MJ, Uden DL, Whitlock DJ, et al. Seizures induced by oral viscous lidocaine. Clin Pharm. 1983;2:110. Hess GP, Walson PD. Seizures secondary to oral viscous lidocaine. Ann Emerg Med. 1988;17:725-727. Yamashita S, Sato S, Kakiuchi Y, et al. Lidocaine toxicity during frequent viscous lidocaine use for painful tongue ulcer. J Pain Symptom Manage. 2002;24:543-545.
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Topical Lidocaine to Improve Oral Intake in Children With Painful Infectious Mouth Ulcers: A Blinded, Randomized, Placebo-Controlled Trial Sandy M. Hopper, FRACP, FACEM; Michelle McCarthy, MN; Chasari Tancharoen, MBBS; Katherine J. Lee, PhD; Andrew Davidson, MD; Franz E. Babl, MD, MPH
Study objective: We establish the efficacy of 2% viscous lidocaine in increasing oral intake in children with painful infectious mouth conditions compared with placebo. Methods: This was a randomized placebo-controlled trial of viscous lidocaine versus placebo at a single pediatric emergency department. Study staff, clinicians, nurses, caregivers, and participants were blinded to the group assignment. Children with acute infectious ulcerative mouth conditions (gingivostomatitis, ulcerative pharyngitis, or hand, foot, and mouth disease) and poor oral fluid intake were randomized to receive 0.15 mL/kg of either 2% viscous lidocaine or placebo with identical appearance and flavor. The primary outcome was the amount of fluid ingested in the 60 minutes after administration of the intervention, with a difference in intake of 4 mL/kg considered clinically important. Secondary outcomes were specific milliliter per kilogram fluid targets and incidence of adverse events. Results: One hundred participants were recruited (50 per treatment group), all of whom completed the 60-minute fluid trial period. Oral intake 1 hour after drug administration was similar in both groups: lidocaine median 8.49 mL/kg (interquartile range 4.07, 13.84 mL/kg) versus placebo 9.31 mL/kg (interquartile range 3.06, 15.18 mL/kg); difference in medians 0.82 mL/kg (95% confidence interval –2.52 to 3.26); Mann-Whitney P¼.90. Likewise, short-term secondary outcomes were similar between the groups and there were no adverse events in either group. Conclusion: Viscous lidocaine is not superior to a flavored gel placebo in improving oral intake in children with painful infectious mouth ulcers. [Ann Emerg Med. 2014;63:292-299.] Please see page 293 for the Editor’s Capsule Summary of this article. A feedback survey is available with each research article published on the Web at www.annemergmed.com. A podcast for this article is available at www.annemergmed.com. 0196-0644/$-see front matter Copyright © 2013 by the American College of Emergency Physicians. http://dx.doi.org/10.1016/j.annemergmed.2013.08.022
INTRODUCTION Background Painful ulcerative infectious mouth conditions in children are a common presentation to emergency departments (EDs). These are predominantly viral conditions such as gingivostomatitis (herpetic and nonherpetic), ulcerative pharyngitis, herpangina, and hand, foot, and mouth disease. Of these, primary herpetic gingivostomatitis is the most studied.1-3 Presentation to the ED is often due to decreased oral intake or pain. The diagnosis of infectious mouth conditions is clinical,4 and treatment primarily involves pain relief and the provision of sufficient oral fluid intake to prevent dehydration.4,5 Randomized trials of acyclovir for primary herpetic gingivostomatitis provide weak evidence in support of its use.1-3,6 However, even if antiviral medications are used, their onset of action limits their effectiveness in resolving the acute issue of fluid refusal. Many topical agents have been described for specific painful
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ulcerative mouth conditions in adults and children, such as cancerrelated mucositis, oral candidiasis, and aphthous ulcers.7 These include viscous lidocaine,8-10 benzocaine preparations, diphenhydramine elixir,11 coating agents (such as sucralfate,12 Maalox,3 milk of magnesia and Kaopectate),13 antibiotics14 (particularly chlorhexidine15 and tetracycline), and combinations of these agents.11,16-19 The few trials that assess the efficacy of treatments for ulcerative mouth conditions focus on pain rather than oral intake and have been in adults with aphthous ulceration8,20 or patients with neoplasia-associated mucositis.12,16,18,21 Importance Although several authorities4,5,22,23 support viscous lidocaine as treatment for acute infectious ulcerative mouth conditions in children, to date there have been no randomized controlled trials to support the use of topical agents for painful ulcerative conditions of the mouth in otherwise healthy children.
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Editor’s Capsule Summary
What is already known on this topic Children with painful mouth ulcers drink less and may become dehydrated. What question this study addressed Does fluid intake improve when 2% viscous lidocaine is applied to oral ulcers? What this study adds to our knowledge In this randomized, placebo-controlled trial of 100 children with mouth ulcers and decreased oral intake, the volume of fluid subsequently ingested was similar between groups. How this is relevant to clinical practice The application of viscous lidocaine to painful oral ulcers does not enhance the willingness of young children to drink.
Goal of This Investigation In this placebo-controlled randomized trial we set out to assess whether topical 2% viscous lidocaine is better than placebo at increasing oral intake in children with infectious mouth conditions. A difference in fluid intake of 4 mL/kg was considered clinically important. The secondary goals were to determine whether there was a difference in the proportions of children ingesting 5, 10, or 20 mL/kg of fluid within 0 to 30 and 0 to 60 minutes from the time of administration of the study drug, the proportion deemed to have an adequate fluid intake according to the treating clinician, the proportion requiring additional treatments (analgesia, intravenous, or nasogastric fluid), the incidence of adverse events, the admission rate, and the duration of stay in the ED between the intervention and placebo group.
MATERIALS AND METHODS We present brief details of the study protocol below. A more detailed version of the trial protocol has been published elsewhere.24 Study Design and Setting This study was a randomized, blinded, placebo-controlled trial conducted at the ED of the Royal Children’s Hospital, a tertiary referral center in Melbourne, Australia, with an annual census of 70,000 patients. Ethics approval was obtained from the Royal Children’s Hospital Human Research and Ethics Committee, approval number 29070C. Parents or guardians gave written informed consent for their child to take part in this study. The trial was registered with the Australian and New Zealand Clinical Trials Registry: ACTRN12609000566235. Volume 63, no. 3 : March 2014
Selection of Participants The study participants were a convenience sample. When research assistants or investigators were present in the department (approximately 50 hours per week), potential participants were screened consecutively by triage or research staff on presentation to the ED and were approached by research staff if potentially eligible. Once consent was obtained, participants were assessed for eligibility. Participants were randomized once eligibility had been confirmed. Eligible participants were patients (1) aged 6 months to 8 years; (2) who presented with gingivostomatitis (herpetic or nonherpetic), ulcerative pharyngitis, herpangina, or hand, foot, and mouth disease as clinically diagnosed by the treating clinician; and (3) had a history of poor oral fluid intake (defined as parent or guardian report of “not drinking well,” as well as a parent-reported oral fluid intake less than 10 mL/kg of fluid in the preceding 2 hours). Exclusion criteria included hypersensitivity to any of the components of lidocaine or other amide local anesthetics, and patients with diseases in which elevated plasma levels of lidocaine may be dangerous (such as epilepsy, impaired cardiac conduction, bradycardia, or impaired hepatic or renal function). We also excluded patients who were severely dehydrated or toxic, requiring immediate resuscitation; patients with more than 2 episodes of vomiting before the ED presentation; dental disease, mouth trauma, or malignancy; patients receiving cardiac or other drugs with possible interactions with lidocaine; patients who had previously received more than 1 dose of oral topical anesthetic for the same illness; patients with preexisting upper airway obstruction or swallowing difficulties; patients who had received analgesia within 1 hour preceding enrollment to the study; and patients with non–English speaking parents/guardians. Interventions After consent, participants were randomized, using block randomization with block sizes of 2 and 4, to receive lidocaine or placebo. Sequentially numbered bottles of study drug were prepared by a pharmacist who was otherwise independent of the study. The randomization allocation sequence was prepared by the Clinical Epidemiology and Biostatistics Unit at the Royal Children’s Hospital. At randomization, participants were given the next available study number, which equated to an allocation of study drug dispensed in 2 bottles (labeled A and B). After randomization, patients received a weight-based dose from bottle A, which contained the allocated study drug (either lidocaine or placebo). Bottle B contained the alternative mixture, ie, lidocaine if randomized to placebo and placebo if randomized to lidocaine. Sixty minutes after the application of the dose from bottle A, the treating clinician was able to administer the contents of this second bottle if clinically warranted, which ensured that all participants in the study had access to the active treatment while maintaining the blinding of the study. All study drugs were packaged in blinded containers stored in a locked cupboard labeled only with the study details, the study number, and bottle A or B. Only the pharmacist and the Annals of Emergency Medicine 293
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Topical Lidocaine for Children With Mouth Ulcers independent person who generated the randomization list were aware of the treatment allocation and could unblind group assignment in an emergency. The participants, caregivers, treating staff, and research staff were blinded to the treatment allocation. Lidocaine was administered as a commercially available viscous mixture of 2% lidocaine hydrochloride (Xylocaine Viscous; AstraZeneca, North Ryde, New South Wales, Australia), made up with methyl hydroxybenzoate, propyl hydroxybenzoate, sodium hydroxide, saccharin sodium, cherry extract (water, flavor, citric acid, and amaranth), carmellose sodium, and water. Dosing of oral 2% viscous lidocaine was as set out according to the Royal Children’s Hospital Pediatric Pharmacopoeia at 0.15 mL/kg.25 The placebo was made up by the Royal Children’s Hospital Pharmacy from stock ingredients of methylcellulose and cherry flavoring and was identical to the study drug in terms of appearance, flavor, and smell. The single dose of 0.15 mL/kg of study drug was administered as soon as possible after randomization. Administration was by the treating nurse by a measured syringe to the oral cavity of the participant, aiming to cover the inflamed mucosa and ulcerative lesions (study flow chart; Figure 1). If the participant was mature enough, he or she was instructed to gargle and spit out the study drug. Younger participants simply swallowed or spat out the study drug. For the 60 minutes after application (the fluid trial period), subjects were actively encouraged to drink a range of fluids. The amount of fluid ingested within 0 to 30 and 30 to 60 minutes after administration was recorded on a hospital fluid balance chart. With the exception of the bottles of study drug, 2% viscous lidocaine was not prescribed by the treating clinician during the 90-minute study period or for the subsequent 90 minutes because of risk of lidocaine toxicity. Sixty minutes after study drug administration, the treating clinician reassessed the participant’s fluid intake and clinical status and then could decide to administer the second bottle of study drug allocated to that participant (bottle B) or administer other oral analgesia, eg, acetaminophen, ibuprofen, The study was terminated 90 minutes after study drug administration (ie, 30 minutes after the end of the 60-minute fluid trial period) (Figure 1), after assessment for adverse events; in particular, a review for signs of aspiration (new cough, decreased oxygen saturation, focal chest signs). A completed participant was defined as a participant who had the solution administered and had their fluid intake monitored for a minimum of 60 minutes from the time of study drug administration. After study termination, the treating physician was free to decide disposition care and further medications, including the prescription of viscous lidocaine. Methods of Measurement and Outcome Measures The primary outcome was the amount of fluid ingested within 60 minutes of administration of the study drug, expressed in milliliters per kilogram. 294 Annals of Emergency Medicine
Potential patient presents at ED Triage
Eligibility assessed and informed consent obtained
Double-blinded randomization
2% viscous lidocaine (bottle A)
Time = 0 minutes
Placebo Gel (bottle A)
60 min trial of fluids
Time = 60 minutes
Treating doctor reviews fluid intake with option to give bottle B and/or oral analgesia
Time = 90 minutes
Clinical review for signs of aspiration
Usual ED care
Description: the study schedule during the 60-minute fluid trial period and the subsequent 30-minute observation period.
Figure 1. Study flow chart.
Secondary outcomes included both short-term outcomes (those within 60 minutes of drug administration) and longer-term outcomes (those more than 60 minutes after drug administration). Longer-term outcomes were not part of the randomized comparison because after 60 minutes both groups had access to lidocaine and nonrandomized interventions (such as provision of additional oral analgesia). Short-term outcome measures included (1) whether the participant ingested more than 5, 10, or 20 mL/kg of fluid within 0 to 30 and 0 to 60 minutes from the time of administration of the study drug; (2) whether oral intake was deemed adequate at 60 minutes (as determined by the treating clinician); and (3) whether additional treatment for mouth ulcers was used at the end of the 60-minute fluid trial period, including bottle B and other oral analgesic agents. Longer-term outcome measures included (1) incidence of adverse events (allergic reactions, seizures, cardiac arrhythmia, and clinical episodes of aspiration) within the 90-minute study period; (2) whether the patient required fluid administration by intravenous line or nasogastric tube (oral hydration failures) within the 90-minute study period; (3) whether the participant required hospital admission; and (4) duration of stay in the ED. Volume 63, no. 3 : March 2014
Hopper et al Fluid amounts ingested were measured by research staff according to calculated measurements of cups, other containers, and syringes in use in the ED or packaged frozen rehydration solution. All adverse experiences observed by the investigator or one of the clinical staff, or reported by the patient’s parents/ guardians spontaneously or in response to a direct question that occurred during the 60-minute study period and the 30-minute observation period, were recorded. To our knowledge, before this study there was no published literature on the effectiveness of 2% viscous lidocaine for improving oral fluid intake in painful infectious mouth conditions in children; hence, we carried out a planned interim analysis after the first 20 patients to estimate the average fluid intake and spread of the data in our 2 treatment groups. The data from the interim analysis were reasonably normal; hence, we compared the mean fluid intake in the 2 groups. We found a mean difference of 4.3 mL/kg (SD¼7 mL/kg) ingested during the 60-minute fluid trial period between the 2 treatment groups. This difference was considered clinically important in a review of expert clinical opinion (10 pediatric emergency attending physicians in Melbourne, Australia). Assuming a slightly conservative estimate of the treatment effect of 4 mL/kg and an SD of 7 mL/kg, we estimated that a sample size of 50 children per group (100 children in total) would be required to find a difference between the 2 groups according to 80% power and 5% significance. No allowance was made for loss to followup because of the short timeframe of this study. Primary Data Analysis Analysis was by intention-to-treat, in which outcome data were available, although as a sensitivity analysis we also present data from a per-protocol analysis. Data were analyzed with Stata (version 12.0; StataCorp, College Station, TX). The planned analysis for the primary outcome according to the interim data was to report the mean intake in each group and its SD, with the comparison between the groups presented as a difference in means and its 95% confidence interval (CI), obtained by using an unadjusted linear regression, and the hypothesis of no difference between the groups tested with a t test. The observed data were reasonably skewed, so instead we summarize the data as the median and interquartile range within each group, present an estimate of the difference in medians and its 95% CI (estimated with the cendif command in Stata), and compare the 2 groups with a Wilcoxon rank sum test. We also present the results from the planned analysis for consistency. Secondary short-term outcomes were compared between the groups with linear regression for continuous data and differences in proportions for categorical data, with results presented as estimates of the difference between the groups and 95% CIs. Longer-term outcomes are reported descriptively only.
RESULTS Characteristics of Study Subjects Between November 2009 and November 2012, Royal Children’s Hospital ED diagnosed infectious mouth ulcers in Volume 63, no. 3 : March 2014
Topical Lidocaine for Children With Mouth Ulcers 710 children, of whom 221 were assessed for inclusion (Figure 2). In total, 101 patients were randomized; however, 1 participant left the ED before completion of the 60-minute fluid trial period. This participant left the ED 40 minutes after administration of the study drug; therefore, there were no outcome data and the participant was excluded from all analyses. Thus, 100 participants were available for analysis. Two participants in the lidocaine group received acetaminophen during the 60-minute fluid trial period, one from a parent and the other from a staff member. Both of these participants are included in the analysis. In addition, 1 family in the lidocaine group and 2 families in the placebo group left during the 30-minute observation period after the 60-minute fluid trial period. These participants had complete data for the 60-minute fluid trial period; hence, they were included in the analysis of the primary and short-term secondary outcomes but are not included in the summaries of the longer-term outcomes. Baseline characteristics of the groups are presented in Table 1. Most participants (73%) were mildly dehydrated and herpetic gingivostomatitis was the most frequent clinical diagnosis (42%). The amount of fluid ingested at 60 minutes was similar in both groups (Figure 3). The median amount of fluid ingested in the lidocaine group was 8.49 mL/kg (interquartile range 4.07, 13.84); in the placebo group, 9.31 mL/kg (interquartile range 3.06, 15.18) (difference in medians 0.82 mL/kg; 95% CI –2.52 to 3.26; Mann-Whitney P¼.9). In keeping with the original analysis plan, the mean amount of fluid ingested in the lidocaine group was 9.48 mL/kg (SD 7.02 mL/kg); in the placebo group, 9.32 mL/kg (SD 7.39 mL/kg). The mean difference between groups was 0.15 mL/kg (95% CI –2.7 to 3.0 mL/kg; t test P¼.9). Likewise, short-term secondary outcomes were similar between the groups (Table 2). Overall, 10 (10%) patients required nasogastric or intravenous fluids and were admitted for fluid administration, 7 (14%) in the lidocaine group and 3 (6%) in the placebo group.
LIMITATIONS This study has a number of limitations. First, the population included in the study was a convenience sample based on availability of research staff to enroll families. In addition, the methodology focused on short-term oral intake and we did not collect pain scores when a difference between groups might have been found. There might also have been more of a difference between the groups if patients had been more dehydrated before enrollment. Longer-term outcome data (intravenous/nasogastric administration and admission) cannot be compared in this study because both groups of participants had potentially received lidocaine at 60 minutes so that we did not have a randomized comparison for outcomes after this point. Although the study was blinded, it is possible that participants would have noticed if their mouth had become numb from lidocaine. However, research staff, parents/carers, treating clinicians, and nurses remained blinded throughout the study. Last, the diagnoses of Annals of Emergency Medicine 295
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Figure 2. Study flow chart in Consolidated Standards of Reporting Trials format.
the patients enrolled in this study were based on clinical diagnosis rather than laboratory testing. This, however, reflects a realistic clinical situation.
DISCUSSION This blinded, randomized, placebo-controlled trial did not find evidence that viscous lidocaine improved oral intake during the first hour after administration compared with placebo. The 296 Annals of Emergency Medicine
estimate of the difference in median fluid intake of 0.82 mL/kg was small, and the 95% CI around the difference of –2.5 to 3.3 mL/kg was within the 4-mL/kg difference that was considered clinically important according to a poll of 10 ED specialists. Children in both the lidocaine and placebo groups drank a surprisingly large amount of just over 9 mL/kg in 1 hour compared with a scant average parent estimate of around 15 mL/kg during the 24 hours before enrollment, although parents’ estimation of previous oral intake may be unreliable. It is unknown what was Volume 63, no. 3 : March 2014
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Table 1. Baseline characteristics of participants, presented separately by treatment group. Characteristic
Lidocaine, n[50
Age, median (IQR), y Male sex, No. (%) Oral intake past 24 h, median (IQR) mL/kg Analgesia in past 24 h, No. (%) Oral Topical Lidocaine viscous Degree of dehydration, No. (%)* Nil Mild Moderate Missing Oral ulcers, No. (%) >50 50 Number of ulcers, mean (SD) Clinical diagnosis, No. (%) Herpetic gingivostomatitis Non herpetic gingivostomatitis Hand foot and mouth disease Herpangina Ulcerative stomatitis/pharyngitis
2 (1.2–2.8) 29 (58) 13 (5.6–25)
Placebo, n[50 1.8 (1.3–2.9) 30 (60) 18.7 (8.4–24)
39 (78) 39 (100) 1 (3) 0
38 34 7 1
9 (19) 35 (73) 4 (8) 2
12 (24) 37 (74) 1 (2) 0
6 (12) 44 (88) 11.7 (8.5)
6 (12) 44 (88) 11.9 (8.5)
24 9 14 1 2
(48) (18) (28) (2) (4)
18 9 15 4 4
(76) (89.5) (18.4) (2.6)
(36) (18) (30) (8) (8)
IQR, Interquartile range. *Percentages of those with data available.
responsible in both placebo and active drug groups for the greater intake compared with that observed at home. It cannot be attributed to the numbing effect of lidocaine despite lidocaine’s providing profound and sustained anesthesia of the oral cavity after an initial bitter taste. We suspect that ED staff providing instructions about how to administer fluid and what fluid to administer, as well as giving encouragement to patients and caregivers, played a major role. Nonetheless, it is unlikely that coaching would have biased the results of this trial because presumably the amount and quality of coaching would have been equivalent in the 2 groups because this was a blinded study. Another possible explanation is that the methylcellulose in both the viscous lidocaine and placebo provided some coating effect on the ulcers, which led to increased oral intake; however, the methylcellulose base in the preparations is washed
Figure 3. Two percent viscous lidocaine versus placebo. Dot plot of amount of fluid ingested (mL/kg) during 60 minutes by the group with 10 mL/kg dichotomous cutoff (horizontal line).
from the mouth after a few swallows. From this study, it would appear that these factors are more important than the pharmacologic action of lidocaine. An alternative study may have been to consider the use of diphenhydramine/antacid mixtures (“magic mouthwash”) for improving oral intake rather than lidocaine because these treatments are frequently used preparations in North America,3 with no good evidence for efficacy. We chose to test lidocaine as an isolated agent in this study because it is widely accepted for use in our department and currently recommended by local guidelines.23 When designing the study, we considered incorporating the use of oral analgesics into the protocol; however, this would have been complex because of heterogeneity of previous dosing and trial dosing. Additionally, these medications are often refused, and the effect of oral analgesics would occur within the lidocaine trial of fluids period and hence would have obscured the treatment comparison. This posed a major confounding limitation of a not dissimilar trial involving topical analgesia for immediate pain relief in otitis media.26,27 A protocol that first tested oral painkillers or used the results of an oral fluid challenge would have led to unacceptably long
Table 2. Secondary outcomes. Oral Intake Able to ingest >5 mL/kg in 30 min Able to ingest >5 mL/kg in 60 min Able to ingest >10 mL/kg in 30 min Able to ingest >10 mL/kg in 60 min Able to ingest >20 mL/kg in 30 min Able to ingest >20 mL/kg in 60 min Adequate oral intake at 60 min Rescue medication at 60 min Given any additional analgesia Given acetaminophen Given ibuprofen Given acetaminophen and codeine Given bottle B
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Lidocaine (n[50), No. (%)
Placebo (n[50), No. (%)
Difference in Proportions (95% CI)
27 35 16 21 1 4 30
(54) (70) (32) (42) (2) (8) (60)
21 30 13 21 1 6 28
(42) (60) (26) (42) (2) (12) (56)
0.12 0.1 0.06 0 0 –0.04 0.04
(–0.07 to 0.31) (–0.09 to 0.29) (–0.12 to 0.24) (–0.19 to 0.19) (–0.05 to 0.05) (–0.16 to 0.08) (–0.15 to 0.23)
25 18 8 4 20
(50) (36) (16) (8) (40)
22 13 4 8 20
(44) (26) (8) (16) (40)
0.06 0.17 0.15 –0.17 0
(–0.14 to 0.26) (–0.09 to 0.44) (–0.08 to 0.38) (–0.4 to 0.06) (–0.19 to 0.19)
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Topical Lidocaine for Children With Mouth Ulcers ED stays and excessive delays in receipt of trial or adjunctive medication. Ethics approval would have been problematic because lidocaine was a widely accepted and used treatment option in this institution. A protocol comparing viscous lidocaine to either oral analgesics or magic mouthwash was also considered; however, this would not have answered the question of whether lidocaine (or any other preparation for that matter) is effective. In the absence of any evidence about the efficacy of medications in this group of diseases, a placebo-controlled trial was considered most appropriate. Instead we chose to compare the effects of lidocaine alone with a viscous placebo, which was more feasible but created the limitation that half of the participants had some delay in treatment. To mitigate, we minimized the trial period to the duration of effect of lidocaine, a relatively short 60 minutes, and also made bottle B available immediately after the study period and excluded patients who needed immediate analgesia. The results of the current study refute the putative value of lidocaine in treatment of painful infectious mouth ulcers.4,5,23 Clinicians should be very cautious in attributing success in increasing oral intake to any specific agent or combination of agents rather than the supportive encouragement of medical and nursing staff or possibly the coating effect of orally administered agents. Without evidence to support their use, if topical agents are deployed, it might be prudent to avoid agents with uncommon but severe adverse effects28-32 in favor of simple coating agents.13,16 Further studies assessing interventions for the treatment of mouth ulcers could be designed to examine the differential effects of combination preparations, that is, pharmacologic versus physical properties, by using multiple treatment arms. The effect of staff encouragement should also be considered because this might eclipse study drug effects. Other helpful data for future studies in this area are that 10% of children with this group of conditions required intravenous/nasogastric fluids and are admitted to the hospital, supplementing results of previous reports.2,3 In conclusion, this study found that viscous lidocaine is not superior to a flavored gel placebo in improving oral intake in otherwise healthy children with painful infectious mouth ulcers. It appears that staff coaching and possibly the coating effect of oral topical agents alone can increase oral intake. The authors acknowledge the participating families and the ED staff at Royal Children’s Hospital for their support in conducting this study; Amanda Fry, B Nurs, research coordinator, ED; Christine Plover, BPharm (Hons), MClinPharm, study pharmacist, Pharmacy Department, Royal Children’s Hospital, Melbourne, Australia; and Francesca Orsini, BSc, MSC, biostatistician, Murdoch Children’s Research Institute, Melbourne, Australia. Supervising editor: Steven M. Green, MD Author affiliations: From the Department of Emergency Medicine (Hopper, McCarthy, Babl) and Department of Anaesthesia and Pain Management (Davidson), Royal Children’s Hospital, Parkville,
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Victoria, Australia; the Murdoch Children’s Research Institute, Parkville, Victoria, Australia (Hopper, Lee, Davidson, Babl); the Department of Paediatrics, Faculty of Medicine, Dentistry, and Health Sciences, University of Melbourne, Victoria, Australia (Tancharoen, Lee, Davidson, Babl); and the Junior Medical Staff Department, St Vincent’s Hospital, Fitzroy, Victoria, Australia (Tancharoen). Author contributions: SMH and FEB were responsible for identifying the research question, for study design and research protocol, and for drafting the article. MM, CT, KJL, and AD contributed to the study design and the development of the protocol. SMH, MM, CT, and FEB collected the data. KJL was responsible for the statistical analysis. All authors provided comments on the drafts and have read and approved the final version of the article. All authors had full access to all of the data (including statistical reports and tables) at the conclusion of the study and take responsibility for the integrity of the data and the accuracy of the data analysis. SMH takes responsibility for the paper as a whole. Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The authors have stated that no such relationships exist or have arisen since submission of the article. Supported by the Murdoch Children’s Research Institute, Melbourne, Australia, and the Victorian Government’s Operational Infrastructure Support Program. Publication dates: Received for publication May 12, 2013. Revisions received July 29, 2013, and August 18, 2013. Accepted for publication August 23, 2013. Available online November 7, 2013. Address for correspondence: Sandy M. Hopper, FRACP, FACEM, E-mail [email protected].
REFERENCES 1. Amir J, Harel L, Smetana Z, et al. Treatment of herpes simplex gingivostomatitis with aciclovir in children: a randomised double blind placebo controlled study. BMJ. 1997;314:1800-1803. 2. Amir J, Harel L, Smetana Z, et al. The natural history of primary herpes simplex type 1 gingivostomatitis in children. Pediatr Dermatol. 1999;16:259-263. 3. Faden H. Management of primary herpetic gingivostomatitis in young children. Pediatr Emerg Care. 2006;22:268-269. 4. Phillips R, Orchard D, Starr M. Dermatology: mouth disorders. In: Cameron P, Jelinek G, Everitt I, et al, eds. Textbook of Paediatric Emergency Medicine. Philadelphia, PA: Churchill Livingstone Elsevier; 2006:365. 5. Elden L, Potsic W. Otolaryngologic emergencies. In: Fleischer G, Ludwig S, eds. Textbook of Pediatric Emergency Medicine. 6th ed. Phildelphia, PA: Lippincott Williams & Wilkin; 2010:1553-1554. 6. Nasser M, Fedorowicz Z, Khoshnevisan MH, et al. Acyclovir for treating primary herpetic gingivostomatitis. Cochrane Database Syst Rev 2008;(4):CD006700. 7. Altenburg A, Zouboulis CC. Current concepts in the treatment of recurrent aphthous stomatitis. Skin Therapy Lett. 2008;13:1-4. 8. Akhionbare O, Ojehanon P. The palliative effects of lidocaine with adrenaline on recurrent aphthous stomatitis (RAS). J Med Sci. 2007;7:860-864. 9. Descroix V, Coudert AE, Vige A, et al. Efficacy of topical 1% lidocaine in the symptomatic treatment of pain associated with oral mucosal
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Volume 63, no. 3 : March 2014
Annals of Emergency Medicine 299