doi: /bja/aew436 Paediatrics

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1 British Journal of Anaesthesia, 118 (2): (2017) doi: /bja/aew436 Paediatrics Children and parental anxiolysis in paediatric ambulatory surgery: a randomized controlled study comparing 0.3 mg kg 21 midazolam to tablet computer based interactive distraction C. Marechal 1,2, J. Berthiller 3, S. Tosetti 1, B. Cogniat 1, H. Desombres 4,2, L. Bouvet 1,2, B. Kassai 2,3, D. Chassard 1,2, * and M. de Queiroz Siqueira 1 1 Department of Anaesthesiology, Hopital Femme Mère Enfant, Bron F-69677, France, 2 University Lyon 1, Lyon F-69000, France, 3 Service de Pharmacologie Clinique, EPICIME-CIC 1407 de Lyon, Inserm, CHU-Lyon, Bron F-69677, France and 4 Department of Child and Adolescent Psychiatry, Hopital Femme Mère Enfant, Bron F-69677, France *Corresponding author. dominique.chassard@chu-lyon.fr Abstract Background. The operating theatre, anaesthesia induction and separation from parents create fear and anxiety in children. Anxiety leads to adverse behavioral changes appearing and sometimes persisting during the postoperative period. Our aim was to compare the effects of midazolam (0.3 mg kg 1 : MDZ) for premedication with age-appropriate tablet game apps (TAB) on children anxiety during and after ambulatory surgery. Methods. A randomized controlled trial was conducted from May 16th, 2013 to March 25th, 2014 at the Children Hospital of Lyon. The primary outcome of this study was the change in m-ypas score at the time of anaesthetic mask induction. Anxiety was also assessed in the waiting surgical area, at the time of separation with parents and when back in the ambulatory surgery ward. Results. One hundred and eighteen patients aged four-11 yr were recruited, 60 in the TAB Group and 58 in the MDZ Group. Main endpoint was missing for three patients from the MDZ Group. At the time of mask induction, there was no significant difference between MDZ and TAB Group for the m-ypas score (40.5 (18.6) vs 41.8 (20.7), P ¼ 0.99). There was no significant correlation between m-ypas score and its evolution over the four period of time between subjects. Conclusions. We were not able to show whether TAB is superior to MDZ to blunt anxiety in children undergoing ambulatory surgery. TAB is a non-pharmacological tool which has the capacity in reducing perioperative stress without any sedative effect in this population. Clinical trial registration. NCT Key words: ambulatory surgical procedures; child; premedication Editorial decision: November 2, 2016; Accepted: December 7, 2016 VC The Author Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please journals.permissions@oup.com 247

2 248 Marechal et al. Editor s key points Anaesthetic induction is frightening for children and stressful for their parents. Distraction techniques may help to reduce the anxiety of children and their parents. The authors randomized children scheduled for surgery to midazolam premedication or computer tablet-based age-appropriate games. M-YPAS paediatric anxiety scores were similar among children assigned to midazolam and tablet games. The operating theatre, anaesthesia induction, and separation from parents create fear and anxiety in children, 1 and this can lead to adverse behavioral changes appearing and sometimes persisting during the postoperative period. 2 Pharmacological interventions such as midazolam (MDZ) are widely used to decrease preoperative anxiety in children. 34 However, premedication may be associated with undesirable effects such as paradoxical reactions, prolonged sedation, and adverse behavioral changes. 56 Distraction is a non-pharmacological and an effective technique that directs children s attention away from anxiogenic stimuli. 7 There is a multitude of techniques and technologies associated with distraction Behavioral preparation programs are sometime cost effective and time consuming. Given the ubiquity of mobile interactive tools and children s attraction to videogames and screens in general, it could be easy to distract children with tablet apps in the operating theatre. Recently, Seiden and colleagues 16 showed that tabletbased interactive distraction was effective to reduce anxiety at both parental separation and anaesthesia induction, and increased parental satisfaction. This previous study included children aged one-11 yr. However, children less than four yr can be uncomfortable with touch, double click, click-and-hold and click-and-drag using touch screen devices. Our aim was to compare the effects of midazolam for premedication with age-appropriate game apps on anxiety in children during and after ambulatory surgery. Parental anxiety was also assessed. Methods This study was conducted from May 16, 2013 to March 25, 2014 at the Children s Hospital of the University of Lyon (France). The study protocol was reviewed and approved by the institutional review board (Comité de Protection des Personnes Lyon Est 2; study number 2013-A : date April 10/2013), and on Clinical Trials.gov (NCT ). Informed and written consent was obtained from either parents or legal guardian of all participating subjects; assent was obtained from children older than seven yr of age. The main objective of this study was to compare the impact of midazolam vs a tablet computer game on anxiety at the time of mask induction for anaesthesia (time 3). Secondary objectives were to compare anxiety between the two groups: upon arrival to the ambulatory surgery ward (time 1), at separation from parents (time 2), at mask induction (time 3) and when back in the ambulatory surgery ward (time 4). We also measured parental anxiety, children s postoperative behavior changes at home and satisfaction of parents, children, and staff in each group. Children of both sexes, undergoing general anaesthesia for various ambulatory minor surgical procedures, aged four-10 yr, and meeting the ASAs physical status I-III, were eligible. Exclusion criteria were children with documented preoperative behavioral disturbances and psychiatric disorders, use of psychoactive medication, and previous history of multiple surgery (>3). Participants were randomized into two groups: the MDZ Group received upon arrival (20-30 min before anaesthesia) to the ambulatory ward midazolam 0.3mg kg 1 per os (PO) or per rectum (PR). This is the current procedure for patients about to undergo surgery in the ambulatory surgery ward. The experimental TAB Group received an ipad electronic tablet (Apple Inc, Cupertino, CA) 20 min before anaesthesia. Several applications, also known as apps, were made available on the device after consensus agreements between anaesthetists of the department, according to adequacy for each age group. Children participating in the study were asked to choose a game among those adequate for their age and according to their preferences. Children and parents were informed of the protocol during the anaesthesia consultation performed at least 48 h before surgery. To avoid frustrating children in the MDZ Group, they were not made aware of the existence of a tablet Group. Parents and children were given at least a 48-h period to decide about enrollment. The signed consent, assent when appropriate, was obtained at the time of arrival to the ambulatory ward. Children were then randomly allocated to one of the two groups (MDZ midazolam or TAB tablet) by the two main investigators (B.C., M.D.Q.S) using a computer-generated list restricted by blocks of four, after calling the coordinating centre. There was no stratification criterion. Parental and child anxiety were measured using the State- Trait Anxiety Inventory (STAI) and the modified Yale Preoperative Anxiety Score (m-ypas score) The STAI was used as a self-evaluation of parental anxiety. The STAI has 40 items, 20 items allocated to each of the state T-Anxiety and S-Anxiety sub-scales. The range of scores for each subtest is 20-80, higher scores indicating higher anxiety. A value of has been suggested as a cut-off to detect clinically significant symptoms on the S-Anxiety scale. The m-ypas score, a heterogeneous questionnaire, has proved to be an appropriate tool for assessing child anxiety during the perioperative period. It contains 27 items (activity, arousal, vocalization, use of parents, and emotional status). The total score ranges from 23 to 100. A m-ypas score > 30 defined anxiety, and a score > 40 defined high anxiety. The assessments using STAI, m-ypas, and the Post Hospital Behavior Questionnaire (PHBQ; described below) were performed by two independent psychologists and not the anaesthetic team. 21 Children were transferred, accompanied by their parents, to the surgical waiting area (SWA) located at the entrance of the operative room. The anaesthesia team (anaesthetist and nurse) awaited the child and parents in the SWA. Anxiety of parents (STAI 2) and children (m-ypas 2) was again measured just before children were transferred from the WSA to the surgical room (separation from the parents-(time 2)). Standard haemodynamic monitoring (non-invasive bp, ECG, and oximetry) was applied upon arrival in the surgical room. The technique of mask induction was explained to children before being performed. Children were allowed to sit, if desired, during induction and those in the TAB Group were encouraged to play until loss of consciousness. A third anxiety score (m- YPAS 3) was recorded during induction (time 3). Of note, as parental presence during induction of anaesthesia was not allowed

3 Children and parental anxiolysis in paediatric ambulatory surgery 249 in both groups, we adapted the m-ypas scale, withdrawing the parents item and allocating a fraction to each sub-group. Immediately after induction, an anaesthetic nurse ranked from 0 (not satisfied) to 10 (highly satisfied) this phase of anaesthesia (nurse satisfaction; Nurse S). All children had face mask inhalation induction with sevoflurane in a 50:50 mixture of oxygen/nitrous oxide. Tracheal intubation or laryngeal masks were used to secure airways at the discretion of the anaesthetists in charge. Anaesthesia was maintained with sevoflurane. At the end of surgery acetaminophen and/or non-steroidal anti-inflammatory drugs were given to prevent postoperative pain, combined or not with a locoregional anaesthesia, when appropriate. At the end of surgery, children were transferred to the PACU. Parents are routinely allowed to enter the PACU in our institution. Nalbuphine for pain management was given as clinically required or according to pain scores (Face Legs Activity Cry Consolability scale, FLACC, or Visual Analogic Scale, VAS). Children in the TAB Group were allowed to resume playing as soon as they were fully awake. Thirty min after the last dose of nalbuphine or 45 min after arrival in the PACU, the children were transferred to the ambulatory surgery ward, when meeting the following criteria: patient fully awake, clear fluids PO without postoperative nausea or vomiting (PONV), and a pain score < 3 (FLACC or VAS). At that time, parental anxiety (STAI 3) and child anxiety (m-ypas 4) were evaluated (Time 4). In addition, parent satisfaction with the anaesthesia procedure (Parental satisfaction; Parent S) was rated (verbal score) from 0 (not satisfied) to 10 (highly satisfied). Postoperative behavior changes were assessed using the PHBQ. 19 Explanations for parents to complete the questionnaire were given before discharge. Parents were encouraged to record this score by phone calls at D þ 1, D þ 7andDþ 14. They were also given pre-paid envelops for return by postal mail. Statistical analysis The primary outcome of this study was the difference between groups in m-ypas score at the time of anaesthetic mask induction. Fifty-three children would be required in each group to demonstrate a 10-point difference in m-ypas score at time of induction (level of significance of P < 0.05 and power of 80%). These calculations were based on one previous study 22 and a feasibility study performed by our team showing that the mean (standard deviation, SD) m-ypas score at time of induction, after midazolam premedication, was (18.32). The final number of patients was set at 59 in each group. Categorical variables were expressed as number (n) and percentage and quantitative variables were expressed as means (SD). The hypothesis of normal distribution of quantitative variables was tested using the Kolmogorov-Smirnov and graphically confirmed with a histogram. Categorical variables were compared using the Fisher s exact test or v 2 test when the conditions of application of Fisher s exact test were not met. Quantitative variables were compared between groups using Student s t-test after verification of equality of variances when data were normally distributed, and with the Wilcoxon nonparametric test when the hypothesis of normality of distribution was not verified. Change of the m-ypas score over time was analysed using mixed model for repeated measures. The m-ypas score was centred on the mean for each period of measure to reach normality. Time was defined as a discrete variable as the periods of measurement were distinct and unequal. Time effect was included both as fixed and as random effects. Random effects were allowed to account for individual differences across time. Treatment and an interaction term between treatment and time were included in the model. For ensuring convergence, we did not to include additional variables in the mixed model. The multilevel model was fitted using the SAS PROC MIXED application. Parameter estimates were obtained by the full maximum likelihood method. An F-statistic was used to test for significance of fixed effects and 95% confidence intervals (CIs) were calculated for each parameter estimate. All the data were analysed by an independent team based on intention to treat (ITT) analysis. The statistical tests were bilateral and the level of significance was set at 5% (P < 0.05). Statistical analyses were conducted using SAS version 9.3 (SAS Institute Inc., Cary, NC, USA). Results One hundred and eighteen patients were recruited and randomized, 60 in the TAB Group and 58 in the MDZ Group (Fig. 1). No difference was found between the two groups for patient characteristics, type of surgery, or type of anaesthesia at the time of randomization (Table 1). Two patients randomized to the MDZ Group did not receive the allocated treatment, one because the surgery was cancelled, and the other for an unknown reason. A third patient who had hypnosis additionally to MZD was not included in the analysis, m-ypas information was not collected (Fig. 1). Three other patients were randomized despite protocol deviations: two in the TAB Group had a history of > 3 surgery, and one in MDZ Group stayed one night at the hospital and did not satisfy the ambulatory surgery condition. Consequently 55 patients, including the latter three, in the MDZ Group and 60 in the TAB Group were considered for the ITT analysis. At the time of mask induction (Time 3), there was no significant difference between MDZ and TAB Group for the mean (SD) m-ypas: 40.5 (18.6) vs 41.8 (20.7), P ¼ 0.99) (Table 2). At the time of parent separation (Time 2), no difference was observed on the STAI 2 and m-ypas 2 between groups. The mean level of m-ypas score over the four measurements were significantly lower in the TAB Group compared with the MDZ Group (P ¼ 0.03). The interaction between treatment and time was not significant, indicating that the mean m-ypas score did not change differentially between the two groups over the four time-points analysed (Fig. 2). Regarding the random effects model and considering the treatment received the m-ypas score significantly differed from one patient to another. There was no significant correlation between the level of the m-ypas score and its evolution over the four period of time between patients. The mean level of STAI as well its evolution over the three period of measurement was not different between the two groups (Table 2). Both parents and nurses found the procedure of anaesthesia more satisfying in the TAB Group vs the MDZ Group [9.1 (1.5) vs 9.6 (0.7) P ¼ 0.04 for parents and 8.0 (2.3) vs 9.7 (0.7) P < for nurses]. Concerning PHBQ scores, no significant difference between groups were found (Table 2). The response rate for this test was low (less than 40%), a rate not enough to ensure valid commentary. Discussion Our prospective randomized study did not find a difference between anxiety measured by m-ypas/stai scores in children

4 250 Marechal et al. Assessed for eligibility (n=118) Enrollment Excluded (n=0) Randomized (n=118) Allocation Allocated to MDZ (n=58) Received MDZ (n=56) Did not received MDZ (n=2; 1 surgery cancelled 1 for unknown reason) Allocated to TAB (n=60) Received TAB (n=60) Follow up Lost to follow up (n=0) Discontinued intervention (n=0) Lost to follow up (n=0) Discontinued intervention (n=0) Analysis Analysed (n=55) mypas not collected (n=1) Analysed (n=60) Fig 1. Consort diagram. Table 1. Patient characteristics data (mean (SD)) n Treatment MDZ (n ¼ 55) TAB (n ¼ 60) Age (yr) (1.8) 6.7 (1.9) Sex Girl 34 (29.6) 17 (30.9) 17 (28.3) Boy 81 (70.4) 38 (69.1) 41 (71.7) Anaesthesia GA þ LA 46 (41.1) 26 (47.3) 20 (33.9) GA 68 (58.9) 29 (52.7) 39 (66.1) Missing 1 1 Surgery Gut and Urologic 48 (48.5) 26 (54.2) 22 (43.1) ENT 31 (31.3) 10 (20.8) 21 (41.2) Eyes 13 (13.1) 7 (14.6) 6 (11.8) Orthopaedic 6 (6.1) 4 (8.3) 2 (3.9) Others 1 (1.0) 1 (2.1) 0 (0.0) Missing and parent between midazolam or tablet groups. However, the satisfaction with induction of anaesthesia as judged by nurses and parents seemed improved in the TAB Group. This could be as a result of the measurement bias, because the intervention was not blinded. The vision of their children gaming provokes probably less anxiety than seeing their children sleep. The interplay between the children and the nurse during tablet computer game use could also influence satisfaction; often nurses help children to play and congratulate them on their ability to play with the Apps they ve chosen. Additionally, communication between children and nurses around the tablet computer also provides a second tool to distract the children. Tablet computer intervention is an easy and time sparing method to blunt anxiety in paediatric surgical patients. In our study, the m-ypas baseline values were around 35 at admission, and around 40 at mask induction, indicating moderate anxiety. These values are very similar to those obtained by a more complex multicomponent behavioral preoperative program (ADVANCE trial) which needs eight interventions. 22 Previous studies have used various distraction methods to decrease child anxiety. Video clips and cartoons have shown significant effects on children s behavior and in reducing anxiety Tablet computer intervention has been previously reported to be superior to midazolam to blunt anxiety at the time of separation with parents and at the induction of anaesthesia in children aged one-11 yr. 16 However, we found that m- YPAS score changes throughout the procedure were not different between the two groups and separation from the parents and induction of anaesthesia had no effect on children or parent s anxiety. This could be explained by the difference in m- YPAS recording from studies. The outcome of our study, anxiety, was measured by a well-recognized anxiety test, the

5 Children and parental anxiolysis in paediatric ambulatory surgery 251 Table 2. ITT analysis (mean (SD)). For ITT six patients will be excluded (MDZ n ¼ 4, TAB n ¼ 2) Time 1: at arrival surgical ward; time 2 ¼ at separation from parents; time 3 ¼ at mask induction: time 4 ¼ in the PACU. *Wilcoxon test # v 2 test Fisher exact test n Mean Treatment P* MDZ (n¼55) TAB (n¼60) m-ypas (13.8) 37.1 (14.0) 34.6 (13.6) 0.41 m-pas (17.1) 38.3 (17.1) 35.3 (17.2) 0.16 m-ypas (19.7) 40.5 (18.6) 41.8 (20.7) 0.99 m-ypas (10.1) 39.7 (10.3) 35.5 (9.6) 0.03 missing Delta m-ypas1/m-ypas (15.2) 2.7 (15.5) 1.0 (15.0) 0.94 Missing STAI (8.5) 39.7 (8.4) 40.1 (8.67) 0.79 missing STAI (10.6) 43.9 (9.3) 42.9 (11.6) 0.59 missing STAI (9.4) 36.5 (97) 35.3 (9.3) 0.48 missing PHBQ (9.0) 3.2 (11.5) 2.9 (3.5) 0.79 Missing PHBQ (5.0) 2.7 (6.2) 0.3 (1.1) 0.05 Missing PHBQ (6.1) 0.4 (7.9) 0.3 (1.4) 0.70 Missing Nurse S (1.9) 8.0 (2.3) 9.7 (0.7) < Parent S (1.2) 9.1 (1.5) 9.6 (0.7) 0.04 missing m-ypas MDZ IPAD MDZ IPAD MDZ IPAD MDZ IPAD Treatment Fig 2. Box plot of scores for the Modified Yale Preoperative Anxiety Scale (m-ypas) by study groups across different study times: admission surgical ward, 1 parent separation, 2 anaesthesia induction 3 and when back to surgical ward. 4 Median values shown as solid line. Whiskers represent 5th and 95th percentile values, and dots represent outliers.

6 252 Marechal et al. m-ypas questionnaire. This test has been validated by several clinical studies. It needs, however, a robust method of data collection. In our study, the anxiety tests were collected by reliable psychologists. Seiden and colleagues 16 did not specify who recorded the tests, and in many studies m-ypas or other tests are performed by a member of staff. This might explain why a large heterogeneity exists at baseline for m-ypas in published clinical trials; for instance Lee and colleagues 9 reported mean baseline values for m-ypas that ranged from 53 to 58, while Patel and colleagues 10 reported scores that ranged from 34 to 45. Furthermore, unlike Seiden and colleagues 16, we included children older than four yr as the reliability of the m-ypas scores might be questioned for younger participants. The unreliability of m-ypas in these two circumstances (Age < four yr and score by staff) could also explain why at anaesthesia induction some studies report a decrease of more than 10 points 9 while others suggest an increase between 5-10 points 16 in the m-ypas scores. We were not able to detect any adverse effect of the interventions on postoperative behavior at home because of the low response rate. The results of this study might be affected by the dose of midazolam given. The dose of midazolam used in our study was 0.3 mg kg 1, a dose routinely given as premedication in our centre. This dose contrasts with higher doses usually given in previous studies exploring children anxiety (0.5 mg kg 1 ). Nonetheless, this dose is in the range of doses recommended for anxiolysis. Coté and colleague 24 showed that children were equally relaxed either 0.25 or 0.5 mg kg 1 midazolam were given. The application of the TAB distraction has several limitations. Children who do not have a tablet computer at home asked their parents to buy one as soon they were discharged from the hospital. The electronic tablet is not an ideal method of premedication in children aged less than two yr because of associated high cost, fragility, low autonomy, and the risk of robbery. Moreover, the use of tablets in daily practice may not be conceivable owing to the large number of children operated on in large pediatric centres every day. A limitation of our study is that it is likely to have been underpowered in order to detect a difference between the two groups, as we probably overestimated the expected effect size, and underestimated the potential influence of staff interventions in reducing anxiety diluting the effect of TAB intervention. Tablet computers have been mainly evaluated in elective surgery, but the emergency context might be of interest as anxiety is often important in the ER and oral premedication is usually not administered when surgery might become necessary. In conclusion, we were not able to show that a tablet computer game was superior to midazolam to blunt anxiety in children two to four yr of age with programmed ambulatory surgery. TAB capacity as a non-pharmacological tool in reducing perioperative stress without any sedative effect in this population should be assessed by larger trials. Authors contributions Study design/planning: M.D.Q.S., S.T., B.K., J.B., D.C., H.D. Study conduct: C.A., B.C., M.D.Q.S., S.T.,D.C., C.M. Data analysis: L.B., J.B., D.C. Writing paper: C.A., J.B., S.T., D.C. Revising paper: all authors Acknowledgements The authors are grateful for the help of Philip Robinson for English revision. Declaration of interest None declared. 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