ORIGINAL ARTICLE. Pediatric Anesthesia ISSN

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1 Pediatric Anesthesia ISSN ORIGINAL ARTICLE Tablet-based Interactive Distraction (TBID) vs oral midazolam to minimize perioperative anxiety in pediatric patients: a noninferiority randomized trial Samuel C. Seiden 1, Susan McMullan 2, Luis Sequera-Ramos 1, Gildasio S. De Oliveira Jr 3, Andrew Roth 1, Audrey Rosenblatt 2, Bill M. Jesdale 4 & Santhanam Suresh 1 1 Department of Pediatric Anesthesiology, Ann & Robert H. Lurie Children s Hospital of Chicago, Northwestern University, Chicago, IL, USA 2 Department of Anesthesiology, Ann & Robert H. Lurie Children s Hospital of Chicago, Chicago, IL, USA 3 Department of Anesthesiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA 4 University of Massachusetts Medical School, Worcester, MA, USA Keywords anxiety; distraction; tablet; interaction; surgery; children; pediatrics; anxiolysis Correspondence Dr. Samuel C. Seiden, Department of Pediatric Anesthesiology, Ann & Robert H. Lurie Children s Hospital of Chicago, Northwestern University, 225 E. Chicago Ave, Box 19, Chicago, IL 60611, USA sseiden@luriechildrens.org Section Editor: Neil Morton Accepted 2 June 2014 doi: /pan Summary Introduction: Perioperative anxiety is a common and undesirable outcome in pediatric surgical patients. The use of interactive tools to minimize perioperative anxiety is vastly understudied. The main objective of the current investigation was to compare the effects of a tablet-based interactive distraction (TBID) tool to oral midazolam on perioperative anxiety. We hypothesized that the TBID tool was not inferior to midazolam to reduce perioperative anxiety. Methods: 108 children, ages 1 11 years, presenting for outpatient surgical procedures were prospectively randomized to oral midazolam (0.5 mgkg 1 ; 20 mg max) or TBID. The primary outcome was the change in anxiety level from baseline to parental separation and anesthetic induction. Other data collected included emergence delirium, parental satisfaction, time-to-pacu discharge, and posthospitalization behavior. Results: The mean difference (95% CI) in the increase of anxiety at parental separation between the TBID and the midazolam group was 9 ( 2.6 to 16.4), P = 0.006, demonstrating superiority to midazolam group (one-sided P = 0.003). For children 2 11 years, the mean difference (95% CI) in anxiety at induction was significant between the TBID and midazolam groups, 14.0 ( 6.1 to 22.0), P < The median (IQR) time-to-pacu discharge was 111 (75 197) min in the midazolam group and 87 (55 137) min in the TBID group, P = Decreased emergence delirium and increased parental satisfaction were also observed in the TBID group. Conclusions: A TBID tool reduces perioperative anxiety, emergence delirium, and time-to-discharge and increases parental satisfaction when compared to midazolam in pediatric patients undergoing ambulatory surgery. Introduction Perioperative anxiety is a very common and undesirable outcome in pediatric surgical patients (1,2). Perioperative anxiety has been associated with worse postoperative pain in children (3). In addition, perioperative anxiety can also affect quality of sleep for up to 6 months postoperatively which resembles the disease spectrum of posttraumatic stress disorder (4). Benzodiazepines are the most common pharmacological intervention to minimize perioperative anxiety; however, the administration of benzodiazepines may lead to prolonged sedation and paradoxical effects with behavioral changes and agitation (5 9). In order to circumvent the side effects of drug interventions and parental desire to avoid unnecessary 2014 John Wiley & Sons Ltd 1

2 TBID vs oral midazolam to minimize perioperative anxiety S.C. Seiden et al. medications, nonpharmacological strategies have been developed and tested to decrease preoperative anxiety with varying results (10 12). A major limitation of previous interventions is the lack of a distraction platform that allows interaction with patients. Patient interaction has been shown to be crucial for the success of multimedia strategies to minimize depression or anxiety disorders (13,14), and interactive techniques have been proven superior to passive ones in pain perception in pediatric patients (15,16). The benefits of an interactive multimedia platform when compared to benzodiazepines to minimize perioperative anxiety have yet to be established in pediatric surgical patients. The main objective of the current investigation was to compare a tablet-based interactive distraction (TBID) tool and oral midazolam to reduce perioperative anxiety in children undergoing surgery. We hypothesized that pediatric patients who used the interactive tool would have similar preoperative anxiety levels as the ones receiving oral midazolam. Methods The study was a prospective and randomized trial. Approval for the study was received by the Institutional Review Board (IRB) of the Ann and Robert H. Lurie Children s Hospital of Chicago. Informed consent was obtained from parents or legal guardian of all participating subjects. Eligible subjects were children aged 1 11 years presenting for outpatient surgical procedures; American Society of Anesthesiologists Physical Status (ASA-PS) score I or II and first time anesthetic for the patient. Subjects were excluded if there was a documented behavioral or psychiatric disorders or the procedure was emergent. Subjects were randomized using a randomly selected sealed envelope to one of the two intervention groups: oral midazolam (Midazolam HCL syrup; Roxane Laboratories Inc, Columbus, OH, USA) (0.5 mgkg 1 orally; up to 20 mg max) or the tablet-based interactive distraction (TBID) platform (Apple ipad mini, Cupertino, CA, USA). Allocation of subjects was kept in a sealed envelope until the subject was consented to participate in the study. Children assigned to the TBID group were allowed to select an age appropriate videogame (Table 1) to play during the induction period starting at the time of parental separation and concluding at induction. After selecting a game, the tablet was taken from intervention group subjects and returned to them one minute before parental separation. Children assigned to the midazolam group received the oral premedication at least 15 min and not more than 45 min prior to departure to the operating room. Both groups received inhalation induction and maintenance with sevoflurane/oxygen/nitrous oxide. Parental presence during anesthetic induction was excluded for both study groups. The primary outcome was the change in anxiety level from the baseline period assessed at two points (parental Table 1 Age appropriate game suggestions for TBID Game iphone (ios) or Android (A) 1-3 years 4-6 years 7-11 years Description Pocket pond ios **** Interactive Koi pond Subway surfers ios/a ** **** Hoverboarding to dodge obstacles Temple run ios/a *** **** First person temple adventure Fruit ninja ios/a *** **** **** Slice and dice fruits Angry Birds ios/a **** **** Shoot birds at pig fortress Bad piggies ios/a *** **** Strategic pig cart building and racing Cut the rope ios/a *** **** Monster feeding puzzle game Flow free ios/a ** *** Puzzle game Lego Juniors ios/a **** ** Lego building skills Shrek Kart ios ** **** Kart racing Talking Tom Cat ios *** **** ** Imitative cat Racing penguin ios **** ** Penguin racing adventure Dragon vale ios/a * **** Feed and raise dragons Action movie ios * *** Add action effects to movies Air hockey ios/a * *** **** Virtual air hockey Draw mania ios ** *** *** Multiplayer drawing game Lego Star Wars ios ** *** Lego Star Wars adventure Ninjago lego ios *** **** Scavenger hunt I hear ewe ios *** Animal sounds when you push on the picture of the animal. 1 4 stars are author s indication of popularity and suitability of the game for given age group John Wiley & Sons Ltd

3 S.C. Seiden et al. TBID vs oral midazolam to minimize perioperative anxiety separation and anesthetic induction) using the Modified Yale Preoperative Anxiety Scale (mypas) a well-established and validated scale (17). Transfer from the OR to PACU was performed at the discretion of the anesthesia provider. Other data collected included subject demographic characteristics, emergence delirium scores using the Post Anesthesia Emergence Delirium (PAED) Scale (18) at emergence and 15 min after PACU admission (a score greater than 12 was used to detect emergence delirium), time-to-pacu arrival until awakening and time-to-pacu discharge. Parental perception of child anxiety was assessed at hospital arrival and at separation on a 7-point Likert scale ranging from 0 not at all anxious to 6 very anxious. Parental satisfaction with child separation was assessed by asking parents on how satisfied are you with the ease with which your child got separated from you? and using a Likert scale ranging from 0 very satisfied to 6 not satisfied. In addition, posthospitalization behavior change assessed by a phone call using the Post Hospitalization Behavioral Questionnaire (PHBQ) at seven and fourteen postoperative days (19,20). The mypas was assigned partial weights to compensate for different number of subscales and to obtain a global score as previously suggested (11,17). The global score ranged from 23 to 100 where 23 represents low anxiety and 100 high levels of anxiety. Power analysis estimated that group sample sizes of 44 patients per group would achieve 90% power to detect noninferiority using a one-sided, two-sample t-test. The margin of noninferiority was -7 points which represents a less than 10% difference in anxiety scores. The significance level of the test was set at 0.025, and the population s standard deviation was 10 (21,22). One hundred and eight subjects were recruited to compensate for expected losses to follow up on secondary outcomes. The Shapiro Wilk and Anderson Darling tests were used to test the assumption of normal distribution (P > 0.1). Normally distributed interval data are reported as mean (SD), non-normally distributed interval and ordinal data are reported as median (range or Interquartile range (IRQ)), and categorical data were presented as counts (n). The primary outcomes of anxiety score change (parent separation and anesthesia induction minus baseline scores) were tested uninvariably using Student s t-test and a noninferiority delta of -7. After noninferiority was evaluated, we then tested for superiority at the level using one-tailed t-test as test direction would have been obtained from the noninferiority test. Additional data were analyzed using Mann Whitney U-test or Fisher s exact test as appropriate (23,24). Kaplan Meyer plots were constructed to evaluate time to event data (25,26). Data were analyzed using STATA version 12 (College Station, TX, USA). Results The details of the conduct of the study are shown in Table 2. One hundred and eight subjects, stratified by age from 1- to 3-, 4- to 6-, and 7- to 11-year-olds, were randomized and 108 completed the study. Patients were enrolled from February 2013 through June Patient s baseline characteristics and surgical factors were not different between the study groups, including baseline preoperative anxiety scores (Table 2). The mean difference (95% CI) in the increase of anxiety at parental separation between the TBID platform group and the midazolam group was -9 (-2.6 to -16.4), where the lower limit of the confidence interval overlapped the noninferiority boundary. In contrast, we could establish superiority of the TBID platform group compared with midazolam group in regard to anxiety at parental separation (one-sided, P = 0.003). This finding was further suggested by parental perception of anxiety at separation with 30 parents in the TBID platform group stating that their child were not at all anxious at separation compared with only 15 in the midazolam group, P = The mean difference (95% CI) in the increase of anxiety at induction between the TBID platform group and the midazolam group was -6 (1.1 to -18), Table 2 Baseline demographic characteristics by study groups Tablet distraction (n = 57) Midazolam (n = 51) P value Age (years) Gender Male Female ASA class I II 9 14 Preoperative Heart Rate (bmin 1 ) Baseline mypas 32 (23 to 45) 28 (23 to 45) 0.93 Procedure Type ENT Urology 7 7 General surgery 6 7 Gastrointestinal 7 3 Ophthalmology 0 1 Gynecologic 0 2 Dental 2 3 Orthopedics 2 2 Data are presented as mean (SD), median (IQR), or counts (n) as appropriate John Wiley & Sons Ltd 3

4 TBID vs oral midazolam to minimize perioperative anxiety S.C. Seiden et al. where the lower limit of the confidence interval overlaps the noninferiority boundary. Superiority of the TBID platform group compared with midazolam could not be established for anxiety at anesthesia induction (onesided P = 0.04). There was no significant change from mypas score from separation to induction, mean difference (95% CI) of 6 (-5 to 37) As the mypas has not been validated for children < 2 years of age, we have performed a subgroup analysis of the study participants with age 2 years. Similarly to the whole study cohort, the mean difference (95% CI) in anxiety at parental separation between the TBID platform group and the midazolam group was (-7.4 to -18.3), P < In contrast to the whole study cohort, by excluding children < 2 years, the mean difference (95% CI) in anxiety at induction was also significant between the TBID and midazolam groups, (-6.1 to -22.0), P < Distribution of changes in mypas score from baseline to parental separation and from baseline to induction show the overall similarity of the two techniques, with a clear preponderance of higher increases in mypas score (indicating greater anxiety) among those in the midazolam group (Figure 1). Of interest, especially at induction of anesthesia, there are outliers in both TBID and midazolam group that show substantial increases in anxiety. Further research is warranted to determine if predictors and alleviators for these patients who are nonresponders to either technique. Of note, there was no significant difference in anxiety scores based upon gender from baseline to separation (P = 0.84) or baseline to induction (P = 0.47). Intraoperative and postoperative data are presented in Table 3. Emergence delirium was not different at 15 min of PACU admission in the midazolam group when the threshold for emergence delirium was set as 12, 6 of 51 (12%) compared with 4 of 57 (7%) subjects in the TBID platform group, P = However, the absolute emergence delirum score was significantly less between TBID and midazolam group (Table 3). Timeto-PACU discharge was prolonged in the midazolam group (Figure 2). The median (IQR) time-to-pacu discharge was 111 (75 197) min in the midazolam group and 87 (55 137) min in the TBID group, P = Postoperative behavior scores were not different between the groups at day 7 and 14, P = 0.23 and P = 0.13, respectively. 43 of 53 (81%) parents of children in the TBID platform group were very satisfied with the child separation process compared with 22 of 37 (59%) in the midazolam group, P = Discussion The most important finding of the current investigation was the reduction of separation anxiety by a tabletbased interactive distraction (TBID) tool when compared to oral midazolam in children undergoing outpatient surgery. This finding was further suggested by parental perception of lower anxiety and greater parental satisfaction in the TBID group compared with the midazolam group. Taken together, our results suggest that TBID tool can be an effective strategy to minimize anxiety in pediatric patients undergoing surgical procedures. Table 3 Intraoperative and postoperative data Tablet distraction (n = 57) Midazolam (n = 51) P value Figure 1 Box plot of scores for the Modified Yale Preoperative Anxiety Scale (mypas) by study groups across different study times (baseline, parent separation, and anesthesia induction). Median values shown as solid line within box of 25th and 75th percentile values. Whiskers represent 5th and 95th percentile values, and dots represent outliers. Represents statistically difference, P < Data were compared using the Mann Whitney U-test. Heart rate at induction (bmin 1 ) Time from PACU arrival to Phase 1 discharge (min) Total time for PACU discharge (min) PAED scale score at emergence PAED scale score at 15 min Data are presented as median (IQR). 110 (98 to 126) 107 (96 to 123) (35 to 68) 45 (30 to 54) (55 to 137) 111 (75 to 197) (2 to 10) 11 (7 to 15) < (0 to 4) 7 (2 to 10) < John Wiley & Sons Ltd

5 S.C. Seiden et al. TBID vs oral midazolam to minimize perioperative anxiety Figure 2 Kaplan Meier plot of proportion of subjects that were discharged from PACU. The median (IQR) time-to-pacu discharge 111 (75 to 197) min in the midazolam group compared with 87 (55 to 137) min in the TBID group, P = Our results are clinically important as preoperative anxiety has been implicated with worse postoperative recovery in surgical patients (27,28). Oral benzodiazepines are likely the most common pharmacological intervention used by clinical practitioners to minimize perioperative anxiety in children. However, oral benzodiazepines can sometimes be quite challenging to administer in perioperative pediatric patients. In addition, paradoxical effects of benzodiazepines can also lead to perioperative agitation. Tablet-based interactive distraction offers an effective and safe alternative to midazolam to reduce perioperative anxiety in pediatric surgical patients. Another important finding of the current investigation was the prolonged time-to-pacu discharge of subjects who received midazolam compared with the TBID group. This finding is important due to the economic implications of prolonged discharge after outpatient surgery (29,30). Other pharmacological strategies used to minimize anxiety such as ketamine and alpha-2-agonists also have prolonged undesirable sedative properties which may also prolong hospital discharge (31,32). Conversely, the TBID intervention reduces separation anxiety while still promoting a faster discharge of ambulatory pediatric patients. We were not able to detect an overall reduction of anxiety at induction by the TBID group compared with oral midazolam group when we examined the whole study cohort. In contrast, when we perform a subgroup analysis and excluded children younger than 2 years of age, we were able to determine a significant reduction of anxiety at induction by the TBID group. The lack of an effect on anxiety at induction of the TBID group compared with oral midazolam group for the overall study cohort could be attributed to either a poor performance of the scale on children younger than 2 years of age or to a true lack of a beneficial effect of the TBID for that age group. Other studies have examined the use of technology distraction tools to reduce perioperative anxiety in children. Patel et al. demonstrated that the use of video game/parental presence reduced anxiety during induction compared with midazolam/parental presence in an older pediatric population (33). Our results differs from the Patel study as we were able to adapt the distraction tool to younger patients do to the simpler and more intuitive interactive options afforded by tablet computing compared with older video game platforms. In addition, we did not use parental presence as part of our protocol. Parental presence has not been consistently shown to reduce perioperative anxiety in children, but it might function as an important confounder in perioperative anxiety studies (34 36). We also observed an increase in the presence of emergence delirium scores in the midazolam group as detected by the pediatric emergence delirium scale compared with the TBID group, although at the threshold defining delirium on this scale the difference between groups was not significant. In contrast, benzodiazepines have been suggested as strategy to reduce emergence delirium in children (37). We believe that our findings were likely due to a greater level of sedation noted in the midazolam group as three of the five elements assessed on the PAED would score higher for a more sedated child and not per se due to increased degree of agitation in the midazolam group (38). As we did not standardize perioperative analgesic management of subjects, our findings should only be considered exploratory and future studies to confirm or refute our results are warranted. Our study should only be interpreted within the context of its limitations. Due to the nature of the examined intervention, we could not ensure that the data collection process was blinded and cannot completely exclude measurement bias. However, the parental perception regarding between group anxiety parallels our findings and, therefore, do not suggest the presence of measurement bias. We only studied children undergoing outpatient surgery, and future studies should attempt to generalize our results in the inpatient population. Lastly, it remains to be determined if the combination of both 2014 John Wiley & Sons Ltd 5

6 TBID vs oral midazolam to minimize perioperative anxiety S.C. Seiden et al. interventions are advantageous when compare to each intervention alone. Several techniques may be helpful for clinicians interested in incorporating TBID into their practice. First, let the child pick an age appropriate game to play in the preoperative area (see Table 1 for suggestions). Apps are often free or several dollars and can even be loaded on patient request with internet access. Second, taking the tablet from the child after they have picked a game allows for maximum anxiolysis during parental separation and induction of anesthesia. Third, during induction, it is often easier for game play for the child to sit upright and cross-legged as opposed to supine allowing them to hold tablet in their lap (see for video demonstration of TBID). Medium-sized tablets (e.g., approximately 5 in x 8 in) are easier for children to hold without being too small to control game or too large to hold. A sturdy case that protects with screen cover protects against impact and allows for germicidal disinfection between each use. In summary, we demonstrated that tablet-based interactive distraction is superior to oral midazolam in minimizing parental separation anxiety in children aged 1 11, and superior to anxiolysis during induction of anesthesia for children aged 2 11 undergoing outpatient surgery. In addition, it seems that the sedative properties of midazolam prolonged discharge from the postanesthesia care unit. In addition, parents support the use of less medications for their children. Our results support the use of interactive nonpharmacological interventions as a viable alternative to benzodiazepines to mitigate perioperative anxiety in pediatric surgical patients. Disclosure/Acknowledgments This study was approved by the Institutional Review Board of the Ann and Robert H. Lurie Children s Hospital of Chicago. There was no external funding for this study. None of the authors have conflicts of interest related to the conduct of this study. The authors wish to thank Dr. C Heddon for contributions to this project. Conflict of interest No conflicts of interest declared. Supporting information Additional Supporting Information may be found in the online version of this article: Video S1. Video shows a 7 year old boy using a tablet for distraction during parental separation and induction of anesthesia. Note that he hardly notices leaving his parents, immediately returning to being engaged in play, and similarly, during the mask induction of anesthesia he is completely distracted and calm. References 1 Cuzzocrea F, Gugliandolo MC, Larcan R et al. A psychological preoperative program: effects on anxiety and cooperative behaviors. Paediatr Anaesth 2013; 23: Lee J, Lee J, Lim H et al. Cartoon distraction alleviates anxiety in children during induction of anesthesia. Anesth Analg 2012; 115: Esteve R, Marquina-Aponte V, Ramirez- Maestre C. 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