Anxiety in Children Undergoing VCUG: Sedation or No Sedation?

Background. Voiding cystourethrograms are distressing for children and parents. Nonpharmacological methods reduce distress. Pharmacological interventions for VCUG focus on sedation as well as analgesia, anxiolysis, and amnesia. Sedation has cost, time, and safety issues. Which agents and route should we use? Are we sure that sedation does not influence the ability to diagnose vesicoureteric reflux? Methods. Literature search of Medline, EMBASE, and the Cochrane Database. Review of comparative studies found. Results. Seven comparative studies including two randomised controlled trials were reviewed. Midazolam given orally (0.5-0.6 mg/kg) or intranasally (0.2 mg/kg) is effective with no apparent effect on voiding dynamics. Insufficient evidence to recommend other sedating agents was found. Deeper sedating agents may interfere with voiding dynamics. Conclusion. Midazolam reduces the VCUG distress, causes amnesia, and does not appear to interfere with voiding dynamics. Midazolam combined with simple analgesia is an effective method to reduce distress to children undergoing VCUG.

Pharmacological interventions primarily focus on sedation but also could include beneficial analgesic, anxiolytic, and amnesic effects [29,30]. Sedation brings with it cost, time, and safety concerns [1,[29][30][31][32][33]. It is unknown whether we can predict which children will go on to have distress or whether we should sedate routinely [34]. Which agents should we use, and what is the best route of administration? The majority of children having VCUG would not have had one previously. Coping styles and parent-child interaction are important determinants of distress during a medical procedure [34]. Safety of sedating agents is excellent in the context of a sedation service with the necessary staff and equipment to manage sedation in young children [35][36][37]. Those who sedate children should be prepared for inadvertent deeper sedation, basic life support, and airway management [29][30][31][38][39][40]. Advanced help should be available. Time and cost factors limit the introduction of this distress-reducing intervention. Sedation recovery area and staff time are being the primary cost factors. The medications themselves are relatively inexpensive. Finally, are we sure that sedation does not influence the VCUGs ability to diagnose vesicoureteric reflux?

METHODS
These methods include a sensitive search of PubMed , EMBASE , Cochrane Database of Systematic Reviews, and Cochrane Randomised Controlled Trials Register. Articles on VCUG were identified through the terms urography (MESH heading exploded), micturating, or voiding cystourethrogram using wildcard search for variations of spelling. Acronyms VCUG and MCUG were also used. To identify sedation articles, the following exploded MESH terms were used: "hyponotics and 2 Advances in Urology sedatives," conscious sedation, midazolam, propofol, chloral hydrate, and nitrous oxide. "Sedation" was searched for as a title word. Results of the VCUG search and sedation search were combined. There were no limits on language for search, but only English language articles were reviewed. Further studies were identified from bibliographies. Unpublished studies were not actively sought.
Any study comparing a sedative against another sedative, placebo, or standard treatment for VCUG was reviewed. One French language article [77] and one Polish language article [56] were not included. Study designs are summarised in Table 1. Outcome measures and results are in Table 2 [41,43,45,47,52,59]. Quality assessment is shown in Table 3. Only two of the studies [45,52] were of high quality with Jadad scores [86] of 4 or more. One unpublished comparative study was found, but not included [68].

DISCUSSION
The best way to avoid the distress of the VCUG is not to do the procedure. A better way to image vesicoureteric reflux has recently been discussed in an editorial by Elder [55]. As much evidence becomes available to show that we are not influencing the outcome of VUR, less VCUGs may be ordered [7,93]. Possible alternatives include Doppler ultrasound [94] or ultrasound with contrast [61]. A suprapubic approach to avoid catheterisation seems promising but still requires filling and voiding [49]. Methods to detect reflux without voiding are impaired as some reflux may be present only on voiding [95], although the fact that whether this is important or not is debated [96]. Nuclear medicine scanning may be an alternative or may be able to select those who are more likely to benefit from VCUG [67]. Nuclear medicine cystoscopy replaces radio-opaque contrast with pharmacolabelled material with lower radiation, but otherwise it is very similar to the VCUG. Currently, VCUG remains the gold standard until less invasive tests are developed [1]. At the very least, we should be perfecting our current technique [12].

DISTRESS, PAIN, AND ANTICIPATORY ANXIETY
Distress is an all encompassing term that may or may not include a painful stimulus. This can be evidenced by fear  of a procedure, pain responses prior to nociceptive stimuli, or anxiety behaviours before a planned event. Distress during the voiding cystourethrogram has been reported in observational and controlled studies. Phillips et al. [13] showed that 52 out of 73 children (71%) experienced serious distress, severe distress, or panic on the Groningen distress rating scale [90]. Herd et al. found that serious or severe distress was detected in 61% of all unsedated children at some stages during the VCUG. This level of distress may have been brief but is generally considered unacceptable. This distress is caused not only by urethral catheterisation, but also by the distension of the bladder and the subsequent voiding of urine in a socially abnormal situation ( Figure 1). Nociceptors related to urethral mucosa and stretch receptors in the bladder provide the peripheral pain signals, but the majority of the distress is cortical.
Distress can also be manifest in the parent. Parents' perceptions of fear, distress, and pain in their children are anticipated to be greater than the reality [51].

PSYCHOLOGICAL THERAPY (NONPHARMACOLOGICAL TREATMENTS)
Psychological treatments should be considered first as they often have little or no risk. There are many ways to reduce the distress of procedures in children [19] and even more challenges researching and implementing psychological interventions for controlling children's pain [97]. Interventions may range between simple educational [28] and more structured play therapy sessions [14,76] and hypnoses [42]. Preparation, distraction, and reassurance before, during, and after the procedure are likely to reduce the distress of the procedure [22,69,75]. Parental presence is comforting for children during painful procedure and should be encouraged despite the lack of specific VCUG evidence [23].  Those who have been previously distressed by VCUG would seem to be ideal candidates for sedation, but the majority of children would not have had a previous VCUG. Factors which may reduce distress in children during VCUG include "effortful control" by the child and coping and distress-promoting behaviours by the parent [34]. No validated prediction tool exists for VCUG distress.

Sedating agents
Sedation continues to be difficult to define [63]. In the case of the VCUG, a degree of consciousness is required. This may be defined as light sedation, and the use of oxymoron "conscious sedation" is being discouraged [98].

Midazolam
Of the selected studies, 5 had midazolam as a treatment arm and 4 of which were oral and one intranasal. Oral midazolam dose was 0.5 mg/kg in two studies [45,47] and 0.6 mg/kg in two other studies [41,43]. Maximum dose was 15 mg in all. Time between ingestion and procedure ranged from 15 to 30 minutes. Intranasal dose in one study was 0.2 mg/kg with a maximum of 5 mg, and it was administered 5 minutes before the procedure [52]. A number of behavioural measures were employed (Table 1). All the studies demonstrate significantly less distress with midazolam in a variety of measurement tools. Few adverse effects were encountered. Midazolam may cause adverse paradoxical agitated reactions in less than 5% of children [99]. These reactions have been shown in case reports to be ameliorated using the antidote for midazolam (flumazenil) both in adults [100] and children [101]. Ketamine, a dissociative anesthetic, has been shown to be more effective than increased doses of midazolam or placebo in a randomised controlled trial [99].
The study by Stockland et al. [52] on 95 children compared intranasal midazolam (0.2 mg/kg with a maximum of 5 mg) to placebo. Nurses reported a trend to easier procedure in the midazolam group (P = .07), with girls reported easier than boys (P = .06). No serious adverse events were reported. Parents felt that the administration of midazolam was more uncomfortable than that of placebo (P < .001). Parents felt that midazolam made catheterisation, voiding, and the overall procedure more comfortable (P = .015, P = .08, and P = .047, resp.). The authors report P-values and no absolute scores, which makes it impossible to estimate treatment effect size or clinical relevance.
A study by the current author and colleagues [45] compared oral midazolam (0.5 mg/kg with a maximum of 15 mg) to placebo in 125 children who had VCUG.
Behavioural observations were completed in 117. This was the only study that calculated a priori power requirement or attempted to quantify the treatment effect. We rated our paper highly using the Jadad score [86]. We found no serious adverse events. The number of children experiencing serious or severe distress (Groningen distress rating scale (GRDS) >2) at any stage of the procedure was 34 (61%) in the placebo group and 16 (26%) in the midazolam group. Number needed to treat to reduce serious or severe distress in one child was 2.9 (95%CI 1.9-5.5). VUR was identified in 16% of all children. This study was limited to children above the age of one year.  [47]. They found no difference between midazolam and 50% nitrous oxide although they did not design this as an equivalence study, and no power calculation was done. There was a trend for the time to micturition to be longer in the nitrous group 6 Advances in Urology   Advances in Urology by the observational tool selected [102]. Wong-Baker FACES scale was the self-report tool used [103]. For the VCUG group (n = 101), BBDS was 44 (range of  in the nonsedated group versus 11 (range of 0-67) for the sedated group (P < .001). Immediately after catheterisation, the Wong-Baker FACES scale median was 6 for the nonsedated group and 0 for the sedated group (P < .001). Both studies reported time of completion, but neither study reported VUR grading or residual volume.

Other agents
Choral hydrate was compared to oral midazolam and placebo in one study [41]. A dose of 25 mg/kg was not found to be statistically different from placebo in reducing distress. This may have been due to inadequate dose or lack of power in the study. The sedation scale was also not significant for chloral versus placebo and, therefore, it suggests too low a dose was selected. There is no enough data to make any assessment of effect on voiding dynamics. One retrospective study of propofol using historical controls was selected for review [48]. While this was an attempt to create a sedative state using low-dose propofol, the study required the presence of an anesthetist. During this study, low-dose propofol infusion followed sevoflurane gas induction and intravenous cannula insertion. This study found that propofol reduced the ability of children to completely void, which may interfere with the diagnosis of VUR.

Anxiolysis
Midazolam in the doses used in the reviewed studies is anxiolytic. Many children may appear fully conscious yet more cooperative, while another child given the same dose may appear sleepy. Where anxiolysis ends and sedation begins is unclear, but there would be a large overlap.

Analgesia
There is a wide range of analgesics available for children [104]. Midazolam does not provide any analgesia and, therefore, should be supplemented with a simple analgesic.

Acetaminophen
Acetaminophen is the most commonly provided childhood analgesic with low side effects and cost. It is routinely offered prior to other potentially painful procedures in children such as vaccination. Acetaminophen is usually provided in a sweet syrup base, and could be used to disguise the bitter taste of midazolam. There are many formulations of acetaminophen syrup, and palatability may vary [105].

Oral sucrose
Oral sucrose is an effective analgesic in new-born babies, and has been subject to several controlled trials and a Cochrane review [106]. While no studies have examined its effect for VCUG distress, it seems a simple likely effective intervention with low risk for children under 3 months of age.

Nitrous oxide
Nitrous oxide is a strong analgesic antagonising central NMDA receptors, and this is a potential advantage over midazolam. Study of Keidan et al. comparing midazolam to continuous flow nitrous oxide found no difference in FLACC scores [91], a measure of pain used more recently for procedural distress [107]. Study of Keidan et al. was not designed as an equivalence study, and no power calculations were done; so a true difference may not have been detected by the study.

Opiates
No studies have looked at opiate use for VCUG distress. Intranasal midazolam has proven effective, and opiates may also be administered by this route. Intranasal fentanyl shows promise as a rapid, easy-to-administer analgesic for severe pain in the children's Emergency Department [108]. Opiates may interfere with bladder function [109].

Local anesthetics
Lignocaine gel has been shown to reduce the pain of catheterisation for VCUG, but a 10-minute process of repeated application of lignocaine gel to the urethral meatus is required. The authors did not measure the effect of this procedure but only the reduced pain of catheterisation that followed. It would seem reasonable to use it with low risk of harm but at added cost [66]. Further study on children is required.

Anesthesia
There is increasing use of deeper sedation outside the operating room by nonanesthesiologists [110]. There is debate about which agents should be used outside the operating room and who should provide this service [63]. For VCUG, anesthetics have been given to avoid the trauma associated with urethral catheterisation, and then the child is allowed to wake and complete the VCUG. This does not avoid the distress caused by bladder distension or micturition. It also requires an anesthetist and the full costs associated with anesthesia and recovery.

WHO SHOULD RECEIVE SEDATION?
Many children do not experience distress during the VCUG. This may be related to previous experience, coping style, parental influence, staff skill, and empathy. Developmental considerations and education level of the child and parent are important. Nevertheless, many children, who would not have been predicted, may go on to experience distress. Parental perceptions of the procedure are such that most parents would request some medication if it were effective, safe, and available [43,47].

DOES SEDATION AFFECT THE ABILITY OF THE VCU TO DIAGNOSE REFLUX?
Effect of sedation on ability to void can be measured with indirect or direct measures. Indirect measures include filling volume, residual volume, and time of micturition. Bozkurt et al. carefully examined urodynamic variables under the influence of midazolam [62]. They used a highintranasal dose of 0.5 mg/kg. Stockland et al. used intranasal midazolam at a dose of 0.2 mg/kg, and found no difference in reflux grading between the groups [52]. They did not perform a power calculation, so there is still the possibility of missing a true effect. Herd et al. considered a clinically important difference in VUR to be a true shift of one grade down by half of the subjects with the use of midazolam [45]. It was important to detect a difference, so a 90% power was used. There was no difference in VUR grading between the groups (nonlinear mixed model analysis, P = .31). There was no evidence of a difference in volume infused between the two groups (P = .08).

CONCLUSIONS
Sedation reduces distress of the micturating cystourethrogram in children previously distressed or likely to be distressed. Midazolam is the agent most studied, and has an excellent safety profile. An oral dose of 0.5-0.6 mg/kg or intranasal dose of 0.2 mg/kg seems effective. Most children have not had a VCUG previously, and it may be difficult to predict which of them will go on to have distress. When giving oral midazolam of 0.5 mg/kg to children routinely, the number needed to treat them is 2.9 (95%CI 1.9-5.5) to eliminate serious or severe distress. Continuous flow nitrous oxide appears promising, particularly with a fast onset and recovery time, but it has greater potential for deeper sedation. This may interfere with voiding, and further studies are required. Midazolam appears not to interfere with the VCUG's ability to diagnose vesicoureteric reflux using indirect (residual volume) and direct (VUR grading) measures. There are many children who would avoid distress if they were given sedation. Local sedation services should be engaged, and safety guidelines should be followed to ensure that this effective treatment might be implemented safely.

ACKNOWLEDGMENT
A grant from the Waikato Medical Research Foundation for the original VCU sedation study made this review possible.