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The Cochrane Library and nocturnal enuresis; an umbrella review

2006; Wiley; Volume: 1; Issue: 1 Linguagem: Inglês

10.1002/ebch.13

2040-4050

Kelly Russell, Darcie Kiddoo,

Pediatric Pain Management Techniques

Editors' note: Umbrella reviews, compiling evidence from multiple Cochrane reviews into one accessible and usable document, will be a regular feature of this Journal. Our aim for each umbrella review is to focus on the treatment question, ‘which treatment should I use for this condition?’, and to highlight the Cochrane reviews and their results in doing so. It is our hope that the umbrella review will serve as a ‘friendly front end’ to The Cochrane Library, allowing the reader a quick overview (and an exhaustive list) of Cochrane reviews relevant to the clinical decision at hand. Nocturnal enuresis is a common childhood disorder that is characterized by bed wetting at the age of five and beyond. The proposed etiologies are difficulties with arousal, nocturnal polyuria or a small nocturnal bladder capacity, although the most common is probably simple developmental delay in achieving bladder control. Therapies attempt to address these etiologies individually. Approximately 13–19% of boys and 9–16% of girls suffer from nocturnal enuresis. It is estimated that nocturnal enuresis will spontaneously resolve in 15% of children each year; however, 2–3% of adolescents and young adults will continue to wet the bed. Treatments for nocturnal enuresis can be classified as alarm training, pharmacological, behavioural, or complementary and miscellaneous treatments. Some of the interventions listed below are now contraindicated, and not a part of current enuresis treatment. An enuresis alarm is activated by micturition; when the child urinates on the alarm, the alarm will sound. The goal of alarm training is for the child to associate the alarm with inhibiting urination, waking, and using the toilet to complete urinating. The two most common pharmacological treatments include desmopressin and tricyclics. Desmopressin is a hormone that induces an anti-diuretic effect and subsequently the potential for water intoxication is a concern. Tricyclics are anti-depressants that act on the central nervous system but they have also been used in the treatment of nocturnal enuresis potentially by affecting arousal. These can be simple or complex in nature. Examples of simple behavioural interventions include rewarding the child for dry nights, lifting the child to the toilet at the anticipated time of bed-wetting, or waking the child progressively earlier during the night to use the toilet until waking time and bed time occur at the same time. Several methods focus on the amount of liquid the child consumes, such as fluid restriction, fluid retention control training by increasing daytime liquids and delaying urination, or overlearning. Complex behavioural interventions include dry bed training and full spectrum home training (FSHT). Dry bed training begins with one night of intensive training; the child is woken up every hour and taken to the toilet. If the child has an accident, the child must clean up following his accident (‘cleanliness training’) and repeatedly practice getting up and going to the toilet. The following night, the child is woken once and on subsequent nights, the child is wakened progressively earlier. FSHT combines an alarm, cleanliness training, retention control training, and overlearning. Complementary and miscellaneous nocturnal enuresis treatments include, but are not restricted to, cognitive therapy, psychotherapy, hypnosis, education/information systems, acupuncture, chiropractic, homeopathy, and diet restriction. The Cochrane Database of Systematic Reviews was searched for all systematic reviews examining any intervention for the treatment of nocturnal enuresis. The term ‘nocturnal enuresis’ was entered and restricted to the record title; this resulted in seven systematic reviews. The inclusion criteria were comparable. All of the reviews included randomized or quasi-randomized trials. All of the reviews included children with nocturnal enuresis. The age range was determined by the individual trials and tended to be up to 16 years of age. While children with daytime enuresis or organic causes were sometimes included, the primary condition must have been non-organic nocturnal enuresis. The intervention was compared to no treatment, placebo, or any other active treatment. The reviews all included variations of the following outcomes: (1) mean number of wet nights during treatment and at follow-up; (2) number of children failing to achieve 14 consecutive dry nights or subsequently relapsing; and (3) adverse events. The search strategies used to identify the included studies were very similar. All included reviews used the search strategy that was developed by the Incontinence Review Group. The Incontinence Review Group has created a specialized registry that contains trials identified from the Medline, CINAHL, Cochrane Central Register of Controlled Trials, and from hand searching pertinent journals and conference proceedings. In addition, the reference lists of included trials were searched. The reviews did not have a language restriction. The review examining complementary and miscellaneous interventions also searched the Traditional Chinese Medical Literature Analysis and Retrieval System database. Within The Cochrane Library, seven systematic reviews examining treatments for nocturnal enuresis have been published. The treatments are enuresis alarms, desmopressin, tricyclics, pharmacological interventions other than desmopressin or tricyclics, simple behavioural interventions, complex behavioural or educational interventions, and complementary and miscellaneous interventions. A total of 230 trials were included but because the comparison group included any other treatment, there is partial overlap of the trials between many of the reviews. The age of the children was not specified by the reviews, but instead age was defined by the individual trials, and was usually up to age 16. All seven of the included reviews concluded that the methodological quality of the included studies was generally poor. A very similar quality assessment tool was applied to each of the studies. Among each review, the proportion of quasi-randomized studies ranged from 2% (simple behavioural interventions) to 50% (complementary and miscellaneous interventions). Adequate concealment of allocation was variable; no trials were adequately concealed in the review of complementary and miscellaneous interventions and 34% of the trials examining drugs other than desmopressin or tricyclics had adequate allocation of concealment. Several of the included trials did not provide adequate data for inclusion in the meta-analysis. The most common reason for this was failing to report a measurement of variance. The results for failure to achieve 14 consecutive dry nights during treatment and at follow-up are presented in Tables 1 and 2 respectively. When compared to placebo or no treatment, enuresis alarms resulted in approximately three more dry nights per week (WMD −3.34 [95% CI −4.14, −2.55]) and the relative risk for not achieving 14 consecutive dry nights was significantly less among children treated with enuresis alarms (RR 0.38 [95% CI 0.33, 0.45]). This difference was maintained when children were assessed at follow-up. Insufficient evidence precluded determining the most effective enuresis alarm or if alarms were superior to behavioral therapy or pharmacological treatment. When compared to placebo, desmopressin at any dose resulted in more dry nights (10 mcg: WMD −2.30 [95% CI −3.42, −1.18]; 20 mcg: WMD −1.34 [95% CI −1.57, −1.11]; 40 mcg: WMD −1.33 [95% CI −1.67, −0.99]; and 60 mcg: WMD −1.50 [95% CI −1.92, −1.08]). The optimal dose or route of delivery could not be established. The relative risk for failing to obtain 14 consecutive dry nights was significantly lower among children who received desmopressin compared to placebo. There was no evidence to suggest that the effectiveness of desmopressin is sustained once the treatment is completed. The effectiveness of adding an alarm to desmopressin treatment remains unclear. The adverse events associated with desmopressin were generally mild. A lack of evidence precluded determining the effectiveness of desmopressin versus behavioural interventions (retention control training with or without psychological therapy) or laser acupuncture. When compared to placebo, treatment with tricyclics resulted in approximately one less wet night a week (WMD −1.19 [95% CI −1.56, −0.82]). Failure to achieve 14 consecutive dry nights was significantly less among children receiving tricyclic treatment (RR 0.77 [95% CI 0.72, 0.83); however, this effect was not sustained once treatment stopped (RR 0.98 [95% CI 0.95, 1.03]). The most effective tricyclic or optimal dose could not be determined. One trial compared alarms to tricyclics and found alarms to be superior both during and after treatment. There was conflicting evidence for tricyclics versus desmopressin. The role of complex behavioral methods and complementary or miscellaneous interventions could not be established. None of the trials reported any major side effects. Only two comparisons were examined in more than one trial: indomethacin versus placebo and diclofenac versus placebo. When compared to placebo, indomethacin significantly reduced the number of wet nights (WMD −3.06 [95% CI −3.89, −2.23]). Children were significantly less likely to fail at attaining 14 consecutive dry nights when treated with diclofenac than placebo (RR 0.52 [95% CI −0.38, 0.70]). In single placebo-controlled trials, the following two drugs resulted in fewer wet nights: diclofenac (WMD −4.21 [95% CI −5.76, −2.66]), and diazepam (WMD −4.87 [95% CI −6.25, −3.49]). The studies did not measure the relapse rate once the treatment was completed. The effectiveness of behavioral treatments versus other drugs could not be assessed. Thirteen studies were included, however all of the comparisons were unique and therefore a meta-analysis was not possible. Significantly fewer wet nights and lower relapse rates were observed with reward systems, lifting, and waking. These conclusions are based upon limited evidence. There is insufficient evidence to determine the effectiveness of retention control training. Simple behavioural interventions appear to be safe; however, they are labor intensive. There was no significant difference in failure among children receiving complex behaviour interventions versus no treatment. However, complex behaviour interventions combined with an alarm resulted in significantly fewer failures than children who were not treated. The relative risk of failure to achieve 14 consecutive dry nights was significantly less when dry bed training with an alarm and FSHT with an alarm were used (RR 0.17 [95% CI 0.11, 0.28] and RR 0.31 [95% CI 0.14, 0.70], respectively). The role of educational interventions on resolving nocturnal enuresis could not be assessed. Hypnosis therapy was significantly more effective than imipramine (RR for failure or relapse 0.42 [95% CI 0.23, 0.78]). Fewer children failed or relapsed after treatment when treated with psychotherapy versus an alarm (RR 0.28 [95% CI% 0.09, 0.85]) or reward system (RR 0.29 [95% CI 0.09, 0.90]). These results were determined from few studies. There was insufficient evidence to determine the appropriateness of psychotherapy, faradization, or diet/food-restriction for treating nocturnal enuresis. Nocturnal enuresis is a common and seemingly mild problem that can result in a great deal of stress for children and family members alike. Parents have a tendency to blame the bedwetting on behavioural problems, while children feel shame and avoid sleep-overs and other activities that may reveal their secret. While the etiologies remain speculative, newer studies examining nocturnal bladder physiology with ambulatory urodynamics and CNS activity with EEG point to a complex interaction between the urinary tract and nervous system. As well, a certain percentage of children likely go undiagnosed who actually have daytime symptoms but don't present because of compensating behaviours such as frequent voiding. It is therefore unlikely that one treatment will be helpful in all children. In clinical practice the bed alarm and desmopressin are the most commonly used interventions. In this umbrella review the bed alarm was found to have the greatest evidence of success. In practice it is difficult for patients and families to persevere and see the benefits of the alarm. Often the child will not waken with the alarm, however the rest of the house may. This may be taken as a failure and the treatment is abandoned. However, if encouraged and properly instructed, families will work together to wake the child with the alarm and eventually the child will succeed. Desmopressin also resulted in an improvement in nocturnal continence although improvement was not as great as the bed alarm. This points to the likely varying reasons for nocturnal enuresis. It is possible that only those children with polyuria will benefit from medication. It is for this reason that some centers record nightly output prior to beginning treatment with desmopressin in order to predict failures. The tricyclics, while useful in some patients, are potent medications and are losing favor with most physicians. Concern over the potential for overdose and the less than promising results as seen in this umbrella review make these medications undesirable. The evidence for other drugs such as indomethacin, diclofenac and diazepam looks promising; however, these are not benign in their potential for side effects, much like the tricyclics and would be unlikely to be used in children when there are more effective and safer treatments available, such as alarms and desmopressin. Behavioural therapies used in isolation are well tolerated and often the support that accompanies them will improve the child's self-esteem. Unfortunately, the lack of evidence makes it difficult to strongly support the time intensive measures. However, because they are simple and do not have dangerous side effects, many parents try them in the first instance, seeking help only if they fail. A variety of interventions have been used to treat nocturnal enuresis in children. It appears that enuresis alarms are the most efficacious method for not only decreasing the number of wet nights, but also for preventing relapse once alarm treatment has ceased. Among the pharmacological interventions, desmopressin and tricyclics are better than placebo at reducing the number of wet nights. This effect was not sustained after cessation of desmopressin or tricyclics. There is a paucity of evidence to determine the efficacy of simple and complex behavioral interventions, drugs other than desmopressin and tricyclics, and complementary and miscellaneous interventions. Few studies measured relapse rates once the treatment was discontinued. Future trials should attempt to determine if the treatment effect continues upon completing the intervention. The authors would like to acknowledge the invaluable contribution made by Dr Charis Glazener to this umbrella review.