Urine flow acceleration in healthy children: A retrospective cohort study

Abstract Aims To establish normal reference values of urine flow acceleration (Qacc) in healthy children, as there is a lack of nomograms for normative reference values of Qacc by voided volumes in the pediatric population so far. Qacc might be an early indicator of autonomic neuropathy in children and adolescents. Methods Data were retrospectively collected from healthy children who underwent uroflowmetry between 1990 and 1992. Exclusion criteria were voided volume less than 20 ml, and postvoid residual more than 15%. Baseline characteristics and uroflowmetry parameters were collected from girls and boys aged between 6 and 18 years. Voided volume, voiding time, time to maximum flow rate, and maximum and average flow rates of urine were measured, and Qacc was calculated. Postvoid bladder diameter was measured by ultrasonography and converted to volume. Results Uroflowmetry parameters of 208 children (≤18 years old, 45.2% girls, mean age 9.68 ± 3.09 years) who performed 404 micturition were analyzed. Median voided volume, voiding time, time to Qmax, Qave, Qmax, Qacc, and postvoid residual volume were 130 [20–460] ml, 10 [3–56] s, 3 [1–14] s, 11.7 [2.5–36.6] ml/s, 20.5 [5–50] ml/s, 6 [0.81–25] ml/s2, and 1.83 [0–38.62] ml, respectively. Qacc nomograms were given in centile forms for girls and boys separately, which show an inversely proportional correlation between voided volumes. Conclusions These are the first nomograms for normative reference values of Qacc in the pediatric population (girls and boys separately) by voided volumes in centile forms. These may be useful to interpret abnormal Qacc values and diagnose lower urinary tract diseases over a wide range of voided volumes.


| INTRODUCTION
Uroflowmetry is an essential, noninvasive, easy-to-use, widely accessible, and quick urodynamic diagnostic tool in the evaluation of voiding function. [1][2][3][4] Urine flow rate measurements are generally used to determine lower urinary tract (LUT) dysfunction. Normative reference values of bladder function in healthy adult women 5,6 have been widely studied, although there are quite a few studies in the healthy pediatric population. 7,8 We have previously established normal reference values for maximum and average urine flow in children, 7 which have been adopted by the International Continence Society and recommended in the 2nd edition of the Book of Incontinence 9 for those who study urine flow in children. The uroflow patterns of children with LUT symptoms [10][11][12][13] are still under evaluation. In our previous study, 7 we did not establish normal reference values for urine flow acceleration (Q acc ), although a difference was observed in children with diabetes mellitus. 14 Acceleration of the detrusor muscle contraction characterizes the bladder function. It is a calculated urodynamic value, which is the ratio of maximum flow rate (Q max ) and time to maximum flow rate (TQ max ), measured in ml/s 2 ; and refers to the increased flow rate in a period of time from the beginning of urination to the peak value. Only a few studies have addressed Q acc 14,15 so far. Q acc may be increased in children with urgent and frequent micturition, as well as with urge incontinence. Possible damage in the detrusor muscle function may also impair Q acc , therefore a change or a decrease in the acceleration of the detrusor muscle contraction can be an early sign of the damage in the muscle and/or of the innervation. Q acc may be changed in outflow obstruction, such as in benign prostate hyperplasia (BPH). Q acc has been found to be superior to Q max in the diagnosis of bladder outlet obstruction (BOO) in adult men with BPH. 15 Furthermore, Q acc may be reduced if a patient has autonomic neuropathy (e.g., diabetic cystopathy [DC]). DC is a well-recognized urological complication of diabetic autonomic neuropathy 16 with the classic triad of decreased bladder sensation, impaired bladder emptying with postvoid residual volume, and increased bladder capacity. [17][18][19][20][21] Patients generally have the symptoms of overactive bladder or overflow incontinence, including urinary frequency, urgency, incontinence, and nocturia; which are listed among the LUT symptoms. DC might develop over time, but in the beginning, only mild symptoms can be observed in children.
Until now, Q acc was a less frequently adapted parameter, but as previous studies suggest that it might indicate the deviation of detrusor muscle function earlier than other uroflowmetry parameters (e.g., Q max , Q ave ), therefore it seems to be a better indicator of diabetic autonomic neuropathy than cardiovascular dysfunction tests (Ewing tests). 22 Since there is no consensus on the cut-off values of Q acc in the pediatric population which limits the use of Q acc , our aim was to establish normal ranges of it in both genders by voided volumes.

| MATERIALS AND METHODS
The study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) 2004 Statement 23 (the STROBE checklist of our work is available in Supporting Information: Table 1). The study was approved by the Heim Pál National Paediatric Institute's Local Ethics Committee (registration number: KUT-37/2021, Date: 23 July 2021). The data were obtained from a previous uroflow study 7 carried out between 1990 and 1992 at Child Health Centre, Borsod Abaúj-Zemplén County Teaching Hospital, Miskolc, Hungary. Some parts of the data have been published previously, 7 but acceleration values have not been reported so far. The research and methodology used for data collection are explained in detail in the previous study. 7

| Study design and eligibility
A single-center, retrospective cohort study was conducted with 270 healthy children and adolescents. Our study protocol was based on the previously designed study. 7 Age (years), gender (boys/girls), weight (kg), and height (cm) were collected. Each child urinated multiple times (spontaneously in calm conditions, at first desire to void after 15 ml/kg liquid consumption, and at the maximal sensation of bladder fullness). The reliability of the tests was not examined as the children's first urination occurred upon arrival at the Urodynamics Laboratory, and the second urination occurred at the first urge to urinate after 15 ml/kg liquid consumption. Thus, almost everyone voided a different volume during the second urination. There were no children with Q acc values below 10th percentile or above 90th percentile.
During spontaneous urination, children voided smaller volumes (20-50 ml) with lower Q ave and Q max values. In 7.9% of the total micturition, either Q max or Q ave was less than 5 ml/s. According to the normal nomograms, 7 the values of Q ave 2.5 ml/s and Q max 5 ml/s are above 5% (between 5 and 10 percentile values), which means they are within the normal range. The first step of the study's protocol, children were asked to void spontaneously regardless of the need for urination. After that these children voided when they felt the first sensation of bladder filling (after drinking 15 ml/kg liquid), which was clearly larger volumes with higher Q max and Q ave values. So they did not void small amounts all the time, which means they did not have small bladder capacity. Therefore, we think these small voided volumes with lower Q max and Q ave values are acceptable. Given there were only a few numbers of voiding, which does not change the normal values of Q acc , we did not exclude these urinations from the analysis to reduce selection bias. These data confirm our hypothesis that at spontaneous voiding, healthy younger children void smaller amounts of volumes with lower Q max and Q ave values.
Since Q max and Q ave values have already been presented (Miskolc Nomograms 7 ), and our current study is focused on Q acc values, we did not wish to publish Q max and Q ave values again. In our previous study 7 Q ave and Q max values were divided into three body surfaces (<0.92 m 2 , between 0.92 and 1.42 m 2 , and >1.42 m 2 ) and not into age (basically younger children have lower body surfaces). As we did not want to deviate from the original study protocol, we planned to have a subgroup analysis based on body surfaces. Unfortunately, due to the low number of children in each subgroup-according to the sample size calculation-data were not enough to make valid analyses.

| Measurements and outcomes
Urinary bladder function was assessed by uroflowmetry, and postvoid residual volume was detected by ultrasonography. All examinations were performed by L.Sz. (nephrologist and urodynamic specialist). Data were collected using a targeted questionnaire, each measurement was documented by LSz. Uroflowmetry was performed using a Uroflow-cystometer (X0002; Metripond) which determined Q max , Q ave, and TQ max . Voided volume (ml), voiding time (s), average and maximum urinary flow rate (ml/s), and time to maximum urinary flow (s) were measured; urine flow acceleration (ml/s 2 ) was calculated. Q max and Q ave were defined according to the International Children's Continence Society. 25 Voided volume was measured manually using a graduated cylinder; boys voided in a standing, girls in a sitting position. Ultrasound was accomplished before and after micturition. Scans were obtained with a real-time ultrasound scanner (Hitachi EUB 40.5 MHz transducer) using a direct scanning technique. Postvoid bladder diameter (mm) was measured by ultrasonography and converted to bladder residual volume (ml). Manual data collection was turned into a digital form which was carried out by Á.R.M., data were tabulated and encoded. Data validation was conducted by P. P., M. F., and Sz.K. All patients' data are stored securely.
Different uroflow parameters can only be compared if voided volumes are the same since uroflow parameters highly depend on voided volumes. Therefore, children were allocated to one of the two groups by gender, and then Q acc was determined by voided volumes.  26 Normal nomograms of Q acc in the pediatric population were visualized in percentile forms and graphically as well. When data show normal distribution mean ± standard deviation (SD), in other cases, median [range] was used. Data imputation has not been applied.

| Statistical analysis
The sample size (n) was estimated by the following equations 27 where z, z score (z = 1.96 for 95% confidence level); e, margin of error; N, population size of healthy children aged between 6 and 18 years; p, population proportion by using with confidence level = 95%, margin error = 5%, population proportion = 85% (healthy children were selected for the nomogram construction, proportion value was set by considering all the illnesses, diseases, medications and health status conditions that can influence uroflowmetry parameters in children) and population size = 1 827 520 (Hungarian Central Statistical Office, data for healthy children aged between 6 and 18 years in Hungary: https://www.ksh.hu/docs/hun/ xstadat/xstadat_eves/i_zoi002a.html). The estimation revealed that a sample size of at least 196 healthy children (aged between 6 and 18 years) would be necessary for the study.

| Study selection and baseline characteristics
Out of 270 healthy children, 208 were enrolled in the analysis and performed 404 micturition total. 62 children were excluded due to the following reasons: 33 children were excluded due to voided volume of less than 20 ml, and 29 children were excluded due to a postvoid residual volume of more than 15% of voided volume. Data quality tables are presented in Supporting Information: Table 2.
The baseline characteristics of girls/boys and all patients and uroflowmetry parameters are presented in Table 1. Out of 208 children, 94 are female, and 114 are male. The mean age of the total population is 9.68 ± 3.09 years, the median weight is 32   Out of the 114 boys with 235 micturition total, the mean age is 9.65 ± 3.21 years, the median weight is 32    Figures 1 and 2 demonstrate the nomograms of Q acc by voided volumes in girls and boys, respectively. Supporting Information: Table 3 (Panel A and B) represents the 3% to 97% centile values of normal Q acc in girls and boys, respectively.

| DISCUSSION
We have established nomograms for normative reference values of Q acc in the pediatric population (girls and boys separately) by voided volumes in centile forms. We found an inversely proportional correlation between voided volumes and Q acc parameters.
The diversity of Q acc by percentiles is huge. We recommend that values between the 25 and 75th percentiles should be accepted as normal, which in boys is between 3.9 and 8 ml/s 2 for a voided volume of 150 ml. If we get values below 25% or above 75%, we recommend further examinations. Theoretically, a Q acc value above 75% could be due to overactive bladder dysfunction.
Up to 350 ml of voided volume, higher Q acc values were observed in girls than in boys. This phenomenon might be explained by the shorter and straighter urethra in the female population. Above 350 ml of voided volume, Q acc values below at the 50th percentile were minimally lower in girls than in boys. A relatively small number of cases may play a role in the latter.
None of the children had BOO, as can be suggested based on the shape of the uroflow curve. According to the Miskolc Nomograms, 7 none of the children had plateau-shaped flow curves. Furthermore, reduced flow parameters can be observed in BOO (Q max and Q ave values are below 5%). Both Q max and Q ave values in the Miskolc Nomograms were above the 10th percentile. These findings can be confirmed with pressure/flow urodynamic tests (and video urodynamics), but due to their invasive nature, they are not performed routinely. We have not examined Q acc in BOO so far, but according to Wen et al., 15 Q acc might be a better indicator than Q max in the examination of BOO.
Micturition represents complex neuromuscular mechanisms involving structures of the LUT and nervous system. Voiding symptoms refer to a disease involving several factors of dysregulation; although the absence of voiding symptoms is not a guarantee of normal micturition.
Hubeaux et al. 28 found that almost one-third of the women without voiding complaint has been actually shown to have abnormal uroflowmetry.
Mattiasson and Teleman investigated the urethral motor function in incontinence women. Q acc has been significantly increased in patients with incontinence: Q acc was 13 ± 17.8 (2.2); 20 ± 18.9 (2.8); and 32 ± 24.9 (4.9) degrees (mean ± SD; [SE]) for incontinence, naive incontinence, and no incontinence, respectively. 29 Cucchi concluded that all of the obstructed patients have lower values of acceleration than the controls, but patients with detrusor instability (today, the correct name is overactive bladder) tend to show higher Q acc than those with stable bladders. 30 He also found that the measurement of Q acc is a simple and reliable test to aid in the diagnosis of detrusor instability in stress-incontinent women. 31 Q acc might have a role in the detection of detrusor muscle dysfunction, as well. Karasu et al. found 32 higher values of Q acc in intrinsic sphincter deficiency stress incontinent women than stress incontinent ones alone, and they hypothesized that Q acc might be a more reliable parameter for urethral resistance and tonus. Wen et al. 15 reported the Q acc is superior to Q max in diagnosing bladder outlet obstruction in men with BPH.
Acceleration of urine flow might provide a finer diagnosis of the relationship between abnormalities of the LUT and diabetes mellitus (DM) 33 as well.
We believe that Q acc might be used primarily to detect damage to the detrusor muscle (especially to detect reduced detrusor contraction caused by DM). We consider that Q acc is a better indicator of diabetic autonomic neuropathy than cardiovascular dysfunction tests (Ewing tests), because in our previous study 14 Q acc levels were significantly decreased not only in diabetic children with cardiovascular autonomic dysfunction (CAD), but also in diabetic patients without CAD.
Theoretically, it can be assumed that Q acc values do not decrease in the case of a reduced Q max -if there is a urethral stricture in the background. While in the event of hypocontractility there might be a decrease. But as the disease progresses, the detrusor muscle transforms, and its contractility deteriorates, therefore reduced Q acc values appear. Thus, Q acc examinations might be suitable even as a replacement for invasive UPP, but we have not performed such tests so far.
By the evaluation of uroflow acceleration, there will be more biological indicators to assess the etiology of the urinary problems and the effect of different diseases and treatments for voiding function to get the appropriate and precise treatment for patients. Since there are only a few studies evaluating Q acc values in adults and pediatric populations with different diseases; furthermore, normative reference values of Q acc are lacking, we found it important to establish normal ranges of Q acc in both genders by voided volumes in children.

| Strength of the study and limitations
The strength of this study is the novelty of the evaluation of normal reference values of Q acc, which includes a relatively large number of children with Q acc calculation.
The main limitation of this study is the possible selection bias due to the retrospective design.

| CONCLUSION
Normal reference values for urinary flow acceleration were established in percentile forms in children. As the acceleration of urine flow can provide a finer diagnosis of abnormalities of the LUT and various chronic diseases (diabetes mellitus etc.), our results could form a basis for studies about the diagnostic significance of uroflow parameters in different diseases in children.

| Implication for practice
As soon as studies-comparing the Q acc values of healthy children and patients with different diseases-identify F I G U R E 2 Urine flow acceleration (Q acc ) nomogram for boys Q acc is demonstrated by voided volumes in the male population ≤18 years of age diagnostic cut-off values, the use of the normal reference values of Q acc can be easily translated to everyday clinical practice. According to the currently available literature, Q acc is an important tool to aid in the diagnosis of LUT symptoms. By establishing normative reference values, interpreting the different Q acc parameters might help clinicians evaluate different diseases.

| Implication for research
Since we evaluated the Q acc patterns of healthy asymptomatic pediatric populations, we formed the basis of future prospective studies. Prospective studies comparing healthy children and pediatric populations of different diseases with or without LUT symptoms will be needed to establish cut-off values to differentiate normal and abnormal uroflow patterns (voided volume, voiding time, Q ave , Q max, TQ max ).