Intravenous ondansetron reduced nausea but not pruritus following intrathecal morphine in children: Interim results of a randomized, double-blinded, placebo-control trial.

STUDY OBJECTIVE: This study's purpose was to determine if ondansetron can prevent pruritus after administration of intrathecal morphine in children, as has been demonstrated in adults. DESIGN: A double-blinded, randomized placebo-controlled trial. SETTING: Operating room and first 24 h postoperative inpatient stay at an academic children's hospital. PATIENTS: Forty-six children aged 3-17 years, who received 4-5 mcg/kg intrathecal morphine for urological or orthopedic procedures were included. INTERVENTIONS: Children were randomized to receive intravenous ondansetron (treatment) or saline placebo (placebo), prior to intrathecal morphine administration, and q6H for 24 h thereafter. Intraoperative anti-emetics and postoperative rescue treatments for pruritus and nausea were standardized. MEASUREMENTS: Patients were interviewed q6H for scored pruritus, nausea, and pain, using standardized scales. MAIN RESULTS: The trial was terminated for futility after interim analysis. Forty-six children were recruited and 45 completed data collection. No significant difference was found between both groups for incidence of pruritus (requiring treatment) [relative risk (RR) 0.9, 95% CI: 0.7, 1.2], during the first postoperative 24 h. Notably, the incidence of pruritus was 84% overall, much higher than rates in previously published studies. Intravenous ondansetron significantly reduced the incidence of nausea, compared with the placebo group [RR 0.5, 95% CI: 0.3, 0.9]. CONCLUSIONS: This study found no evidence for intravenous ondansetron as an effective preventative for pruritus following intrathecal morphine in children. However, this RCT did find that the rate of pruritus following intrathecal morphine administration may be significantly higher than previously thought. Nausea and vomiting (a secondary outcome) were reduced significantly in the treatment group. The negative findings of this study reinforce the potential dangers of extrapolating the drug effects seen in adults onto pediatric patients.

Investigation of Fiber-Driven Mechanical Behavior of Human and Porcine Bladder Tissue Tested Under Identical Conditions.

The urinary bladder is a highly dynamic organ that undergoes large deformations several times per day. Mechanical characteristics of the tissue are crucial in determining the function and dysfunction of the organ. Yet, literature reporting on the mechanical properties of human bladder tissue is scarce and, at times, contradictory. In this study, we focused on mechanically testing tissue from both human and pig bladders using identical protocols to validate the use of pigs as a model for the human bladder. Furthermore, we tested the effect of two treatments on tissue mechanical properties. Namely, elastase to digest elastin fibers, and oxybutynin to reduce smooth muscle cell spasticity. Additionally, mechanical properties based on the anatomical direction of testing were evaluated. We implemented two different material models to aid in the interpretation of the experimental results. We found that human tissue behaves similarly to pig tissue at high deformations (collagen-dominated behavior) while we detected differences between the species at low deformations (amorphous matrix-dominated behavior). Our results also suggest that elastin could play a role in determining the behavior of the fiber network. Finally, we confirmed the anisotropy of the tissue, which reached higher stresses in the transverse direction when compared to the longitudinal direction.

Intranodal lymphangiography and interstitial lymphatic embolization to treat chyluria caused by a lymphatic malformation in a pediatric patient.

Chyluria is characterized by chyle in the urinary tract and often presents as milky-white urine. We present a case of chyluria from a lymphatic malformation in a 13-year-old boy diagnosed using dynamic intranodal contrast-enhanced magnetic resonance (MR) lymphangiography. This report demonstrates the utility of intranodal lymphangiography and interstitial lymphatic embolization to treat a pediatric patient presenting with persistent chyluria. Glue migration into the urinary collecting system is a potential complication of this procedure that can be mitigated by adjusting the n-butyl cyanoacrylate dilution with Lipiodol.

Impact of Clinical Guidelines on Voiding Cystourethrogram Use and Vesicoureteral Reflux Incidence.

PURPOSE: To prevent over diagnosis and overtreatment of vesicoureteral reflux the 2007 NICE (National Institute for Health and Care Excellence) and 2011 AAP (American Academy of Pediatrics) guidelines recommended against routine voiding cystourethrograms in children presenting with first febrile urinary tract infections. The impact of these guidelines on clinical practice is unknown. MATERIALS AND METHODS: Using an administrative claims database (Clinformatics™ Data Mart) children who underwent voiding cystourethrogram studies or had a diagnosis of vesicoureteral reflux between 2001 and 2015 were identified. The cohort was divided into children age 0 to 2 and 3 to 10 years. Single and multiple group interrupted time series analyses (difference-in-difference) were performed with the guidelines as intervention points. The incidence of vesicoureteral reflux was compared across each period. RESULTS: Of the 51,649 children who underwent voiding cystourethrograms 19,422 (38%) were diagnosed with vesicoureteral reflux. In children 0 to 2 years old voiding cystourethrogram use did not decrease after the 2007 NICE guidelines were announced (-0.37, 95% CI -1.50 to 0.77, p = 0.52) but did decrease significantly after the 2011 AAP guidelines were announced (-2.00, 95% CI -3.35 to -0.65, p = 0.004). Among children 3 to 10 years old voiding cystourethrogram use decreased during the entire study period. There was a decrease in the incidence of vesicoureteral reflux in both groups that mirrored patterns of voiding cystourethrogram use. CONCLUSIONS: The 2011 AAP guidelines led to a concurrent decrease in voiding cystourethrogram use and incidence of vesicoureteral reflux among children 0 to 2 years old. Further studies are needed to assess the risks and benefits of reducing the diagnosis of vesicoureteral reflux in young children.

Unexpected ethical dilemmas in sex assignment in 46,XY DSD due to 5-alpha reductase type 2 deficiency.

Sex assignment at birth remains one of the most clinically challenging and controversial topics in 46,XY disorders of sexual development (DSD). This is particularly challenging in deficiency of 5-alpha reductase type 2 given that external genitalia are typically undervirilized at birth but typically virilize at puberty to a variable degree. Historically, most individuals with 5-alpha reductase deficiency were raised females. However, reports that over half of patients who underwent a virilizing puberty adopted an adult male gender identity have challenged this practice. Consensus guidelines on assignment of sex of rearing at birth are equivocal or favor male assignment in the most virilized cases. While a male sex of rearing assignment may avoid lifelong hormonal therapy and/or allow the potential for fertility, female sex assignment may be more consistent with external anatomy in the most severely undervirilized cases. Herein, we describe five patients with 46,XY DSD due 5-alpha-reductase type 2 deficiency, all with a severe phenotype. An inter-disciplinary DSD medical team at one of two academic centers evaluated each patient. This case series illustrates the complicated decision-making process of assignment of sex of rearing at birth in 5-alpha reductase type 2 deficiency and the challenges that arise when the interests of the child, parental wishes, recommendations of the medical team, and state law collide.

Pediatric urethral catheter consultations: understanding driving factors.

PURPOSE: Pediatric urethral catheterization is often straightforward. However, it can be challenging and may require urological consultation. Possible critical factors are patient anatomy and comorbidities, and insertion technique. To better understand pediatric catheter consultations, we reviewed our experience. MATERIALS AND METHODS: All pediatric catheter consultations between July 2009 and June 2012 were identified. A retrospective review was then performed, focusing on demographics, reasons for consultation and difficulty of catheter placement. The 4 categories of difficulty noted were easy, challenging, extremely difficult and could not be placed. Patients were excluded from analysis if catheter placement was not needed, the consultation was for a catheterizable stoma or they were status post urological surgery. Statistical analyses were performed to evaluate associations between patient factors and difficulty of placement. RESULTS: A total of 93 consultations were identified, of which 57% were inpatient, 28% intraoperative and 15% other source. Of the inpatient consultations 75% were from an intensive care unit, the majority (80%) of which were for catheter placement, with the remainder for removal, nondraining catheter, trauma or other. After exclusions 65 patients remained, of whom 80% were male and 32% had a urological comorbidity. By difficulty level 69.2% of cases were easy, 15.4% were challenging, 9.2% were extremely difficult and 6.2% could not be placed. Location of consult, gender, urological comorbidity and history of prematurity were not significantly associated with difficult catheter placement. CONCLUSIONS: Pediatric catheter consultations are largely straightforward. Comorbidities do not significantly impact catheter placement. Correct catheter technique may be more important than patient comorbidities, giving us a basis to shape catheter insertion training within pediatric hospitals.

The distal left Malone antegrade continence enema--is it better?

PURPOSE: The Malone antegrade continence enema is used for refractory fecal dysfunction in the pediatric neuropathic population. While various locations along the colon have been described, the optimal site for achieving efficient enemas remains unknown. We reviewed our experience with the Malone antegrade continence enema procedure and investigated functional outcomes and complications associated with proximal and distal locations. MATERIALS AND METHODS: We performed an institutional review board approved, retrospective chart review of 109 consecutive MACE procedures done by a single surgeon from 2000 to 2012. Preoperative patient characteristics, intraoperative techniques and postoperative outcomes were reviewed and statistical analysis was performed. RESULTS: Included in analysis were 90 patients treated with a total of 109 MACE procedures. Average age at operation was 13.8 years. Myelomeningocele was the most common diagnosis. Most patients underwent simultaneous urinary reconstruction. Stomal complications were most common (49% of patients). We compared the outcomes of proximal (cecal) MACE in 48 cases and distal (sigmoid colon) MACE in 55. Location did not affect the overall efficiency of fecal continence. Flush time was shorter for distal than for proximal MACE stomas (37.2 vs 61.2 minutes, p <0.001). Of the patients 15 underwent a total of 20 complete MACE revisions, including 12 proximal and 6 distal MACEs. As a channel, appendix was associated with a higher but not statistically significant stomal complication rate compared to colon (42% vs 25%). CONCLUSIONS: A cecal, transverse or colonic location for MACE results in acceptable outcomes. Distal MACE is associated with significantly shorter flush time and possibly fewer stomal complications. Stomal complications remain a frustrating reality of the MACE procedure.

9p partial monosomy and disorders of sex development: review and postulation of a pathogenetic mechanism.

Deletion of the distal segment of 9p causes a syndrome comprising trigonocephaly, minor anomalies, and intellectual disability. Patients with this condition also frequently present with genitourinary abnormalities including cryptorchidism, hypospadias, ambiguous genitalia, or 46,XY testicular dysgenesis. The region responsible for the gonadal dysgenesis has been localized to 9p24.3 with the likely responsible gene identified as DMRT1. Similar to patients with other molecular causes of 46,XY gonadal dysgenesis, patients with partial del 9p have an increased risk of gonadoblastoma. We present two patients with 46,XY gonadal dysgenesis due to partial 9p monosomy. Both patients were also diagnosed with gonadoblastoma following gonadectomy at an early age. Chromosomal microarray analyses refined the cytogenetic abnormalities and allowed potential genotype-phenotype relationships to be determined. We also review the literature as it pertains to partial 9p monosomy, genital abnormalities and gonadoblastoma and note that a large percentage of affected patients present with two copy number variations. We propose that a two-hit mechanism may be involved in the incomplete penetrance and variable expressivity of partial 9p monosomy and an abnormal genital phenotype. The significant percentage of gonadoblastoma in patients with 46,XY complete gonadal dysgenesis due to partial 9p monosomy also continues to support the necessity of gonadectomy in this patient population.

Prospective tracking of pediatric urology consults: knowing is half the battle.

PURPOSE: The planned clinical activity of pediatric urologists has been well described. However, little is known about nonscheduled work (eg consultation requests). We describe the unplanned clinical activity of pediatric urologists at a high volume academic medical center. MATERIALS AND METHODS: Demographic data regarding inpatient, operating room and emergency department pediatric urology consults were prospectively entered into an internal database. Consults from July 2008 through June 2010 underwent retrospective chart abstraction to identify reasons for consultation. Bivariate and multivariate statistics were used to evaluate 1) temporal trends in unplanned clinical activity, and 2) patient and service specific factors associated with whether a consult was billable (ie seen by attending physician within 24 hours). RESULTS: During the study period 665 pediatric consults were obtained. Mean ± SD patient age was 8.4 ± 7.7 years. Nearly all consults were seen at the emergency department (51%) or the inpatient wards (47%). The most common primary diagnoses were infection, obstruction/hydronephrosis and neurogenic bladder. The number of consults per month decreased during the course of the academic year (r(2) = 0.1422). Nearly three fourths of consults were eligible for billing. The factors associated with consult eligibility for billing included specific attending physician (p = 0.03), location (p <0.0001) and house officer experience (p = 0.007). CONCLUSIONS: At our academic pediatric hospital we averaged nearly 1 unplanned pediatric urology consult per day. Several service specific factors (unrelated to patient diagnosis or acuity) were associated with whether the consult had the potential to generate revenue. Unplanned clinical activity is an important factor to consider when planning departmental funding, staffing and training.

Kielin/chordin-like protein, a novel enhancer of BMP signaling, attenuates renal fibrotic disease.

The bone morphogenetic proteins (BMPs) profoundly affect embryonic development, differentiation and disease. BMP signaling is suppressed by cysteine-rich domain proteins, such as chordin, that sequester ligands from the BMP receptor. We describe a novel protein, KCP, with 18 cysteine-rich domains. Unlike chordin, KCP enhances BMP signaling in a paracrine manner. Smad1-dependent transcription and phosphorylated Smad1 (P-Smad1) levels are increased, as KCP binds to BMP7 and enhances binding to the type I receptor. In vivo, Kcp(-/-) mice are viable and fertile. Because BMPs have a pivotal role in renal disease, we examined the phenotype of Kcp(-/-) mice in two different models of renal injury. Kcp(-/-) animals show reduced levels of P-Smad1, are more susceptible to developing renal interstitial fibrosis, are more sensitive to tubular injury and show substantial pathology after recovery. The data indicate an important role for KCP in attenuating the pathology of renal fibrotic disease.

Comprehensive genetic analysis of OEIS complex reveals no evidence for a recurrent microdeletion or duplication.

Omphalocele-exstrophy of the bladder-imperforate anus-spinal defects (OEIS) complex, or cloacal exstrophy (EC), is a rare constellation of malformations in humans involving the urogenital, gastrointestinal, and skeletal systems, and less commonly the central nervous system. Although OEIS complex is well-recognized in the clinical setting, there remains a significant lack of understanding of this condition at both the developmental and the genetic level. While most cases are sporadic, familial cases have been reported, suggesting that one or more specific genes may play a significant role in this condition. Several developmental mechanisms have been proposed to explain the etiology of OEIS complex, and it is generally considered to be a defect early in caudal mesoderm development and ventral body wall closure. The goal of this study was to identify genetic aberrations in 13 patients with OEIS/EC using a combination of candidate gene analysis and microarray studies. Analysis of 14 candidate genes in combination with either high resolution SNP or oligonucleotide microarray did not reveal any disease-causing mutations, although novel variants were identified in five patients. To our knowledge, this is the most comprehensive genetic analysis of patients with OEIS complex to date. We conclude that OEIS is a complex disorder from an etiological perspective, likely involving a combination of genetic and environmental predispositions. Based on our data, OEIS complex is unlikely to be caused by a recurrent chromosomal aberration.

Urodynamic and imaging findings in infants with myelomeningocele may predict need for future augmentation cystoplasty.

INTRODUCTION: Urologic issues are persistent and important causes of morbidity and mortality in patients with myelomeningocele. Classically, patients with elevated bladder pressures despite adherence to clean intermittent catheterization (CIC) and pharmacotherapy undergo augmentation cystoplasty (AC). Currently, there is little understanding of which infants are more likely to require AC later. OBJECTIVE: In this context, the authors studied whether unfavorable urodynamic or imaging findings in patients with myelomeningocele during infancy could predict future AC. The authors hypothesized that infants born with elevated bladder pressures, vesicoureteral reflux (VUR), and/or hydronephrosis would be more likely to undergo AC. STUDY DESIGN: The authors retrospectively identified patients with myelomeningocele at their institution who were followed-up since infancy (<1 year of age), with a minimum of eight continuous years of follow-up. Standard care protocol included cystometrogram, voiding cystourethrogram (VCUG), and renal ultrasound during infancy. The primary outcome was AC for elevated bladder pressures despite attempts at more conservative management with medical therapy and CIC. Specifically, the authors evaluated for differences in augmentation rates based on gender, level of lesion, presence of detrusor leak point pressure (DLPP) or end-fill pressure (EFP) greater than 40 cm H2O, presence of hydronephrosis, VUR, initiation of CIC, and initiation of antimuscarinics in infancy. The authors excluded patients who underwent surgical intervention for urinary incontinence. RESULTS: A total of 97 patients met the inclusion criteria. The median follow-up time was 13.8 years. Augmentation cystoplasty was performed for 17 patients (17.5%) at a median age of 114 months (9.5 years). Detrusor leak point pressure/EFP was greater than 40 cm H2O in 34.0% (33/97) of infant cystometrogram studies, while 30.9% (30/97) had VUR on infant VCUG and 20.6% (20/97) had hydronephrosis on infant renal ultrasound. Patients with DLPP/EFP greater than 40 cm H2O or VUR during infancy were more likely to undergo AC (P = 0.02 and P = 0.03, respectively). Binomial logistic regression revealed that DLPP/EFP greater than 40 cm H2O (odds ratio [OR]: 4.28, 95% confidence interval [CI]: 1.34-13.62) and VUR (OR: 3.73, 95% CI: 1.18-11.77) were independent risk factors for future AC. DISCUSSION: Infants with myelomeningocele and elevated bladder pressures and VUR should be closely monitored by urodynamic testing and imaging studies. Parents can be counseled regarding the potentially higher risk for future AC in these patients. Nonetheless, the majority of high-risk infants will safely avoid AC with conservative management.

Disruption of Rb/E2F pathway results in increased cyclooxygenase-2 expression and activity in prostate epithelial cells.

The loss of the retinoblastoma tumor suppressor gene (RB) is common in many human cancers, including prostate. We previously reported that engineered deletion of RB in prostate epithelial cells results in sustained cell growth in serum-free media, a predisposition to develop hyperplasia and dysplasia in prostate tissue recombinant grafts, and sensitization to hormonal carcinogenesis. Examining the molecular consequence of RB loss in this system, we show that cyclooxygenase-2 (COX-2) is significantly up-regulated following RB deletion in prostate tissue recombinants. To study the effect of RB deletion on COX-2 regulation, we generated wild-type (PrE) and Rb-/- (Rb-/-PrE) prostate epithelial cell lines rescued by tissue recombination. We show elevated COX-2 mRNA and protein expression in Rb-/-PrE cell lines with increased prostaglandin synthesis. We also find that loss of Rb leads to deregulated E2F activity, with increased expression of E2F target genes, and that exogenous expression of E2F1 results in elevated COX-2 mRNA and protein levels. COX-2 promoter studies reveal that E2F1 transcriptionally activates COX-2, which is dependent on the transactivation and DNA-binding domains of E2F1. Further analysis revealed that the E2F1 target gene, c-myb, is elevated in Rb-/-PrE cells and E2F1-overexpressing cells, whereas ectopic overexpression of c-myb activates the COX-2 promoter in prostate epithelial cells. Additionally, cotransfection with E2F1 and a dominant-negative c-myb inhibited E2F1 activation of the COX-2 promoter. Taken together, these results suggest activation of a transcriptional cascade by which E2F1 regulates COX-2 expression through the c-myb oncogene. This study reports a novel finding describing that deregulation of the Rb/E2F complex results in increased COX-2 expression and activity.

Vesicoureteral reflux and continuous prophylactic antibiotics.

Vesicoureteral reflux (VUR) management must be tailored based on the risk for further infections and renal scarring, gender, likelihood of spontaneous resolution, and parental preferences. Because we now understand that sterile VUR is benign and most reflux spontaneously resolves over time, the initial approach in majority of children is non-surgical with continuous antibiotic prophylaxis (CAP) and correction of bladder and bowel dysfunction. Despite increasing utilization of CAP over the past four decades, the efficacy of antibiotic prophylaxis has been questioned due to conflicting results of studies plagued with design flaws and inadequate subject sample size. The Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) trial, which was designed to address many of the limitations from previous studies, provided much needed answers. In this review, we sought to describe the controversy surrounding VUR management, highlight the results of RIVUR trial, and discuss how the RIVUR findings impact our understanding of CAP in the management of VUR.

Bladder perforation after augmentation cystoplasty: Determining the best management option.

INTRODUCTION: Delayed bladder perforation is a well-described complication after augmentation cystoplasty. Although the frequency, risk factors, and diagnostic challenges are well documented, discussions regarding management strategies are sparse. OBJECTIVE: We evaluated our experience of managing augmented bladder perforation to interrogate the hypothesis that non-operative management can be used effectively. STUDY DESIGN: We retrospectively evaluated the management of 10 patients with augmented bladder perforations over a 16-year period (Jan 2000-Jan 2016). Patients who demonstrated clinical deterioration, severe peritonitis, or extensive extravasation on imaging underwent exploratory laparotomy and primary closure. Clinically stable patients with minimal extravasation were managed non-operatively with maximal bladder drainage, and those with loculated fluid collections in feasible locations for drainage underwent an image-guided percutaneous drain placement. RESULTS: Underlying diagnoses included four patients with myelomeningocele, three with sacral agenesis, two with spinal cord injuries, and one with bladder exstrophy. Three of the four patients with myelomeningocele had concomitant ventriculoperitoneal shunts. Six patients had continent catheterizable channel creation and two patients had bladder neck reconstructions during the original operation. Four patients were managed with exploratory laparotomy and primary closure. Among the six patients managed non-operatively, three underwent image-guided drain placement in addition to maximal bladder drainage. Four patients developed re-perforation. Two of the four surgically managed patients developed re-perforation. Two of the three patients managed only with maximal bladder drainage developed re-operation. None of the patients managed non-operatively with drain placement suffered from re-perforation. Four perforation episodes were alcohol-related, two occurred after high-impact sporting activity, and two patients reported non-compliant catheterization. DISCUSSION: Non-operative management with maximal bladder drainage and selective image-guided drain placement can be successfully deployed in clinically stable patients with limited extravasation. Ensuring low intraluminal detrusor pressures and empty bladder with maximal drainage is critical for spontaneous sealing of the perforation site. Exploratory laparotomy and primary closure remains our approach for those presenting with clinical deterioration or significant extravasation on imaging. The majority of our perforations and re-perforation episodes seemed to stem from preventable behavioral risk factors. CONCLUSIONS: Our findings support the hypothesis that non-operative management with maximal bladder drainage and image-guided drain placement can be effective in stable patients with limited extravasation.