Experimental short-term fetal bladder outflow obstruction: I. Morphology and cell biology associated with urinary flow impairment.

PURPOSE: In fetal sheep, combined urethral and urachal obstruction initiated at 75 days' gestation and maintained for 30 days led to dysmorphic bladders, similar to those found in humans with prune belly syndrome, and uniformly disrupted kidney development. We aimed to create a less severe model of fetal bladder outlet obstruction, more closely resembling infants with posterior urethral valves, and additionally to further our understanding on the role of the urachus. We hypothesized that milder morphological renal tract changes would occur after shorter term experimental obstruction. MATERIALS AND METHODS: Male fetal lambs were assigned to urachal and urethral ligation, urachal ligation only or sham operations. Analyses were performed after 9 days. RESULTS: Concurrent urachal and urethral obstruction resulted in increased bladder weight, and protein and DNA content. Detrusor smooth muscle was well maintained, as assessed by light and electron microscopy, although urothelia showed basal apoptosis. Bladder obstruction led to hydronephrosis but failed to produce significant perturbations in urine osmolality. The nephrogenic cortex was either well preserved or was replaced by glomerular cysts; the latter group tended to have heavier bladders. Urachal obstruction alone produced similar changes suggesting that the male sheep fetal urethra is a high-resistance conduit in mid-gestation. CONCLUSIONS: Concurrent urachal and urethral obstruction, or urachal obstruction alone, initiated in mid-gestation and maintained for 9 days leads to bladder overgrowth but preserved renal tubular function. In future, it will be interesting to determine whether bladder decompression around this stage leads to reversal of bladder overgrowth and/or ameliorates severe renal tract damage described after longer term fetal bladder outflow obstruction.

Experimental short-term partial fetal bladder outflow obstruction: II. Compliance and contractility associated with urinary flow impairment.

PURPOSE: Posterior urethral valves (PUV) is the commonest cause of congenital bladder outlet obstruction. Despite valve ablation in the neonatal period, up to 70% of patients develop renal failure by their teenage years, and progressive bladder dysfunction. This study forms part of a continuing project examining the relationship between severity and duration of obstruction and urinary tract dysfunction. Here is the assessed result of short-term (9-day) obstruction. MATERIALS AND METHODS: Fourteen male fetal lambs at 75 days' gestation were assigned to one of three groups: urachal ligation, urachal ligation with partial urethral obstruction, sham-operated controls. Pregnancy proceeded for 9 days. At autopsy, filling cystometry was performed with the urinary tract in situ and the bladder harvested for nerve counts using PGP 9.5 immunohistochemistry, or in vitro measurement of contractile function. RESULTS: Obstruction was associated with an increase in bladder:fetal weight ratio. Compliance was variable in the obstructed bladders, but the calculated wall stress per unit strain was either similar or less than controls. Nerve-mediated or agonist-induced contraction magnitude in tissue from obstructed bladders and nerve counts did not differ from controls. CONCLUSIONS: Nine days of outflow obstruction at mid-gestation generated a bladder of increased weight but without evidence of contractile failure. An increase in bladder compliance as a function of bladder growth was observed even at this stage, and represents one of the initial responses to outflow tract obstruction.

A preliminary study of natural-fill radiotelemetered ovine fetal cystometry.

OBJECTIVE: To determine whether fetal cystometric studies by radiotelemetry are feasible in the fetal lamb, and potentially suitable for chronically monitoring fetal bladder pressures in an experimental fetal model of bladder outlet obstruction (BOO), as in utero BOO (e.g. caused by posterior urethral valves) results in significant postnatal bladder dysfunction but the pathophysiological progression of fetal bladder maldevelopment remains poorly understood. MATERIALS AND METHODS: The procedure required fetal sheep surgery and anaesthesia. Radiotelemetry implants comprised catheters that transmitted pressure fluctuations to an implant body; data were then transmitted using radio frequency to a receiver that passed this information to a computer. Four fetuses were used with different methods of catheter placement to optimize the technique. RESULTS: Recordings were possible in three of the four sheep; during observation there were: (i) quiet periods with no abdominal or bladder pressure rises; (ii) synchronous activity in the bladder and abdomen; and (iii) discriminate activity, associated with intravesical activity only. Four patterns of discriminate bladder activity were observed, defined as void, immature void, staccato activity and 'unstable' type activity. CONCLUSIONS: Radiotelemetry cystometry for long-term monitoring is feasible in the experimental fetus without causing death or morbidity, or inhibiting growth. The method can discriminate reproducible patterns of detrusor activity. Recorded 'voiding' types were consistent between experiments and as reported in other fetal animal studies.

The validity of sacral ratios to identify sacral abnormalities.

OBJECTIVE: To test the repeatability and validity of a previously described sacral ratio measurement as a method for detecting sacral abnormalities, as the association between sacral abnormalities and neuropathic bladder is well known but the diagnosis of subtle sacral anomalies is often delayed. MATERIALS AND METHODS: Fifty sacral radiographs (from 30 patients with anorectal anomalies and 20 normal children) were viewed and reported as normal or abnormal by an expert spinal radiologist (reference standard). Sacral ratios (anteroposterior, AP, and lateral) were measured while unaware of origin by four investigators and the inter- and intra-observer variability examined. Validity was assessed by comparing individual sacral ratio values with the radiological diagnosis, using Pena's criteria for a normal sacrum (normal >/= 0.74 AP; >/= 0.77 lateral). RESULTS: Sacral ratio estimates were possible in 48 of the 50 selected radiographs. There was good repeatability of measurements and moderate variability among investigators (P > 0.1). For the 20 normal children the mean (sd) AP sacral ratio was 0.74 (0.156); in the 14 with anorectal conditions and a normal sacrum it was 0.87 (0.16) and in the 12 with an abnormal sacrum 0.64 (0.27). There was a difference (P < 0.02) among the three groups (analysis of variance) but there was wide variability in individual sacral ratios within each group, and considerable overlap of values between normal and abnormal sacra. When all sacra were defined as normal or abnormal using Pena's criteria, there was poor agreement using Cohen's kappa (AP and lateral view) with the radiological diagnosis by all four investigators. CONCLUSION: The sacral ratio has good inter- and intra-observer repeatability. The mean value for a normal AP ratio concurred with that described previously by Pena but the variability of values among similar patients was large, suggesting this single value is of limited value in discriminating a normal from an abnormal sacrum.

The relationship between early renal status, and the resolution of vesico-ureteric reflux and bladder function at 16 months.

OBJECTIVE: To examine, in infants presenting with vesico-ureteric reflux (VUR), the relationship between the presence of initial renal abnormalities with the outcome of VUR and bladder function at 16 months of age. PATIENTS AND METHODS: The study group comprised 40 infants (32 boys) presenting consecutively (29 after prenatal detection) with VUR grade III or greater (bilateral in 29) on the initial micturating cystogram (median age 8 weeks). The initial presence of abnormal kidneys was determined from isotopic renography and/or ultrasonography. These data were correlated with the outcome of VUR, from direct isotope cystography, and bladder function assessed by natural filling urodynamics, examined at age 16 months (mean 16.4 months, SD 2.1). RESULTS: Three groups were identified. Group 1 (eight boys and six girls) had normal kidneys bilaterally; initially grade III VUR was common. At 16 months bladder function was normal in 10 children and none had VUR (complete resolution). Group 2 (14 boys and two girls) had unilateral renal abnormalities; initially VUR was predominantly grade IV or grade V. At 16 months bladder function was normal in eight children and VUR resolved in eight, five of these with normal bladder function. Group 3 (10 boys) had bilateral renal abnormalities. Initially grade V VUR predominated; at 16 months the bladder function was normal in only one, and in the rest the emptying dynamics were abnormal. All 10 boys had persisting VUR (no resolution). CONCLUSIONS: In infants with moderate or severe VUR, resolution at 16 months old is associated with normal kidneys in a similar proportion of boys and girls. Resolution also correlates well with normal bladder function. Presentation in infancy with bilateral abnormal kidneys, associated with severe VUR in boys, is a poor prognostic sign for the early outcome of VUR and for bladder function.

Quantitative 99mTc-DMSA uptake in experimental pyelonephritis.

UNLABELLED: Quantitative 99mTc-dimercaptosuccinic acid (DMSA) renal uptake was studied in unilateral reflux-related pyelonephritis in pigs. The changes to absolute % dose uptake and differential uptake occurring with induction and after treatment of pyelonephritis were correlated with the DMSA images and renal pathology. METHODS: Quantitative uptake in 53 young pigs was obtained from planar images acquired 6 h after injecting the dose. Baseline studies were made (Q1), and studies were made again after urinary infection was established (Q2), when 8 pigs had normal (no defect) renal images (group A), 23 had photon-deficient (reversible) focal defects (group B) and 22 had photon absent (irreversible) focal defects (group C). Q3 studies were made in 21 animals from groups B and C after 3-wk antimicrobial treatment. RESULTS: At Q2 the affected kidney differential uptake was unchanged for group A and reduced for groups B and C (respective mean changes -1.7%, P < 0.01; and -5.5%, P < 0.01). The absolute % dose uptake was unchanged in pyelonephritic kidneys, but increased in the contralateral nondiseased kidneys in groups B and C (respective mean increases +1.4%, P < 0.05; and +5.4%, P < 0.01), while remaining unchanged for group A. In group C, global renal accumulation was actually increased above the Q1 values. After treatment (Q3) the reduced pyelonephritic kidney differential uptake persisted in groups B and C. In group C, however, the increased absolute % dose uptake by the contralateral kidney was less marked and not significantly different from Q1 values in this small group. CONCLUSION: Induction of unilateral pyelonephritis produced a small reduction in diseased kidney differential uptake that was greatest in the group with irreversible imaging defects. The method did not discriminate individuals with reversible and irreversible imaging defects. The decrease in pyelonephritic kidney differential uptake resulted from increased DMSA accumulation (absolute % dose uptake) by the nondiseased contralateral kidney, while that in pyelonephritic kidneys remained unchanged. After treatment, the reduced pyelonephritic kidney differential uptake persisted, but the elevated global DMSA accumulation seen for group C (with irreversible imaging defects) was not sustained and was variable.

Urodynamic patterns in infants with normal lower urinary tracts or primary vesico-ureteric reflux.

OBJECTIVE: To compare bladder function in infants with primary vesico-ureteric reflux (VUR) and those with normal lower urinary tracts. PATIENTS AND METHODS: The study comprised 42 patients (36 males) with VUR (grades III to V) and 21 (16 males) without VUR (mean age in both groups, 6 months). Intravesical catheters were placed suprapubically under general anaesthesia and, after at least 24 h, natural-tilling urodynamics were monitored for three or more filling and voiding cycles. RESULTS: Various urodynamics patterns were defined: for infants without VUR these were either normal or normal-immature (discoordinated micturition) and none showed features indicating abnormal bladder function. By comparison, 24 of 42 infants with VUR showed abnormal urodynamic patterns (57%, 95% confidence interval 41% to 72%, P < 0.001). Seven (17%) were defined as unstable with small voided volumes, five (12%) had inadequate voiding dynamics, 10 (24%) showed a markedly dyssynergic pattern and two (5%) had obstructive patterns. The unstable, inadequate and obstructive patterns occurred only in boys. Detrusor activity during the filling phase occurred in 14 infants (13 boys) with VUR and in only one without VUR, when it was trivial. Post-void residual volumes of > 30% capacity were seen only in the VUR group (in 24 patients). There were 18 infants with VUR that showed the normal or immature urodynamics patterns, but for the 14 males the voiding pressures were higher than for those without VUR (mean maximum detrusor pressure, 161 and 117 cmH2O, respectively: P < 0.02). CONCLUSIONS: There is an association between abnormal urodynamic variables and a diagnosis of primary VUR in young infants (notably males) that may have important implications for concepts about the genesis and persistence of VUR.

The characteristics of primary vesico-ureteric reflux in male and female infants with pre-natal hydronephrosis.

OBJECTIVE: To examine the characteristics of primary vesico-ureteric reflux (VUR) in young infants following prenatal hydronephrosis. PATIENTS AND METHODS: The study comprised 155 consecutive infants with VUR detected at a mean age of 8.7 weeks (SD 6.3). Reflux units (n = 236) were analysed for relationships between gender, severity of reflux, exposure to urinary tract infection (UTI) and the presence of focal and generalized types of kidney damage on imaging. Bladder wall thickness (from ultrasonography) was examined in comparison with a further group of 29 males without VUR. RESULTS: Male infants predominated (117 of 155, 75%); bilateral VUR affected the same proportion (52%) of males and females. Most kidneys exposed to VUR (158 of 236. 67%) were normal and of the 78 abnormal kidneys (57 without UTI), 53 showed generalized damage (only eight exposed to UTI) and 71 (91%) were associated with severe (grades IV and V) reflux that predominantly affected males (P < 0.001). Grade V reflux was almost exclusively a male disorder. Most female units (45 of 58, 78%) compared with 46% (82/178) of male units had mild (grades I to III) reflux that was independently associated with normal kidneys. The mean bladder wall thickness was significantly greater for males with VUR than for females with VUR and for males without VUR. CONCLUSIONS: Two distinct but not exclusive patterns of VUR were identified: (i) mild reflux associated with normal kidneys that affected most females and a proportion of males; (ii) severe reflux combined with kidney damage, most likely fetal in origin, that is almost exclusively a male disorder.

Use of LMA for awake intubation for caesarean section.

PURPOSE: This case report describes the use of a Laryngeal Mask Airway in a morbidly obese parturient with the H.E.L.L.P. syndrome. An urgent Caesarean section was required because of vaginal bleeding and fetal distress. CLINICAL FEATURES: The patient was a 32 year old G3, T1, P1, L1 who presented with epigastric pain, headache, vomiting, and diarrhoea. She was hypertensive (180/110 mmHg) and thrombocytopaenic (18 x 10(-9). L-1). Examination of the airway revealed a short neck, receded jaw, full dentition, large breasts and she was considered to be a potential intubation problem. The patient required an awake intubation using a technique that minimized hypertension, aspiration risk, airway trauma, and hypoxia. A laryngeal mask was used to facilitate tracheal intubation, and the patient tolerated the procedure with no adverse outcome. CONCLUSION: The LMA has a place to facilitate potentially difficult awake tracheal intubation with the pregnant patient.

Some new insights into bladder function in infancy.

OBJECTIVES: To evaluate normal bladder function and micturition patterns in infants. PATIENTS, SUBJECTS AND METHODS: Twenty-one infants (16 boys, five girls; mean age 5.9 months) with no lower urinary tract pathology underwent natural filling cystometry. Micturition patterns were also observed simultaneously with polysomnography in 26 healthy neonates (16 boys, 10 girls; mean age 7.4 days). RESULTS: In infants, cystometry showed (95% CI) a capacity of 42-53 mL, a maximum rise in detrusor pressure during voiding of 95-120 cmH2O and a voiding efficiency (voided volume/capacity) of 0.86-0.91. On micturition, urinary flow was discoordinated from peak detrusor pressures in 10 infants. Detrusor instability occurred in one of 21 infants. Micturition was observed only during wakefulness or on arousal from sleep. In neonates, 17 of 61 recorded voids (28%) were during full wakefulness and 44 (72%) during arousal from sleep. Notably, none of the recorded voids occurred during quiet sleep. CONCLUSIONS: The normal infant's bladder was stable and emptied almost completely. Voiding with incomplete co-ordination between detrusor contraction and urinary sphincter relaxation could be normal. Micturition never occurred during quiet sleep. There was cortical arousal in response to a full bladder even in new-born infants. This contradicts the traditional concept of a totally uninhibited bladder in infancy. There are potential implications for the management of children with nocturnal enuresis.

Natural filling cystometry in infants and children.

OBJECTIVE: To evaluate natural filling cystometry in infants and young children. PATIENTS AND METHODS: The study group comprised 37 infants and young children (mean age, 4.1 years) with various urological conditions. Suprapubic catheters were used in all patients with urethral sensation. Natural filling urodynamic (NFU) studies were performed using an ambulatory recorder and with an observer present throughout. For comparison, 17 of the 37 patients also had slow filling conventional cystometry (CMG). RESULTS: All NFU studies were successfully completed and the great majority of patients were unaffected by the investigation procedures. In comparison with conventional cystometry there were significant differences. For NFU, there was a lower bladder capacity (means, NFU 122 mL vs CMG 188 mL, P < 0.03); lower pressure rise on filling (means, NFU 5.7 cmH2O vs CMG 16.1 cmH2O, P < 0.001) and higher maximum detrusor pressures during micturition (means, NFU 130 cmH2O vs CMG 78 cmH2O, P < 0.01). Voiding efficiency was also slightly greater with NFU compared with CMG. Detrusor instability was recorded in five patients only during NFU and in two other patients only during CMG. CONCLUSION: A natural filling cystometry method which incorporates an unobtrusive recording system is likely to be superior to conventional CMG for assessing bladder function in infants and children. This is because (i) bladder function is investigated in near to natural conditions, (ii) the patients are mostly unaffected by the investigation procedures, (iii) there are significant differences between NFU and CMG in the measurements obtained, indicating that CMG may give false indices of bladder function.

Renal pathology and the 99mTc-DMSA image before and after treatment of the evolving pyelonephritic scar: an experimental study.

This study reports the effects of 3-weeks' antimicrobial treatment on the pathology and appearance of the 99mTc-DMSA renal image in piglets with pyelonephritis induced by a combination of vesicoureteral reflux (VUR) and urinary infection. Before treatment, either photon-deficient (B1, B2) or photon-absent (C) scintigraphic abnormalities were present in the refluxing kidney in all 22 animals examined. All (100%) of the initially B1 and the majority (71%) of B2 photon deficient defects resolved with treatment, leaving only insignificant residual pathologic lesions. Conversely almost all (93%) of the C photon-absent scintigraphic abnormalities persisted after treatment and were always associated with significant scarred or cratered pathologic lesions in the refluxing kidney at sacrifice.

99Tcm-DMSA as a dynamic imaging agent for estimating renal blood flow. A comparison with 99Tcm-DTPA.

A technique for estimating fractional renal blood flow (RBF) from the early part of the 99Tcm-diethylenetriaminepentaacetate (DTPA) renogram has been described previously and its reproducibility validated in the pig model. The technique is assumed to be applicable to any recirculating gamma-emitting tracer compound. The aim of this study was to determine whether the same method could be applied to 99Tcm-dimercaptosuccinic acid (DMSA) which has been largely neglected as a dynamic imaging agent. Paired estimates of fractional RBF were obtained in Large White (n = 16) and Göttingen miniature pigs (n = 6) in three groups: group 1, paired 99Tcm-DTPA studies; group 2, paired 99Tcm-DMSA studies; group 3, alternate 99Tcm-DTPA and 99Tcm-DMSA studies. The results showed good agreement between paired results independent of whether 99Tcm-DTPA or 99Tcm-DMSA was used, supporting the assumption that the technique is applicable to any recirculating gamma-emitting tracer compound. The demonstration that fractional RBF can be reliably estimated from the DMSA renogram means that, if required, it may be combined in a single nuclear medicine procedure with conventional static DMSA renal imaging.

Case management services for adolescent substance abusers: a program description.

A case management model for adolescent substance abusers whose problems are severe enough to warrant residential treatment is presented, based on the experience of a demonstration project. The five integral functions of case management (assessment, planning, linking, advocacy, and support) are described within the framework of each phase of an adolescent's treatment program (screening, residential treatment, and continuing care). Detailed descriptions of case management activities and the philosophy underlying case management are addressed. The integrated client tracking and program evaluation monitoring system developed for the case management project is described, and evaluation data are presented. Among the advantages case managers are able to offer to the entire treatment process include encouragement of family involvement in the youth's recovery; providing support; tracking substance abuse relapse episodes following treatment; connecting the youth with school, work, and community resources; and helping youth to fulfill legal obligations.

Renal pathology and the 99mTc-DMSA image during the evolution of the early pyelonephritic scar: an experimental study.

This study describes the pathologic changes underlying the appearances of the 99mTc-DMSA renal image during acute pyelonephritis induced in piglets by a combination of vesicoureteral reflux (VUR) and urinary infection. In a total of 42 animals examined, pathologic lesions were identified in 36 of the 46 kidneys subjected to VUR and urinary infection, but no lesions developed in the remaining 10 refluxing kidneys. While scintigraphic defects were invariably associated with pyelonephritic lesions (specificity 100%), some small lesions were not identified (sensitivity 80%). There was a significant association (p = < 0.001) between the degree of photon deficiency seen scintigraphically and the histologic changes (early and late lesions). However, the scintigraphic appearance of individual lesions was also influenced by factors such as their extent and density, so that consideration of the macroscopic characteristics was also important for precise correlation.

Renal transplantation in young boys with posterior urethral valves: preliminary report.

Seven boys (mean age 38 months) with posterior urethral valves underwent renal transplantation between June 1988 and August 1991. Urodynamic studies were performed before transplantation in 6/7 patients. In 4 the investigation indicated bladders of capacity and compliance which were deemed suitable for transplantation. Two patients had poorly compliant bladders; one of these underwent bladder augmentation before engraftment and the other proceeded to transplantation without bladder surgery. Six patients have functioning renal allografts with a mean follow-up of 1.3 years and a mean plasma creatinine of 51.6 mumol/l. Mean glomerular filtration rate (ml/min/1.73 m2 SA) 6 months after transplantation was 76.8 and at 1 year it was 84.5. In one patient early rejection was followed by transplant nephrectomy. Careful pre-operative evaluation is mandatory for a successful outcome of renal transplantation in young boys with posterior urethral valves.

Urinary endothelin (ET1) in complete ureteric obstruction in the miniature pig.

Segmental renal scarring occurs in experimental obstructive uropathy in the multipapillary porcine kidney, and segmental abnormalities in renal perfusion are likely to be responsible. This preliminary study examines the urinary excretion of the potent locally active vasoconstrictor endothelin 1 (ET 1) in a pig model of renal obstruction and subsequent relief. Significant urinary excretion of ET 1 from the postobstructive kidney was found to occur after longstanding obstruction. Preglomerular arteriolar stenosis may be the cause of the renal ischaemia in obstruction that is at first reversible but later becomes irreversible if the stimulus persists. ET 1 may be implicated in the pathogenesis of this injury.

A comparison of epanolol and nifedipine in stable angina patients: results of a multicentre trial.

Epanolol (200 mg once daily) was compared with nifedipine (20 mg twice daily) in a multicentre, double-blind, randomised, crossover study in which 571 patients with stable angina pectoris were entered. Efficacy was assessed by anginal attack rate and short-acting nitrate consumption. Symptoms and treatment preference of the patients were assessed by questionnaires. Assessments were made at baseline and after each 4-week treatment period. Both treatments were equally efficacious as demonstrated by weekly anginal attack rates and nitrate usage. Of those patients who expressed a preference for treatment, 61% expressed a preference for epanolol compared with 39% for nifedipine. Significantly fewer patients reported experiencing flushing, pedal oedema or feeling generally unwell (p less than 0.01) during the epanolol treatment period. Patients withdrew from nifedipine treatment more often than from epanolol because of adverse effects. Hence, epanolol was found to be as efficacious as nifedipine in patients with stable angina pectoris, but exhibited a superior tolerability profile and was preferred by more patients.