The impact of pelvic venous pressure on blood loss during open radical cystectomy and urinary diversion: Results from a secondary analysis of a randomized clinical trial

PURPOSE Blood loss and blood substitution are associated with higher morbidity after major abdominal surgery. During major liver resection, low local venous pressure, has been shown to reduce blood loss. Ambiguity persists concerning the impact of local venous pressure on blood loss during open radical cystectomy. We aimed to determine the association between intraoperative blood loss and pelvic venous pressure (PVP) and determine factors affecting PVP. MATERIAL AND METHODS In the frame of a single-center, double-blind, randomized trial, PVP was measured in 82 patients from a norepinephrine/low-volume group and in 81 from a control group with liberal hydration. For this secondary analysis, patients from each arm were stratified into subgroups with PVP <5 mmHg or ≥5 mmHg measured after cystectomy (optimal cut-off value for discrimination of patients with relevant blood loss according to the Youden's index). RESULTS Median blood loss was 800 ml [range: 300-1600] in 55/163 patients (34%) with PVP <5 mmHg and 1200 ml [400-3000] in 108/163 patients (66%) with PVP ≥5 mmHg; (P<0.0001). A PVP <5 mmHg was measured in 42/82 patients (51%) in the norepinephrine/low-volume group and 13/81 (16%) in the control group (P<0.0001). PVP dropped significantly after removal of abdominal packing and abdominal lifting in both groups at all time points (at begin and end of pelvic lymph node dissection, end of cystectomy) (P<0.0001). No correlation between PVP and central venous pressure could be detected. CONCLUSIONS Blood loss was significantly reduced in patients with low PVP. Factors affecting PVP were fluid management and abdominal packing.

Treatment and outcomes of urethral recurrence of urinary bladder cancer in women after radical cystectomy and orthotopic neobladder: a series of 12 cases

INTRODUCTION The incidence, treatment, and outcome of urethral recurrence (UR) after radical cystectomy (RC) for muscle-invasive bladder cancer with orthotopic neobladder in women have rarely been addressed in the literature. PATIENTS AND METHODS A total of 12 patients (median age at recurrence: 60 years) who experienced UR after RC with an orthotopic neobladder were selected for this study from a cohort of 456 women from participating institutions. The primary clinical and pathological characteristics at RC, including the manifestation of the UR and its treatment and outcome, were reviewed. RESULTS The primary bladder tumors in the 12 patients were urothelial carcinoma in 8 patients, squamous cell carcinoma and adenocarcinoma in 1 patient each, and mixed histology in 2 patients. Three patients (25%) had lymph node-positive disease at RC. The median time from RC to the detection of UR was 8 months (range 4-55). Eight recurrences manifested with clinical symptoms and 4 were detected during follow-up or during a diagnostic work-up for clinical symptoms caused by distant metastases. Treatment modalities were surgery, chemotherapy, radiotherapy, and bacillus Calmette-Guérin urethral instillations. Nine patients died of cancer. The median survival after the diagnosis of UR was 6 months. CONCLUSIONS UR after RC with an orthotopic neobladder in females is rare. Solitary, noninvasive recurrences have a favorable prognosis when detected early. Invasive recurrences are often associated with local and distant metastases and have a poor prognosis. © 2014 S. Karger AG, Basel.

Protocol for a randomized, placebo-controlled, double-blind clinical trial investigating sacral neuromodulation for neurogenic lower urinary tract dysfunction

BACKGROUND Sacral neuromodulation has become a well-established and widely accepted treatment for refractory non-neurogenic lower urinary tract dysfunction, but its value in patients with a neurological cause is unclear. Although there is evidence indicating that sacral neuromodulation may be effective and safe for treating neurogenic lower urinary tract dysfunction, the number of investigated patients is low and there is a lack of randomized controlled trials. METHODS AND DESIGN This study is a prospective, randomized, placebo-controlled, double-blind multicenter trial including 4 sacral neuromodulation referral centers in Switzerland. Patients with refractory neurogenic lower urinary tract dysfunction are enrolled. After minimally invasive bilateral tined lead placement into the sacral foramina S3 and/or S4, patients undergo prolonged sacral neuromodulation testing for 3-6 weeks. In case of successful (defined as improvement of at least 50% in key bladder diary variables (i.e. number of voids and/or number of leakages, post void residual) compared to baseline values) prolonged sacral neuromodulation testing, the neuromodulator is implanted in the upper buttock. After a 2 months post-implantation phase when the neuromodulator is turned ON to optimize the effectiveness of neuromodulation using sub-sensory threshold stimulation, the patients are randomized in a 1:1 allocation in sacral neuromodulation ON or OFF. At the end of the 2 months double-blind sacral neuromodulation phase, the patients have a neuro-urological re-evaluation, unblinding takes place, and the neuromodulator is turned ON in all patients. The primary outcome measure is success of sacral neuromodulation, secondary outcome measures are adverse events, urodynamic parameters, questionnaires, and costs of sacral neuromodulation. DISCUSSION It is of utmost importance to know whether the minimally invasive and completely reversible sacral neuromodulation would be a valuable treatment option for patients with refractory neurogenic lower urinary tract dysfunction. If this type of treatment is effective in the neurological population, it would revolutionize the management of neurogenic lower urinary tract dysfunction. TRIAL REGISTRATION TRIAL REGISTRATION NUMBER http://www.clinicaltrials.gov; Identifier: NCT02165774.

Urinary diversion: how experts divert

OBJECTIVE To determine the rates of the available urinary diversion options for patients treated with radical cystectomy for bladder cancer in different settings (pioneering institutions, leading urologic oncology centers, and population based). METHODS Population-based data from the literature included all patients (n = 7608) treated in Sweden during the period 1964-2008, from Germany (n = 14,200) for the years 2008 and 2011, US patients (identified from National Inpatient Sample during 1998-2005, 35,370 patients and 2001-2008, 55,187 patients), and from Medicare (n = 22,600) for the years 1992, 1995, 1998, and 2001. After the International Consultation on Urologic Diseases-European Association of Urology International Consultation on Bladder Cancer 2012, the urinary diversion committee members disclosed data from their home institutions (n = 15,867), including the pioneering institutions and the leading urologic oncology centers. They are the coauthors of this report. RESULTS The receipt of continent urinary diversion in Sweden and the United States is <15%, whereas in the German high-volume setting, 30% of patients receive a neobladder. At leading urologic oncology centers, this rate is also 30%. At pioneering institutions up to 75% of patients receive an orthotopic reconstruction. Anal diversion is <1%. Continent cutaneous diversion is the second choice. CONCLUSION Enormous variations in urinary diversion exist for >2 decades. Increased attention in expanding the use of continent reconstruction may help to reduce these disparities for patients undergoing radical cystectomy for bladder cancer. Continent reconstruction should not be the exclusive domain of cystectomy centers. Efforts to increase rates of this complex reconstruction must concentrate on better definition of the quality-of-life impact, technique dissemination, and the centralization of radical cystectomy.

Associations of ambulatory blood pressure with urinary caffeine and caffeine metabolite excretions.

Intake of caffeinated beverages might be associated with reduced cardiovascular mortality possibly via the lowering of blood pressure. We estimated the association of ambulatory blood pressure with urinary caffeine and caffeine metabolites in a population-based sample. Families were randomly selected from the general population of Swiss cities. Ambulatory blood pressure monitoring was conducted using validated devices. Urinary caffeine, paraxanthine, theophylline, and theobromine excretions were measured in 24 hours urine using ultrahigh performance liquid chromatography tandem mass spectrometry. We used mixed models to explore the associations of urinary excretions with blood pressure although adjusting for major confounders. The 836 participants (48.9% men) included in this analysis had mean age of 47.8 and mean 24-hour systolic and diastolic blood pressure of 120.1 and 78.0 mm Hg. For each doubling of caffeine excretion, 24-hour and night-time systolic blood pressure decreased by 0.642 and 1.107 mm Hg (both P values <0.040). Similar inverse associations were observed for paraxanthine and theophylline. Adjusted night-time systolic blood pressure in the first (lowest), second, third, and fourth (highest) quartile of paraxanthine urinary excretions were 110.3, 107.3, 107.3, and 105.1 mm Hg, respectively (P trend <0.05). No associations of urinary excretions with diastolic blood pressure were generally found, and theobromine excretion was not associated with blood pressure. Anti-hypertensive therapy, diabetes mellitus, and alcohol consumption modify the association of caffeine urinary excretion with systolic blood pressure. Ambulatory systolic blood pressure was inversely associated with urinary excretions of caffeine and other caffeine metabolites. Our results are compatible with a potential protective effect of caffeine on blood pressure.

New anthropometry-based age- and sex-specific reference values for urinary 24-hour creatinine excretion based on the adult Swiss population.

BACKGROUND Urinary creatinine excretion is used as a marker of completeness of timed urine collections, which are a keystone of several metabolic evaluations in clinical investigations and epidemiological surveys. The current reference values for 24-hour urinary creatinine excretion rely on observations performed in the 1960s and 1970s in relatively small and mostly selected groups, and may thus poorly fit to the present-day general European population. The aim of this study was to establish and validate anthropometry-based age- and sex-specific reference values of the 24-hour urinary creatinine excretion on adult populations with preserved renal function. METHODS We used data from two independent Swiss cross-sectional population-based studies with standardised 24-hour urinary collection and measured anthropometric variables. Only data from adults of European descent, with estimated glomerular filtration rate (eGFR) ≥60 ml/min/1.73 m(2) and reported completeness of the urinary collection were retained. A linear regression model was developed to predict centiles of the 24-hour urinary creatinine excretion in 1,137 participants from the Swiss Survey on Salt and validated in 994 participants from the Swiss Kidney Project on Genes in Hypertension. RESULTS The mean urinary creatinine excretion was 193 ± 41 μmol/kg/24 hours in men and 151 ± 38 μmol/kg/24 hours in women in the Swiss Survey on Salt. The values were inversely correlated with age and body mass index (BMI). Based on current reference values (177 to 221 μmol/kg/24 hours in men and 133 to 177 μmol/kg/24 hours in women), 56% of the urinary collections in the whole population and 67% in people >60 years old would have been considered as inaccurate. A linear regression model with sex, BMI and age as predictor variables was found to provide the best prediction of the observed values and showed a good fit when applied to the validation population. CONCLUSIONS We propose a validated prediction equation for 24-hour urinary creatinine excretion in the general European population, based on readily available variables such as age, sex and BMI, and a few derived normograms to ease its clinical application. This should help healthcare providers to interpret the completeness of a 24-hour urine collection in daily clinical practice and in epidemiological population studies.

Noninvasive Urinary Metabolomic Profiling Identifies Diagnostic and Prognostic Markers in Lung Cancer

Lung cancer remains the most common cause of cancer deaths worldwide, yet there is currently a lack of diagnostic noninvasive biomarkers that could guide treatment decisions. Small molecules (<1,500 Da) were measured in urine collected from 469 patients with lung cancer and 536 population controls using unbiased liquid chromatography/mass spectrometry. Clinical putative diagnostic and prognostic biomarkers were validated by quantitation and normalized to creatinine levels at two different time points and further confirmed in an independent sample set, which comprises 80 cases and 78 population controls, with similar demographic and clinical characteristics when compared with the training set. Creatine riboside (IUPAC name: 2-{2-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)-oxolan-2-yl]-1-methylcarbamimidamido}acetic acid), a novel molecule identified in this study, and N-acetylneuraminic acid (NANA) were each significantly (P < 0.00001) elevated in non-small cell lung cancer and associated with worse prognosis [HR = 1.81 (P = 0.0002), and 1.54 (P = 0.025), respectively]. Creatine riboside was the strongest classifier of lung cancer status in all and stage I-II cases, important for early detection, and also associated with worse prognosis in stage I-II lung cancer (HR = 1.71, P = 0.048). All measurements were highly reproducible with intraclass correlation coefficients ranging from 0.82 to 0.99. Both metabolites were significantly (P < 0.03) enriched in tumor tissue compared with adjacent nontumor tissue (N = 48), thus revealing their direct association with tumor metabolism. Creatine riboside and NANA may be robust urinary clinical metabolomic markers that are elevated in tumor tissue and associated with early lung cancer diagnosis and worse prognosis.

Human Urinary Composition Controls Siderocalin's Antibacterial Activity.

During Escherichia coli urinary tract infections, cells in the human urinary tract release the antimicrobial protein siderocalin (SCN; also known as lipocalin 2, neutrophil gelatinase-associated lipocalin/NGAL, or 24p3). SCN can interfere with E. coli iron acquisition by sequestering ferric iron complexes with enterobactin, the conserved E. coli siderophore. Here we find that human urinary constituents can reverse this relationship, instead making enterobactin critical for overcoming SCN-mediated growth restriction. Urinary control of SCN activity exhibits wide ranging individual differences. We used these differences to identify elevated urinary pH and aryl metabolites as key biochemical host factors controlling urinary SCN activity. These aryl metabolites are well-known products of intestinal microbial metabolism. Together, these results identify an innate antibacterial immune interaction that is critically dependent upon individualistic chemical features of human urine.

Pelvic floor muscle activation and strength components influencing female urinary continence and stress incontinence: A systematic review

AIMS A better understanding of pelvic floor muscle (PFM) activation and strength components is a prerequisite to get better insight in PFM contraction mechanisms and develop more specific PFM-training regimens for female stress urinary incontinence (SUI) patients. The aim of this systematic review (2012:CRD42012002547) was to evaluate and summarize existing studies investigating PFM activation and strength components influencing female continence and SUI. METHODS PubMed, EMBASE, and Cochrane databases were systematically searched for literature from January 1980 to November 2013 for cross-sectional studies comparing female SUI patients with healthy controls and intervention studies with SUI patients reporting on the association between PFM activation and strength components and urine loss. Trial characteristics, evaluated PFM components, their definitions, measurement methods, study outcomes, as well as quality measures, based on the Cochrane risk of bias tool, were independently extracted. The high heterogeneity of the retrieved data made pooling of results impossible and therefore restricted the analysis to a systematic review. RESULTS Cross-sectional studies showed group differences in favor of the continent women compared to SUI patients for PFM activation or PFM maximal strength, mean strength or sustained contraction. All intervention studies showed an improvement of PFM strength and decrease in urine loss in SUI patients after physical therapy. CONCLUSIONS Higher PFM activation and strength components influence female continence positively. This systematic review underscored the need for a standardized PFM components' terminology (similar to rehabilitation and training science), standardized test procedures and well matched diagnostic instruments. Neurourol. Urodynam. © 2014 Wiley Periodicals, Inc.

Orthotopic Ileal Bladder Substitution in Women: Factors Influencing Urinary Incontinence and Hypercontinence.

BACKGROUND Urinary incontinence or the inability to void spontaneously after ileal orthotopic bladder substitution is a frequent finding in female patients. OBJECTIVE To evaluate how hysterectomy and nerve sparing affect functional outcomes and whether these relate to pre- and postoperative urethral pressure profile (UPP) results. DESIGN, SETTING, AND PARTICIPANTS Prospectively performed pre- and postoperative UPPs of 73 female patients who had undergone cystectomy and bladder substitution were correlated with postoperative voiding and continence status. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Outcome analyses were performed with the Kruskal-Wallis test, Wilcoxon-Mann-Whitney, or two-group post hoc testing with the Bonferroni correction. Chi-square or Fisher exact tests were applied for the categorical data. RESULTS AND LIMITATIONS Of postoperatively continent or hypercontinent patients, 22 of 43 (51.2%) had the uterus preserved; of incontinent patients, only 4 of 30 (13.3%, p<0.01) had the uterus preserved. Of postoperatively continent or hypercontinent patients, 27 of 43 patients (62.8%) had bilateral and 15 of 43 (34.9%) had unilateral attempted nerve sparing. In incontinent patients, 11 of 30 (36.7%) had bilateral and 16 of 30 (53.3%) had unilateral attempted nerve sparing (p=0.02). When compared with postoperatively incontinent patients, postoperatively continent patients had a longer functional urethral length (median: 32mm vs 24mm; p<0.001), a higher postoperative urethral closing pressure at rest (56cm H2O vs 35cm H2O; p<0.001) as well as a higher preoperative urethral closing pressure at rest (74cm H2O vs 47.5cm H2O; p=0.01). The main limitation was the limited number of patients. CONCLUSIONS In female patients undergoing radical cystectomy and bladder substitution, preservation of the uterus and attempted nerve sparing results in better functional outcomes. The preoperative UPPs correlate with postoperative voiding and continence status and may predict which patients are at a higher risk of functional failure after bladder substitution. PATIENT SUMMARY If preservation of the urethra's innervation is not possible during cystectomy, poor functional results with bladder substitutes are likely.

Estimation of reference curves for the urinary steroid metabolome in the first year of life in healthy children: tracing the complexity of human postnatal steroidogenesis

CONTEXT Complex steroid disorders such as P450 oxidoreductase deficiency or apparent cortisone reductase deficiency may be recognized by steroid profiling using chromatographic mass spectrometric methods. These methods are highly specific and sensitive, and provide a complete spectrum of steroid metabolites in a single measurement of one sample which makes them superior to immunoassays. The steroid metabolome during the fetal-neonatal transition is characterized by a) the metabolites of the fetal-placental unit at birth, b) the fetal adrenal androgens until its involution 3-6 months postnatally, and c) the steroid metabolites produced by the developing endocrine organs. All these developmental events change the steroid metabolome in an age- and sex-dependent manner during the first year of life. OBJECTIVE The aim of this study was to provide normative values for the urinary steroid metabolome of healthy newborns at short time intervals in the first year of life. METHODS We conducted a prospective, longitudinal study to measure 67 urinary steroid metabolites in 21 male and 22 female term healthy newborn infants at 13 time-points from week 1 to week 49 of life. Urine samples were collected from newborn infants before discharge from hospital and from healthy infants at home. Steroid metabolites were measured by gas chromatography-mass spectrometry (GC-MS) and steroid concentrations corrected for urinary creatinine excretion were calculated. RESULTS 61 steroids showed age and 15 steroids sex specificity. Highest urinary steroid concentrations were found in both sexes for progesterone derivatives, in particular 20α-DH-5α-DH-progesterone, and for highly polar 6α-hydroxylated glucocorticoids. The steroids peaked at week 3 and decreased by ∼80% at week 25 in both sexes. The decline of progestins, androgens and estrogens was more pronounced than of glucocorticoids whereas the excretion of corticosterone and its metabolites and of mineralocorticoids remained constant during the first year of life. CONCLUSION The urinary steroid profile changes dramatically during the first year of life and correlates with the physiologic developmental changes during the fetal-neonatal transition. Thus detailed normative data during this time period permit the use of steroid profiling as a powerful diagnostic tool.