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We investigated the efficacy and safety of fluoxetine, a selective serotonin reuptake inhibitor, for treating refractory primary monosymptomatic nocturnal enuresis in children.Children 8-18 years old with severe primary monosymptomatic nocturnal enuresis unresponsive to alarm therapy, desmopressin, and anticholinergics were screened for eligibility. After excluding children with daytime urinary symptoms, constipation, underlying urological, neuropsychiatric, endocrinological, or cardiac conditions, patients were randomly and equally assigned to 10 mg fluoxetine once daily or placebo for 12 weeks. The primary outcome was treatment response according to the International Children's Continence Society terminology. Treatment-related adverse effects and nighttime arousal were secondary outcomes.A total of 150 children were enrolled, of whom 110 (56 in fluoxetine group and 54 in placebo group) with a mean age of 11.8 (SD 2.46) years were finally analyzed. After 4 weeks, 7.1% and 66.1% of the fluoxetine group achieved complete response and partial response (defined as 50%-99% reduction of the number of wet nights), respectively, versus 0% and 16.7% of the placebo group (Fluoxetine is safe treatment for refractory primary monosymptomatic nocturnal enuresis in children with good initial response that declines at 12 weeks.

Urinary uromodulin, secreted by renal tubular cells, protects against urinary tract infections and kidney stones. In contrast, the intracellular accumulation of uromodulin is associated with hypertension and chronic kidney disease. However, the physiological stimuli for urinary uromodulin secretion remain largely unknown. Here, we showed that desmopressin, a vasopressin type 2 receptor agonist, dramatically increased short-term tubular uromodulin secretion in mice. Immunofluorescence studies and ultracentrifugation-based polymerization assay suggested that desmopressin induced intraluminal polymeric filaments of uromodulin, indicating physiologically functional secretion. As a result of increased excretion, uromodulin abundance in the murine kidney was clearly reduced by desmopressin. We investigated kidney epithelial cells stably expressing uromodulin to clarify the molecular mechanism. Apical uromodulin secretion was clearly increased in response to vasopressin/cAMP signaling, consistent with in vivo experiments. We also demonstrated that the response was dependent on epithelial cell polarity and cyclic AMP-dependent PKA (protein kinase A) signaling pathway. cAMP-mediated activation of proteases was suggested to be involved. In contrast, basolateral secretion of uromodulin was independent of cAMP signaling. Our work revealed vasopressin/cAMP/PKA signaling as a physiological stimulus of urinary uromodulin secretion. This finding may provide the basis for novel treatment strategies for urinary tract infections, kidney stones, and potentially hypertension and chronic kidney disease.

Background Fibrosis is a major cause of loss of renal function in autosomal dominant polycystic kidney disease (ADPKD). In this study, we examined whether vasopressin type-2 receptor (V2R) activity in cystic epithelial cells can stimulate interstitial myofibroblasts and fibrosis in ADPKD kidneys. Methods We treated Pkd1 gene knockout (Pkd1KO) mice with dDAVP, a V2R agonist, for 3 days and evaluated the effect on myofibroblast deposition of extracellular matrix (ECM). We also analyzed the effects of conditioned media from primary cultures of human ADPKD cystic epithelial cells on myofibroblast activation. Because secretion of the profibrotic connective tissue growth factor (CCN2) increased significantly in dDAVP-treated Pkd1KO mouse kidneys, we examined its role in V2R-dependent fibrosis in ADPKD as well as that of yes-associated protein (YAP). Results V2R stimulation using dDAVP increased the renal interstitial myofibroblast population and ECM deposition. Similarly, conditioned media from human ADPKD cystic epithelial cells increased myofibroblast activation in vitro, suggesting a paracrine mechanism. Renal collecting duct-specific gene deletion of CCN2 significantly reduced cyst growth and myofibroblasts in Pkd1KO mouse kidneys. We found that YAP regulates CCN2, and YAP inhibition or gene deletion reduces renal fibrosis in Pkd1KO mouse kidneys. Importantly, YAP inactivation blocks the dDAVP-induced increase in myofibroblasts in Pkd1KO kidneys. Further in vitro studies showed that V2R regulates YAP by an ERK1/2-dependent mechanism in human ADPKD cystic epithelial cells. Conclusions Our results demonstrate a novel mechanism by which cystic epithelial cells stimulate myofibroblasts in the pericystic microenvironment, leading to fibrosis in ADPKD. The V2R-YAP-CCN2 cell signaling pathway may present a potential therapeutic target for fibrosis in ADPKD.

Objectives To investigate the hemostatic efficacy of combined desmopressin (1-deamino-8-D-arginine vasopressin) and platelet transfusion in reducing hematoma expansion in acute, spontaneous intracerebral hemorrhage under antiplatelet treatment. Design Single-center, nonrandomized study, performed between 2006 and 2014. Setting Tertiary University Hospital of Tuebingen, Germany. Patients Adult patients with intracerebral hemorrhage under antiplatelet treatment and follow-up CT at 24 ± 12 hours were included. Exclusion criteria included other intracerebral hemorrhage causes, anticoagulation, coagulopathy, or immediate surgery after baseline-CT. Interventions Treatment with IV 1-deamino-8-D-arginine vasopressin (0.4 µg/kg) + platelet transfusion (2 U) within 60 minutes of intracerebral hemorrhage under antiplatelet treatment diagnosis on brain imaging. Measurements and main results Primary outcome was relative hematoma expansion from baseline to follow-up CT. Secondary outcomes included secondary intraventricular hemorrhage or hydrocephalus upon follow-up CT, thromboembolic events before discharge, and the 3-month functional outcome (assessed by modified Rankin Scale). One-hundred forty patients were included, 72 treated versus 68 controls. Times of symptom-onset-to-baseline-CT (hr) (median [interquartile range]: 3 [4] vs 5 [5]; p = 0.468) and follow-up CT (26 [18] vs 19 [12]; p = 0.352) were similar between groups. No between-group differences of total intracerebral hematoma expansion (%) (median [interquartile range]: 8.5 [12.4] vs 9.1 [16.5]; p = 0.825), intraparenchymal (10.7 [23.1] vs 9.2 [20.7]; p = 0.900), and intraventricular hematoma expansion (14.5 [63.2] vs 6.1 [40.4]; p = 0.304) were noted. Among patients with hematoma expansion greater than or equal to 33% compared with baseline, 16 (52%) received treatment versus 15 (48%) controls. The occurrence of hematoma expansion greater than or equal to 33% was similar between groups (p = 0.981). Rates of secondary intraventricular hemorrhage, hydrocephalus, and thromboembolic events were similar between groups. Treatment with 1-deamino-8-D-arginine vasopressin + platelet transfusion was not associated with the 3-month functional outcome (adjusted odds ratio, 1.570; 95% CI, 0.721-3.419; p = 0.309). Conclusions In line with the randomized Platelet Transfusion Versus Standard Care After Acute Stroke Due to Spontaneous Cerebral Hemorrhage Associated With Antiplatelet Therapy trial, our results suggest no hemostatic efficacy of early platelet transfusion in intracerebral hemorrhage under antiplatelet treatment. Contrary to results of preclinical and clinical nonintracerebral hemorrhage studies, adjunct 1-deamino-8-D-arginine vasopressin showed no benefit in limiting hematoma expansion or improving functional outcome.

SER120 desmopressin intranasal spray is the first U.S. Food and Drug Administration approved pharmacotherapy for nocturia. We evaluated its efficacy and safety in 2 randomized, double-blind, placebo controlled studies, DB3 and DB4.A total of 1,333 intent to treat patients 50 years old or older with 2.16 or more nocturic voids per night during a 2-week screening period were randomized equally to SER120 intranasal spray 1.66 or 0.83 mcg, or placebo for a 12-week treatment. Co-primary end points were the mean change from baseline in nocturic episodes per night and the percent of patients with a 50% or greater reduction in mean nocturic episodes per night. Secondary end points were the validated INTU (Impact of Nighttime Urination) quality of life questionnaire in DB4, time to the first nocturic void and the percent of nights with 1 or fewer nocturic voids.Each SER120 dose showed statistical significance vs placebo for the 2 co-primary end points, including the mean nocturic episodes per night (-1.4 with 0.83 mcg and -1.5 with 1.66 mcg vs -1.2 with placebo, each p0.0001), the percent of patients with a 50% or greater reduction in mean nocturic episodes per night (37.9% with 0.83 mcg and 48.7% with 1.66 mcg vs 30.3% with placebo, p = 0.0227 and0.0001, respectively) as well as for all secondary end points in the pooled analyses. The 1.66 mcg dose demonstrated significant improvements in the INTU score (p = 0.0255). The incidence of hyponatremia, defined as serum sodium 125 mmol/l or less regardless of symptoms or less than 130 mmol/l with symptoms, was 1.1%, 0% and 0.2% in the 1.66 and 0.83 mcg, and placebo groups, respectively. Other adverse events were similar across treatment groups.SER120 demonstrated significant improvements over placebo for co-primary and secondary efficacy end points that corresponded with quality of life improvements. SER120 at each dose had an acceptable safety profile.

BACKGROUND Prasugrel is a thienopyridine that inhibits platelet aggregation more rapidly and effectively than clopidogrel, with an increased bleeding risk. OBJECTIVE The current study aimed to evaluate the efficacy of three nonspecific haemostatic drugs - recombinant activated factor VII (rFVIIa), tranexamic acid and desmopressin (DDAVP) - to limit blood loss after administration of prasugrel in a rabbit model of bleeding while also evaluating any prothrombotic effects. DESIGN Randomised, placebo-controlled study. SETTING Faculty of Medicine, University of Geneva, Switzerland, in 2013. ANIMALS Anaesthetised and artificially ventilated rabbits (n=56). INTERVENTIONS Animals were randomly allocated to one of five groups: control (placebo-placebo), prasugrel-placebo, rFVIIa (prasugrel-rFVIIa 150 μg kg), tranexamic acid (prasugrel-tranexamic acid 20 mg kg) or DDAVP (prasugrel-DDAVP 1 μg kg). Two hours after an oral prasugrel loading dose (4 mg kg), a stenosis and an injury were inflicted on the carotid artery to induce cyclic flow reductions (CFRs) due to thrombosis. Haemostatic drugs were administered during the ensuing observation period. MAIN OUTCOME MEASURES Standardised hepatosplenic sections were performed to evaluate the primary endpoint of blood loss, monitored for 15 min. Ear-immersion bleeding time and incidence of CFRs were secondary endpoints. RESULTS Prasugrel decreased ADP-induced platelet aggregation (light transmission method) from 66 ± 4% (mean ± SD) to 41 ± 7% (P

HYPOTHESIS A vasopressin-induced endoymphatic hydrops model can represent an acute vertiginous attack in Meniere's disease (MD). BACKGROUND Previous animal models are not appropriate to evaluate the efficacy of new treatments for hydrops because they cannot represent an acute attack of MD. Recently, a new dynamic model was introduced for acute hydrops exacerbation using the vasopressin type 2 receptor agonist, desmopressin (1-deamino-8-D-Arginine vasopressin, VP); however, resulting changes in vestibular function have not been investigated. METHODS A total of 37 guinea pigs were used. Two to 4 weeks after surgical ablation of endolymphatic sacs in 33 guinea pigs, acute exacerbation of hydrops was induced by a single VP injection in 18 animals (group A). Next, two VP injections at 1 hour interval were administered to investigate the effect of multiple VP doses on vestibular function in the other 15 animals (group B). In the remaining four animals, VP was injected without surgery for the control group (control). Bidirectional sinusoidal harmonic acceleration (SHA) tests of vestibular function were performed. "Type I response" was defined as when the maximum slow-phase velocity (SPV) during left rotation (toward the operated ear) was lower than that during right rotation (toward the normal ear). In contrast, "Type II response" was defined as when maximum SPV at the left rotation was higher than that at the right rotation. Vestibular symmetry scores were analyzed at baseline and after each of two VP injections given 1 hour apart. RESULTS Vestibular symmetry scores increased at 1 hour after VP injection in all 18 animals in group A (p

Desmopressin is a synthetic V2 specific analogue of antidiuretic hormone (arginine vasopressin) that is widely used as first line treatment for monosymptomatic nocturnal enuresis. However, no biomarkers to predict desmopressin effectiveness have yet been established. Because arginine vasopressin is unstable, we prospectively measured the major urine concentration factor aquaporin 2 and serum copeptin (as a surrogate marker for vasopressin) in patients with monosymptomatic nocturnal enuresis, and evaluated whether they are useful for predicting desmopressin treatment outcome.The study included 32 children 6 to 11 years old with monosymptomatic nocturnal enuresis and nocturnal polyuria. Exclusion criteria were daytime urinary symptoms and underlying diseases causing nocturnal enuresis. Subjects were treated with 120 μg or 240 μg desmopressin oral disintegrating tablet and were divided into responders (at 120 or 240 μg) and nonresponders (at 240 μg). Day/night ratios of plasma copeptin and urinary aquaporin 2 were measured during desmopressin treatment.There was no significant difference in baseline day/night ratio of urinary aquaporin 2 between desmopressin responders and nonresponders. After 8 weeks of treatment there was a significant correlation between day/night ratio of aquaporin 2 and percentage of wet nights. In responders (but not nonresponders) there was a significant difference in the change in aquaporin 2 day/night ratio from before treatment to complete remission (p = 0.0004). For plasma copeptin the baseline day/night ratio for responders at 120 μg was significantly lower than in the 240 μg nonresponder group (p = 0.02).Urinary aquaporin 2 appears to be a biomarker of desmopressin treatment effectiveness during therapy, while plasma copeptin levels before treatment are predictive of desmopressin response.

Patients with end-stage liver disease are often hyponatremic due to multiple physiological processes associated with hepatic failure. For severely hyponatremic patients undergoing liver transplantation, intraoperative management of serum sodium concentration ([Na]s) is challenging. [Na]s tends to increase during transplantation by the administration of fluids with higher sodium concentration than the patient's [Na]s. An overly rapid increase in [Na]s (>1 mEq·L·hour) is difficult to avoid and increases the risk of serious perioperative complications. We report the successful use of intravenous desmopressin to reverse an overly rapid rise in [Na]s during living donor liver transplantation.

Correction of profound hyponatremia requires careful planning and close monitoring to reduce the risks of neurologic injury. Although there are various suggested treatment strategies in the setting of a medical ward or intensive care unit, reports of intraoperative management to prevent rapid increases in serum sodium are lacking. We present a case of profound hyponatremia of 102 mmol/L in a patient who required emergent operative repair for bowel obstruction. This is the first case to our knowledge that demonstrates a perioperative fluid and desmopressin treatment strategy to prevent overly rapid changes of sodium concentration in a patient with severe hyponatremia.

We investigated the efficacy and safety of desmopressin add-on therapy for men with persistent nocturia on α-blocker for lower urinary tract symptoms in this placebo controlled study.The study included men 40 to 65 years old with lower urinary tract symptoms and persistent nocturia despite α-blocker therapy for at least 8 weeks. Patients were randomized to once daily placebo or desmopressin 0.2 mg for 8 weeks. The primary end point was to assess changes in the mean number of nocturia episodes from baseline to the final assessment. Other secondary end points and adverse events were evaluated.A total of 86 patients were randomized to treatment, including placebo in 39 and desmopressin 0.2 mg in 47. Baseline characteristics were similar in the 2 groups. The desmopressin add-on group was significantly superior to placebo in terms of the change from baseline in the mean number of nocturia episodes (-1.13 ± 0.92 vs -0.68 ± 0.79, p = 0.034), the changes in nocturnal urine volume (p0.001), total I-PSS (International Prostate Symptom Score) (p = 0.041), the nocturnal polyuria index (p = 0.001) and ICIQ-N (International Consultation on Incontinence Questionnaire-Nocturia) (p = 0.001), and the willingness to continue (p = 0.025). The incidence of adverse events in the desmopressin add-on group was similar to that in the placebo group. Most adverse events were mild.Desmopressin add-on therapy in men 40 to 65 years old with persistent nocturia on α-blocker monotherapy for lower urinary tract symptoms is effective and well tolerated.

Extracellular vesicles (ECVs) facilitate intercellular communication along the nephron, with the potential to change the function of the recipient cell. However, it is not known whether this is a regulated process analogous to other signaling systems. We investigated the potential hormonal regulation of ECV transfer and report that desmopressin, a vasopressin analogue, stimulated the uptake of fluorescently loaded ECVs into a kidney collecting duct cell line (mCCDC11) and into primary cells. Exposure of mCCDC11 cells to ECVs isolated from cells overexpressing microRNA-503 led to downregulated expression of microRNA-503 target genes, but only in the presence of desmopressin. Mechanistically, ECV entry into mCCDC11 cells required cAMP production, was reduced by inhibiting dynamin, and was selective for ECVs from kidney tubular cells. In vivo, we measured the urinary excretion and tissue uptake of fluorescently loaded ECVs delivered systemically to mice before and after administration of the vasopressin V2 receptor antagonist tolvaptan. In control-treated mice, we recovered 2.5% of administered ECVs in the urine; tolvaptan increased recovery five-fold and reduced ECV deposition in kidney tissue. Furthermore, in a patient with central diabetes insipidus, desmopressin reduced the excretion of ECVs derived from glomerular and proximal tubular cells. These data are consistent with vasopressin-regulated uptake of ECVs in vivo. We conclude that ECV uptake is a specific and regulated process. Physiologically, ECVs are a new mechanism of intercellular communication; therapeutically, ECVs may be a vehicle by which RNA therapy could be targeted to specific cells for the treatment of kidney disease.

Introduction: Diabetes insipidus can be a common cause of polyuria and hydronephrosis in the kidneys. However, there is few reported case of urinary obstruction induced nephrogenic diabetes insipidus. Patient concerns: A 60-year-old Chinese man came to our hospital with the complaints of polydipsia and polyuria for 1 month. His examination showed chronic kidney disease stage III with eGFR of 48.274 ml/min, and the plasma osmolality was 338.00 mOsm/(kg·H2O) with a urinary osmolality of 163.00 mOsm/(kg·H2O). Moreover, imagological examination of the urinary system showed benign prostatic hyperplasia and hydronephrosis. Diagnosis: He was considered with benign prostatic hyperplasia induced ureter hydronephrosis and nephrogenic diabetes insipidus. Interventions: He got the transurethral resection of the prostate to alleviate urinary retention. Outcomes: After that, the urine output gradually decreased, and the administered hydrochlorothiazide was stopped due to the improved renal function. Conclusion: Our study presents a case of nephrogenic diabetes insipidus caused by urinary obstruction. Differential diagnoses for diabetes insipidus as well as the relationship between nephrogenic diabetes insipidus and urinary obstruction are also considered in this study.

This study is to compare the efficacy of enuresis alarm and desmopressin therapy in managing pediatric monosymptomatic enuresis. We performed systematic literature searches on different databases from inception until April 2017 without language restriction. All randomized control trials comparing an enuresis alarm and desmopressin in managing children with monosymptomatic enuresis were included. A total of 15 studies with 1502 participants (aged 5 to 16 years) were included for pooled analysis. Overall, an enuresis alarm outperformed desmopressin in achieving at least a partial response (>50% reduction in wet nights) in per-protocol analysis (OR: 1.53, 95% CI 1.05 to 2.23) but not in intention-to-treat analysis (OR: 0.97, 95% CI 0.73 to 1.30) as the alarm was hampered by a high dropout rate (OR: 2.20, 95% CI 3.41 to 4.29). However, alarm therapy yielded a better sustained response (OR: 2.89, 95% CI 1.38 to 6.04) and lower relapse rate (OR: 0.25, 95% CI 0.12 to 0.50). In the intention to treat analysis, the results revealed that alarm and desmopressin therapy are comparable in efficacy with regards to achieving >50% reduction in baseline wet nights in enuretic children. However, enuresis alarms offer a superior treatment response and a lower relapse rate in well-motivated children.

We compared the long-term success of desmopressin sublingual lyophilisate formulation and enuretic alarm therapy in children with primary monosymptomatic nocturnal enuresis, and determined predictive factors for treatment success.A total of 142 children with primary monosymptomatic nocturnal enuresis were randomized to receive treatment consisting of desmopressin or enuretic alarm for 6 months. Treatment compliance and response were reviewed monthly in each patient using a 30-day bed-wetting diary. Outcomes were assessed according to International Children's Continence Society criteria, and success rates at 6 and 12 months were compared for desmopressin and enuretic alarm. Additional intention to treat analyses were performed, considering cases with missing data as failures. Possible demographic factors predicting success were investigated by logistic regression analysis.Overall 4 children (5.2%) in the desmopressin group and 20 (30.7%) in the enuretic alarm group withdrew after randomization. Based on patients who completed 6 months of treatment, success (more than 90% reduction in wet nights per month) was achieved in 76.8% and 61.8% of children in the desmopressin and enuretic alarm groups, respectively. At 12 months 77.8% of those receiving desmopressin and 75% of those treated with enuretic alarm had success. However, long-term success rate was significantly higher with desmopressin (68.8% vs 46.2%) if intention to treat population was considered. Multivariate analysis revealed treatment group, severity of enuresis and monthly income as independent predictors of cure at 6 months.In compliant patients desmopressin lyophilisate and enuretic alarm provided equivalent success at the end of treatment and after extended followup. Alarm therapy had a high rate of early withdrawal from therapy and consequently lower rates of success on intention to treat analyses. Severe enuresis (more than 5 wet nights weekly) is an important predictive factor for cure after first-line treatment.

Autosomal dominant polycystic kidney disease (ADPKD) is a leading cause of ESRD. A central defect associated with ADPKD pathology is elevated levels of 3', 5'-cyclic AMP (cAMP). Compounds such as tolvaptan and pasireotide, which indirectly reduce adenylyl cyclase 6 (AC6) activity, have hence proven effective in slowing cyst progression. Here, we tested the efficacy of these compounds individually and in combination in a hypomorphic PKD1 model, Pkd1(R3277C/R3277C) (Pkd1(RC/RC)), in a 5-month preclinical trial. Initially, the Pkd1(RC/RC) model was inbred into the C57BL/6 background, minimizing disease variability, and the pathogenic effect of elevating cAMP was confirmed by treatment with the AC6 stimulant desmopressin. Treatment with tolvaptan or pasireotide alone markedly reduced cyst progression and in combination showed a clear additive effect. Furthermore, combination treatment significantly reduced cystic and fibrotic volume and decreased cAMP to wild-type levels. We also showed that Pkd1(RC/RC) mice experience hepatic hypertrophy that can be corrected by pasireotide. The observed additive effect reinforces the central role of AC6 and cAMP in ADPKD pathogenesis and highlights the likely benefit of combination therapy for patients with ADPKD.

Desmopressin (DDAVP) is commonly used in the treatment of patients with type 1 von Willebrand disease (VWD) and mild hemophilia A. A patient's responsiveness to DDAVP based on a 0.3 μg/kg dose determines future therapeutic efficacy of the drug. The aim of the study was to determine whether a capped dose of 15 μg subcutaneous DDAVP is able to achieve the same level of DDAVP responsiveness as previously reported. This is a retrospective chart review of patients from 1995 to 2013 in adults and children with type 1 VWD and hemophilia A weighing more than 50 kg. Levels of factor VIII, ristocetin cofactor, and von Willebrand factor antigen were measured before and after 1 h of administration of 15 μg of DDAVP. In patients with type 1 VWD, the complete response rate was 82.5% with a partial response rate of 12.5% and 5% nonresponders. In patients with mild hemophilia A, the complete response rate was 53.8% with a partial response rate of 38.5% and 7.7% nonresponders. These results using a capped 15-μg dose of DDAVP are similar to previously published reports using the 0.3-μg/kg dose.

Relapse after cessation of desmopressin is an important problem in treating patients with enuresis. Structured withdrawal of desmopressin tablets has been shown to decrease relapse rates. However, scientific data are lacking on the structured withdrawal of the fast melting oral formulation of desmopressin. We compared relapse rates of structured withdrawal using placebo and direct cessation in a population of patients with enuresis who were desmopressin responders.Patients diagnosed with enuresis and responding to desmopressin from 13 different centers were involved in the study. Patients were randomized into 4 groups. Two different structured withdrawal strategies were compared to placebo and direct withdrawal. Sample size was estimated as 240 (60 patients in each group), with a power of 0.80 and an effect size of 30%. Randomization was performed using NCSS statistical software (NCSS, Kaysville, Utah) from a single center. The relapse rates of the groups were compared using chi-square testing. Logistic regression analysis was performed to define the independent factors having an effect on relapse rates.Desmopressin treatment was initiated in 421 patients, and 259 patients were eligible for randomization. Relapse rates were 39 (1%) and 42 (4%) for the structured withdrawal groups, which were significantly less than for direct withdrawal (55, 3%) and placebo (53, 1%). Logistic regression analysis revealed that initial effective dose of 240 μcg, greater number of wet nights before treatment and nonstructured withdrawal were associated with higher relapse rates.We found that structured withdrawal with the fast melting oral formulation of desmopressin results in decreased relapse rates. Application of a structured withdrawal program was also an independent factor associated with reduced relapse rates, together with lower initial effective dose and number of wet nights per week. Relapse after cessation of desmopressin is an important problem, and in this study structured withdrawal was observed to be associated with decreased relapse rates compared to placebo and direct withdrawal.

Desmopressin (DDAVP) 1-deamino-8-D-arginine vasopressin is used in patients with bleeding disorders, including mild factor VIII deficiency, types 1 and 2 von Willebrand disease, and platelet function defects, undergoing surgeries to help control bleeding. We conducted a retrospective chart review of bleeding disorder patients undergoing inpatient surgery at Toledo Children's Hospital, OH, from 2005 to 2009. Our study population included 107 patients aged 2 to 19 years with platelet function defects and von Willebrand disease. Our study aimed to evaluate the extent of hyponatremia caused by DDAVP and to propose a safe and effective treatment regimen for these patients. The mean change in sodium level before and after DDAVP was statistically significant within each age group. Thirteen patients had second dose of DDAVP withheld, and 11 patients had postoperative sodium levels ≤ 130 mEq/L. There were 2 patients with significant complications: a 6-year-old with postoperative bleeding and a 2-year-old with post-DDAVP tonic-clonic seizures. We conclude that DDAVP causes significant hyponatremia, despite appropriate fluid restrictions. On the basis of our analysis, we recommend monitoring sodium levels before each dose of DDAVP and fluid restriction. These patients should be observed in the hospital setting after DDAVP administration for complications such as seizures and postoperative bleeding.

PURPOSE OF REVIEW: The purpose of this review is to highlight the use of tranexamic acid, point-of-care testing, algorithm-based treatment of trauma-associated coagulopathy with factor concentrates to reduce blood loss and transfusion requirements in order to improve outcome. In addition, the management of patients on new oral anticoagulants, drugs with renewed interest and the tolerance of relatively low hemoglobin levels in the context of trauma will be discussed. RECENT FINDINGS: Early administration of tranexamic acid reduces mortality without increasing the risk of thromboembolic events. Point-of-care testing is increasingly recommended. Goal-directed individualized coagulation algorithms with the use of factor concentrates allow reducing the amount of allogeneic blood products to be administered. Treatment of trauma patients with one of the new oral anticoagulants is challenging. Furthermore, new mechanisms have been discovered such as deep neuromuscular blockade to better tolerate acute anemia. SUMMARY: Applying Patient Blood Management concept to the trauma patient is possible and efficacious. Antihyperfibrinolytics such as tranexamic acid, point-of-care testing and coagulation algorithms with the use of factor concentrates allow a reduction of the number of transfusions, the costs and will likely ameliorate outcome of major trauma patients.

Excessive correction of chronic and profound hyponatremia may result in central pontine myelinolysis and cause permanent brain damage. In the case of foreseeable or established hyponatremia overcorrection, slowing down the correction rate of sodium plasma levels (PNa) or reinducing mild hyponatremia may prevent this neurologic complication.This retrospective and observational study was performed with 20 consecutive patients admitted to two intensive care units for severe hyponatremia, defined by PNa120 mmol/L and/or neurologic complications ascribable to hyponatremia and subsequently treated by desmopressin acetate (DDAVP) during correction of hyponatremia when the rate of correction was overtly or predictably excessive. The primary endpoint was the effectiveness of DDAVP on PNa control.DDAVP dramatically decreased the rate of PNa correction (median 0.81 mmol/L per hour [interquartile range, 0.46, 1.48] versus -0.02 mmol/L per hour [-0.16, 0.22] before and after DDAVP, respectively; P0.001) along with a concurrent decrease in urine output (650 ml/h [214, 1200] versus 93.5 ml/h [43, 143]; P=0.003), and a rise in urine osmolarity (86 mmol/L [66, 180] versus 209 mmol/L [149, 318]; P=0.002). The maximal magnitude of PNa variations was also markedly reduced after DDAVP administration (11.5 mmol/L [8.25, 14.5] versus 5 mmol/L [4, 6.75]; P0.001). No patient developed seizures after DDAVP or after subsequent relowering of PNa that occurred in 11 patients.Desmopressin acetate is effective in curbing the rise of PNa in patients admitted in the intensive care unit for severe hyponatremia, when the initial rate of correction is excessive.

Vasopressin regulates water excretion, in part, by controlling the abundances of the water channel aquaporin-2 (AQP2) protein and regulatory proteins in the renal collecting duct. To determine whether vasopressin-induced alterations in protein abundance result from modulation of protein production, protein degradation, or both, we used protein mass spectrometry with dynamic stable isotope labeling in cell culture to achieve a proteome-wide determination of protein half-lives and relative translation rates in mpkCCD cells. Measurements were made at steady state in the absence or presence of the vasopressin analog, desmopressin (dDAVP). Desmopressin altered the translation rate rather than the stability of most responding proteins, but it significantly increased both the translation rate and the half-life of AQP2. In addition, proteins associated with vasopressin action, including Mal2, Akap12, gelsolin, myosin light chain kinase, annexin-2, and Hsp70, manifested altered translation rates. Interestingly, desmopressin increased the translation of seven glutathione S-transferase proteins and enhanced protein S-glutathionylation, uncovering a previously unexplored vasopressin-induced post-translational modification. Additional bioinformatic analysis of the mpkCCD proteome indicated a correlation between protein function and protein half-life. In particular, processes that are rapidly regulated, such as transcription, endocytosis, cell cycle regulation, and ubiquitylation are associated with proteins with especially short half-lives. These data extend our understanding of the mechanisms underlying vasopressin signaling and provide a broad resource for additional investigation of collecting duct function (http://helixweb.nih.gov/ESBL/Database/ProteinHalfLives/index.html).

We investigated the efficacy and safety of 50 and 75 μg desmopressin orally disintegrating tablets in men with nocturia (2 or more nocturnal voids).In this 3-month, randomized, double-blind, parallel study 50 and 75 μg desmopressin were compared with placebo. The co-primary efficacy end points were changes from baseline in mean number of nocturnal voids and proportions of patients achieving at least a 33% reduction from baseline in nocturnal voids (33% responders) during a 3-month treatment period.The full analysis set comprised 385 men (age range 20 to 87 years). The 50 and 75 μg doses significantly reduced the number of nocturnal voids (-0.37, p0.0001 and -0.41, p = 0.0003, respectively) and increased the odds of a 33% or greater response (OR 1.98, p = 0.0009 and OR 2.04, p = 0.0004, respectively) compared with placebo during 3 months. Desmopressin 50 and 75 μg increased the time to first void from baseline by approximately 40 minutes compared to placebo (p = 0.006 and p = 0.003, respectively). The response to desmopressin was seen by 1 week of treatment and was sustained. Significant increases in health related quality of life and sleep quality were observed compared to placebo. Desmopressin was well tolerated as only 2 subjects (age 74 and 79 years) on 50 μg had a serum sodium level of less than 130 mmol/L (vs 9 subjects on 75 μg).Desmopressin (orally disintegrating tablet) is an effective and well tolerated treatment for men with nocturia. Treatment with 50 μg desmopressin, the minimum effective dose, provided sustained improvement of nocturia throughout the study and meaningful benefits to patients with an improved safety profile.

Previous studies suggest a lower dose of desmopressin orally disintegrating tablet may be effective in females compared to males with nocturia. We confirm the efficacy and safety of 25 μg desmopressin orally disintegrating tablet compared to placebo in female patients.In this 3-month, randomized, double-blind, parallel group study 25 μg desmopressin once daily was compared to placebo in women with nocturia (2 or more nocturnal voids). The co-primary efficacy end points were change from baseline in mean number of nocturnal voids and proportion of patients achieving at least a 33% reduction from baseline in the mean number of nocturnal voids (33% responders).The full analysis set comprised 261 patients (age range 19 to 87 years). Desmopressin significantly reduced the mean number of nocturnal voids and increased the odds of a 33% or greater response compared to placebo during 3 months, assessed by longitudinal analysis (-0.22, p = 0.028 and OR 1.85, p = 0.006, respectively). Desmopressin increased the mean time to first nocturnal void by 49 minutes compared to placebo at 3 months (p = 0.003). The response to desmopressin was seen by week 1 of treatment and was sustained throughout the trial. Significant increases in health related quality of life and sleep quality were observed compared to placebo. Desmopressin was well tolerated. Serum sodium levels remained greater than 125 mmol/L throughout the trial and 3 transient decreases to less than 130 mmol/L were recorded.At a dose of 25 μg, desmopressin orally disintegrating tablet is an effective and well tolerated treatment for women with nocturia. Treatment provides rapid and sustained improvement in nocturia and quality of life.

Background The shortage of organs is a limitation for transplantation, making the care of potential organ donors an important issue. The present systematic review and meta-analysis was carried out to assess the efficacy of interventions to stabilize hemodynamics in brain-dead donors or to improve organ function and outcomes of transplantation. Methods Medline, Embase, and Cochrane databases were searched. Of 5096 articles retrieved, 39 randomized controlled trials were selected. Twenty were included in a qualitative synthesis, providing data on 1277 patients. The main interventions described were desmopressin use, triiodothyronine and methylprednisolone replacement, fluid management, vasopressor therapy, mechanical ventilation strategies, and surgical techniques. Results Three meta-analyses were conducted: the first included two studies and showed that desmopressin administered to brain-dead patients was not advantageous with respect to early organ function in kidney recipients (relative risk, 0.97; 95% confidence interval [CI], 0.85-1.10; I(2) = 0%; P = 0.809). The second included four studies and showed that triiodothyronine did not add hemodynamic benefits versus standard management (weighted mean difference, 0.15; 95% CI, -0.13 to 0.42; I(2) = 17.4%; P = 0.304). The third meta-analysis (two studies) showed that ischemic liver preconditioning during harvesting procedures did not benefit survival (relative risk, 1.0; 95% CI, 0.93-1.08; I(2) = 0%; P = 0.459). Conclusion The present results suggest limited efficacy of interventions focusing on the management of brain-dead donors.

OBJECTIVES To determine the occurrence rate of central diabetes insipidus in pediatric patients with severe traumatic brain injury and to describe the clinical, injury, biochemical, imaging, and intervention variables associated with mortality. DESIGN Retrospective chart and imaging review. SETTING Children's Hospital, level 1 trauma center. PATIENTS Severely injured (Injury Severity Score ≥ 12) pediatric trauma patients (>1 month and

Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent hereditary renal disease, characterized by cyst formation in the kidneys leading to end stage kidney failure. It is clinically acknowledged that ADPKD patients have impaired urine concentrating capacity, but the mechanism behind this observation is unknown.Fifteen ADPKD patients (estimated GFR ≥60 ml/min per 1.73 m(2)) and 15 age- and sex-matched healthy controls underwent a standard prolonged water deprivation test in which urine and plasma osmolality, vasopressin, and copeptin were measured. The effect of a synthetic vasopressin analog (desmopressin) injected at the moment of maximal urine concentrating capacity was also studied.After 14 hours of water deprivation, ADPKD patients tended to have higher plasma osmolality (P=0.07) and significantly higher vasopressin and copeptin levels (both P0.05), whereas urine osmolality was similar in ADPKD patients and controls (710 versus 742 mOsmol/kg; P=0.61). Maximal urine concentrating capacity was lower in ADPKD patients (758 versus 915 mOsmol/kg in controls; P0.001). At maximal urine concentrating capacity, plasma osmolality, vasopressin, and copeptin levels were significantly higher in ADPKD patients. The median increase in urine osmolality after desmopressin administration in ADPKD patients was less than in healthy controls.Already early in their disease, ADPKD patients have impaired maximal urine concentrating capacity brought out upon dehydration, with no evidence of impaired hypothalamic response. To maintain fluid balance, vasopressin concentration increases, which is hypothesized to play a role in ADPKD disease progression.

UNLABELLED Factor XI deficiency is a rare bleeding disorder that is more commonly found in Ashkenazi Jews. Bleeding manifestations of this disorder are varied and poorly correlate with factor XI levels. Spontaneous bleeding is uncommon, whereas delayed postoperative bleeding is often the presentation of factor XI deficiency. To date, there are no standard recommendations for prophylactic treatment in women undergoing gynecologic surgery. Here, we review published cases of gynecological surgery in women with factor XI deficiency and discuss the risks and benefits of various therapeutic options. TARGET AUDIENCE Obstetricians And Gynecologists. LEARNING OBJECTIVES After participating in this activity, physicians should be better able to identify the pathophysiology of factor XI deficiency. Compare previous outcomes of prophylactic treatment in patients with factor XI deficiency undergoing gynecological surgery. Implement possible prophylactic therapies for patients with factor XI deficiency undergoing gynecological surgery.

In this single-center retrospective study, we evaluated the accuracy of laboratory tests in diagnosing acquired von Willebrand syndrome associated with lymphoproliferative disorders in 36 consecutive patients diagnosed at the University Hospital of Nantes, France. We also compared hemostatic treatments in the following groups: 21 patients with Waldenström macroglobulinemia (WM), 14 with monoclonal gammopathy of undetermined significance (MGUS) (10 with IgG-MGUS and 4 with IgM-MGUS), and 1 with IgA multiple myeloma (IgA-MM). The diagnosis was made in 18 (50%) patients during systematic screening, in 6 (17%) during active mild hemorrhage, and in 12 (33%) during an active, severe bleed. Of the laboratory tests studied, only closure times measured on the Platelet Function Analyzer (PFA)-100 device reliably diagnosed the hemostatic problem. There was no relationship between the factor VIII activity (FVIII:C) or von Willebrand factor activity (VWF:RCo) levels and the previous history of hemorrhage described by patients.We studied hemostatic treatment in most patients: IgG-MGUS patients responded well to high-dose intravenous immunoglobulin (IVIg) infusions (1 g/kg per d), although patients with IgM-MGUS did not. Desmopressin infusions were effective in 3 patients with IgG-MGUS and 2 patients with IgM-MGUS when the baseline values were above 10 IU/dL, but levels soon returned to the baseline. The 7 WM patients had a good response to desmopressin. These results confirm the efficacy of IVIg in IgG-MGUS patients and the prominent role of closure time in the diagnosis of acquired von Willebrand syndrome.

Desmopressin is a standard treatment for monosymptomatic nocturnal enuresis. Different formulations are promoted as bioequivalent, although these claims are not supported by comparative pharmacodynamic data in children. Food interaction is known to influence the bioavailability of desmopressin. We compared the pharmacodynamics of the 2 most frequently used desmopressin formulations, tablet and lyophilizate, with a standardized meal, allowing extrapolation to clinical reality, where the interval between evening meal and medication intake is limited for school-age children. We hypothesized there would be a faster pharmacodynamic response, and greater concentrating and antidiuretic activity for the fast dissolving (melt) formulation compared to the tablet with simultaneous food intake.Two tests were performed on separate days in identical standardized conditions, starting with a 15 ml/kg water load. After achieving maximal diluting capacity a standardized meal was administered, followed by desmopressin tablet (t test) or melt (M-test). Diuresis rate and urinary osmolality were measured hourly. Paired data from 4 girls and 15 boys with a mean age of 12.1 years were obtained.In the early response phase more than 25% of patients had a higher diuresis rate with tablet vs melt formulation, reaching statistical significance in the plateau phase (urine collected at hours 3 to 5, p0.02) and in duration of action (urine collected at hours 5 to 8, p0.005). For desmopressin melt smaller standard deviations in diuresis rate were remarkable. Concentrating capacity demonstrated no significant differences between formulations in the early response phase, in contrast to the plateau phase (p0.036) and duration of action (p0.001).With meal combination desmopressin melt formulation has a superior pharmacodynamic profile to tablet, making it more suitable for the younger age group with a limited interval between meal and drug administration.

Acquired von Willebrand syndrome (AVWS) usually mimics von Willebrand disease (VWD) type 1 or 2A. However, in rare cases, the characteristics of other VWD types can predominate in AVWS that might require careful consideration of differential treatment options. The diagnosis and the treatment of a case of type 2B-like AVWS are discussed. Diagnosis of AVWS was ascertained by determining ristocetin cofactor activity, ristocetin-induced platelet aggregation, von Willebrand factor antigen, collagen binding and characterization of von Willebrand factor (VWF) multimers. Inhibitor presence was sought through mixing experiments, the Bethesda method, and calculation of the in-vivo recovery and plasma half-life of VWF after administration of factor VIII/VWF concentrate. Mutations in the A1 domain of VWF were ruled out by sequencing of exon 28 of the VWF gene. A 34-year-old male patient, putatively diagnosed with type 2B VWD, and undergoing laparoscopic cholecystectomy, did not respond adequately to perioperative hemostatic treatment with desmopressin and high doses of factor VIII/VWF concentrate, requiring the administration of recombinant activated factor VII. Further diagnostic workup revealed AVWS mimicking type 2B VWD, most likely owing to an autoantibody developed in the course of underlying monoclonal gammopathy of undetermined significance. The presence of AVWS should be considered before a diagnosis of type 2B VWD is made, especially in patients with a history atypical for inherited disease.

We evaluated the long-term efficacy and safety of low dose oral desmopressin in elderly patients with benign prostatic hyperplasia with more than nocturnal voids and nocturnal polyuria more than 30% of total daily urine volume.Eligible patients with benign prostatic hyperplasia older than 65 years with nocturia, nocturnal polyuria and International Prostate Symptom Score 14 or greater were included in the study. All patients received placebo or 0.1 mg desmopressin orally at bedtime. Patients were required to visit the outpatient clinic from the first visit, and after 1, 3, 6 and 12 months of treatment. Patients maintained flow volume charts and used diaries to record voiding data throughout the study. During followup urinalysis, urine sodium, urine osmolality, serum electrolytes, prostate specific antigen, International Prostate Symptom Score, quality of life, transrectal ultrasonography of prostate, uroflowmetry and post-void residual urine volume were performed at each visit.A total of 115 patients were enrolled in the study and randomized as 58 in the placebo group and 57 in the desmopressin group. Desmopressin significantly decreased nocturnal urine output and the number of nocturia episodes, and prolonged the first sleep period (p0.01). Compared to before treatment desmopressin gradually decreased serum sodium and induced statistically but not clinically significant hyponatremia after 12 months of treatment. No serious systemic complications were found during medication.Low dose oral desmopressin is an effective and well tolerated treatment for nocturnal polyuria in the lower urinary tract symptoms of patients with benign prostatic hyperplasia. Long-term desmopressin therapy gradually decreases serum sodium and it might induce hyponatremia even in patients without initial hyponatremia. For long-term desmopressin administration serum sodium should be assessed carefully, at least at 1 week after treatment.

Background and Purpose— Minimizing hematoma growth in high-risk patients is an attractive strategy to improve outcomes after intracerebral hemorrhage. We tested the hypothesis that desmopressin (DDAVP), which improves hemostasis through the release of von Willebrand factor, improves platelet activity after intracerebral hemorrhage. Methods— Patients with reduced platelet activity on point-of-care testing alone (5), known aspirin use alone (1), or both (8) received desmopressin 0.4 μg/kg IV. We measured Platelet Function Analyzer-epinephrine (Siemens AG, Germany) and von Willebrand factor antigen from baseline to 1 hour after infusion start and hematoma volume from the diagnostic to a follow-up computed tomographic scan. Results— We enrolled 14 patients with of mean age 66.8±14.6 years, 11 (85%) of whom were white and 8 (57%) were men. Mean Platelet Function Analyzer-epinephrine results shortened from 192±18 seconds pretreatment to 124±15 seconds ( P =0.01) 1 hour later, indicating improved plate activity. von Willebrand factor antigen increased from 242±96% to 289±103% activity ( P =0.004), indicating the expected increase in von Willebrand factor. Of 7 (50%) patients who received desmopressin within 12 hours of intracerebral hemorrhage symptom onset, changes in hematoma volume were modest, −0.5 (−1.4 to 8.4) mL and only 2 had hematoma growth. One patient had low blood pressure and another had a new fever within 6 hours of desmopressin administration. Conclusions— Intravenous desmopressin was well tolerated and improved platelet activity after acute intracerebral hemorrhage. Larger studies are needed to determine its potential effects on reducing hematoma growth versus platelet transfusion or placebo. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00961532.

Protein phosphorylation is an important component of vasopressin signaling in the renal collecting duct, but the database of known phosphoproteins is incomplete. We used tandem mass spectrometry to identify vasopressin-regulated phosphorylation events in isolated rat inner medullary collecting duct (IMCD) suspensions. Using multiple search algorithms to identify the phosphopeptides from spectral data, we expanded the size of the existing collecting duct phosphoproteome database from 367 to 1187 entries. Label-free quantification in vasopressin- and vehicle-treated samples detected a significant change in the phosphorylation of 29 of 530 quantified phosphopeptides. The targets include important structural, regulatory, and transporter proteins. The vasopressin-regulated sites included two known sites (Ser-486 and Ser-499) present in the urea channel UT-A1 and one previously unknown site (Ser-84) on vasopressin-sensitive urea channels UT-A1 and UT-A3. In vitro assays using synthetic peptides showed that purified protein kinase A (PKA) could phosphorylate all three sites, and immunoblotting confirmed the PKA dependence of Ser-84 and Ser-486 phosphorylation. These results expand the known list of collecting duct phosphoproteins and highlight the utility of targeted phosphoproteomic approaches.

Background: Experimental studies of uncontrolled hemorrhage demonstrated that permissive hypotension (PH) reduces blood loss, but its effect on clot formation remains unexplored. Desmopressin (DDAVP) enhances platelet adhesion promoting stronger clots. We hypothesized PH and DDAVP have additive effects and reduce bleeding in uncontrolled hemorrhage. Methods: Rabbits (n = 42) randomized as follows: sham; normal blood pressure (NBP) resuscitation; PH resuscitation—60% baseline mean arterial pressure; NBP plus DDAVP 1 hour before (DDAVP NBP) or 15 minutes after beginning of shock (DDAVP T1 NBP); and PH plus DDAVP I hour before (DDAVP PH) or 15 minutes after beginning of shock (DDAVP T1 PH). Fluid resuscitation started 15 minutes after aortic injury and ended at 85 minutes. Intraabdominal blood loss was calculated, aortic clot sent for electron microscopy. Activated partial thromboplastin time, platelet count, thromboelastometry, arterial blood gases, and complete blood count were performed at baseline and 85 minutes. Analysis of variance was used for comparison. Results: NBP received more fluid volume and had greater intraabdominal blood loss. DDAVP, when administered preshock, significantly reduced blood loss in NBP and fluid requirement when given postshock. Platelets, arterial blood gas, complete blood count, and activated partial thromboplastin time were similar at 85 minutes. NBP delayed clot formation and worsened thrombodynamic potential on thromboelastometry, whereas PH and DDAVP improved. Electron microscopy showed lack of fibrin on NBP clots, whereas DDAVP and PH clots displayed exuberant fibrin/platelet aggregates. DDAVP NBP presented intermediate clots. Conclusion: PH reduced bleeding and improved hemostasis compared with normotensive resuscitation. DDAVP given preshock exerted similar effects with normotensive resuscitation.

In this national, multicenter, retrospective survey we tested whether structured withdrawal of desmopressin, in which dose frequency rather than dose quantity was gradually decreased, would improve outcome.Enrolled in the study were 487 monosymptomatic enuretic patients from a total of 181 centers (The Enuresis Algorithm of Marschall Survey Group). At study outset 41% of patients had 7 wet nights per week, 45% had 3 to 6 and 14% had fewer than 3. All patients were treated with desmopressin, which was abruptly terminated or tapered with analogue by a structured scheme. Response rates were compared in the groups according to International Children's Continence Society guidelines.The 173 children with abrupt termination had a 51% response rate, including a full and partial response in 44.1% and 27%, respectively, and no response in 22%. The 314 children with tapering had a 72% response rate, including a full and partial response in 66.8% and 24%, and no response in 4% (p0.0001). Enuresis frequency with abrupt termination decreased from 21 wet nights per month before treatment to 6. The tapering group had 21 wet nights per months before and 2 after treatment (p0.0001). Followup at 1 month showed fewer than 2 wet nights per month in 57% of cases with abrupt termination and in 80% with tapering (p0.0001). Pretreatment had no influence. No severe side effects occurred.This national, multicenter, retrospective analysis proves that antidiuretic treatment followed by a structured withdrawal program is superior to regular treatment with abrupt termination in enuretic children. Hence, desmopressin followed by structured withdrawal should be the standard. It is also superior to published outcomes of alarm treatment.

This review examines the science and methodology of blood conservation in modern anaesthetic and surgical practice. Blood transfusion is associated with increased morbidity and mortality in all surgical patients, and the reduction or even elimination of transfusion has been and continues to be the subject of much research. Blood substitutes, despite extensive investigation, have not been proved successful in trials to date, and none have entered clinical practice. Pharmacological treatments include antifibrinolytic drugs (although aprotinin is no longer in clinical use), recombinant factor VIIa, desmopressin, erythropoietin and topical haemostatic agents, and the role of each of these is discussed. Autologous blood transfusion has recently fallen in popularity; however, cell salvage is almost ubiquitous in its use throughout Europe. Anaesthetic and surgical techniques may also be refined to improve blood conservation. Blood transfusion guidelines and protocols are strongly recommended, and repetitive audit and education are instrumental in reducing blood transfusion.

We performed a retrospective audit of cross-laboratory testing of desmopressin and factor concentrate therapy to assess the potential utility of supplementary testing using the PFA-100 with functional von Willebrand factor (VWF) activity testing. Data were evaluated for a large number of patients with von Willebrand disease of type 1, type 2A or type 2M, as well as a comparative subset of individuals with haemophilia or carriers of haemophilia. Laboratory testing comprised pre and postdesmopressin, or pre and postconcentrate, evaluation of factor VIII, VWF antigen (VWF:Ag) and VWF ristocetin cofactor activity as traditionally performed, supplemented with collagen-binding (VWF:CB) testing and PFA-100 closure times. In brief, both therapies tended to normalize VWF test parameters and closure times in individuals with type 1 von Willebrand disease, with the level of correction in closure times related to the level of normalization of VWF, particularly the VWF:CB. However, although occasional correction of closure times was observed in patients with type 2A or type 2M von Willebrand disease, these did not in general normalize PFA-100 closure times either with desmopressin or factor concentrate therapy. In these patients, improvement in closure times was more likely in those in whom VWF:CB values normalized or when VWF:CB/VWF:Ag ratios normalized. This study confirms that there is a strong relationship between the presenting levels of plasma VWF and PFA-100 closure times, and that the supplementary combination of PFA-100 and VWF:CB testing might provide added clinical utility to current broadly applied testing strategies limited primarily to VWF:Ag, VWF ristocetin cofactor and factor VIII:coagulant. Future prospective investigations are warranted to validate these relationships and to investigate their therapeutic implications.

Trauma and emergency department clinicians encounter a growing number of patients admitted with traumatic head injury on prehospital antithrombotic therapies. These patients appear to be at increased risk of developing life-threatening intracranial hemorrhage. It is imperative that trauma clinicians understand the mechanism and duration of commonly prescribed outpatient antithrombotics in order to appropriately assess and treat patients who develop intracranial hemorrhage. This review summarizes current literature on the morbidity and mortality associated with premorbid non-steroidal anti-inflammatory drugs, aspirin, clopidogrel, warfarin, and heparinoids in the setting of traumatic head injury, and also examines the current strategies for reversal of these therapies.

Desmopressin is an evidence-based medicine level I, category A therapy for monosymptomatic nocturnal enuresis. However, in up to 40% of patients only partial desmopressin response is obtained. While the poor pharmacokinetic characteristics of the different available formulations may have a role in apparent therapy resistance, there are limited data available to support this theory. We sought to identify pharmacodynamic factors involved in partial desmopressin response or desmopressin resistance in children with monosymptomatic nocturnal enuresis, with special emphasis on concentrating performance, and time to reach and duration of maximal urine concentration.We evaluated 64 children with monosymptomatic nocturnal enuresis and proved nocturnal polyuria lacking full response to desmopressin treatment. The study involved 2 separate home based test days (A and B), each consisting of 9 timed urine collections starting in the evening 1 hour before desmopressin administration and continuing for 16 hours following desmopressin administration. Test A was done during fluid restriction, and test B was done during an oral fluid load.Under fluid restriction 16 patients failed to achieve urine concentration greater than 850 mOsmol/l at the midnight collection following desmopressin administration. After an oral fluid load given at the start of the test the majority of patients failed to reach maximal concentration of urine as voided during hydropenia, and 45 patients failed to regain appropriate dilution of urine even when an oral water load of 15 ml/kg (urine osmolality less than 750 mOsmol/l) was given in the morning at the end of the test. This finding is suggestive of a prolonged duration of action of the drug.Pharmacodynamic tests reveal a suboptimal effect of desmopressin on urine concentration in a significant percentage of patients, which worsens when fluid is not restricted before desmopressin administration. Also the time to reach maximal antidiuretic effect and the duration of pharmacodynamic action show a wide range, requiring individualization of mode and time of administration. Our data demonstrate that a simple pharmacodynamic test as described may give important information on time of dosing, duration of action and influence of oral fluid intake, allowing individualization of therapy. Data also reveal that desmopressin should be administered at least 1 hour before bedtime, and that in case of therapy resistance a longer interval, up to 2 hours, might further reduce diuresis rate in the early night. Because of the documented prolonged action of desmopressin in some patients, increasing the dose without performing pharmacodynamic testing is no longer acceptable.

The mechanisms by which arginine vasopressin (AVP) exerts its antidiuretic and pressor effects, via activation of V2 and V1a receptors, respectively, are relatively well understood, but the possible associated effects on sodium handling are a matter of controversy. In this study, normal conscious Wistar rats were acutely administered various doses of AVP, dDAVP (V2 agonist), furosemide, or the following selective non-peptide receptor antagonists SR121463A (V2 antagonist) or SR49059 (V1a antagonist). Urine flow and sodium excretion rates in the next 6 h were compared with basal values obtained on the previous day, after vehicle treatment, using each rat as its own control. The rate of sodium excretion decreased with V2 agonism and increased with V2 antagonism in a dose-dependent manner. However, for comparable increases in urine flow rate, the V2 antagonist induced a natriuresis 7-fold smaller than did furosemide. Vasopressin reduced sodium excretion at 1 μg/kg but increased it at doses >5 μg/kg, an effect that was abolished by the V1a antagonist. Combined V2 and V1a effects of endogenous vasopressin can be predicted to vary largely according to the respective levels of vasopressin in plasma, renal medulla (acting on interstitial cells), and urine (acting on V1a luminal receptors). In the usual range of regulation, antidiuretic effects of vasopressin may be associated with variable sodium retention. Although V2 antagonists are predominantly aquaretic, their possible effects on sodium excretion should not be neglected. In view of their proposed use in several human disorders, the respective influence of selective (V2) or mixed (V1a/V2) receptor antagonists on sodium handling in humans needs reevaluation.

Background: Hemorrhage in trauma is a significant challenge, accounting for 30% to 40% of all fatalities, second only to central nervous system injury as a cause of death. However, hemorrhagic death is the leading preventable cause of mortality in combat casualties and typically occurs within 6 to 24 hrs of injury. In cases of severe hemorrhage, massive transfusion may be required to replace more than the entire blood volume. Early prediction of massive transfusion requirements, using clinical and laboratory parameters, combined with aggressive management of hemorrhage by surgical and nonsurgical means, has significant potential to reduce early mortality. Discussion: Although the classification of massive transfusion varies, the most frequently used definition is ten or more units of blood in 24 hrs. Transfusion of red blood cells is intended to restore blood volume, tissue perfusion, and oxygen-carrying capacity; platelets, plasma, and cryoprecipitate are intended to facilitate hemostasis through prevention or treatment of coagulopathy. Massive transfusion is uncommon in civilian trauma, occurring in only 1% to 3% of trauma admissions. As a result of a higher proportion of penetrating injury in combat casualties, it has occurred in approximately 8% of Operation Iraqi Freedom admissions and in as many as 16% during the Vietnam conflict. Despite its potential to reduce early mortality, massive transfusion is not without risk. It requires extensive blood-banking resources and is associated with high mortality. Summary: This review describes the clinical problems associated with massive transfusion and surveys the nonsurgical management of hemorrhage, including transfusion of blood products, use of hemostatic bandages/agents, and treatment with hemostatic medications. (Crit Care Med 2008; 36:[Suppl.]:S325-S339)

Udgivelsesdato: 2008-Jun PURPOSE: We correlated the circadian rhythm of plasma arginine vasopressin and urine output profile to desmopressin response, presence or absence of an enuretic episode, and age and gender in children with nocturnal enuresis. MATERIALS AND METHODS: We studied 125 children 6 to 17 years old (mean age 10.4 +/- 3 years) with monosymptomatic nocturnal enuresis. Circadian inpatient studies were performed with standardized fluid intake, 7 blood sampling times and 6 urine collection periods. Subsequently, nocturnal urine volume was measured at home by diaper weighing for 4 weeks in 78 patients (2 weeks without treatment followed by 2 weeks of dose titration from 20 to 40 mug desmopressin at bedtime). RESULTS: The circadian studies showed that all groups of patients had an attenuated arginine vasopressin rhythm, females generally had lower circadian plasma arginine vasopressin levels than males, desmopressin responders with enuresis during the study night had the largest nocturnal urine excretion rate and most pronounced arginine vasopressin deficiency, and nocturnal urine output was significantly greater during nights with enuresis than nights without. Part of this polyuria was caused by increased sodium excretion. The home recordings confirmed higher nocturnal urine volume on enuresis nights. CONCLUSIONS: In addition to providing further pathophysiological support for the role of a nocturnal arginine vasopressin deficiency behind nocturnal polyuria in a subset of patients with enuresis, the results emphasize the clinical value of estimating nocturnal urine production on wet nights before selecting a therapeutic modality.

Udgivelsesdato: 2008-Mar PURPOSE: We sought to evaluate the combination of the enuresis alarm and desmopressin in treating children with enuresis. MATERIALS AND METHODS: A retrospective analysis was performed on data from 423 children treated at our clinics with the enuresis alarm during the years 2000 to 2004. Frequency volume charts and desmopressin titration facilitated characterization of the participants using the current International Children's Continence Society standardization. Children were treated with the enuresis alarm as monotherapy before the addition of desmopressin, which commenced after 6 weeks in patients exhibiting inadequate response to alarm or after 2 weeks in patients experiencing multiple enuretic episodes per night or showing no indication of improvement. RESULTS: Of the initial population 315 children (74%) were treated only with alarm, of whom 290 became dry. A total of 108 children (26%) were treated with a combination of alarm and desmopressin, with 80 being cured. Children dry on alarm therapy were not different from those needing the addition of desmopressin in terms of demographics. Children dry on desmopressin plus alarm had higher average nocturnal urine production on wet nights (303 +/- 12 ml compared to 269 +/- 5 ml, p

Background and objectives: Adherence to therapeutic guidelines for the treatment of hyponatremia becomes difficult when water diuresis emerges during therapy. The objective of this study was to assess the effectiveness and safety of desmopressin acetate as a therapeutic agent to avoid overcorrection of hyponatremia and to lower the plasma sodium concentration again after inadvertent overcorrection. Design, setting, participants, & measurements: Retrospective chart review was conducted of all patients who were given desmopressin acetate during the treatment of hyponatremia during 6 yr in a 528-bed community teaching hospital. Results: Six patients (group 1) were given desmopressin acetate after the 24-h limit of 12 mmol/L had already been reached or exceeded; correction was prevented from exceeding the 48-h limit of 18 mmol/L in five of the six. Fourteen patients (group 2) were given desmopressin acetate in anticipation of overcorrection after the plasma sodium concentration had increased by 1 to 12 mmol/L. In all 14 patients who were treated with desmopressin acetate as a preventive measure, correction was prevented from exceeding either the 24- or 48-h limits. After desmopressin acetate was administered, the plasma sodium concentration of 14 of the 20 patients fell by 2 to 9 mmol/L. In all six group 1 patients and in five of the group 2 patients, the plasma sodium concentration was actively lowered again by the concurrent administration of desmopressin acetate and 5% dextrose in water; no serious adverse consequences from this maneuver were observed. Conclusion: Desmopressin acetate is effective in preventing and reversing inadvertent overcorrection of hyponatremia.

There is increasing evidence that a subgroup of patients with monosymptomatic nocturnal enuresis and nocturnal polyuria resistant to desmopressin may have an abnormal circadian rhythm of renal tubular sodium handling. The pathogenesis of this phenomenon remains to be elucidated. If the increased sodium excretion overnight results in desmopressin resistance, decreasing the sodium excretion overnight may result in subsequently better desmopressin response.We conducted a pilot study of the anti-enuretic and antidiuretic effects of desmopressin combined with 0.5 mg/kg furosemide daily in patients with desmopressin resistant nocturnal polyuria despite dietary sodium and protein restriction. Values were plotted against the reference frame of a desmopressin responsive enuresis group.Baseline values revealed significantly lower urinary osmolality and higher diuresis rate overnight compared to the reference population (monosymptomatic nocturnal enuresis desmopressin responders). Introduction of desmopressin resulted in normalization of nocturnal urinary osmolality. However, nocturnal polyuria persisted, despite reaching maximal urinary concentration overnight. Although protein and sodium restriction resulted in a significant decrease in urinary osmolality and diuresis rate, the difference was not clinically important enough to reach normal values or to achieve continence. Furosemide in the morning resulted in a significant increase in diuresis and osmotic and sodium excretion during the day, and decreased nighttime diuresis and osmotic excretion. In 9 of 12 patients the nocturnal antidiuretic effect resulted in an anti-enuretic effect, defined as enuresis less than 1 wet night per month. In 3 patients insufficient anti-enuretic effects were obtained despite significant antidiuresis.This pilot study clearly demonstrates that introduction of early morning furosemide results in a significantly lower nocturnal diuresis rate. Reduced diuresis associated with unchanged urinary osmolality results in decreased nocturnal osmotic excretion in compensation for increased osmotic (sodium) excretion during the daytime.

Monosymptomatic polyuric nocturia is a consequence of aging. We investigated physiological differences between nonpolyuric and polyuric nocturia in the elderly population in relation to urine production regulation in young volunteers with special reference to gender.We performed a study in 37 elderly healthy volunteers 65 years or older and 30 young healthy volunteers 20 to 40 years old who were hospitalized for 48 hours. Before admittance and during hospitalization fluid intake was standardized. The first 24 hours were at baseline conditions. On night 2 participants were given a single oral dose of desmopressin (0.4 mg). During 48 hours urine and blood samples were taken at predetermined time points to measure urine output and plasma arginine vasopressin levels.Elderly individuals with nocturnal polyuria had an inverted rhythm in urine output, which was restored after a single dose of desmopressin. There was an age related change in the circadian rhythm of arginine vasopressin secretion, which was associated with the presence or absence of nocturnal polyuria. A novel and unexpected finding was a decreased circadian rhythm of arginine vasopressin secretion in young women, similar to the pattern observed in elderly women but with a preserved decrease in nighttime urine production. Compensatory diuresis following the induction of temporary antidiuresis was markedly postponed in elderly participants.Age and gender related decreased arginine vasopressin secretion at night underscores the fact that other factors modulate urine production. The pharmacodynamics of desmopressin as an antidiuretic in the elderly population are different from those in young individuals.

We compared the remission of pediatric primary nocturnal enuresis in groups of children who used a physician advised practice plan vs a parent chosen alternative.Between January 2004 and January 2006 there were 119 patients with primary nocturnal enuresis enrolled in this prospective, nonrandomized study. For this study primary nocturnal enuresis was defined as wetting at night during sleep during any 6-month interval without any known causative problem. A total of 76 children received the physician advised treatment plan and used an alarm, oxybutynin, desmopressin, an elimination diet and a bowel program, as indicated. A total of 43 children received a parent chosen alternative treatment plan, which consisted of any single or combination of treatments involving an alarm, oxybutynin, desmopressin and an elimination diet or bowel program. Parents from each group completed an intake survey that measured functional bladder capacity using a 3-day home diary and they identified demographic variables. Followup occurred at 2 weeks and then monthly for 12 weeks to study end.We found that the probability of remission by the end of the study for the physician advised treatment group was significantly higher than that of the parent choice group (88% vs 29%, Kaplan-Meier curve p0.0001).The group of children who followed physician advised treatment for primary nocturnal enuresis showed significantly earlier remission of primary nocturnal enuresis than children who followed the parent choice treatment (25th percentile 2 vs 10 weeks).

Children with attention deficit hyperactivity disorder disproportionately experience voiding dysfunction and persistent nocturnal enuresis due to a combination of sphincter and detrusor overactivity and nocturnal polyuria. The different treatment approaches to nocturnal enuresis often fail in these patients. Therefore, we performed a prospective study to compare the efficacy of combination therapy with desmopressin and oxybutynin vs the tricyclic antidepressant imipramine in patients with attention deficit hyperactivity disorder who have nocturnal enuresis.A total of 54 patients with attention deficit hyperactivity disorder and nocturnal enuresis were randomly stratified into 2 groups. Demographic data on patient age and gender were identical in the 2 groups. Functional bladder symptoms were judged using the dysfunctional voiding symptoms survey. The initial dysfunctional voiding symptoms survey score was similar in the 2 groups. The total survey score was compared between the 2 groups in aggregate as well as specifically regarding the incidence of nocturnal enuresis following treatment.The first group consisted of 27 patients who received desmopressin and oxybutynin, and the second group of 27 was treated with imipramine. Of the 27 children in each group 23 (85%) received methylphenidate for attention deficit hyperactivity disorder. The mean +/- SD initial dysfunctional voiding symptoms survey score in groups 1 and 2 was 20.5 +/- 3.3 and 20.9 +/- 4.1, respectively. Following treatment the mean survey score decreased significantly in groups 1 and 2 (6.5 +/- 2.5 and 9.4 +/- 2.1, respectively, p0.001). However, between groups analysis showed that the dysfunctional voiding symptoms survey score was significantly lower in group 1 than in group 2 (mean 6.5 +/- 0.5 vs 9.6 +/- 0.4, p0.001). There was also a statistically significant decrease in the incidence of nocturnal enuresis in group 1 (survey question 2 score 0.9 +/- 0.2 vs 2.9 +/- 0.2).Our data show that there is a high incidence of voiding dysfunction in children with attention deficit hyperactivity disorder. Combination therapy with desmopressin and oxybutynin is a feasible, safe and effective treatment for nocturnal enuresis in these children.

Obesity continues to be a leading public health concern in the United States. Our previous studies have suggested that there is a high rate of obesity in children with dysfunctional voiding, especially nocturnal enuresis. We investigated the correlation between body mass index and the efficacy of treatment in obese patients.We evaluated retrospectively records from patients seen with a diagnosis of nocturnal enuresis or dysfunctional voiding between January 2004 and July 2005. Bladder and bowel symptoms and urinary diary data were evaluated, and body mass index percentile was determined. Response to treatment was evaluated and correlated with body mass index percentile.We evaluated 250 children, of whom 96 (38%) had nocturnal enuresis and 154 (62%) had dysfunctional voiding. Body mass index was normal in about half of the patients, and half were above the 85th percentile for body mass index. Patients with a body mass index above the 85th percentile had a reduced response to therapy. After treatment patients with a normal body mass index had a lower nocturnal accident frequency than those above the 85th percentile. Similarly, in those with voiding dysfunction the response rate was 65% in association with a normal body mass index vs 35% with a high body mass index. Furthermore, patients with a normal body mass index had a significantly higher rate of completing a urinary diary compared to those with a high body mass index.Obesity correlates with a lower voiding diary completion rate and lower efficacy of treatment in children with nocturnal enuresis or dysfunctional voiding.