Unravelling the effect of blood group on FVIII:C levels and response to DDAVP in 20 males with a single genotype (Twillingate Variant) causing Haemophilia A.

INTRODUCTION: The genetic variant responsible for haemophilia A (HA) significantly impacts endogenous coagulant factor VIII (FVIII:C) level, thus impacting DDAVP responsiveness. Blood group (BG) also impacts FVIII:C levels, but this is difficult to evaluate in a genetically heterogeneous population. Canada has a large cohort of mild-moderate HA due to a single point variant: c.6104T>C, p.Val2035Ala-the Twillingate variant. AIM: To evaluate the impact of BG on endogenous FVIII:C levels and DDAVP responsiveness in a single genotype of mild-moderate HA. METHODS: This was a retrospective, single-centre study. BG and FVIII:C levels were obtained for males with the Twillingate variant. One-hour absolute and fold increases in FVIII:C post-DDAVP were calculated. T-tests and Mann-Whitney U tests were used to compare FVIII:C levels and DDAVP challenge variables between individuals according to BGs (O vs. non-O). RESULTS: Twenty males were included. There were significant differences between BGs (O vs. non-O) in their lowest FVIII:C level at age <12 years (medians: 0.05 vs. 0.08 IU/mL; P = .05). Fifteen subjects underwent DDAVP challenges. Mean 1-h FVIII:C were 0.29 (O BG) versus 0.41 IU/mL (non-O BG); P = .04. There were no significant differences between BGs (O vs. non-O) in mean absolute FVIII:C increase (0.20 vs. 0.27 IU/mL; P = .10) and FVIII:C fold increase (3.3-fold vs. 3.8-fold; P = .51). CONCLUSION: In HA subjects with an identical genotype, BG significantly impacts baseline FVIII:C levels and FVIII:C levels post-DDAVP, but does not impact absolute and fold increases in FVIII:C with DDAVP.

Management of Microvascular Bleeding after On-Pump Cardiac Surgery in a Patient with Perioperative Diagnosis of Impairment of Platelet Responses to Adenosine Diphosphate: A Case Report and a Literature Review.

BACKGROUND: Impairment of platelet responses to adenosine diphosphate (ADP) is typified by mild to severe bleeding diathesis, easy bruising, excessive mucosal and post-operative bleeding. Patients lack full platelet activation and aggregation in response to ADP. Following research of the literature in Scopus, PubMed/MEDLINE, ScienceDirect, and the Cochrane Library, we report only 18 patients described to date with impaired platelet response to ADP, none of whom in the high bleeding-risk surgical setting or exploring potential therapeutic options. Data regarding population, putative genetic mutations, modes of inheritance, functional defects, and related clinical manifestations were retrieved from case series and case reports. CASE PRESENTATION: A 40-year-old woman was scheduled for on-pump cardiac surgery. Her past medical history included episodes of spontaneous mucocutaneous hemorrhages of the mild entity since childhood. Multiple electrode aggregometry (MEA, Multiplate® Roche Diagnostics, Rotkreuz, Switzerland) was used to evaluate platelet response to thrombin-activated peptide-6 (TRAP), arachidonic acid (ASPI), and ADP. An inadequate platelet aggregation induced using a high concentration of ADP with normal TRAP and ASPI tests was detected preoperatively. Therefore, intravenous desmopressin (DVVAP) 0.3 µg/kg body weight was administered to manage microvascular bleeding developed after weaning from cardiopulmonary bypass (CPB). CONCLUSIONS: Proper management of impaired platelet response to ADP requires a systematic assessment. The Multiplate analyzer is a valuable tool to promptly detect the disorder when a high clinical suspect is present and obtain insights during high bleeding-risk surgical procedures. DVVAP can be beneficial as first-line therapy in bleeding patients to improve platelet function.

Desmopressin (DDAVP) use in patients with von Willebrand disease: A single-centre retrospective review of test response and clinical outcomes.

INTRODUCTION: Peri-procedural management of von Willebrand disease (VWD) utilizes von Willebrand factor (VWF) concentrates or desmopressin (DDAVP) to increase VWF levels. DDAVP is safe, easily administered, and inexpensive. Currently, a consensus definition for adequate DDAVP response is lacking, and outcomes of peri-procedural DDAVP use in VWD patients are seldom reported. AIM: This single-centre retrospective review aims to characterize DDAVP-responsiveness and assess clinical outcomes of peri-procedural DDAVP use in VWD. PATIENTS AND METHODS: We reviewed records for all our adult VWD patients (age ≥18 years) who underwent DDAVP challenge testing between January 2007 and January 2022. DDAVP-responsiveness was assessed using six definitions. Bleeding outcomes following procedures covered by DDAVP were classified as excessive or expected bleeding. RESULTS: Eighty-four of 94 (89.4%) patients were DDAVP-responsive by our definition (1-h VWF Activity/Factor VIII ≥0.50 IU/mL). However, the proportion of DDAVP-responders varied from 53.2% to 91.5%, depending on the literature definition used. Ninety-nine procedures pre-treated with DDAVP were performed during the study period. Eighty-six (86.7%) procedures (31 major; 55 minor) were covered with only DDAVP ± tranexamic acid (TXA). Excessive bleeding occurred following 4/31 major procedures and 2/55 minor procedures (both performed in a single patient with a bleeding score of 16). When covered with DDAVP+Factor ± TXA, one each of 10 major and 3 minor procedures (performed in 2 patients with bleeding scores 15-16) resulted in post-procedural bleeding. CONCLUSIONS: Peri-procedural DDAVP prophylaxis appears to be effective among individuals with VWD. Beyond DDAVP-responsiveness, patient bleeding history and procedure invasiveness should be considered in determining suitability for DDAVP prophylaxis.

Laying the foundation for enhancing safety of desmopressin in older people: Validation of capillary blood sodium levels.

PURPOSE: We aim to make desmopressin a safe treatment option for (older) patients at risk for hyponatremia, by introducing a new way of sodium monitoring. The goal is to reduce the risk of hyponatremia, enhance patient safety and ultimately introduce self-monitoring of sodium levels. The first step in the aforementioned is to validate capillary sodium. MATERIALS AND METHODS: 100 randomly selected patients admitted to the urology department received a single finger prick to collect capillary blood (250 µl) in a lithium-heparin tube. Each patient acted as its own control for the capillary and venous blood sample. Venous and capillary plasma sodium were analyzed by indirect ion-selective electrode measurement. The primary outcome was the agreement between capillary and venous sodium measurements, measured by the intra-class correlation coefficient (ICC). RESULTS: One hundred paired blood samples were obtained of which four were excluded. There was no significant statistical difference observed between venous and capillary sodium (-0.23 mmol/L, p = 0.374). The ICC for single measures between capillary and venous sodium was 0.82 (95% confidence interval 0.75-0.88). Inter-method differences analyzed by a Bland-Altman plot and a Passing-Bablock regression did not reveal a statistically significant difference between both groups. CONCLUSIONS: We demonstrated that venous and capillary sodium levels are interchangeable, taken into account the inter- and intravariability between analyses. We provided the first step towards a simple and safe solution for frequent sodium monitoring through a minimal invasive capillary blood collection. The results are of direct clinical relevance to safely use desmopressin in (older) patients at risk.

Idiopathic partial central diabetes insipidus

ABSTRACT Diabetes insipidus is a rare disorder characterized by the inability to concentrate urine, which results in hypotonic urine and increased urinary volume. It may occur because of antidiuretic hormone deficiency or resistance to its action in the renal tubules. When there is a deficiency in the synthesis of antidiuretic hormones, diabetes insipidus is called central; when there is resistance to its action in the renal tubules, it is said to be nephrogenic. We report a case of idiopathic partial central diabetes insipidus and highlight the management and treatment of the disease.

Korean guideline of desmopressin for the treatment of nocturia in men.

PURPOSE: Nocturia is the most bothersome of lower urinary tract symptoms in men. Desmopressin, a synthetic analog of the human hormone vasopressin, has been used for the treatment of nocturia. However, the guidelines include varying recommendations for the use of desmopressin for the management of nocturia in men. Therefore, the Korean Urological Association (KUA) developed recommendations for desmopressin for the treatment of nocturia in men. MATERIALS AND METHODS: A rigorous systematic review was performed and Grading of Recommendations, Assessment, Development, and Evaluation methodology was used to rate the certainty of evidence for patient outcomes and to develop the evidence into recommendations. The steering group, guidelines development group, systematic review team, and external review group consisted of members of the Korean Continence Society, Korean Society of Geriatric Urological Care, and KUA, respectively, who were involved in the guidelines development process. RESULTS: The guidelines address the benefits, harms, patients' values and preferences, costs, and resources related to desmopressin by using a single clinical question: What is the effectiveness of desmopressin compared to that of placebo, behavior modification, or other pharmacological therapies? CONCLUSIONS: The guidelines development panel suggests desmopressin for men with nocturia instead of placebo, behavior modification, or alpha-blocker monotherapy (low certainty of evidence, weak recommendation). Additionally, the panel suggests desmopressin combination therapy with alpha-blockers for men with nocturia instead of alpha-blocker monotherapy or alpha-blocker combination therapy with anticholinergic agents (low certainty of evidence, weak recommendation).

Diagnostic Power of Bilateral Inferior Petrosal Sinus Sampling with Desmopressin in Paediatric Cushing's Disease

Objective: The aim of this study was to evaluate the diagnostic accuracy of bilateral inferior petrosal sinus sampling (BIPSS) with desmopressin for pediatric Cushing's disease (CD). Methods: We reviewed studies performed in children that evaluated the accuracy of BIPSS with desmopressin. Results: All included studies were case series of children with adrenocorticotropin hormone (ACTH)-dependent Cushing's syndrome. The overall accuracy of BIPSS before stimulation was 84.1% (37/44), and after stimulation it was 92.3% (36/39). The overall lateralizing accuracy of BIPSS was 50.0%. Conclusion: Considering that available evidence is limited, it appears that BIPSS with desmopressin stimulation is accurate for the diagnosis of pediatric CD, but its lateralizing accuracy is probably not suitable for pediatric clinical practice.

Diabetis insípida associada a holoprosencefàlia / Diabetes insípida asociada a holoprosencefalia / Diabetes insipidus associated with holoprosencephaly

Introducció. L’holoprosencefàlia és una malformació congènita greu que compromet estructures cerebrals situades ala línia mitjana. Per la seva localització, l’hipotàlem i lahipòfisi són estructures afectades sovint en aquesta entitat. La seva disfunció pot provocar trastorns de l’homeòstasii endocrinopaties com l’adípsia i la diabetis insípida.Cas clínic. Es presenta el cas d’una nena de 6 anys diagnosticada d’holoprosencefàlia als 9 mesos de vida. Consulta per somnolència i febre de 48 hores d’evolució i enl’exploració presenta signes de deshidratació. La mare refereix que no reclama ingesta hídrica tot i trobar-se deshidratada. Analíticament destaca deshidratació hipernatrèmica greu amb disfunció renal. A les 72 hores d’ingrés,després d’haver corregit les diselectrolitèmies i amb lapacient normohidratada, reapareix la hipernatrèmia ambpoliúria i osmolalitat urinària disminuïda. Es fa un test dedesmopressina que confirma la sospita diagnòstica de dèficit d’hormona antidiürètica associat a adípsia. S’instauratractament amb desmopressina i restricció hídrica amb elqual s’assoleix un bon control hidroelectrolític que esmanté en controls posteriors.Comentaris. Els pacients amb holoprosencefàlia tenen riscde presentar endocrinopaties per disfunció hipotalamohipofisiària. Per aquest motiu cal buscar-les activament encas de presentar-se la clínica clàssica de poliúria, hipernatrèmia i hipoosmolalitat urinària. (AU)

Introducción. La holoprosencefalia es una malformación congénitagrave que compromete estructuras cerebrales situadas en la líneamedia. Por su localización, el hipotálamo y la hipófisis son estructuras frecuentemente afectadas en esta entidad. Su disfunciónpuede generar trastornos de la homeostasis y endocrinopatíascomo la adipsia y la diabetes insípida.Caso clínico. Se presenta el caso de una niña de 6 años diagnosticada de holoprosencefalia a los 9 meses de vida. Consulta por somnolencia y fiebre de 48 horas de evolución y en la exploración físicadestacan signos de deshidratación. La madre refiere que no reclama ingesta hídrica pese a encontrarse deshidratada. Analíticamente destaca deshidratación hipernatrémica grave y disfunciónrenal. A las 72 horas de ingreso, corregidas las diselectrolitemias yencontrándose la paciente normohidratada, reaparece hipernatremia asociando poliuria e hipoosmolalidad urinaria. Se realiza untest de desmopresina que confirma la sospecha diagnóstica de déficit de hormona antidiurética asociado a adipsia. Se instaura tratamiento con desmopresina y restricción hídrica, alcanzando un buencontrol hidroelectrolítico que mantiene en controles posteriores.Comentarios. Los pacientes con holoprosencefalia tienen riesgo depresentar endocrinopatías por disfunción hipotálamo-hipofisaria.Por ese motivo es necesario buscarlas activamente en caso depresentarse la clínica clásica de poliuria, hipernatremia e hipoosmolalidad urinaria. (AU)

Introduction. Holoprosencephaly is a severe developmental defectthat compromise midline brain structures. Due to their location,the hypothalamus and the hypophysis are frequently involvedin this illness. Their dysfunction can lead to homeostatic andendocrine disorders such as thirst disturbances and diabetesinsipidus.Case report. Herein we report the case of a 6-year-old girl who wasdiagnosed with holoprosencephaly at 9 months old. She presentedwith a 48-hours history of somnolence and fever with signs of dehydration on examination. Her mother stated that despite beingdehydrated, she did not demand water intake. Laboratory evaluation revealed a severe hypernatremic dehydration with renal impairment. Seventy-two hours after admission, having successfullyattained fluid and electrolyte correction, she presented hypernatremia with polyuria and urine hypoosmolality. A desmopressin testwas performed confirming the suspected diagnosis of antidiuretichormone deficiency and adipsia. She responded well to desmopressin treatment and fluid restriction with restoration of serumelectrolytes, which remained within acceptable limits at follow-up.Discussion. Children with holoprosencephaly are at risk for endocrine disorders related to hypothalamic-pituitary dysfunction. It isimportant to rule out these disturbances if they present with theclassic triad of hypernatremia, polyuria and urine hypoosmolality. (AU)

Platelet function assessed by ROTEM®platelet in patients receiving antiplatelet therapy during cardiac and vascular surgery.

Patients undergoing coronary artery bypass graft (CABG) surgery or carotid endarterectomy (CEA) continue antiplatelet therapy perioperatively, which may increase bleeding risk. We aimed to investigate whether Rotational thromboelastometry (ROTEM®) platelet, a newly marketed platelet function analysis, would detect antiplatelet therapy in CABG and CEA patients; whether detection of reduced platelet function was associated with increased bleeding; and whether ex vivo desmopressin increased platelet function. We included 20 CABG patients continuing aspirin and 20 CEA patients continuing clopidogrel (n = 1) or clopidogrel and aspirin (n = 19). Platelet function was analyzed with ROTEM®platelet and light transmission aggregometry (LTA). According to the lower reference limit, ROTEM®platelet managed to detect aspirin, but clopidogrel detection was inadequate compared to LTA. Using a previously published cut-off for bleeding risk, 6 (30%) patients receiving aspirin and 4 (21%) patients receiving both clopidogrel and aspirin demonstrated platelet function below this cut-off. One of the four CEA patients below the cut-off died from intracerebral hemorrhage postoperatively. CABG patients below (n = 6) and above (n = 14) the cut-off did not differ in chest tube output (median [range]: 373 ml [250-900] vs. 368 ml [195-820]). Ex vivo addition of desmopressin did not increase platelet function. In conclusion, ROTEM®platelet does reveal aspirin treatment whereas clopidogrel treatment is most often overlooked. Due to low bleeding in the study population, it was not possible to conclude on the association with bleeding risk.

Otorhinolaryngological adverse effects of urological drugs

ABSTRACT Purpose: To describe the otorhinolaryngological adverse effects of the main drugs used in urological practice. Materials and Methods: A review of the scientific literature was performed using a combination of specific descriptors (side effect, adverse effect, scopolamine, sildenafil, tadalafil, vardenafil, oxybutynin, tolterodine, spironolactone, furosemide, hydrochlorothiazide, doxazosin, alfuzosin, terazosin, prazosin, tamsulosin, desmopressin) contained in publications until April 2020. Manuscripts written in English, Portuguese, and Spanish were manually selected from the title and abstract. The main drugs used in Urology were divided into five groups to describe their possible adverse effects: alpha-blockers, anticholinergics, diuretics, hormones, and phosphodiesterase inhibitors. Results: The main drugs used in Urology may cause several otorhinolaryngological adverse effects. Dizziness was most common, but dry mouth, rhinitis, nasal congestion, epistaxis, hearing loss, tinnitus, and rhinorrhea were also reported and varies among drug classes. Conclusions: Most of the drugs used in urological practice have otorhinolaryngological adverse effects. Dizziness was most common, but dry mouth, rhinitis, nasal congestion, epistaxis, hearing loss, tinnitus, and rhinorrhea were also reported. Therefore, doctors must be aware of these adverse effects to improve adherence to the treatment and to minimize damage to the health of patients.

Effect of desmopressin lyophilisate (MELT) plus anticholinergics combination on functional bladder capacity and therapeutic outcome as the first-line treatment for primary monosymptomatic nocturnal enuresis: A randomized clinical trial.

PURPOSE: To assess the efficacy of desmopressin plus anticholinergic combination therapy as first-line treatment for children with primary monosymptomatic nocturnal enuresis (PMNE) and to analyze this combination's effect on functional bladder capacity (FBC). MATERIALS AND METHODS: A total of 99 children with PMNE were prospectively enrolled from 2015 to 2019 and randomly allocated to a monotherapy group (n=49), with oral desmopressin lyophilisate (MELT) only; and a combination group (n=50), with desmopressin plus an anticholinergic (propiverine 5 mg). Efficacy and FBC were evaluated at 1 and 3 months after treatment initiation; the relapse rate was assessed at 6 months after treatment cessation. RESULTS: The combination therapy group showed a higher rate of complete response than the monotherapy group after 3 months of treatment (44.0% vs. 22.4%, p=0.002). A significant increase in mean FBC was observed only in the combination group, from 88.72±26.34 mL at baseline to 115.52±42.23 mL at 3 months of treatment (p=0.024). Combination therapy was significantly associated with treatment success at 3 months after treatment initiation (odds ratio [OR], 3.527; 95% confidence interval [CI], 1.203-6.983; p=0.011) and decreased risk of relapse at 6 months after treatment cessation (OR, 0.306; 95% CI, 0.213-0.894; p=0.021), by multivariable analysis. CONCLUSIONS: This study represents the first prospective, randomized controlled trial showing higher response rates and lower relapse rates with desmopressin plus anticholinergic combination therapy compared with desmopressin monotherapy as first-line treatment for children with PMNE.

Otorhinolaryngological adverse effects of urological drugs.

PURPOSE: To describe the otorhinolaryngological adverse effects of the main drugs used in urological practice. MATERIALS AND METHODS: A review of the scientific literature was performed using a combination of specific descriptors (side effect, adverse effect, scopolamine, sildenafil, tadalafil, vardenafil, oxybutynin, tolterodine, spironolactone, furosemide, hydrochlorothiazide, doxazosin, alfuzosin, terazosin, prazosin, tamsulosin, desmopressin) contained in publications until April 2020. Manuscripts written in English, Portuguese, and Spanish were manually selected from the title and abstract. The main drugs used in Urology were divided into five groups to describe their possible adverse effects: alpha-blockers, anticholinergics, diuretics, hormones, and phosphodiesterase inhibitors. RESULTS: The main drugs used in Urology may cause several otorhinolaryngological adverse effects. Dizziness was most common, but dry mouth, rhinitis, nasal congestion, epistaxis, hearing loss, tinnitus, and rhinorrhea were also reported and varies among drug classes. CONCLUSIONS: Most of the drugs used in urological practice have otorhinolaryngological adverse effects. Dizziness was most common, but dry mouth, rhinitis, nasal congestion, epistaxis, hearing loss, tinnitus, and rhinorrhea were also reported. Therefore, doctors must be aware of these adverse effects to improve adherence to the treatment and to minimize damage to the health of patients.

Desmopressin responsiveness by age in type 1 von Willebrand disease.

BACKGROUND: Patients with type 1 von Willebrand disease (VWD) undergo a desmopressin (DDAVP) responsiveness challenge at diagnosis to assess whether DDAVP reverses their coagulation deficits. Current practice assumes DDAVP responsiveness remains constant over the lifetime. In patients with type 1 VWD, VWF-related parameters increase with age. This study explores whether DDAVP responsiveness also differs with age in this population. METHODS: We conducted a retrospective chart review of 106 patients enrolled at our center since 1990. Our primary outcome was DDAVP responsiveness at 1 hour after DDAVP challenge. Locally weighted scatterplot smoothing fit and Spearman correlation coefficients were used to study the relationship between age and DDAVP responsiveness. For female participants, we used the Kruskal-Wallis test to compare absolute and relative changes in DDAVP responsiveness at various ages. RESULTS: We had 79 patients (56 female) with type 1 VWD with at least 1 DDAVP challenge. In women with type 1 VWD, the absolute change in DDAVP responsiveness did not vary significantly with age (VWF:antigen [Ag], -0.08, P = .56; VWF:ristocetin cofactor [RCo], -0.16, P = .26; low-molecular-weight component of factor VIII [FVIII:C], -0.01, P = .93), nor did the relative change in DDAVP responsiveness (VWF:Ag, -0.03, P = .86; VWF:RCo, -0.25, P = .09; FVIII:C, -0.14, P = .34). The data plot suggested a relationship. CONCLUSION: In women with type 1 VWD, DDAVP responsiveness may vary over the life cycle. Our exploratory findings are limited by our retrospective data, cross-sectional design, and small sample. Future studies should investigate the relationship between age and DDAVP responsiveness prospectively to evaluate whether there is clinical utility in rechallenging postpubertal female patients with type 1 VWD.

Cohort analysis of desmopressin effect on hematoma expansion in patients with spontaneous intracerebral hemorrhage and documented pre-ictus antiplatelet use.

Antiplatelet therapy at the time of spontaneous intracerebral hemorrhage (sICH) may increase risk for hemorrhage expansion and mortality. Current guidelines recommend considering a single dose of desmopressin in sICH associated with cyclooxygenase-1 inhibitors or adenosine diphosphate receptor inhibitors. Adult subjects with sICH and concomitant antiplatelet therapy admitted to a large, tertiary care center were included. We sought to compare the risk of hematoma expansion in patients that received desmopressin for antiplatelet reversal in the setting of sICH to similar patients that did not receive desmopressin. The primary outcomes were the incidence of relative and absolute hematoma expansion. In total, 71 patients (29 received desmopressin, 42 did not receive desmopressin) were analyzed. All patients in the desmopressin group received a 0.3 mcg/kg intravenous dose prior to hematoma expansion assessment. Relative hematoma expansion occurred in 5/29 (17%) with desmopressin compared to 11/42 (26%) without desmopressin (OR 0.59 [95% CI 0.18-1.92]). Absolute hematoma expansion occurred in 9/29 (30%) with desmopressin compared to 12/42 (28%) without desmopressin (OR 1.13 [95% CI 0.40-3.16]). Multiple logistic regression controlling for significant covariates did not reveal a significant effect of desmopressin on relative or absolute hematoma expansion (OR 0.65 [95% CI 0.18-2.43] and OR 1.55 [0.48-4.99], respectively). We failed to find evidence that desmopressin administration for antiplatelet reversal in sICH reduces the incidence of hematoma expansion. Larger studies, focusing on the early phase of sICH, are needed to characterize the clinical efficacy and safety of desmopressin for antiplatelet reversal before widespread implementation.

Derivation and Validation of a Novel Risk Score to Predict Overcorrection of Severe Hyponatremia: The Severe Hyponatremia Overcorrection Risk (SHOR) Score.

BACKGROUND AND OBJECTIVES: Osmotic demyelination syndrome is the most concerning complication of severe hyponatremia, occurring with an overly rapid rate of serum sodium correction. There are limited clinical tools to aid in identifying individuals at high risk of overcorrection with severe hyponatremia. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We identified all patients who presented to a tertiary-care hospital emergency department in Ottawa, Canada (catchment area 1.2 million) between January 1, 2003 and December 31, 2015, with serum sodium (corrected for glucose levels) <116 mmol/L. Overcorrection was determined using 14 published criteria. Latent class analysis measured the independent association of baseline factors with a consensus overcorrection status on the basis of the 14 criteria, and was summarized as a risk score, which was validated in two cohorts. RESULTS: A total of 623 patients presented with severe hyponatremia (mean initial value 112 mmol/L; SD 3.2). The prevalence of no, unlikely, possible, and definite overcorrection was 72%, 4%, 10%, and 14%, respectively. Overcorrection was independently associated with decreased level of consciousness (2 points), vomiting (2 points), severe hypokalemia (1 point), hypotonic urine (4 points), volume overload (-5 points), chest tumor (-5 points), patient age (-1 point per decade, over 50 years), and initial sodium level (<110 mmol/L: 4 points; 110-111 mmol/L: 2 points; 112-113 mmol/L: 1 point). These points were summed to create the Severe Hyponatremic Overcorrection Risk (SHOR) score, which was significantly associated with overcorrection status (Spearman correlation 0.45; 95% confidence interval, 0.36 to 0.49) and was discriminating (average dichotomized c-statistic 0.77; 95% confidence interval, 0.73 to 0.81). The internal (n=119) and external (n=95) validation cohorts had significantly greater use of desmopressin, which was significantly associated with the SHOR score. The SHOR score was significantly associated with overcorrection status in the internal (P<0.001) but not external (P=0.39) validation cohort. CONCLUSIONS: In patients presenting with severe hyponatremia, overcorrection was common and predictable using baseline information. Further external validation of the SHOR is required before generalized use.

The effects of sampling lateralization on bilateral inferior petrosal sinus sampling and desmopressin stimulation test for pediatric Cushing's disease.

PURPOSE: Bilateral inferior petrosal sinus sampling (BIPSS) is useful for differential diagnosis of adult Cushing's disease (CD) but may not be so reliable in pediatric cases. The purpose of this study was to evaluate the sensitivity of BIPSS before and after desmopressin stimulation in pediatric CD, and to explore related factors of false-negative results and meanings of sampling lateralization. METHODS: We retrospectively analyzed 16 pediatric CD patients who underwent 17 BIPSS procedures from 2006 to 2017. CD was diagnosed if inferior petrosal sinus (IPS) to peripheral adrenocorticotropic hormone (ACTH) ratio was >2 at baseline or >3 after desmopressin stimulation. Sampling lateralization was yielded if interpetrosal sinus gradient was >1.4. Magnetic resonance imaging (MRI) was conducted. All the patients underwent surgery and the diagnosis was confirmed. RESULTS: The sensitivity was 64.7% (11/17) at baseline and 83.3% (10/12) after desmopressin stimulation. After stimulation, BIPSS reached its best sensitivity at 3 min. Sampling lateralization rate was 62.5% and 63.6% before and after stimulation, and the accordant rate with actual tumor lateralization was 50.0% and 42.9%, respectively. The accuracy of MRI in predicting the tumor lateralization was 80.0%. Sampling lateralization rate (81.8% in true-positive, 20.0% in false-negative, p = 0.036) and ACTH at dominant IPS (p = 0.001) was lower among false-negative patients. CONCLUSIONS: The sensitivity of BIPSS in pediatric CD was low at baseline, but increased after desmopressin stimulation. Sampling lateralization cannot accurately indicate the tumor lateralization, but the absence of sampling lateralization with low ACTH at IPS is a hint of false-negative cases in BIPSS.

Efficacy and Safety of SER120 Nasal Spray in Patients with Nocturia: Pooled Analysis of 2 Randomized, Double-Blind, Placebo Controlled, Phase 3 Trials.

PURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: 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 p <0.0001), 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 and <0.0001, 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. CONCLUSIONS: 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.

Comparison of Two Weight-Based Desmopressin Dosing Strategies for Spontaneous Bleeding.

BACKGROUND: The pharmacokinetics and pharmacodynamics of desmopressin are appropriate for adjusted body weight-based dosing, particularly in obese patients. OBJECTIVE: The objective of this study was to describe desmopressin dosing strategies, with emphasis on hemostatic outcomes among patients without preexisting bleeding disorders. METHODS: This was a single-center, retrospective cohort study of patients who received intravenous weight-based desmopressin for a hemostatic indication. Demographics, comorbidities, treatment setting, indication, site of bleeding, and outcomes were collected from the medical record. Primary outcomes included need for procedural intervention to achieve hemostasis, transfusion requirement, and death. Association between desmopressin dose and outcome was evaluated using χ2 or Fischer's exact tests and logistic and linear regression models. Multiple regression analysis was conducted to identify other predictors of outcome in the data set. RESULTS: A total of 109 patients were included (n = 26, dose adjustment; n = 83, no dose adjustment). Baseline characteristics were well-matched between groups: mean (SD) age of 57.0 (13.5) years; mean (SD) Charlson Comorbidity Score of 6.5 (2.8); 37% were obese; 76% were critically ill; 81% were actively bleeding without differences in site of bleeding; and crude mortality was 39%. No differences in death, mean units of packed red blood cells transfused, or need for procedural hemostasis were observed between adjusted weight- and actual weight-based desmopressin dosing. CONCLUSIONS: When used adjunctively to blood product transfusion in actively bleeding patients, use of adjusted body weight-based desmopressin did not negatively affect clinical outcomes. More data are needed to confirm this dosing strategy.

Tumour lateralization in Cushing's disease by inferior petrosal sinus sampling with desmopressin.

BACKGROUND: Bilateral inferior petrosal sinus sampling (IPSS) with corticotropin-releasing hormone (CRH) is currently the gold standard in the diagnosis of Cushing's disease (CD) and has also been used in tumour lateralization. Our objective was to determine the diagnostic value and lateralization accuracy of IPSS with desmopressin. METHODS: We retrospectively analysed 91 patients with Cushing's syndrome who had either negative findings on pituitary dynamic enhanced magnetic resonance imaging (MRI) or nonsuppressed high-dose dexamethasone suppression tests (HDDST). Thin-slice thoracoabdominal computed tomography (CT) and octreotide receptor imaging of whole body were also negative to rule out ectopic adrenocorticotropin hormone (ACTH) syndrome. All patients went through IPSS with desmopressin. Afterwards, transsphenoidal pituitary surgery, light microscope pathology and immunohistological staining for ACTH were performed in all patients. RESULTS: Diagnosis of CD. Among the 91 patients included, 90 were confirmed with CD, of whom 89 had positive IPSS findings, therefore the sensitivity was 98.9%. The one patient who was negative for CD also had negative IPSS findings, therefore the specificity was 100%. Tumour lateralization. Among the 51 patients who were ultimately diagnosed with CD and whose lateralization by IPSS and surgery was either left or right, 37 had IPSS lateralization in concordance with surgery, therefore the concordance rate was 72.5%. Patients in the concordant group had a higher frequency of right lateralization by surgery. CONCLUSIONS: IPSS with desmopressin is a sensitive approach in the diagnosis of CD and has moderate accuracy in tumour lateralization, making it an alternative choice to IPSS with CRH.

Evaluation of Urinary Aquaporin 2 and Plasma Copeptin as Biomarkers of Effectiveness of Desmopressin Acetate for the Treatment of Monosymptomatic Nocturnal Enuresis.

PURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.