Eastern Association for the Surgery of Trauma Multicenter Trial: Comparison of pre-injury antithrombotic use and reversal strategies among severe traumatic brain injury patients.

BACKGROUND: Trauma teams are often faced with patients on antithrombotic (AT) drugs, which is challenging when bleeding occurs. We sought to compare the effects of different AT medications on head injury severity and hypothesized that AT reversal would not improve mortality in severe traumatic brain injury (TBI) patients. METHODS: An Eastern Association for the Surgery of Trauma-sponsored prospective, multicentered, observational study of 15 trauma centers was performed. Patient demographics, injury burden, comorbidities, AT agents, and reversal attempts were collected. Outcomes of interest were head injury severity and in-hospital mortality. RESULTS: Analysis was performed on 2,793 patients. The majority of patients were on aspirin (acetylsalicylic acid [ASA], 46.1%). Patients on a platelet chemoreceptor blocker (P2Y12) had the highest mean Injury Severity Score (9.1 ± 8.1). Patients taking P2Y12 inhibitors ± ASA, and ASA-warfarin had the highest head Abbreviated Injury Scale (AIS) mean (1.2 ± 1.6). On risk-adjusted analysis, warfarin-ASA was associated with a higher head AIS (odds ratio [OR], 2.43; 95% confidence interval [CI], 1.34-4.42) after controlling for Injury Severity Score, Charlson Comorbidity Index, initial Glasgow Coma Scale score, and initial systolic blood pressure. Among patients with severe TBI (head AIS score, ≥3) on antiplatelet therapy, reversal with desmopressin (DDAVP) and/or platelet transfusion did not improve survival (82.9% reversal vs. 90.4% none, p = 0.30). In severe TBI patients taking Xa inhibitors who received prothrombin complex concentrate, survival was not improved (84.6% reversal vs. 84.6% none, p = 0.68). With risk adjustment as described previously, mortality was not improved with reversal attempts (antiplatelet agents: OR 0.83; 85% CI, 0.12-5.9 [p = 0.85]; Xa inhibitors: OR, 0.76; 95% CI, 0.12-4.64; p = 0.77). CONCLUSION: Reversal attempts appear to confer no mortality benefit in severe TBI patients on antiplatelet agents or Xa inhibitors. Combination therapy was associated with severity of head injury among patients taking preinjury AT therapy, with ASA-warfarin possessing the greatest risk. LEVEL OF EVIDENCE: Prognostic, level II.

Low Creatininuria due to Hyponatremia Is Reversible in Many Patients.

BACKGROUND: Chronic hyponatremia has been reported to be associated with low solute intake and low creatinine excretion (reflecting likely sarcopenia). We wanted to study the effect, on the long term, of correction of hyponatremia on solute and creatinine excretion in chronic SIADH. METHODS: We made a retrospective review of clinical and biochemical data of patients with euvolemic hyponatremia. We analyzed 24-h urine solute and creatinine excretion in volunteers with hyponatremia induced by dDAVP over 4 days, in 12 patients with chronic SIADH (>1 month) before and after a few days of SNa correction and in 12 patients (6 women and 6 men) before and after 3 months of SNa correction by a vaptan or urea. RESULTS: We confirm a low urine creatinine and solute excretion only in patients with chronic hyponatremia (>1 month). Correction of SNa (from 127 ± 2.3 mEq/L to 139 ± 2.8 mEq/L) for >3 months, in the 12 patients (mean age 58 ± 18), was associated with an increase in 24-h creatinine excretion (from 986 ± 239 to 1,238 ± 220 mg; p < 0.02) and in patients treated with a vaptan (n = 5) solute excretion increased from 656 ± 207 mmol/24 h to 960 ± 193 mmol/24 h (p < 0.02). Sodium excretion increased also in the 12 patients (from 100 ± 53 mEq/24 h to 169 ± 38 mEq/24 h; p < 0.01). CONCLUSION: Chronic hyponatremia (>1 month) is associated with a decrease in solute output (or intake) and in creatinine excretion. In many patients, these abnormalities are reversible in the long term.

Platelet dysfunction in patients with traumatic intracranial hemorrhage: Do desmopressin and platelet therapy help or harm?

BACKGROUND: Pre-injury anti-platelet use has been associated with increased risk of progression of traumatic intracranial hemorrhage (TICH) and worse outcomes. VerifyNow® assays assess platelet inhibition due to aspirin/clopidogrel. This study assesses the outcomes of patients with TICH and platelet dysfunction treated with desmopressin and/or platelets. METHODS: We performed a retrospective chart review of patients with mild TICH at a level 1 trauma center 1/1/2013-6/1/2016. Patients with documented platelet dysfunction who received desmopressin and/or platelets were compared to those who were untreated. Primary outcomes were progression of TICH and neurologic outcomes at discharge. RESULTS: Of 565 patients with a mild TICH, 200 patients had evidence of platelet dysfunction (a positive VerifyNow® assay). Patients had similar baseline demographics, injury characteristics, and rate of TICH progression; but patients who received desmopressin and/or platelets had worse Glasgow Outcomes Score at discharge. CONCLUSION: Treatment of patients with mild TICH and platelet dysfunction with desmopressin and/or platelets did not affect TICH progression but correlated with worse neurologic status at discharge.

Variability in Oral Desmopressin Dose Requirements in Children with Central Diabetes Insipidus.

There is inconsistency in the amount of oral desmopressin that children with central diabetes insipidus require. We investigated whether clinical characteristics influenced desmopressin dose requirements in 100 children with central diabetes insipidus. Extremely large doses were associated with acquired etiology (P = .04), greater body mass index z score, intact thirst, and additional pituitary hormone deficiencies (P < .001).

Desmopressin acetate the first sublingual tablet to treat nocturia due to nocturnal polyuria.

Introduction: Desmopressin was widely used to treat nocturnal polyuria in adults under the age of 65 due to the well-established risk of hyponatremia. Since the prevalence of nocturia increases with age, and with an aging population, those most affected were excluded from treatment. Recently, a new lower dose sublingual tablet formulation that optimizes the balance between efficacy and tolerability has been licensed for symptomatic treatment of nocturia due to idiopathic nocturnal polyuria in adults of any age, with the caveat of regular serum monitoring for those over 65. This newer formulation aims to achieve the same clinical outcomes as previous formulations while reducing the risk of hyponatremia.Areas covered: This review will look at the pharmacology of the newly formulated desmopressin and examine the results of the clinical trials that would support its treatment of adult nocturia with idiopathic nocturnal polyuria.Expert opinion: When reporting on the clinical efficacy of desmopressin on nocturia, it is important for clinical trials to publish their complete data on nocturnal and 24-hour urine voided volumes. Further research examining the physiological reasoning behind this gender-specific dosing for desmopressin and the optimal recommended treatment duration of desmopressin for those over 65 is needed.

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.

Desmopressin effects on bleeding during functional endoscopic sinus surgery on patients with chronic rhinosinusitis.

OBJECTIVE: In this study we aimed to determine whether Desmopressin (DDAVP) can alter bleeding and improves surgeon visual field and decrease operation time or lessen use of anesthesiology medication in a clinical trial study. METHOD: This study is a randomized clinical trial using the permuted block randomization method. 44 patients were enrolled in study and divided into two equal intervention-control groups. The intervention group received maximum dose of 0/2 micrograms per kg of DDAVP. In the control group, 30 min before the surgery, 100 ml of normal saline will be injected. RESULTS: The amount of bleeding was 517/17 cc in control group during surgery while it was 387/72 cc in group receiving DDAVP which is significantly lower. The satisfaction of surgeon regarding suitable visual field was 6/45 in control group while it was 3/77 in DDAVP receivers which is lower. CONCLUSION: It seems that intravenous DDAVP can reduce bleeding during surgery and offer an enhanced vision for surgeon during surgery but it has no potential efficacy on reduction of period of surgery and need for anesthesiology medication like remifentanil and isoflurane.

Pretreatment morning urine osmolality and oral desmopressin lyophilisate treatment outcome in patients with primary monosymptomatic enuresis.

PURPOSE: To determine the association between urine osmolality (Uosm) in patients with primary monosymptomatic enuresis (PMNE) and response to desmopressin (dDAVP) lyophilisate. METHODS: This was a prospective cohort study that included 419 children with enuresis seen in outpatient clinic between October 2017 and October 2019. Patient workup included symptom checklist, 48 h frequency/volume chart, kidney and bladder ultrasound, uroflow, urinalysis and culture, spot urine Ca/creatinine, and first-morning Uosm. Patients < 5 years, with secondary enuresis, or loss of follow-up were excluded. Oral dDAVP lyophilisate was recommended to all with PMNE and normal bladder capacity. After 1 month of therapy, initial success was assessed according to ICCS. Significant predictor variables for complete response were identified and analyzed using correlation coefficients and binary logistic regression. RESULTS: There were 48 patients with PMNE who received dDAVP and were followed for treatment success. Partial and complete responses were achieved for 14 (29.2%) and 20 cases (41.7%), respectively. Older age and lower Uosm were found to be significantly in favor of complete response to dDAVP lyophilisate, P = 0.007 and 0.033, respectively. ROC analysis determined the Uosm of ≤ 814 mOsm/kg as a cut-off value for complete success (sensitivity 65% and specificity 75%, AUC = 68.2%). The odds ratio for complete success for selected cut-off value was 5.57 (95% CI 1.588-19.551, P = 0.007). CONCLUSION: High pretreatment morning Uosm (> 814 mOsm/kg) might be suggestive of an alternative treatment to dDAVP lyophilisate in PMNE because of the higher risk of treatment failure.

Effect of perioperative desmopressin in cats with mammary carcinoma treated with bilateral mastectomy.

Perioperative administration of desmopressin has shown to significantly decrease rates of local recurrence and metastasis, and increase survival times in dogs with grade II and III mammary carcinomas. The objective of this study was to compare the oncologic outcome of cats with mammary carcinoma treated with bilateral mastectomy with or without perioperative administration of desmopressin. Medical records from nine veterinary institutions were searched to identify cats diagnosed with mammary carcinoma treated with bilateral mastectomy. Sixty cats treated with single-session or staged bilateral mastectomy were included. There were no significant differences in oncologic outcomes found between cats treated and not treated with desmopressin. No adverse effects were seen in any of the cats treated with perioperative desmopressin. Postoperative complications occurred in 18 cats (38.3%) treated with single-session bilateral mastectomy and in three cats (23.1%) treated with staged bilateral mastectomy (P = .48). Histologic grade and a modification of a proposed five-stage histologic staging system were both prognostic for disease-free interval. Incomplete histologic excision was associated with significantly increased rates of metastasis and tumour progression, and a shorter median survival time (MST). Cats that developed local recurrence also had a significantly shorter MST. The results of this study do not support the use of perioperative desmopressin to improve outcome when performing bilateral mastectomy for the treatment of mammary carcinoma in cats.

Achieving clinically meaningful quality of life benefits in nocturia takes time: Results from a long-term, multicenter phase 3 study of desmopressin in Japanese patients.

OBJECTIVES: To investigate the long-term efficacy, quality of life (QoL), and safety of desmopressin orally disintegrating tablets (ODTs) in Japanese patients with nocturia. METHODS: A long-term, multicenter phase 3 study was conducted that enrolled Japanese male and female patients with nocturia (NCT03051009). Male patients received desmopressin 25- or 50-µg ODTs, and female patients received desmopressin 25-µg ODTs for up to 1 year. The primary endpoint was safety. Secondary endpoints included change from baseline in number of nocturnal voids, time to first awakening to void, and QoL assessments (nocturia-specific zQoL [N-QoL], Insomnia Severity Index [ISI], and Hsu bother score). RESULTS: Overall, 503 patients were enrolled. Reductions from baseline in mean number of nocturnal voids were observed in all treatment groups from week 1 (-0.62 to -1.00), with improvements continuing through week 52 (-1.39 to -1.71). Changes from baseline above or approximating a clinically meaningful improvement were seen by week 52 in the disease-specific N-QoL total score (improved by 11.5-22.6), ISI (improved by -3.9 to -7.1), and Hsu bother scores (improved by -1.5 to -2.0). Adverse events (AEs) were reported in 54.9% of desmopressin-treated patients. Most AEs were mild or moderate in severity. CONCLUSIONS: Desmopressin ODTs (25 and 50 µg) demonstrated long-term efficacy, improved QoL, and were well tolerated in Japanese male and female patients with nocturia treated for up to 1 year. Clinically meaningful improvements in patients' QoL, assessed by N-QoL, sleep quality, and bother, occur later than objective symptom improvements, such as voids.

Desmopressin oral lyophilisate in young children: new insights in pharmacokinetics and pharmacodynamics.

OBJECTIVE: To study the pharmacokinetic (PK)/pharmacodynamic (PD) characteristics of desmopressin (dDAVP) oral lyophilisate in children below the age of 8 years with special emphasis on age-related and size-related differences in bioavailability. DESIGN: Open label, non-randomised, interventional PK and PD trial. SETTING: Single-centre study. PATIENTS: Children (age: 6 months to 8 years) with nocturnal polyuria, including both children with uropathy or nephropathy (glomerular filtration rate >60 mL/min/1.73 m²) and children (age: 5-8 years) with severe monosymptomatic nocturnal enuresis, who were unresponsive to treatment with 400 µg of the dDAVP tablet for at least 1 month. INTERVENTIONS: After a water load, dDAVP was administered sublingually as a single dose of oral lyophilisate. Subsequently, blood and urine samples were collected until 7 hours post-administration. MAIN OUTCOME MEASURES: Non-compartmental analysis of PK parameters was performed based on dDAVP concentrations in both plasma and urine. To evaluate the effect of dDAVP lyophilisate (PD parameters), the urinary concentration capacity (urine osmolality (mOsm/kg)) and antidiuretic effect (diuresis rate (mL/kg/h)) were calculated. RESULTS: The PK data support the need for size-dependent dosing in children. Body weight was shown to be a significant covariate for apparent clearance (CL/F) and apparent volume of distribution (Vd/F). A double absorption peak of dDAVP lyophilisate in the first 2 hours post-administration was demonstrated. CONCLUSIONS: For the first time, a double absorption profile of dDAVP lyophilisate was found in children, questioning extrapolation of bioequivalence from adults towards children. Moreover, the need for size-adapted dosing regimens of dDAVP lyophilisate in young children is indicated. TRIAL REGISTRATION NUMBER: NTC02584231.

A snake toxin as a theranostic agent for the type 2 vasopressin receptor.

Rationale: MQ1, a snake toxin which targets with high nanomolar affinity and absolute selectivity for the type 2 vasopressin receptor (V2R), is a drug candidate for renal diseases and a molecular probe for imaging cells or organs expressing V2R. Methods: MQ1's pharmacological properties were characterized and applied to a rat model of hyponatremia. Its PK/PD parameters were determined as well as its therapeutic index. Fluorescently and radioactively labeled MQ1 were chemically synthesized and associated with moderate loss of affinity. MQ1's dynamic biodistribution was monitored by positron emission tomography. Confocal imaging was used to observe the labeling of three cancer cell lines. Results: The inverse agonist property of MQ1 very efficiently prevented dDAVP-induced hyponatremia in rats with low nanomolar/kg doses and with a very large therapeutic index. PK (plasma MQ1 concentrations) and PD (diuresis) exhibited a parallel biphasic decrease. The dynamic biodistribution showed that MQ1 targets the kidneys and then exhibits a blood and kidney biphasic decrease. Whatever the approach used, we found a T1/2α between 0.9 and 3.8 h and a T1/2ß between 25 and 46 h and demonstrated that the kidneys were able to retain MQ1. Finally, the presence of functional V2R expressed at the membrane of cancer cells was, for the first time, demonstrated with a specific fluorescent ligand. Conclusion: As the most selective V2 binder, MQ1 is a new promising drug for aquaresis-related diseases and a molecular probe to visualize in vitro and in vivo V2R expressed physiologically or under pathological conditions.

Central diabetes insipidus caused by a pituitary stalk germinoma resembling infundibuloneurohypophysitis.

We report the case of a pituitary stalk germinoma initially misdiagnosed and treated as infundibuloneurohypophysitis (INH). A 27-year-old man presented with a 1-year history of polydipsia, polyuria, nycturia consistent with central diabetes insipidus and a hyperintense pituitary stalk lesion on MRI. A possible INH diagnosis was considered, after excluding other pathologies. Lesion biopsy was discarded at that time on the ground of a small target and the high risk of added morbidity. Oral desmopressin led to initial symptoms resolution but, in the following months, an anterior panhypopituitarism developed, in spite of appropriate treatment and, by that time, the brain MRI also revealed lesion growth, which prompted a biopsy recommendation. The pathology analysis revealed a germinoma. After chemotherapy and radiotherapy, there was complete disappearance of the pituitary lesion, but the panhypopituitarism persisted. In conclusion, this case highlights the importance and difficulty of precise diagnosis in the initial assessment of pituitary stalk lesions and the need for close monitoring of treatment response. Diagnostic reassessment and biopsy in atypical cases is the only path to achieve the correct diagnosis and treatment.

Rationale, design, and methods of electroencephalography-based investigation of the effects of oral desmopressin on improving slow-wave sleep time in nocturnal polyuria patients (the DISTINCT study): protocol for a single-arm, open-label, single-assignment trial.

BACKGROUND: Nocturia is one of the most bothersome lower urinary tract symptoms and often impairs sleep quality in the elderly. Although previous studies on nocturia have indicated that the successful treatment of nocturia improves sleep quality, most used questionnaires and activity devices to analyze sleep/wake patterns. Therefore, there is little information about the treatment effects of desmopressin on objective sleep quality. The aim of the DISTINCT study is to investigate the change in subjective and objective sleep quality using electroencephalography (EEG) and the Pittsburgh Sleep Quality Index (PSQI) after the administration of desmopressin in patients with nocturia due to nocturnal polyuria. METHODS: A total of 20 male patients, ≥65 years old, with nocturnal polyuria, defined as a nocturnal polyuria index (NPi) (nocturnal urine volume / 24 h urine volume) value ≥0.33, will participate in this study. The participants must have a nocturnal frequency of ≥2 and the first uninterrupted sleep period (FUSP) must occur within < 2.5 h. Desmopressin 50 µg per day will be orally administered before going to bed for 4 weeks. Urinary frequency volume charts (FVC) and EEG will be recorded prior to treatment and at 1 week and 4 weeks after the initiation of treatment. The PSQI will be completed before and 4 weeks after treatment. The primary endpoint is the change from baseline in the mean time of slow-wave sleep (sleep stages N3 and N4) at 4 weeks. The secondary endpoints include the change in the mean value of each sleep variable, the mean delta power during the FUSP, the correlation between nocturnal urinary frequency and slow-wave sleep time, and the change in PSQI score before and after treatment. DISCUSSION: The DISTINCT study will provide valuable evidence to indicate that oral desmopressin treatment for nocturnal polyuria prolongs the FUSP, resulting in the extension of slow-wave sleep time associated with sleep quality. TRIAL REGISTRATION: The Japan Registry of Clinical Trials ( jRCTs051190080 ). Registered 9 December, 2019.

Therapeutic challenges in the management of osmotic demyelination syndrome: A case report of a favorable outcome from a tertiary center.

RATIONALE: There is an increasing and compelling need for early recognition of features of osmotic demyelination syndrome (ODS), and a further attempt at correcting this even where presentation is late. PATIENT CONCERNS: A 49-year-old male admitted into the emergency department with a complaint of lethargy and severe hyponatremia, with subsequent ODS supervening on initial attempts at correction. DIAGNOSIS: Rapid rise in serum sodium concentration (121 mmol/L in 8 hours from a nadir of 101 mmol/L), concomitant deterioration in patient's conscious level support the diagnosis of ODS. INTERVENTION: Concomitant administration of 5% dextrose water with desmopressin with a therapeutic objective of gradual relowering of serum sodium concentration. OUTCOMES: Significant improvement in patients' conscious level and motor function with the commencement of sodium relowering therapy. The patient was eventually discharged home. LESSONS: Regardless of the temporal profile of neurologic sequelae following ODS due to hyponatremia, its worthwhile attempting initial sodium relowering with dextrose 5% and desmopressin and then monitoring of biochemical and neurologic markers.

Non-invasive Diagnostic Strategy in ACTH-dependent Cushing's Syndrome.

CONTEXT: Inferior petrosal sinus sampling (IPSS) is used to diagnose Cushing's disease (CD) when dexamethasone-suppression and CRH tests, and pituitary magnetic resonance imaging (MRI), are negative or give discordant results. However, IPSS is an invasive procedure and its availability is limited. OBJECTIVE: To test a noninvasive diagnostic strategy associated with 100% positive predictive value (PPV) for CD. DESIGN: Retrospective study. SETTING: Two university hospitals. PATIENTS: A total of 167 patients with CD and 27 patients with ectopic ACTH-syndrome investigated between 2001 and 2016. MAIN OUTCOME MEASURE(S): Performance of a strategy involving the CRH and desmopressin tests with pituitary MRI followed by thin-slice whole-body computed tomography (CT) scan in patients with inconclusive results. RESULTS: Using thresholds of a cortisol increase > 17% with an ACTH increase > 37% during the CRH test and a cortisol increase > 18% with an ACTH increase > 33% during the desmopressin test, the combination of both tests gave 73% sensitivity and 98% PPV of CD. The sensitivity and PPV for pituitary MRI were 71% and 99%, respectively. CT scan identified 67% EAS at presentation with no false-positives. The PPV for CD was 100% in patients with positive responses to both tests, with negative pituitary MRI and CT scan. The Negative Predictive Value was 100% in patients with negative responses to both tests, with negative pituitary MRI and positive CT scan. Using this strategy, IPPS could have been avoided in 47% of patients in whom it is currently recommended. CONCLUSIONS: In conjunction with expert radiologic interpretation, the non-invasive algorithm studied significantly reduces the need for IPSS in the investigation of ACTH-dependent Cushing's syndrome.

Pediatric Pharmacology of Desmopressin in Children with Enuresis: A Comprehensive Review.

Desmopressin is a synthetic analogue of the natural antidiuretic hormone arginine vasopressin. Over the years, it has been clinically used to manage nocturnal polyuria in children with enuresis. Various pharmaceutical formulations of desmopressin have been commercialized for this indication-nasal spray, nasal drops, oral tablet and oral lyophilizate. Despite the fact that desmopressin is a frequently prescribed drug in children, its use and posology is based on limited pediatric data. This review provides an overview of the current pediatric pharmacological data related to the different desmopressin formulations, including their pharmacokinetics, pharmacodynamics and adverse events. Regarding the pharmacokinetics, a profound food effect on the oral bioavailability was demonstrated as well as different plasma concentration-time profiles (double absorption peak) of the desmopressin lyophilizate between adults and children. Literature about maturational differences in distribution, metabolism and excretion of desmopressin is rather limited. Regarding the pharmacodynamics, formulation/dose/food effect and predictors of response were evaluated. The lyophilizate is the preferred formulation, but the claimed bioequivalence in adults (200 µg tablet and 120 µg lyophilizate), could not be readily extrapolated to children. Prescribing the standard flat-dose regimen to the entire pediatric population might be insufficient to attain response to desmopressin treatment, whereby dosing schemes based on age and weight were proposed. Moreover, response to desmopressin is variable, whereby complete-, partial- and non-responders are reported. Different reasons were enumerated that might explain the difference in response rate to desmopressin observed: different pathophysiological mechanisms, bladder capacity and other predictive factors (i.e. breast feeding, familial history, compliance, sex, etc.). Also, the relapse rate of desmopressin treatment was high, rendering it necessary to use a pragmatic approach for the treatment of enuresis, whereby careful consideration of the position of desmopressin within this treatment is required. Regarding the safety of the different desmopressin formulations, the use of desmopressin was generally considered safe, but additional measures should be taken to prevent severe hyponatremia. To conclude the review, to date, major knowledge gaps in pediatric pharmacological aspects of the different desmopressin formulations still remain. Additional information should be collected about the clinical relevance of the double absorption peak, the food effect, the bioequivalence/therapeutic equivalence, the pediatric adapted dosing regimens, the study endpoints and the difference between performing studies at daytime or at nighttime. To fill in these gaps, additional well designed pharmacokinetic and pharmacodynamic studies in children should be performed.

Perioperative management for patients with von Willebrand disease: Defining the optimal approach.

von Willebrand disease (VWD) is the most common inherited bleeding disorder characterised by a quantitative or qualitative deficiency in von Willebrand factor (VWF). During invasive surgical procedures, patients with VWD require additional treatment to maintain haemostasis; however, due to the complexity of VWD, there is a lack of consensus on the optimal management. In the perioperative period, patients are usually treated with VWF and factor FVIII (FVIII)-containing concentrates to provide an immediate haemostatic response to prevent excessive bleeding during both elective and emergency surgery. With the introduction of recombinant VWF (rVWF), there is a need for guidance on the use of the various VWF products in the perioperative period for all types of patients and surgeries. This review provides an overview of the current evidence for the surgical management of patients with VWD and, summarises the optimal treatment approach during the perioperative period, and highlights key unanswered questions and the research needed to address the evidence gaps.