Single-dose Tadalafil Reduces Opening Urethral Pressure: A Randomized, Double-blind, Placebo-controlled, Crossover Trial in Healthy Women.

INTRODUCTION AND HYPOTHESIS: Phosphodiesterase enzymes are widely distributed in female urogenital tissues. Yet, the understanding of their physiological roles and the impact of phosphodiesterase inhibitors on lower urinary tract symptoms in women remains limited. Current hypotheses are conflicting: one suggests that vasodilation might expand the periurethral vascular plexus, leading to increased urethral pressure, whereas the other proposes a relaxation of urethral musculature, resulting in decreased pressure. To further clarify this, we investigated the effect of tadalafil on the opening urethral pressure and voiding function in healthy women. METHODS: We conducted a randomized, double-blind, placebo-controlled crossover trial involving 24 healthy women. Participants were randomly assigned to receive a single dose of tadalafil (40 mg) or placebo during their initial visit and then switched to the alternative treatment during their second visit. Opening urethral pressure was measured with urethral pressure reflectometry during both resting and squeezing conditions of the pelvic floor. Subsequently, voiding parameters were recorded. RESULTS: Compared with placebo, a single dose of tadalafil significantly reduced opening urethral pressure during both resting (-6.8 cmH20; 95% confidence interval [CI], -11.8 to -1.9; p = 0.009) and squeezing conditions (-8.8 cmH20; 95% CI, -14.6 to -3.1; p = 0.005). Voiding parameters did not show significant differences (average flow rate: -0.8 ml/s [95% CI, -2.0 to 0.4; p = 0.2]; maximum flow rate: -1.7 ml/s [95% CI, -4.8 to 1.5; p = 0.3]). CONCLUSIONS: A single dose of 40 mg tadalafil moderately reduced urethral pressure in healthy women, without affecting voiding parameters. The clinical implications of this are yet to be determined.

Octreotide improves human lymphatic fluid transport a translational trial.

OBJECTIVES: Chylothorax is a complex condition and many different pharmacological agents have been tried as treatment. Octreotide is used off-label to treat chylothorax, but the efficacy of octreotide remains unclear. A decrease in lymph production is suggested as the mechanism. In this cross-over study, we explore the direct effect of octreotide on human lymphatic drainage. METHODS: Pre-clinical: the effect of octreotide on force generation was assessed during acute and prolonged drug incubation on human lymphatic vessels mounted in a myograph. Clinical: in a double-blinded, randomized, cross-over trial including 16 healthy adults, we administered either octreotide or saline as an intravenous infusion for 2.5 h. Near-infrared fluorescence imaging was used to examine spontaneous lymphatic contractions and lymph pressure in peripheral lymphatic vessels and plethysmography was performed to assess the capillary filtration rate, capillary filtration coefficient and isovolumetric pressures of the lower leg. RESULTS: Pre-clinical: human thoracic duct (n = 12) contraction rate was concentration-dependently stimulated by octreotide with a maximum effect at 10 and 100 nmol/l in the myograph chamber. Clinical: spontaneous lymphatic contractions and lymph pressure evaluated by near-infrared fluorescence did not differ between octreotide or placebo (P = 0.36). Plethysmography revealed similar capillary filtration coefficients (P = 0.057), but almost a doubling of the isovolumetric pressures (P = 0.005) during octreotide infusion. CONCLUSIONS: Octreotide stimulated lymphatic contractility in the pre-clinical setup but did not affect the spontaneous lymphatic contractions or lymph pressure in healthy individuals. Plethysmography revealed a doubling in the isovolumetric pressure. These results suggest that octreotide increases lymphatic drainage capacity in situations with high lymphatic afterload.

Effect of single doses of citalopram and reboxetine on urethral pressure: A randomized, double-blind, placebo- and active-controlled three-period crossover study in healthy women.

AIMS: Urethral closure function is essential for urinary continence in women and decreased urethral pressure is associated with stress urinary incontinence (SUI). For decades, the effects of serotonergic drugs on central neural control of urethral closure have been investigated and discussed. Epidemiological studies suggest that the use of selective serotonin reuptake inhibitors (SSRIs), such as citalopram, is associated with SUI. However, the literature findings are conflicting. This study aimed to evaluate citalopram's effect on opening urethral pressure (OUP) in healthy women. METHODS: We conducted a randomized, double-blind, placebo- and active-controlled crossover study in 24 healthy women. On three study days, which were separated by 8 days of washout, the subjects received single doses of either 40 mg citalopram (and placeboreboxetine ), 8 mg reboxetine (and placebocitalopram ), or two placebos. Study drugs were administered at a 1-h interval due to a difference in estimated time to peak plasma concentration (tmax ). We measured OUP with urethral pressure reflectometry under both resting and squeezing conditions of the pelvic floor at estimated tmax for both study drugs (one timepoint). RESULTS: Compared to placebo, citalopram increased OUP by 6.6 cmH2 0 (95% confidence interval [CI] 0.04-13.1, p = 0.048) in resting condition. In squeezing condition, OUP increased by 7.1 cmH2 0 (95% CI: 1.3-12.9, p = 0.01). Reboxetine increased OUP by 30.0 cmH2 0 in resting condition compared to placebo (95% CI: 23.5-36.5, p < 0.001), and 27.0 cmH2 0 (95% CI: 21.2-32.8, p < 0.001) in squeezing condition. CONCLUSION: Citalopram increased OUP slightly compared to placebo suggesting that SSRI treatment does not induce or aggravate SUI.

High-Dose Glucagon Has Hemodynamic Effects Regardless of Cardiac Beta-Adrenoceptor Blockade: A Randomized Clinical Trial.

Background Intravenous high-dose glucagon is a recommended antidote against beta-blocker poisonings, but clinical effects are unclear. We therefore investigated hemodynamic effects and safety of high-dose glucagon with and without concomitant beta-blockade. Methods and Results In a randomized crossover study, 10 healthy men received combinations of esmolol (1.25 mg/kg bolus+0.75 mg/kg/min infusion), glucagon (50 µg/kg), and identical volumes of saline placebo on 5 separate days in random order (saline+saline; esmolol+saline; esmolol+glucagon bolus; saline+glucagon infusion; saline+glucagon bolus). On individual days, esmolol/saline was infused from -15 to 30 minutes. Glucagon/saline was administered from 0 minutes as a 2-minute intravenous bolus or as a 30-minute infusion (same total glucagon dose). End points were hemodynamic and adverse effects of glucagon compared with saline. Compared with saline, glucagon bolus increased mean heart rate by 13.0 beats per minute (95% CI, 8.0-18.0; P<0.001), systolic blood pressure by 15.6 mm Hg (95% CI, 8.0-23.2; P=0.002), diastolic blood pressure by 9.4 mm Hg (95% CI, 6.3-12.6; P<0.001), and cardiac output by 18.0 % (95% CI, 9.7-26.9; P=0.003) at the 5-minute time point on days without beta-blockade. Similar effects of glucagon bolus occurred on days with beta-blockade and between 15 and 30 minutes during infusion. Hemodynamic effects of glucagon thus reflected pharmacologic glucagon plasma concentrations. Glucagon-induced nausea occurred in 80% of participants despite ondansetron pretreatment. Conclusions High-dose glucagon boluses had significant hemodynamic effects regardless of beta-blockade. A glucagon infusion had comparable and apparently longer-lasting effects compared with bolus, indicating that infusion may be preferable to bolus injections. Registration Information URL: https://www.clinicaltrials.gov; Unique identifier: NCT03533179.

Effect of imipramine on urethral opening pressure: A randomized, double-blind, placebo-controlled crossover study in healthy women.

AIMS: In two open-label trials, imipramine alleviated symptoms in patients with stress urinary incontinence and is therefore used off-label for this indication. However, it has never been confirmed that imipramine increases urethral pressure in a placebo-controlled setting. The purpose of this study was to investigate whether imipramine increases the opening urethral pressure compared to placebo in healthy women using urethral pressure reflectometry. METHODS: A randomized, double-blind, placebo-controlled, crossover study in 16 healthy women. Opening urethral pressure was measured predose and 1 hour after a single dose of 50 mg imipramine or placebo. The washout period was minimum of 1 week. The study was approved by the local ethics committee, conducted according to the Good Clinical Practice guidelines, and registered on ClinicalTrials.gov and EudraCT before recruitment of subjects. Funding was provided by the clinical department. RESULTS: There were no dropouts and no serious adverse events. There were 13 adverse drug reactions related to imipramine in seven subjects, one adverse event related to placebo, and two adverse events related to the measurements with urethral pressure reflectometry. Imipramine compared to placebo increased opening urethral pressure in the resting condition with 6.5 cmH2 O (95% confidence interval [CI]: -0.5, 13.5), P = 0.07, and in the squeeze condition with 7.9 cmH 2 O (95% CI: -0.3, 16.1), P = 0.06. CONCLUSIONS: In conclusion, the increase in opening urethral pressure after imipramine treatment compared to placebo was neither statistically significant nor clinically relevant, and we do therefore not recommend the off-label use of imipramine for the treatment of stress urinary incontinence.

Re-amputations and mortality after below-knee, through-knee and above-knee amputations.

INTRODUCTION: From January 2013, we changed the surgical strategy in our department and ceased to perform the through-knee amputation (TKA). The primary aim of this study was to investigate re-amputation rates ≤ 90 days after non-traumatic major lower-extremity amputations performed before and after this change of practice. Furthermore, we reported mortality before and after the change of practice. METHODS: All non-traumatic major lower-extremity amputations performed in a single centre in two study periods (before and after the change of practice); 2009-2012 (cohort A) and 2014-2015 (cohort B) were included. Re-amputations and all-cause mortality ≤ 90 days after the index amputations were analysed. RESULTS: Cohort A: Included 180 amputations with 27 below-knee amputations (BKA), 68 TKAs and 85 above-knee amputations (AKA). 86.7% of patients were American Society of Anesthesiologists (ASA) score 3-5. The re-amputation rate ≤ 90 days was 29.6% (95% confidence interval (CI): 12.7-47.3%) after BKA, 33.8% (95% CI: 22.7-45.3%) after TKA, 9.4% (95% CI: 2.9-15.1%) after AKA and 21.6% (95% CI: 15.6-27.6%) overall. The overall mortality ≤ 90 days was 35.2% (95% CI: 26.2-44.2%). Cohort B: Included 116 amputations with 21 BKA and 95 AKA. 92.7% of patients were ASA score 3-5. The re-amputation rate ≤ 90 days was 19.1% (95% CI: 7.7-40.0%) after BKA, 2.1% (95% CI: 0.6-7.4%) after AKA and 5.2% (95% CI: 2.4-10.8%) overall. The overall mortality ≤ 90 days was 32.8% (95% CI: 26.2-44.2%). CONCLUSIONS: The overall re-amputation rate ≤ 90 days following major lower-extremity amputation decreased significantly from 22% to 5% after cessation of the TKA procedures, but mortality remained unchanged. FUNDING: none. TRIAL REGISTRATION: not relevant.

Hyperkalemia is Associated with Increased 30-Day Mortality in Hip Fracture Patients.

Abnormal plasma concentrations of potassium in the form of hyper- and hypokalemia are frequent among hospitalized patients and have been linked to poor outcomes. In this study, we examined the prevalence of hypo- and hyperkalemia in patients admitted with a fractured hip as well as the association with 30-day mortality in these patients. A total of 7293 hip fracture patients (aged 60 years or above) with admission plasma potassium measurements were included. Data on comorbidity, medication, and death was retrieved from national registries. The association between plasma potassium and mortality was examined using Cox proportional hazards models adjusted for age, sex, and comorbidities. The prevalence of hypo- and hyperkalemia on admission was 19.8% and 6.6%, respectively. The 30-day mortality rates were increased for patients with hyperkalemia (21.0%, p < 0.0001) compared to normokalemic patients (9.5%), whereas hypokalemia was not significantly associated with mortality. After adjustment for age, sex, and individual comorbidities, hyperkalemia was still associated with increased risk of death 30 days after admission (HR = 1.93 [1.55-2.40], p < 0.0001). After the same adjustments, hypokalemia remained non-associated with increased risk of 30-day mortality (HR = 1.06 [0.87-1.29], p = 0.6). Hyperkalemia, but not hypokalemia, at admission is associated with increased 30-day mortality after a hip fracture.

Orthogeriatric Service Reduces Mortality in Patients With Hip Fracture.

INTRODUCTION: Orthogeriatric service has been shown to improve outcomes in patients with hip fracture. The purpose of this study is to evaluate the effect of orthogeriatrics at Bispebjerg University Hospital, Denmark. The primary outcome is mortality inhospital and after 1, 3, and 12 months for patients with hip fracture. The secondary outcome is mortality for home dwellers and nursing home inhabitants. MATERIALS AND METHODS: This is a retrospective clinical cohort study with an historic control group including all patients with hip fracture admitted from 2007 to 2011. Patients with hip fracture are registered in a local database, and data are retrieved retrospectively using the Danish Civil Registration Number. RESULTS: We included 993 patients in the intervention group and 989 patients in the control group. A univariate analysis showed only significantly decreased mortality inhospital 6.3% vs 3.1% (P = .009) after orthogeriatrics. However, when adjusting for age, gender, and American Society of Anaesthesiologists (ASA) score in a multivariate analysis, including all patients with hip fracture, we find significantly reduced mortality inhospital (odds ratio [OR] 0.35), after 30 [OR 0.66] and 90 days [OR 0.72] and 1 year [OR 0.79]). When using a univariate analysis for home-dwelling patients, we found significantly reduced mortality inhospital (8.3-2.0%, P < .0001), after 30 days (12.2-6.8%, P = .004) and 90 days (20.5-13.0%, P = .002). One-year mortality was not significant. Patients from nursing homes had no significant decreasing mortality at any point of time in the univariate analysis. CONCLUSION: We have shown significant decreases for inhospital, 30 day, 90 day, and 1-year mortality after implementation of orthogeriatric service at Bispebjerg Hospital when adjusting for age, gender, and ASA score. Future trials should include frail patients with other fracture types who can benefit from orthogeriatrics.

Daily number of fractures is associated with road temperature in an urban area.

INTRODUCTION: Different factors related to winter are known to influence the fracture incidence, but little is known about the effect of road surface temperature. This study examines the association between road surface temperature and the daily number of fractures in an urban area during two winters. MATERIAL AND METHODS: Retrospective data collection was conducted on all patients treated at Bispebjerg Hospital, Denmark, for a humeral, ankle, distal radius or hip fracture during the periods October to April 2009/2010 and 2010/2011. Patients were grouped according to age into the following categories: < 15, 15-30, 30-45, 45-60 and > 60 years. Data on road surface temperature (Tp.) were obtained from The Danish Road Directorate and grouped into the following categories: Days with Tp. > 0 °C, Tp. < 0 °C, Tp. > -5 °C, Tp. < -5 °C and ice alert (IA). RESULTS: A total of 4,892 patients (4,938 fractures) were treated during the study periods. The daily number of distal radius, humeral and ankle fractures increased significantly with decreasing road surface temperature and the presence of IA. For hip fractures no significant association was found. Decreasing temperature was associated with a significant decrease in the daily number of fractures for patients < 15 years, whereas patients > 30 years experienced a significant increase. CONCLUSION: Decreasing road temperature results in increased numbers of all fractures except hip fractures. Low temperatures is a risk factor for patients > 30 years and a protective factor for patients < 15 years. FUNDING: not relevant. TRIAL REGISTRATION: not relevant.

Preoperative factors associated with red blood cell transfusion in hip fracture patients.

INTRODUCTION: Red blood cell (RBC) transfusion is a frequently used treatment in patients admitted with a fractured hip, but the use remains an area of much debate. The aim of this study was to determine preoperative factors associated with the risk of receiving a red blood cell transfusion in hip fracture patients. METHOD: The study included 986 consecutive hip fracture patients (aged 60 years or above). The patients were identified from a database of all hip fracture patients admitted to Bispebjerg University Hospital. Data for the database are collected via chart review and data extraction from the hospitals laboratory system, public registries and from the Capital Region Blood Bank Database. RESULTS: Overall transfusion rate was 58.7 %. The univariate analyses showed that transfusion rate was higher among women (p = 0.004), older patients (p < 0.0001), patients with high ASA scores (p < 0.0001), patients with more severe fractures (p < 0.0001), patients with lower admission haemoglobin levels (p < 0.0001), patients not admitted from own home (p = 0.02) and patients taking aspirin (p = 0.007) or other platelet inhibitors (p = 0.01) on admission. In the multivariate analysis, increasing age, ASA ≥3, being admitted from own home, extracapsular fractures, decreasing admission haemoglobin and use of platelet inhibitors were all significantly associated with the risk of receiving a RBC transfusion. CONCLUSION: Several readily available preoperative factors in the form of age, residence, ASA, admission haemoglobin, medication and type of fracture were independently associated with the likelihood of receiving a red blood cell transfusion in patients admitted with a fractured hip.

Is mortality after hip fracture associated with surgical delay or admission during weekends and public holidays? A retrospective study of 38,020 patients.

BACKGROUND AND PURPOSE: Hip fractures are associated with high mortality, but the cause of this is still not entirely clear. We investigated the effect of surgical delay, weekends, holidays, and time of day admission on mortality in hip fracture patients. PATIENTS AND METHODS: Using data from the Danish National Indicator Project, we identified 38,020 patients admitted from 2003 to 2010. Logistic regression analysis was used to study the association between sex, age, weekend or holiday admission, night-time admission, time to surgery, and ASA score on the one hand and mortality on the other. RESULTS: The risk of death in hospital increased with surgical delay (odds ratio (OR) = 1.3 per 24 h of delay), ASA score (OR (per point added) = 2.3), sex (OR for men 2.2), and age (OR (per 5 years) = 1.4). The mortality rate for patients admitted during weekends or public holidays, or at night, was similar to that found for those admitted during working days. INTERPRETATION: Minimizing surgical delay is the most important factor in reducing mortality in hip fracture patients.

Secondary hyperparathyroidism and mortality in hip fracture patients compared to a control group from general practice.

INTRODUCTION: Previously, little attention has been paid as to how disturbances in the parathyroid hormone (PTH)-calcium-vitamin D-axis, such as secondary hyperparathyroidism (SHPT), relate to mortality amongst hip fracture patients. This study aimed to (1) determine if SHPT is associated with mortality in this group of patients, (2) investigate the association between serum (s-) PTH, s-total calcium, s-25-hydroxyvitamin D (s-25(OH)D) and mortality and (3) determine the prevalence of SHPT amongst hip fracture patients and a control group. METHOD: The study included 562 hip fracture patients (HF) (age ≥ 70 years) admitted to a Danish university hospital. The hip fracture patients were prospectively enrolled in a dedicated hip fracture database. Each hip fracture patient was exactly matched according to age and sex with two controls randomly chosen from a control population of 21,778 subjects who had s-PTH, s-total calcium and s-25(OH)D measured at the Copenhagen General Practitioners Laboratory after referral from their general practitioner. The control group (Con) thus consisted of 1124 subjects. RESULTS: General 1-year mortality: Con-female 8.4%, Con-male 15.3%, HF-female 24.6%, HF-male 33.3%, p<0.0001 (log rank). SHPT AND RELATED 1-YEAR MORTALITY: Con-no SHPT 8.9%, Con-SHPT 16.8%, HF-no SHPT 22.7%, HF-SHPT 34.9%, p<0.0001 (log rank). The mortality rates were higher for controls with SHPT (OR 2.06, 95% CI: 1.32-3.23), hip fracture patients without SHPT (OR 3.00, 95% CI: 2.14-4.20) and hip fracture patients with SHPT (OR 5.46, 95% CI: 3.32-8.97) compared to the controls without SHPT. PREVALENCE OF SHPT: Con 16%, HF 20%, p=0.09 (Chi-square). CONCLUSIONS: Our study clearly shows that SHPT is significantly associated with mortality in both hip fracture patients and the control group. In the multivariate Cox regression analysis, s-PTH and s-total calcium were both significantly associated with mortality, whereas s-25(OH)D was not associated with mortality in this analysis. Our study furthermore indicates that SHPT is almost equally prevalent amongst the hip fracture patients and the control group.

Value of routine blood tests for prediction of mortality risk in hip fracture patients.

BACKGROUND: There is a 5- to 8-fold increased risk of mortality during the first 3 months after a hip fracture. Several risk factors are known. We studied the predictive value (for mortality) of routine blood tests taken on admission. METHODS: 792 hip fracture patients were included prospectively; blood tests were taken on admission. Follow-up data on mortality were obtained from the civil registration system. Patients were divided into 2 groups based on whether they had survived at least 90 days after the hip fracture. To estimate which laboratory tests could be used to predict outcome, we used receiver operation characteristic (ROC) curves. RESULTS: 3-month mortality could be predicted with 69% accuracy from the level of plasma creatinine in standard admission blood tests. The mortality in patients with elevated levels of creatinine was almost 3-fold that of the patients with normal creatinine. Mortality was also associated with age, low blood hemoglobin, high plasma potassium, and low plasma albumin levels. INTERPRETATION: Our findings could be of use in identifying patients who might benefit from increased attention perioperatively.