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Background: Blood pressure (BP) control is far from optimal. Studies on factors influencing BP control in the elderly are limited, yet identification of factors contributing to the low rate of BP control is a prerequisite to improvement of clinical management.Objective: To evaluate the rate of BP control and the relationship between different clinical characteristics and BP control in treated hypertensive outpatients aged >/=65 years.Methods: The PAPY-65 Survey was a prospective cross-sectional survey conducted in primary care in Belgium in 2007. Participating primary-care physicians were required to include consecutive hypertensive patients aged >/=65 years and treated with antihypertensive drugs. Demographic and anthropometric data as well as data on cardiovascular risk factors and history were obtained. BP was measured in accordance with the European Society of Hypertension/European Society of Cardiology guidelines.Results: The mean+/-standard deviation (SD) age of the 1272 patients enrolled in the survey was 75+/-7 years; 702 (55%) patients were women. The mean+/-SD systolic/diastolic BP was 134/79+/-13/8mmHg. BP was normalized (reduced to <140/90mmHg, or <130/80 mmHg in patients with diabetes mellitus) in 617 (48.5%) patients overall and in 88 (24%) patients with diabetes (n=371). The majority of patients (921; 72%) were treated with two or more antihypertensive drugs. Both general obesity (body mass index >/=30 vs <25 kg/m[2]) and abdominal obesity were associated with lack of BP control (unadjusted odds ratio [OR] 2.988, 95% CI 2.200, 4.057 and OR 2.066, 95% CI 1.649, 2.588, respectively). Abdominal obesity was no longer related to BP control when adjusted for the presence of diabetes. Diabetes was strongly associated with lack of BP control only when a stringent definition of BP control (<130/80mmHg) was used. The combined presence of subclinical organ damage and a history of cardiovascular disease was associated with less uncontrolled BP (OR 0.62, 95% CI 0.48, 0.80).Conclusion: Compared with previous data in the elderly in Belgium, a clear improvement in BP control was observed, probably related to the use of more antihypertensive agents. The presence of diabetes, excess bodyweight and abdominal obesity were all associated with poor BP control. [ABSTRACT FROM AUTHOR]

The effects of 4 weeks of placebo on clinic and on ambulatory blood pressure, measured non-invasively using the Remler M 2000 portometer, were studied in 46 hypertensive patients who were included in three consecutive double-blind randomized placebo-controlled trials with antihypertensive drugs. Placebo significantly reduced clinic blood pressure, but had no significant effect on ambulatory blood pressure. [ABSTRACT FROM AUTHOR]

The effect of guanfacine (2 mg once daily) on ambulatory blood pressure was studied with the Remler M 2000 recorder in 16 elderly hypertensive patients during a randomized, double-blind, placebo-controlled, balanced, cross-over study. Guanfacine significantly reduced heart rate and systolic and diastolic ambulatory blood pressure. The antihypertensive effect was maintained over the whole recording period. Systolic and diastolic blood pressure variability was not changed by guanfacine, neither when defined as standard deviation or variation coefficient of the mean, nor when defined as the range between the highest and lowest ambulatory blood pressure, suggesting that blood pressure variability is unrelated to sympathetic nervous system activity. [ABSTRACT FROM AUTHOR]

Chronic administration of nadolol has been reported to reduce blood pressure either without or with a concomitant fall of renal blood flow. We therefore studied the effects of nadolol 80 mg once daily on ambulatory blood pressure, renal and systemic haemodynamics in patients with mild to moderate essential hypertension. Ten patients took part in this randomized, double-blind, placebo-controlled, crossover study, each phase of which lasted 4 weeks. Nadolol significantly reduced ambulatory blood pressure and heart rate, but had no effect on blood pressure variability. Cardiac output was significantly reduced by nadolol and total peripheral resistance increased but without reaching statistical significance. Despite the fall in blood pressure and cardiac output, renal blood flow and glomerular filtration rate remained unchanged. The fraction of cardiac output reaching the kidneys rose significantly and renal vascular resistance was significantly reduced. Body weight, urinary sodium excretion and urine flow rate remained unchanged. We conclude that nadolol 80 mg once daily lowers ambulatory blood pressure in patients with mild to moderate hypertension without impairment of renal blood flow, indicating a redistribution of cardiac output to the kidneys. The mechanism of the renal vasodilator effect of nadolol remains to be determined. [ABSTRACT FROM AUTHOR]

Objective: Intravenous (IV) fluid therapy is a known source of iatrogenic complications. Guideline implementation can be used to educate and guide physicians on adequate fluid management. In the emergency department (ED), a complex and interruption-driven environment, workload is high and active documentation is required to facilitate audits of fluid management quality., Patients and Methods: Fluid management was evaluated in the ED records of adult non-critically ill patients admitted to a tertiary care center before (PRE: 1/12/2016-31/3/2017) and after (POST: 1/12/2018-31/3/2019) implementation of an educational intervention aiming to optimize IV fluid therapy in November 2018. First, the appropriateness of the 24-hour IV maintenance fluid prescription was evaluated, as prescribed by the emergency physician. Second, factors associated with appropriate prescribing were assessed, as well as the quality of fluid management documentation practice. Prescription appropriateness and documentation quality were evaluated retrospectively using a structured audit instrument and additional review by experts., Results: A total of 237 patients (2.3%) were included in the PRE-intervention group and 253 patients (2.4%) in the POST-intervention group. The expert panel evaluated 214 prescriptions in 82.3% of patients (PRE: 99, POST: 115), and appropriateness increased significantly (19.2% vs. 61.2%, p=0.002). A higher odds of an appropriate IV maintenance fluid prescription was determined, attributed to the intervention (adjOR=2.580; 95% CI 1.363-4.884) and in patients having a prehospital intervention (adjOR=1.914, 95% CI 1.022-3.586). Appropriateness of fluid management documentation did not significantly improve after the implementation of the intervention (15.6% vs. 16.2%, p=0.858)., Conclusions: The IV fluid prescriptions' appropriateness was significantly higher after guideline implementation. However, documentation quality of fluid management was poor in the studied ED records. Active stewardship programs are warranted to further monitor fluid management quality in the ED.

Background: Acute myocardial infarction complicated by cardiogenic shock (AMI-CS) is associated with significant morbidity and mortality. Mechanical circulatory support (MCS) devices increase systemic blood pressure and end organ perfusion while reducing cardiac filling pressures., Methods and Results: The National Cardiogenic Shock Initiative (NCT03677180) is a single-arm, multicenter study. The purpose of this study was to assess the feasibility and effectiveness of utilizing early MCS with Impella in patients presenting with AMI-CS. The primary end point was in-hospital mortality. A total of 406 patients were enrolled at 80 sites between 2016 and 2020. Average age was 64±12 years, 24% were female, 17% had a witnessed out-of-hospital cardiac arrest, 27% had in-hospital cardiac arrest, and 9% were under active cardiopulmonary resuscitation during MCS implantation. Patients presented with a mean systolic blood pressure of 77.2±19.2 mm Hg, 85% of patients were on vasopressors or inotropes, mean lactate was 4.8±3.9 mmol/L and cardiac power output was 0.67±0.29 watts. At 24 hours, mean systolic blood pressure improved to 103.9±17.8 mm Hg, lactate to 2.7±2.8 mmol/L, and cardiac power output to 1.0±1.3 watts. Procedural survival, survival to discharge, survival to 30 days, and survival to 1 year were 99%, 71%, 68%, and 53%, respectively., Conclusions: Early use of MCS in AMI-CS is feasible across varying health care settings and resulted in improvements to early hemodynamics and perfusion. Survival rates to hospital discharge were high. Given the encouraging results from our analysis, randomized clinical trials are warranted to assess the role of utilizing early MCS, using a standardized, multidisciplinary approach.

Aims: Many clinical decision support systems trigger warning alerts for drug-drug interactions potentially leading to QT prolongation and torsades de pointes (QT-DDIs). Unfortunately, there is overalerting and underalerting because stratification is only based on a fixed QT-DDI severity level. We aimed to improve QT-DDI alerting by developing and validating a risk prediction model considering patient- and drug-related factors., Methods: We fitted 31 predictor candidates to a stepwise linear regression for 1000 bootstrap samples and selected the predictors present in 95% of the 1000 models. A final linear regression model with those variables was fitted on the original development sample (350 QT-DDIs). This model was validated on an external dataset (143 QT-DDIs). Both true QTc and predicted QTc were stratified into three risk levels (low, moderate and high). Stratification of QT-DDIs could be appropriate (predicted risk = true risk), acceptable (one risk level difference) or inappropriate (two risk levels difference)., Results: The final model included 11 predictors with the three most important being use of antiarrhythmics, age and baseline QTc. Comparing current practice to the prediction model, appropriate stratification increased significantly from 37% to 54% appropriate QT-DDIs (increase of 17.5% on average [95% CI +5.4% to +29.6%], p adj  = 0.006) and inappropriate stratification decreased significantly from 13% to 1% inappropriate QT-DDIs (decrease of 11.2% on average [95% CI -17.7% to -4.7%], p adj  ≤ 0.001)., Conclusion: The prediction model including patient- and drug-related factors outperformed QT alerting based on QT-DDI severity alone and therefore is a promising strategy to improve DDI alerting., (© 2022 British Pharmacological Society.)

Background: The quality of allergy documentation in electronic health records is frequently poor., Objective: To compare the usability of 3 graphical user interfaces (GUIs) for drug allergy documentation., Methods: Physicians tested 3 GUIs by means of 5 fictional drug allergy scenarios: the current GUI (GUI 0), using mainly free-text, and 2 new coded versions (GUI 1 and GUI 2) asking information on allergen category, specific allergen, symptom(s), symptom onset, timing of initial reaction, and diagnosis status with a semiautomatic delabeling feature. Satisfaction was measured by the System Usability Scale questionnaire, efficiency by time to complete the tasks, and effectiveness by a task completion score. Posttest interviews provided more in-depth qualitative feedback., Results: Thirty physicians from 7 different medical specialties and with varying degrees of experience participated. The mean System Usability Scale scores for GUI 1 (77.25, adjective rating "Good") and GUI 2 (78.42, adjective rating "Good") were significantly higher than for GUI 0 (56.58, adjective rating "OK") (Z, 6.27, P adj < .001 and Z, 6.62, P adj < .001, respectively). There was no significant difference in task time between GUIs. Task completion scores of GUI 1 and GUI 2 were higher than for GUI 0 (Z, 9.59, P adj < .001 and Z, 11.87, P adj < .001, respectively). Quantitative and qualitative findings were combined to propose a GUI 3 with high usability., Conclusions: The usability and quality of allergy documentation was higher for the newly developed coded GUIs with a semiautomatic delabeling feature without being more time-consuming., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

In clinical practice, many drug therapies are associated with prolongation of the QT interval. In literature, estimation of the risk of prescribing drug-induced QT prolongation is mainly executed by means of logistic regression; only one paper reported the use of machine learning techniques. In this paper, we compare the performance of both techniques on the same dataset. High risk for QT prolongation was defined as having a corrected QT interval (QTc) ≥ 450 ms or ≥ 470 ms for respectively male and female patients. Both conventional statistical methods (CSM) and machine learning techniques (MLT) were used. All algorithms were validated internally and with a hold-out dataset of respectively 512 and 102 drug-drug interactions with possible drug-induced QTc prolongation. MLT outperformed the best CSM in both internal and hold-out validation. Random forest and Adaboost classification performed best in the hold-out set with an equal harmonic mean of sensitivity and specificity (HMSS) of 81.2% and an equal accuracy of 82.4% in a hold-out dataset. Sensitivity and specificity were both high (respectively 75.6% and 87.7%). The most important features were baseline QTc value, C-reactive protein level, heart rate at baseline, age, calcium level, renal function, serum potassium level and the atrial fibrillation status. All CSM performed similarly with HMSS varying between 60.3% and 66.3%. The overall performance of logistic regression was 62.0%. MLT (bagging and boosting) outperform CSM in predicting drug-induced QTc prolongation. Additionally, 19.2% was gained in terms of performance by random forest and Adaboost classification compared to logistic regression (the most used technique in literature in estimating the risk for QTc prolongation). Future research should focus on testing the classification on fully external data, further exploring potential of other (new) machine and deep learning models and on generating data pipelines to automatically feed the data to the classifier used., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Rationale: Intravenous (IV) fluids are frequently involved in iatrogenic complications in hospitalized patients. Knowledge of IV fluids seems inadequate and is not covered sufficiently in standard medical education., Methods: Two surveys were developed, based on the 2016 British National Institute for Health and Care Excellence guideline 'IV fluid therapy in adults in hospital', to provide insight on the learning needs and expectations of physicians and nurses. Each survey focused on profession-specific practice and consisted of three parts: demographics, knowledge questions and evaluation of current habits. Physicians and nurses practicing in a Belgian university hospital were invited to complete the survey electronically, respectively, in January and May 2018., Results: A total of 103 physicians (19%) and 259 nurses (24%) participated. Although every indication for fluid therapy may require a specific fluid and electrolyte mixture, and hence, knowledge of their exact composition, most physicians and nurses did not know the composition of commonly prescribed solutions for IV infusion. Senior physicians did not score better than juniors did on questions concerning the daily needs of a nil-by-mouth patient. The availability of an IV fluid on the ward guides physicians to prescribe IV fluids (17%). Nurses (56%) feel they share responsibility in fluid management as they frequently intervene in urgent situations. More than half of participants (70% of physicians, 79% of nurses) indicated a need for additional information., Conclusions: A clear need for more structured information on IV fluids was identified. Both physicians and nurses struggle with fluid therapy. Continuing education on IV fluid management, emphasizing multidisciplinary collaboration, and monitoring evidence-based practice is essential to support the clinical decision process in daily practice., (© 2022 John Wiley & Sons Ltd.)

Objective: Evaluation of the effect of six optimization strategies in a clinical decision support system (CDSS) for drug-drug interaction (DDI) screening on alert burden and alert acceptance and description of clinical pharmacist intervention acceptance., Methods: Optimizations in the new CDSS were the customization of the knowledge base (with addition of 67 extra DDIs and changes in severity classification), a new alert design, required override reasons for the most serious alerts, the creation of DDI-specific screening intervals, patient-specific alerting, and a real-time follow-up system of all alerts by clinical pharmacists with interventions by telephone was introduced. The alert acceptance was evaluated both at the prescription level (i.e. prescription acceptance, was the DDI prescribed?) and at the administration level (i.e. administration acceptance, did the DDI actually take place?). Finally, the new follow-up system was evaluated by assessing the acceptance of clinical pharmacist's interventions., Results: In the pre-intervention period, 1087 alerts (92.0 % level 1 alerts) were triggered, accounting for 19 different DDIs. In the post-intervention period, 2630 alerts (38.4 % level 1 alerts) were triggered, representing 86 different DDIs. The relative risk forprescription acceptance in the post-intervention period compared to the pre-intervention period was 4.02 (95 % confidence interval (CI) 3.17-5.10; 25.5 % versus 6.3 %). The relative risk for administration acceptance was 1.16 (95 % CI 1.08-1.25; 54.4 % versus 46.7 %). Finally, 86.9 % of the clinical pharmacist interventions were accepted., Conclusion: Six concurrently implemented CDSS optimization strategies resulted in a high alert acceptance and clinical pharmacist intervention acceptance. Administration acceptance was remarkably higher than prescription acceptance., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

The nucleus tractus solitarius (NTS), paraventricular nucleus (PVN), and rostral ventrolateral medulla (RVLM) are the most targeted regions of central blood pressure control studies. Glutamate and gamma-aminobutyric acid (GABA) interact within these brain regions to modulate blood pressure. The brain renin-angiotensin system also participates in central blood pressure control. Angiotensin II increases blood pressure through the stimulation of angiotensin II type 1 (AT 1 ) receptors within the PVN and RVLM and attenuates baroreceptor sensitivity, resulting in elevated blood pressure within the NTS. Angiotensin II type 2 (AT 2 ) receptors in cardiovascular control centers in the brain also appear to be involved in blood pressure control and counteract AT 1 receptor-mediated effects. The current review is focused on the interaction of GABA with AT 1 and AT 2 receptors in the control of blood pressure within the RVLM, PVN and NTS. Within the NTS, GABA is released from local GABAergic interneurons that are stimulated by local AT 1 receptors and mediates a hypertensive response. In contrast, the local increase in GABA levels observed after AT 2 receptor stimulation within the RVLM, likely from GABAergic nerve endings originating in the caudal ventrolateral medulla, is important in the mediation of the hypotensive response. Preliminary results suggest that the hypertensive response to AT 1 receptor stimulation within the RVLM is associated with a reduction in GABA release. The current experimental evidence therefore indicates that GABA is an important mediator of brainstem responses to AT 1 and AT 2 receptor stimulation and that increased GABA release may play a role in hypertensive and hypotensive responses, depending on the site of action.

Objective: To investigate whether context-specific alerts for potassium-increasing drug-drug interactions (DDIs) in a clinical decision support system reduced the alert burden, increased alert acceptance, and had an effect on the occurrence of hyperkalemia., Materials and Methods: In the pre-intervention period all alerts for potassium-increasing DDIs were level 1 alerts advising absolute contraindication, while in the post-intervention period the same drug combinations could trigger a level 1 (absolute contraindication), a level 2 (monitor potassium values), or a level 3 alert (informative, not shown to physicians) based on the patient's recent laboratory value of potassium. Alert acceptance was defined as non-prescription or non-administration of the interacting drug combination for level 1 alerts and as monitoring of the potassium levels for level 2 alerts., Results: The alert burden decreased by 92.8%. The relative risk (RR) for alert acceptance based on prescription rates for level 1 alerts and monitoring rates for level 2 alerts was 15.048 (86.5% vs 5.7%; 95% CI 12.037-18.811; P < 0.001). With alert acceptance for level 1 alerts based on actual administration and for level 2 alerts on monitoring rates, the RR was 3.597 (87.6% vs 24.4%; 95% CI 3.192-4.053; P < 0.001). In the generalized linear mixed model the effect of the intervention on the occurrence of hyperkalemia was not significant (OR 1.091, 95% CI 0.172-6.919)., Conclusion: The proposed strategy seems effective to get a grip on the delicate balance between over- and under alerting., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aim: The nucleus tractus solitarii (NTS) densely expresses angiotensin II type 2 receptors (AT2R), which are mainly located on inhibitory gamma-aminobutyric acid (GABA) neurons. Central AT2R stimulation reduces blood pressure, and AT2R stimulation in the rostral ventrolateral medulla (RVLM), mediates a hypotensive response through a GABAergic mechanism. We aimed to test the hypothesis that an AT2R mediated inhibition of the GABA release within the NTS might be involved in this hypotensive response, by assessing possible alterations in blood pressure and heart rate, as well as in GABA levels in normotensive Wistar rats., Methods: In vivo microdialysis was used for measurement of extracellular GABA levels and for perfusion of the selective AT2R agonist, Compound 21, within the NTS. Our set-up allowed to determine simultaneously the excitatory glutamate dialysate levels. The mean arterial pressure and heart rate responses were monitored with a pressure transducer., Results: Local perfusion of Compound 21 into the NTS did not modify blood pressure and heart rate, nor glutamate and GABA levels compared to baseline concentrations. A putative effect was also not unmasked by concomitant angiotensin II type 1 receptor blockade with candesartan. Positive control experiments confirmed that the experimental set up had enough sensitivity to detect a reduction in GABA dialysate levels and blood pressure., Conclusion: The results did not provide evidence for a role of the AT2R within the NTS in the control of blood pressure, nor for an interaction with local GABAergic signaling in normotensive rats.

Aim: It is well-established that angiotensin II exerts a dampening effect on the baroreflex within the nucleus tractus solitarii (NTS), the principal brainstem site for termination of baroreceptor afferents and which is densely populated with gamma-aminobutyric acid (GABA)ergic neurons and nerve terminals. The present study was designed to investigate whether local release of GABA is involved in the effects mediated by local angiotensin II within the NTS., Methods: In vivo microdialysis was used for measurement of extracellular glutamate and GABA levels and for infusion of angiotensin II within the NTS of conscious normotensive Wistar rats. The mean arterial pressure (MAP) and heart rate response to local infusion of angiotensin II were subsequently monitored with a pressure transducer under anesthesia. The angiotensin II type 1 receptor (AT1R) antagonist, candesartan, was used to assess whether responses were AT1R dependent and the nitric oxide (NO) synthase inhibitor, N (ω)-nitro-L-arginine methyl ester (L-NAME), was used to assess the involvement of NO in the evoked responses by infusion of angiotensin II. The MAP and heart rate responses were monitored with a pressure transducer., Results: Local infusion into the NTS of angiotensin II induced a significant to ninefold significantly increase in extracellular GABA levels; as well as MAP was increased by 15 mmHg. These responses were both abolished by co-infusion of either, the angiotensin II type 1 receptor antagonist, candesartan, or the NO synthase inhibitor, L-NAME, demonstrating that the effect is not only AT1R dependent but also NO dependent. The pressor response to angiotensin II was reversed by co-infusion with the GABA A receptor antagonist, bicuculline. Local blockade of NO synthase decreased both, GABA and glutamate concentrations., Conclusion: Our results suggest that the AT1R mediated hypertensive response to angiotensin II within the NTS in normotensive rats is GABA and NO dependent. Nitric oxide produced within the NTS tonically potentiates local GABA and glutamate release.

Background: Worldwide, the burden of allergies-in particular, drug allergies-is growing. In the process of prescribing, dispensing, or administering a drug, a medication error may occur and can have adverse consequences; for example, a drug may be given to a patient with a documented allergy to that particular drug. Computerized physician order entry (CPOE) systems with built-in clinical decision support systems (CDSS) have the potential to prevent such medication errors and adverse events., Objective: The aim of this review is to provide a comprehensive overview regarding all aspects of CDSS for drug allergy, including documenting, coding, rule bases, alerts and alert fatigue, and outcome evaluation., Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed as much as possible and searches were conducted in 5 databases using CPOE, CDSS, alerts, and allergic or allergy as keywords. Bias could not be evaluated according to PRISMA guidelines due to the heterogeneity of study types included in the review., Results: Of the 3160 articles considered, 60 met the inclusion criteria. A further 9 articles were added based on expert opinion, resulting in a total of 69 articles. An interrater agreement of 90.9% with a reliability Κ=.787 (95% CI 0.686-0.888) was reached. Large heterogeneity across study objectives, study designs, study populations, and reported results was found. Several key findings were identified. Evidence of the usefulness of clinical decision support for drug allergies has been documented. Nevertheless, there are some important problems associated with their use. Accurate and structured documenting of information on drug allergies in electronic health records (EHRs) is difficult, as it is often not clear to healthcare providers how and where to document drug allergies. Besides the underreporting of drug allergies, outdated or inaccurate drug allergy information in EHRs poses an important problem. Research on the use of coding terminologies for documenting drug allergies is sparse. There is no generally accepted standard terminology for structured documentation of allergy information. The final key finding is the consistently reported low specificity of drug allergy alerts. Current systems have high alert override rates of up to 90%, leading to alert fatigue. Important challenges remain for increasing the specificity of drug allergy alerts. We found only one study specifically reporting outcomes related to CDSS for drug allergies. It showed that adverse drug events resulting from overridden drug allergy alerts do not occur frequently., Conclusions: Accurate and comprehensive recording of drug allergies is required for good use of CDSS for drug allergy screening. We found considerable variation in the way drug allergy are recorded in EHRs. It remains difficult to reduce drug allergy alert overload while maintaining patient safety as the highest priority. Future research should focus on improving alert specificity, thereby reducing override rates and alert fatigue. Also, the effect on patient outcomes and cost-effectiveness should be evaluated., (©Laura Légat, Sven Van Laere, Marc Nyssen, Stephane Steurbaut, Alain G Dupont, Pieter Cornu. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 07.09.2018.)

Objectives: Angiotensin II, glutamate and gamma-aminobutyric acid (GABA) interact within the rostral ventrolateral medulla (RVLM) and the paraventricular nucleus (PVN) modulating the central regulation of blood pressure and sympathetic tone. Our aim was to assess the effects of local angiotensin II type 2 receptor stimulation within the RVLM and the PVN on neurotransmitter concentrations and mean arterial pressure (MAP). Methods: In vivo microdialysis was used for measurement of extracellular glutamate and GABA levels and for local infusion of the angiotensin II type 2 receptor agonist Compound 21 in the RVLM and the PVN of conscious normotensive Wistar rats. The MAP response to local Compound 21 was monitored with a pressure transducer under anaesthesia. Angiotensin II type 2 receptor selectivity was assessed using the angiotensin II type 2 receptor antagonist PD123319; the GABA-A receptor antagonist bicuculline was used to assess the involvement of GABA-A receptors. Results: Infusion of Compound 21 (0.05 μg/μl/h) in the RVLM significantly increased GABA levels and lowered blood pressure. These effects were abolished by co-infusion with PD123319. No changes in neurotransmitter levels or effects on blood pressure were seen with PD123319 infusion alone. Co-infusion of bicuculline abolished the Compound 21 evoked decrease in MAP. Infusion of Compound 21 within the PVN did not change extracellular neurotransmitter levels nor MAP. Conclusion: Selective stimulation of angiotensin II type 2 receptor within the RVLM by local Compound 21 infusion reduces blood pressure and increases local GABA levels in normotensive rats. This hypotensive response requires functional GABA-A receptors, suggesting that GABAergic neurons are involved in the sympatho-inhibitory action underlying this hypotensive response.

Purpose: To identify the proportion of real-life patients with atrial fibrillation (AF) eligible for direct oral anticoagulant (DOAC) therapy, based on the inclusion and exclusion criteria used in the clinical studies and based on the officially approved indications as mentioned in the Summary of Product Characteristics (SmPC)., Methods: Data for this retrospective cross-sectional study was extracted from the UZ Brussel Stroke Registry, containing anonymized data of 2205 patients with a suspected stroke. Characteristics of patients with documented AF were compared with the patient characteristics in clinical trials and the approved indications in the SmPC., Results: Data of 468 patients with AF was analyzed. Based on the selection criteria of the clinical trials, significantly less patients were eligible for treatment with rivaroxaban compared to dabigatran etexilate (39.3 versus 47.6 %; p = 0.010), but not compared to apixaban (45.5 %; p = 0.055). Based on the indications and contraindications in the SmPC, significantly fewer patients were eligible for apixaban compared to dabigatran etexilate and rivaroxaban (62.0 % for apixaban, 72.9 % for dabigatran etexilate, and 75.6 % for rivaroxaban; p < 0.001 and p < 0.001, respectively). Significantly, more patients were eligible for DOAC therapy based on the indications and contraindications in the SmPC compared to the inclusion and exclusion criteria of the clinical trials (72.9 versus 47.6 %; p < 0.001 for dabigatran; 75.6 versus 39.3 %; p < 0.001 for rivaroxaban and 62.0 versus 45.5 %; p < 0.001 for apixaban)., Conclusion: When taking into account the selection criteria from the pivotal clinical trials with DOACs for stroke prevention in AF, less than half of real-life patients are eligible for therapy with one of the DOACs. However, the indications mentioned in the SmPCs of these drugs are less strict.

Objectives: The use of medication plays an important role in secondary stroke prevention and treatment of post-stroke comorbidities. The Collaborative Evaluation of Rehabilitation in Stroke across Europe (CERISE) was set up to investigate the inpatient stroke rehabilitation process in four centres, each in a different European country: Belgium, Germany, United Kingdom and Switzerland., Patients and Methods: Patients' medication use 5 years post-stroke was compared between countries. Focus was put on cerebrovascular secondary prevention, including (a) adequate antithrombotic treatment, (b) treatment of cardiovascular comorbidities and diabetes, and (c) the use of lipid-lowering drugs; as well as on the treatment of stroke-related disorders such as depression, anxiety and pain., Results: Medication data were available for 247 patients. Data about depression and anxiety were available for 233., Conclusion: There were no significant differences between the four centres in antithrombotic treatment and in the treatment of cardiovascular comorbidities and diabetes. However, significantly more patients from the UK were treated with lipid-lowering drugs compared to Belgian patients. Significant differences were also observed between the centres in the prevalence and treatment of depression. More Belgian patients suffered from depression compared to German patients and significantly more Belgian patients took antidepressants than patients in Germany. This was in contrast to the prevalence and treatment of anxiety and pain, for which no significant differences between the centres were seen. Related to pain treatment, it was observed that almost 40% of all patients suffering from pain, used no specific medication., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Introduction: Stroke is a major health problem with important morbidity and mortality. Various risk factors and cardiovascular medication groups are known to have an influence on stroke incidence, but less is known about the relation between medication use and stroke severity., Aim: To determine if relationships exist between the pre-stroke cardiovascular medication use and stroke severity., Methods: A retrospective study was conducted on a database with anonymized data of 1974 patients with a suspected stroke, admitted to the Universitair Ziekenhuis (UZ) Brussel. Stroke severity was quantified using the National Institute of Health Stroke Scale (NIHSS). Cardiovascular medication groups were first included in a multivariable linear regression model. Second, to obtain clinically interpretable results, all variables that were retained in the final linear regression model were introduced in a cumulative odds ordinal logistic regression model with proportional odds., Results: Angiotensin II receptor blockers (ARBs), statins, and antiarrhythmics were significantly associated with stroke severity at the 10 % α level in a multivariable linear regression model, suggesting a possible effect of these medication groups on stroke severity. Only pre-stroke statin use showed a significant relationship with the NIHSS score in the ordinal logistic regression model with an adjusted odds ratio of 0.740 (95 % CI 0.580-0.944; p = 0.015)., Conclusion: Pre-stroke use of statins is significantly associated with lower stroke severity. No significant relationship was detected between pre-stroke use of other medication groups and stroke severity, defined by the NIHSS score.

Objectives: Clinical decision support (CDS) systems are frequently used to reduce unwanted drug-drug interactions (DDIs) but often result in alert fatigue. The main objective of this study was to investigate whether a newly developed context-specific DDI alerting system would improve alert acceptance., Methods: A controlled pre-post intervention study was conducted in 4 departments in a university hospital. After a 7-month pre-intervention period, the new system was activated in the intervention departments, while the old system remained activated in the control departments. Post-intervention data was collected for a 7-month period., Results: A significant increase of the overall acceptance rate was observed between the pre- and post-intervention period (2.2% versus 52.4%; p<0.001) for the intervention departments and between the intervention and control departments (2.5% versus 52.4%; p<0.001) in the post-intervention period. There were no significant differences in acceptance rates between the pre- and post-intervention period in the control departments and also not between the control and intervention departments in the pre-intervention period., Conclusions: The improvement was probably related to several optimization strategies including the customization of the severity classification, the creation of individual screening intervals, the inclusion of context factors for risk assessment, the new alert design and the creation of a follow-up system. The marked increase in alert acceptance looks promising and should be further evaluated after hospital wide implementation. System aspects that require further optimization were identified and will be developed. Further research is warranted to develop context-aware algorithms for complex class-class interactions., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Community pharmacists have an important task in the follow-up of patients treated with antithrombotics. When delivering these medicines, pharmacists can encounter drug-related problems (DRPs) with substantial clinical and economic impact., Objective: To investigate the amount and type of antithrombotic related DRPs as well as how community pharmacists handled these DRPs., Setting: Belgian community pharmacies., Methods: MSc pharmacy students of six Belgian universities collected data about all DRPs encountered by a pharmacist during ten half days of their pharmacy internship. Data were registered about DRPs detected at delivery and in an a posteriori setting, when consulting the medical history of the patient. Classification of the DRP, cause of the DRP, intervention and result of the intervention were registered., Main Outcome Measure: Amount and type of antotrombitocs related DRPs occurring in community pharmacies, as well as how community pharmacists handled these DRPs., Results: 3.1 % of the 15,952 registered DRPs concerned antithrombotics. 79.3 % of these DRPs were detected at delivery and 20.7 % were detected a posteriori. Most antithrombotic-related DRPs concerned problems with the choice of the drug (mainly because of drug-drug interactions) or concerned logistic problems. Almost 80 % of the antithrombotic-related DRPs were followed by an intervention of the pharmacist, mainly at the patient's level, resulting in 90.1 % of these DRPs partially or totally solved., Conclusion: Different DRPs with antithrombotic medication occurred in Belgian community pharmacies. About 20 % was detected in an a posteriori setting, showing the benefit of medication review. Many of the encountered DRPs were of technical nature (60.7 %). These DRPs were time-consuming for the pharmacist to resolve and should be prevented. Most of the DRPs could be solved, demonstrating the added value of the community pharmacist as first line healthcare provider.

The type 2 angiotensin receptor (AT2R) has been suggested to counterbalance the type 1 angiotensin receptor (AT1R) in the central regulation of blood pressure and sympathetic tone. In the present study we investigated the blood pressure responses to stimulation of central AT2Rs by the selective agonist Compound 21 in conscious spontaneously hypertensive rats (SHRs) and normotensive Wistar Kyoto rats (WKY rats). We also assessed the impact on noradrenaline [norepinephrine (NE)] plasma levels, autonomic function, spontaneous baroreflex sensitivity, and the possible involvement of the nitric oxide (NO) pathway and the AT1Rs. Chronic intracerebroventricular Compound 21 infusion lowered blood pressure and NE plasma levels in both rat strains. The night-time hypotensive effect was greater in SHRs compared with WKY rats. Compound 21 improved spontaneous baroreflex sensitivity more in SHRs than in WKY rats. These effects were abolished by co-administration of the AT2R antagonist PD123319 or the NO synthase inhibitor Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME). Central AT1R blockade did not enhance the hypotensive response to Compound 21. Chronic selective stimulation of central AT2Rs lowers blood pressure through sympathoinhibition, and improves spontaneous baroreflex sensitivity more in SHRs than in WKY rats. These responses appear to require a functioning central NO pathway, but are not modified by central AT1R blockade. Collectively, the data demonstrate specific beneficial effects of stimulation of central AT2Rs in hypertension associated with increased sympathetic tone, and suggest that central AT2Rs may represent a potential new therapeutic target for the treatment of neurogenic hypertension.

Introduction: Patients with atrial fibrillation (AF) and treated with coumarins need a close follow-up of the international normalized ratio (INR)-values. This can be done by the general practitioner (GP) or by a haematologist in an outpatient hospital clinic., Objective: To compare both ways of follow-up and to investigate determinants of stable INR-patterns., Methods: Cross-sectional single-centre study in patients with AF treated at the UZ Brussel, a university hospital in Brussels. Of the 113 patients included in the study, 71 had their INR followed-up by their GP and 42 similar patients were followed-up by a haematologist. Data of these 113 patients were further analysed to identify possible determinants for stable INR-values., Results: The time in therapeutic range (TTR) did not significantly differ between both groups. However, patients in the GP-group had significantly more INR-values under 2.0 compared to patients from the haematologist-group (P =  0.044), whereas patients in the haematologist-group had significantly more INR-values above 3.0 compared to patients from the GP-group (P = 0.038). Reimbursement costs of both ways of follow-up were comparable, but the out-of-pocket costs for the patient were lower in the GP-group. The time since AF diagnosis was the only significant determinant predicting a higher TTR., Conclusion: Both approaches of follow-up seem to lead to the same TTR, yielding no reason to advocate one approach above the other. However, the patient costs were lower when followed-up by the GP.

Objectives: Developing and implementing clinical decision support systems (CDSSs) is time-consuming and costly. Therefore, prioritization of the most relevant systems is warranted. The physician's perceived usefulness has been identified as a decisive reason for using CDSSs. The objective of this study was to investigate the physician's perceived usefulness of different types of CDSSs and to identify the user needs and expectations regarding future CDSSs., Methods: Cross-sectional single-centre survey among physicians with a clinical assignment in a university hospital. Physicians were questioned about their current experiences with drug prescribing and the perceived usefulness and desired features of future CDSSs., Results: One hundred and sixty-four physicians completed the survey (52·6%). The majority acknowledged that it is very difficult to take all relevant information into account when prescribing drugs. Drug-drug interaction checking, drug-allergy checking, and dosing guidance were considered as most useful. Automated clinical guidelines and adverse drug event monitoring were considered as least useful. The user-friendliness of the systems, clinical relevance of the alerts, and prevention of alert fatigue were perceived as important aspects for a successful implementation., Conclusions: From the physicians' perspective drug-drug interaction checking, drug-allergy checking, and dosing guidance should receive the highest priority for development and implementation. Because the perceived usefulness has been identified as a decisive reason for using CDSSs, it seems feasible to take into account this prioritization when developing and implementing CDSSs. In order to overcome the physicians' perceived disadvantages, attention should go to the development of user-friendly systems that deliver clinical relevant alerts.

Background: Drug-drug interactions (DDIs) can lead to adverse drug events and compromise patient safety. Two common approaches to reduce these interactions in hospital practice are the use of clinical decision support systems and interventions by clinical pharmacists., Objective: To compare the performance of both approaches with the main objective of learning from one approach to improve the other., Setting: Acute geriatric ward in a university hospital., Methods: Prospective single-centre, cohort study of patients admitted to the geriatric ward. An independent pharmacist compared the clinical decision support alerts with the DDIs identified by clinical pharmacists and evaluated their interventions. Contextual factors used by the clinical pharmacists for evaluation of the clinical relevance were analysed. Adverse drug events related to DDIs were investigated and the causality was evaluated by a clinical pharmacologist based on validated criteria., Main Outcome Measure: Number of alerts, interventions and the acceptance rates., Results: Fifty patients followed by the clinical pharmacists, were included. The clinical pharmacists identified 240 DDIs (median of 3.5 per patient) and advised a therapy change for 16 of which 13 (81.2 %) were accepted and three (18.8 %) were not. The decision support system generated only six alerts of which none were accepted by the physicians. Thirty-seven adverse drug events were identified for 29 patients that could be related to 55 DDIs. For two interactions the causality was evaluated as certain, for 31 as likely, for ten as possible and for 12 as unlikely. Mainly intermediate level interactions were related to adverse drug events. Contextual factors taken into account by the clinical pharmacists for evaluation of the interactions were blood pressure, international normalised ratio, heart rate, potassium level and glycemia. Additionally, the clinical pharmacists looked at individual administration intervals and drug sequence to determine the clinical relevance of the interactions., Conclusion: Clinical pharmacists performed better than the decision support system mainly because the system screened only for high level DDIs and because of the low specificity of the alerts. This specificity can be increased by including contextual factors into the logic and by defining appropriate screening intervals that take into account the sequence in which the drugs are given.

Objectives: To investigate determinants of medication use among multi-ethnic pregnant women., Methods: A total of 641 pregnant women participated in this cross-sectional study in a Brussels university hospital. A questionnaire was used to obtain data on socio-demographic characteristics and medication use. Chi-squared tests and binary logistic regression analyses were performed using SPSS 19., Results: Medication use during pregnancy (37%) was positively associated with age older than 35 years, Western origin, being born in Belgium, high education and employment status. Highly educated Western women had a greater exposure to drugs with an unknown safety profile than Arab/Turkish and 'Other (non-Western) origins' women. In the latter two groups, low education and nulliparity were the most important determinants of lower drug use. Nulliparous Arab/Turkish women used significantly less medications (17%) during pregnancy than parous women with the same ethnic background (34%; p = 0.024)., Conclusions: Medication use during pregnancy is considerable but differs according to ethnicity. Age, parity, educational level, occupational status and duration of stay in Belgium are important determinants that should be taken into account for risk assessment and preventive measures targeting pregnant women.

Purposes: Relative efficacy and effectiveness assessment (REA) of a pharmaceutical product is critical in reimbursement decisions. The Pharmaceutical Forum (2005-2008) asked European Union (EU) member states (MS) to strengthen the methodological quality and rigor of REA and identify any scope for common approaches. Here, we have compared REA practices and results within three EU MS with similar reimbursement procedures for the period 2007-2010 to describe the actual situation., Methods: Assessment procedures and reports from the Belgian, Dutch and French Agency websites were retrieved and corresponding products matched. The REA-outcome was coded as added therapeutic value (ATV) yes or no. The strength of agreement between the three MS was estimated and analyzed in relation to some explanatory variables., Results: Of the 144 Belgian, 122 Dutch and 236 French assessment reports retrieved, ATV was granted in 35, 39 and 23 % of cases, respectively, with 72 matches between the three MS. In all MS the results of at least one randomized trial were available in >90 % of reports. Between two MS significant agreement was achieved in ≥ 72 % of cases; this was 54 % between the three MS. Differences in ATV existed for treatments in severe chronic diseases. Assessment procedures were poorly documented in Belgium and France., Conclusions: Our findings reveal that the three similar EU MS under study agree on the REA-outcome of only half of the new drugs. Differences in applied methodology (e.g. inferences from study results, handling of uncertainty) between MS may exist. We suggest that a joint REA approach would benefit from a common understanding and application of the scientific assessment process using shared guidelines.

Angiotensin II type 2 receptor (AT2R)-mediated vasodilation has been demonstrated in different vascular beds in vitro and in perfused organs. In vivo studies, however, consistently failed to disclose renal vasodilator responses to compound 21, a selective AT2R agonist, even after angiotensin II type 1 receptor blockade. Here, we investigated in vivo whether angiotensin-converting enzyme inhibition, reducing endogenous angiotensin II levels, could unmask the effects of selective AT2R stimulation on blood pressure and renal hemodynamics in normotensive and hypertensive rats. After pretreatment with the angiotensin-converting enzyme inhibitor captopril, intravenous administration of compound 21 did not affect blood pressure and induced dose-dependent renal vasodilator responses in spontaneously hypertensive but not in normotensive rats. The D1 receptor agonist fenoldopam, used as positive control, reduced blood pressure and renal vascular resistance in both strains. The AT2R antagonist PD123319 and the nitric oxide synthase inhibitor L-NMMA (N(G)-monomethyl-L-arginine acetate) abolished the renal vasodilator response to compound 21 without affecting responses to fenoldopam. The cyclooxygenase inhibitor indomethacin partially inhibited the renal vascular response to compound 21, whereas the bradykinin B2 receptor antagonist icatibant was without effect. Angiotensin-converting enzyme inhibition unmasked a renal vasodilator response to selective AT2R stimulation in vivo, mediated by nitric oxide and partially by prostaglandins. AT2R may have a pathophysiological role to modulate renal hemodynamic effects of angiotensin II in the hypertensive state.

Objective: To investigate the differences in exposure to medications in a cohort of multi-ethnic pregnant women., Methods: Six hundred and forty-one pregnant women of Western, Arab/Turkish and "other origins" participated in this cross-sectional study using a questionnaire in a university hospital in Brussels, Belgium. Assessment of the drug safety was done using the food and drug administration (FDA) risk classification system. Data analysis was performed using SPSS (Chicago, IL)., Results: In overall cohort, 83.8% used at least one preparation (including multivitamins) during pregnancy and 37.0% of women used at least one drug (excluding multivitamins). Significantly more Western women (43.7%) used one or more medications compared to Arab/Turkish women (28.7%; p = 0.000). This difference in exposure was most pronounced for over-the-counter (OTC) drugs for occasional and pregnancy-related complaints, and was observed for potentially unsafe drugs or drugs with unknown safety. None of the women reported use of FDA X category drugs., Conclusions: The use of drugs known to be harmful was not observed, but a higher prevalence of exposure to potentially harmful drugs (FDA C/D) was found among Western women who also consumed more OTC drugs. This highlights the need for cautious prescribing for women in the fertile age in general and for continuous monitoring of medication use during pregnancy.