Clinically relevant potential drug-drug interactions in intensive care patients: A large retrospective observational multicenter study.

PURPOSE: Potential drug-drug interactions (pDDIs) may harm patients admitted to the Intensive Care Unit (ICU). Due to the patient's critical condition and continuous monitoring on the ICU, not all pDDIs are clinically relevant. Clinical decision support systems (CDSSs) warning for irrelevant pDDIs could result in alert fatigue and overlooking important signals. Therefore, our aim was to describe the frequency of clinically relevant pDDIs (crpDDIs) to enable tailoring of CDSSs to the ICU setting. MATERIALS & METHODS: In this multicenter retrospective observational study, we used medication administration data to identify pDDIs in ICU admissions from 13 ICUs. Clinical relevance was based on a Delphi study in which intensivists and hospital pharmacists assessed the clinical relevance of pDDIs for the ICU setting. RESULTS: The mean number of pDDIs per 1000 medication administrations was 70.1, dropping to 31.0 when considering only crpDDIs. Of 103,871 ICU patients, 38% was exposed to a crpDDI. The most frequently occurring crpDDIs involve QT-prolonging agents, digoxin, or NSAIDs. CONCLUSIONS: Considering clinical relevance of pDDIs in the ICU setting is important, as only half of the detected pDDIs were crpDDIs. Therefore, tailoring CDSSs to the ICU may reduce alert fatigue and improve medication safety in ICU patients.

Doctors' beliefs and knowledge on corticosteroid-induced osteoporosis: identifying barriers to improve prevention.

WHAT IS KNOWN AND OBJECTIVE: Despite the availability of effective treatments for the management of corticosteroid-induced osteoporosis (CIOP), the condition is undertreated. Our objective was to assess prescribers' knowledge and likely prescribing patterns concerning the diagnosis and treatment of CIOP. Another goal was to identify key barriers to the use of preventive therapy in patients using long-term corticosteroids. METHODS: We used a postal survey of general practitioners (GPs) and specialists in the Netherlands. The survey comprised of questions on: demographic data, perceived barriers to the use of preventive therapy for CIOP, and knowledge of diagnosis and treatment of CIOP. Case scenarios were questioned to assess practice patterns. RESULTS: Responding prescribers correctly answered an average of 55% of knowledge questions and 69% of case scenarios. Multiple questions and cases showed that knowledge on the use of bone mineral density (BMD) determination was poor. BMD was determined in patients who, according to the national osteoporosis guideline, should be treated with bisphosphonates independent of BMD. Moreover, only 18% of doctors correctly answered that the BMD cutoff in CIOP patients is a T-score of ≤-1 or ≤-1·5. Key barriers identified were: (i) GPs, significantly more than specialists, consider prescription of preventive therapy the responsibility of another doctor; (ii) discontinuation of anti-resorptive medication due to adverse effects and (iii) the reluctance to prescribe preventive therapy in patients already prescribed multiple medications. WHAT IS NEW AND CONCLUSION: Doctors did not identify many barriers to the prescribing of anti-resorptive therapies. Lack of knowledge, especially concerning use of BMD-results, likely led to the under-treatment of the presented patients.

Systematic review of trends in prophylaxis of corticosteroid-induced osteoporosis: the need for standard audit guidelines.

UNLABELLED: Corticosteroid-induced osteoporosis (CIOP) is currently undertreated. Systematic review of the literature revealed that the percentage of patients treated adequately is dependent on study quality. Therefore, it remains unknown whether adherence to the guidelines is really so poor. Five major quality criteria provide the standard for future studies on this scope. INTRODUCTION: It has recently been stated that the degree of prophylaxis of corticosteroid-induced osteoporosis (CIOP) is low and effort should be put into determining reasons for non-prescribing of preventive agents. The aim of this study was to identify: how many studies adequately audit the prevalent guideline; the longitudinal trends in prevention of CIOP; which patient groups appear to be most undertreated; and which intervention strategies are effective. METHODS: We performed a comprehensive search of MEDLINE and systematically recorded the outcomes and quality of published studies, using five major criteria. RESULTS: Twenty-four studies were included in the analysis. The quality of the included studies was poor (31%) or moderate (37%). There was a longitudinal increase in quality of the studies and percentage of prevention. Multivariable linear regression showed that the quality of the study was the only independent predictor of the prevention rate reported in the study. CONCLUSIONS: The results show undertreatment of CIOP might be due to insufficient quality of the studies rather than poor practice or failure to recognise the right patients. Future interventions should comply with five major quality criteria, and a multifaceted approach is required in order to make an impact on the underprescribing of CIOP prophylaxis.

Corticosteroid-induced osteoporosis prevention: longitudinal practice patterns in The Netherlands 2001-2005.

UNLABELLED: We investigated prevention trends and predictors for osteoporosis prevention in long term corticosteroid users. The use of bisphosphonates increased from 2001 to 2005. Longer duration of corticosteroid use and DMARD use were predictors for receiving prevention. Females appear reasonably well treated; however, men require more attention. INTRODUCTION: Previous studies have shown that long-term corticosteroid users are undertreated for osteoporosis prevention. Our aim was to identify prevention trends in long-term corticosteroid users from 2001-2005 in The Netherlands and to identify predictors for bisphosphonate prophylaxis. METHODS: Pharmacy dispensing data were used from 9 community pharmacies. All oral corticosteroid doses were converted to "prednisolone equivalents". We then identified long-term (> or =90 days) corticosteroid episodes, which required bisphosphonate prophylaxis as per 2002 Dutch guidelines; Multivariate logistic regression was used to identify predictors for receiving prevention. RESULTS: We identified 615 different corticosteroid patients requiring prophylaxis. From 2001-2005 the use of bisphosphonates increased from 38% to 54% (p = 0.001). In 2005 females were prescribed more bisphosphonates than males (61% vs. 39%; p = 0.002), or any treatment (72% vs. 45%; p < 0.001). Multivariate analysis showed that longer duration of corticosteroid use and disease-modifying anti-rheumatic drug (DMARD) use were independent predictors of bisphosphonate use. Use of respiratory medication was a negative predictor of bisphosphonate use. CONCLUSION: There has been a significant increase in osteoporosis prophylaxis in a population at high risk for osteoporosis/fractures. In particular, females appear reasonably well treated; however, men are still not receiving prevention to the same degree as women.

Role of L-arginine in the deficiency of nitric oxide and airway hyperreactivity after the allergen-induced early asthmatic reaction in guinea-pigs.

1. Using a guinea-pig model of allergic asthma, we investigated the role of L-arginine limitation in the allergen-induced deficiency of nitric oxide (NO) and airway hyperreactivity (AHR) after the early asthmatic reaction, by examining the effects of various concentrations of the NO synthase (NOS) substrate on the responsiveness to methacholine of isolated perfused tracheae from unchallenged (control) animals and from animals 6 h after ovalbumin challenge. 2. Preparations from ovalbumin-challenged guinea-pigs showed a 1.9 fold increase in the maximal response (Emax) to intraluminal (IL) administration of methacholine compared to controls (P<0.001). A similar 2.0 fold (P<0.05) increase in Emax to methacholine was observed in control airways incubated with the NOS inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME; 0.1 mM, IL), while L-NAME had no further effect on the airways from ovalbumin-challenged animals. 3. In control airways, extraluminal (EL) administration of 0.3, 1.0 and 5.0 mM L-arginine all suppressed the Emax for methacholine by approximately 40% (P<0.01 all), whereas 5.0 mM D-arginine (EL) had no effect. 4. L-Arginine dose-dependently reduced the AHR to methacholine in tracheae from ovalbumin-challenged guinea-pigs, the responsiveness being normalized in the presence of 5.0 mM L-arginine. As in controls, 5.0 mM D-arginine was without effect. 5. The results demonstrate that deficiency of endogenous NO contributes to the allergen-induced AHR to methacholine after the early asthmatic reaction, which is reversed by exogenous administration of L-arginine. This indicates that limitation of substrate may underly the reduced cNOS activity and subsequent AHR after the acute asthmatic response.

Deficiency of nitric oxide in polycation-induced airway hyperreactivity.

Using a perfused guinea-pig tracheal tube preparation, we investigated the role of endogenous nitric oxide (NO) in polycation-induced airway hyperreactivity (AHR) to methacholine. Intraluminal (IL) administration of the NO synthase inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME; 100 microM) caused a 1.8 fold increase in the maximal contractile response (Emax) to IL methacholine compared to control, without an effect on the pEC50 (-log10 EC50). The polycation poly-L-arginine (100 microg ml(-1), IL) similarly enhanced the Emax for methacholine; however, the pEC50 value was also increased, by one log10 unit. L-NAME had no effect on the enhanced methacholine response of poly-L-arginine-treated airways, while the enhanced agonist response was completely normalized by the polyanion heparin (25 u ml(-1), IL). In addition, the effect of L-NAME was fully restored in the poly-L-arginine plus heparin treated airways. The results indicate that, in addition to enhanced epithelial permeability, a deficiency of endogenous NO contributes to polycation-induced AHR. The latter finding may represent a novel mechanism of AHR induced by eosinophil-derived cationic proteins in allergic asthma.