Community-Acquired Acute Kidney Injury Induced By Drugs In Older Patients: A Multifactorial Event.

PURPOSE: Community-acquired acute kidney injury (CA-AKI) is a frequent and severe adverse drug reaction (ADR) among older patients. The combination of drugs and other CA-AKI risk factors was barely evaluated. The objectives of our study were to both accurately identify CA-AKI induced by drugs in older patients, and to describe their combination with other risk factors. PATIENTS AND METHODS: We conducted a retrospective, single-center study in a general hospital over a two-year period. An automated detection identified CA-AKI according to KDIGO criteria, amongst 4,767 eligible inpatient stays among patients aged 75 years or older. Two independent experts reviewed all CA-AKI events to adjudicate drug involvement (Naranjo scale), identify inappropriate prescriptions (STOPP criteria), evaluate avoidability (Hallas criteria) and identify combined risk factors. RESULTS: An expert review confirmed 713 CA-AKI (15.0% of inpatient stays) and determined that 419 (58.8%) CA-AKI were induced by drugs. A multifactorial cause (i.e., at least one drug with a precipitating factor) was found in 63.2% of drug-induced CA-AKI. Most of the drug-induced events were avoidable (66.8%), mainly in relation to a multifactorial cause. CONCLUSION: Drug-induced CA-AKI were frequent, multifactorial events in hospitalized older patients and their prevention should focus on combinations with precipitating factors.

Hospital-Acquired Hyperkalemia Events in Older Patients Are Mostly Due to Avoidable, Multifactorial, Adverse Drug Reactions.

Drug-induced hyperkalemia is a frequent and severe complication in the hospital setting. Other risk factors may also induce hyperkalemia but the combination of drugs and precipitating factors has not been extensively studied. The aim was to identify drug-induced hyperkalemia events in hospitalized older patients and to describe their combinations with precipitating factors. Two experts independently analyzed retrospective data of patients aged 75 years or more. Experts identified 471 hyperkalemia events and concluded that 379 (80.5%) were induced by drugs. The cause was multifactorial (i.e., at least one drug with a precipitating factor) in 300 (79.2%) of the 379 drug-induced hyperkalemia. Most of the drug-induced hyperkalemia events were avoidable (79.9%)-mainly because of the multifactorial cause (e.g., dosage adaptation during acute kidney injury). Drug-induced hyperkalemia events are frequently combined with precipitating factors in hospitalized older patients and their prevention should focus on these combinations.

Evaluation of a Computer Application for Retrospective Detection of Vitamin K Antagonist Treatment Imbalance.

OBJECTIVE: Management of vitamin K antagonists (VKAs) is difficult, and overdoses can have dramatic hemorrhagic consequences. The adverse drug event (ADE) scorecards is a tool intended for the detection and description of adverse drug reaction/ADE developed during a European computerized medical data processing project. It is used in a quality assurance process. Our objective was to evaluate the performance of the ADE scorecards in the detection of the contributing factors for VKA overdoses, among the cases where a VKA overdose is observed. METHODS: Twenty-eight rules allow the detection of VKA treatment overdose related to drug or a clinical situation. They were applied on 14,748 electronic medical records from a community hospital. Among 582 records including a VKA prescription, 59 cases of VKA overdoses (international normalized ratio ≥ 5) during the hospital stay have been identified. The ADE scorecards detected 49 of them. We evaluated the positive predictive value and sensitivity of these rules, by an expert review of the cases. RESULTS: The expert review confirmed the contribution of a detected risk factor to the VKA overdose in 11 cases. Therefore, the precision of the rules is 22.4%. The sensitivity is 84.6%. The risk factors were mainly infection and amiodarone introduction. The 4 cases of clinical injury related to a drug were properly designated by the rules. CONCLUSIONS: Our study shows the great potential of the ADE scorecards for detecting cofactors of VKA overdoses and gives an argument to include complex rules in the knowledge bases used for the detection and identification of ADEs in large medical databases.

Inappropriate anticholinergic drugs prescriptions in older patients: analysing a hospital database.

Background Although many anticholinergics are inappropriate in older patients, the prescription of these drugs in a hospital setting has not been extensively studied. Objective To describe prescriptions of anticholinergic drugs in terms of frequency, at risk situations and constipation in hospitalized, older adults. Setting Using a database from a French general hospital (period 2009-2013), we extracted information on 14,090 hospital stays by patients aged 75 and over. Methods Anticholinergic drug prescriptions were automatically detected, with a focus on prescriptions in three well-known at-risk situations: falls, dementia, and benign prostatic hyperplasia. Cases of constipation that might have been causally related to the administration of anticholinergic drugs were screened for and reviewed. Main outcome measure Prescriptions with a high associated risk of anticholinergic related adverse reactions. Results Administration of an anticholinergic drug was detected in 1412 (10.0%) of the hospital stays by older patients. At-risk situations were identified in 413 (36.5%) of these stays: 137 (9.7%) for falls, 243 (17.2%) for dementia, and 114 (8.1%) for benign prostatic hyperplasia; 78 (18.9%) of these 413 stays featured a combination of two or three at-risk situations. Cases of constipation induced by anticholinergic drug administration were identified in 188 (13.3%) patient stays by using validated adjudication rules for adverse drug reactions: 85 and 103 cases were respectively evaluated as "possible" or "probable" adverse drug reactions. Conclusions Anticholinergic drugs prescription was found in 10.0% of hospitalized, older patients. More than one third of these prescriptions occurred in at-risk situations and more than one in ten prescriptions induced constipation.

Underuse of Oral Anticoagulants and Inappropriate Prescription of Antiplatelet Therapy in Older Inpatients with Atrial Fibrillation.

BACKGROUND: Several studies have shown that the prescription of antiplatelet therapy (APT) is associated with an increased risk of oral anticoagulant (OAC) underuse in patients aged 75 years and over with atrial fibrillation (AF). An associated atheromatous disease may be the underlying reason for APT prescription. The objective of the study was to determine whether the association between underuse of OAC and APT prescription was explained by the presence of an atheromatous disease. METHODS AND RESULTS: We performed a retrospective, observational, single-centre study between 2009 and 2013 based on administrative data. Patients aged 75 years and over with non-valvular AF were identified in a database of 72,090 hospital stays. Prescriptions of anti-thrombotic medications and their association with the presence of atheromatous disease were evaluated by the mean of a logistic regression. A total of 2034 hospital stays were included (mean age 84.3 ± 5.2 years). The overall prevalence of known atheromatous disease was 25.9%. OAC underuse was observed in 58.5% of the stays. In multivariable analysis, the prescription of an APT was associated with an increased risk of OAC underuse [odds ratio (OR) 6.85; 95% confidence interval (CI) 5.50-8.58], independently of the presence of a concomitant known atheromatous disease (OR 0.78; 95% CI 0.60-1.01). Among the 692 stays with APT monotherapy (34.0%), 232 (33.5%) displayed an atheromatous disease. CONCLUSIONS: The underuse of OAC is associated with the prescription of APT in older patients with AF, regardless of the presence or absence of known atheromatous disease. Our results suggest that APT is often inappropriately prescribed instead of OAC.

Docking study: PPARs interaction with the selected alternative plasticizers to di(2-ethylhexyl) phthalate.

Phthalates, used in medical devices (MDs), have been identified as reproductive and developmental toxicants. Their toxicity varies somewhat depending on the specific phthalate and is in part linked to the activation of Peroxisome Proliferating-Activated Receptors (PPARs). So, the use of MDs containing targeted phthalates such as di(2-ethylhexyl) phthalate (DEHP) has been challenged by European directive 2007/47/EC. Therefore, MDs manufacturers were forced to quickly find replacement plasticizers. However, very little toxicological and epidemiological studies are available on human health. So, we proceeded to dock these chemicals in order to identify compounds that are likely to interact with PPARs binding sites. The results obtained are generally very mixed on the harmlessness of these alternatives. Moreover, no data exist on the biological effects of their possible metabolites. As DEHP toxicity resulted mainly from its major metabolites, generalizing the use of these plasticizers without conducting extensive studies on the possible effects on human health of their metabolites seems inconceivable.

Evaluation of compliance with recommendations of prevention of thromboembolism in atrial fibrillation in the elderly, by data reuse of electronic health records.

Under-prescription of anticoagulants in the elderly with atrial fibrillation (AF) has been described in several studies, showing that only 15 to 44% of them receive anticoagulants. However, the European Society of Cardiology recommendations state that anticoagulants should be systematically prescribed. In case of refusal of the treatment by the patient, a platelet aggregation inhibitor should be prescribed in monotherapy or bitherapy according to the HAS-BLED bleeding risk score. In all the cases the patient should receive an antithrombotic treatment. In this work we observe the adequacy of prescription practices to the recommendations for AF in the elderly by data reuse on a monocentric observational retrospective cohort. Data of a 222 beds French community hospital were extracted for the year 2013. The patients aged over 75 years and presenting AF were selected. The HAS-BLED score was calculated and the consistency of the prescriptions with the recommendations of the European Society of Cardiology was verified. Then the compliance rate to the recommendations was calculated. The rules detected 433 patients with AF and aged over 75 years. From those patients, 45% received an anticoagulant, 32.1% received platelet aggregation inhibitors and 22.9% did not receive any antithrombotic treatment. When a platelet aggregation inhibitor was prescribed the recommendation for bitherapy was not followed in 97% of the cases. The compliance rate to the recommendations was 47.8%. This work highlights a major problem of quality of the prescriptions in the hospital field and shows how data reuse can help describing this type of issues.

Pharmacokinetic evaluation of a novel benzopyridooxathiazepine derivative as a potential anticancer agent.

BACKGROUND/AIMS: The in vivo metabolic profile of a benzopyridooxathiazepine (BPT) derivative, a potent tubulin polymerization inhibitor with a promising in vitro activity, was investigated. METHODS: The quantification of the BPT derivative and the identification of metabolites in the plasma of Wistar rats after i.p. and oral administration of 10 mg/kg were performed by the HPLC-mass spectrometry method. RESULTS: Following a single i.p. dose of the BPT derivative, the plasma concentrations showed a biexponential decay (with a rapid decline) followed by a slow decay with a terminal half-life of 77.90 min. The area under the concentration-time curve from time 0 to infinity (AUC0-∞) was 18.90 µg/ml·min. After oral administration, the plasmatic concentrations reached a peak of 0.06 µg/ml at 35 min and then decayed with a half-life of 108 min. The AUC0-∞ was 10.25 µg/ml·min, representing 54.2% of the relative bioavailability. The compound was well distributed in the body, and its elimination seemed to be fast, regardless of the administration route. The major metabolic pathways were demethylation and hydroxylation reactions, both followed by conjugation with glucuronic acid. CONCLUSION: In rats, the BPT derivative is well distributed and undergoes extensive metabolism, leading to several metabolites. With promising in vitro activity and very good oral bioavailability, this compound seems to be an attractive candidate for further development as an anticancer agent.

Adverse drug events with hyperkalaemia during inpatient stays: evaluation of an automated method for retrospective detection in hospital databases.

BACKGROUND: Adverse drug reactions and adverse drug events (ADEs) are major public health issues. Many different prospective tools for the automated detection of ADEs in hospital databases have been developed and evaluated. The objective of the present study was to evaluate an automated method for the retrospective detection of ADEs with hyperkalaemia during inpatient stays. METHODS: We used a set of complex detection rules to take account of the patient's clinical and biological context and the chronological relationship between the causes and the expected outcome. The dataset consisted of 3,444 inpatient stays in a French general hospital. An automated review was performed for all data and the results were compared with those of an expert chart review. The complex detection rules' analytical quality was evaluated for ADEs. RESULTS: In terms of recall, 89.5% of ADEs with hyperkalaemia "with or without an abnormal symptom" were automatically identified (including all three serious ADEs). In terms of precision, 63.7% of the automatically identified ADEs with hyperkalaemia were true ADEs. CONCLUSIONS: The use of context-sensitive rules appears to improve the automated detection of ADEs with hyperkalaemia. This type of tool may have an important role in pharmacoepidemiology via the routine analysis of large inter-hospital databases.

Plasma malondialdehyde levels in children on 12-hour cyclic parenteral nutrition: are there health risks?

In children undergoing total parenteral nutrition (PN), lipids provide a key source of calories preventing or correcting energy deficits and improving outcomes. However, some of these lipids may undergo oxidation leading to the formation of malondialdehyde (MDA), a cytotoxic byproduct found in these patients. This paper aims to describe a sensitive method for detecting MDA and discuss its role in certain diseases commonly found in children on regular PN. To quantify MDA levels in children benefitting from long-term cyclic PN, a reliable and sensitive high-performance liquid chromatographic method based on a 1-step derivatization/extraction procedure analysis with ultraviolet determination at 305 nm wavelength was achieved. In control children without PN, MDA levels were on average 3.30 ± 0.08 µM. However, in children nourished intravenously by fat emulsion for a long time, in which liver problems have been identified, the circulating concentrations of MDA ranged widely at both the start and the end of a session, 3- to 10-fold, respectively, in comparison with the levels measured in controls. This finding indicates that PN administrated long term raises plasma MDA levels, indicating chronic exposure and therefore a possible health risk, particularly liver damage. This preliminary study using a limited number of patients and controls showed that children undergoing long-term PN are strongly exposed to MDA, which must be considered as a potent toxic compound rather than a simple marker of lipid peroxidation.

Clinical evaluation of the ADE scorecards as a decision support tool for adverse drug event analysis and medication safety management.

AIMS: The prevention of adverse drug events (ADEs) demands co-ordination of different health care professionals. ADE scorecards are a novel approach to raise the team awareness regarding ADE risks and causes. It makes information on numbers and on possible causes of possible ADE cases available to the clinical team. The aim of the study was to investigate the usage and acceptance of ADE scorecards by healthcare professionals and their impact on rates of possible ADEs. METHODS: ADE scorecards were introduced in three departments of a French hospital. A controlled time series analysis of ADE data was conducted to assess the impact of the ADE scorecards. In addition, qualitative interviews and a standardized survey with all participating staff members were performed. RESULTS: Physicians, nurses and pharmacists found ADE scorecards effective to increase medication safety and recommended future usage. The time-series analysis did not show changes in rates of possible ADEs. CONCLUSION: ADE scorecards appear to be useful to raise awareness of ADE-related issues among professionals. Although the evaluation did not show significant reductions of ADE rates, the participating physicians, nurses and pharmacists believed that the ADE scorecards could contribute to increased patient safety and to a reduction in ADE rates. Strategies need to be designed to integrate ADE scorecards better into the clinical routine and to increase the precision of ADE detection.

Supervised analysis of drug prescription sequences.

Hospitals have at their disposal large databases that may be considered for reuse. The objective of this work is to evaluate the impact of a drug on a specific laboratory result by analyzing these data. This analysis first involves building a record of temporal patterns, including medical context, of drug prescriptions. Changes in outcome due to these patterns of drug prescription are assessed using short phases of the inpatient stay compared to monotonous changes in the laboratory result. To illustrate this technique, we investigated potassium chloride supplementation and its impact on kalemia. This method enables us to assess the impact of a drug (in its frequent context of prescription) on a laboratory result. This kind of analysis could play a role in post-marketing studies.

Routine use of the "ADE scorecards", an application for automated ADE detection in a general hospital.

Retrospective detection of Adverse Drug Events (ADEs) is challenging, notably because ADEs result from complex interactions between many factors. Data mining techniques have recently emerged in the field of automated retrospective ADE detection. The "ADE Scorecards" are a research application based on data-mining that has been built in the framework of the PSIP European Project, and potentially enables automated ADE retrospective detection. The objective of this paper is to evaluate the use of the ADE Scorecards in a real-life healthcare situation. For that purpose, the ADE Scorecards have been implemented in a French general hospital and have been used by the physicians and pharmacists for three years (corresponding to 73,000 inpatient stays). According to the results, 2% of the analyzed inpatient stays have a potential ADE with hyperkalemia, and 1% of them have a potential ADE with vitamin K antagonist overdose. In practice, the application, which was first designed to be a standalone web-based application for the physicians, has been used as a part of a more global quality improvement approach led by the pharmacists.

Evaluation of a computerized tool allowing retrospective detection of potential vitamin K antagonist overdoses in complex contexts.

Management of vitamin K antagonists (VKA) is difficult, and overdoses can have dramatic hemorrhagic consequences. These works form part of a European computerized medical data processing project, which aims to develop IT tools for describing adverse drug events (ADEs). Materials and methods A tool enabling retrospective research of potential ADE cases was developed, using complex ADE detection rules taking into account chronological parameters: the ADE scorecards. The rules were applied on 14,748 medical records from a community hospital. We evaluated the predictive positive value of the rules related to INR elevation by an expert review of the detected cases. The severity of the clinical consequences was evaluated. Results 49 cases were detected, among which 11 cases were ADEs. The predictive positive value of the rules is 22.44%, mostly related to antibiotics and amiodarone introduction. The four cases of clinical damage related to a drug were properly designated by the rules. Discussion - Conclusion Our study shows the great potential of developing complex rules for the identification of adverse drug events in large medical databases.

Strong variability of di(2-ethylhexyl)phthalate (DEHP) plasmatic rate in infants and children undergoing 12-hour cyclic parenteral nutrition.

BACKGROUND: Medical devices such as perfusion materials in polyvinyl chloride may contain di(2-ethylhexyl)phthalate (DEHP). Several studies have questioned the harmlessness of phthalates, which have been shown to have toxic effects on the reproductive system and general development. This study was designed to assess DEHP exposure in infants and children benefitting from cyclic parenteral nutrition (PN). The results are compared with those obtained from children used as controls and receiving no PN, to estimate the potential risk to this pediatric population, taking into account exposure levels and already published data. METHODS: Plasmatic concentrations of DEHP were assessed by high-performance liquid chromatography from blood samples taken from 22 children at the start and finish of a 12-hour cyclic PN period and compared with those obtained from 20 control children of comparable age and gender. RESULTS: After a 12-hour cyclic PN period, DEHP migration varied widely among the patients. The concentrations were not quantifiable in 4 children at the start of PN. In 1 child, they were quantifiable neither at the start nor at the end of PN. However, for 17 children, DEHP concentrations were quantifiable at the start of PN and were very variable from one child to another. At the end, DEHP concentrations had significantly but variably increased in these children. No trace of DEHP was found in the blood samples from 20 healthy controls. CONCLUSION: Considering published data on phthalate toxicity, it would appear advisable to encourage the use of medical devices that are either phthalate or DEHP free.

Data mining to generate adverse drug events detection rules.

Adverse drug events (ADEs) are a public health issue. Their detection usually relies on voluntary reporting or medical chart reviews. The objective of this paper is to automatically detect cases of ADEs by data mining. 115,447 complete past hospital stays are extracted from six French, Danish, and Bulgarian hospitals using a common data model including diagnoses, drug administrations, laboratory results, and free-text records. Different kinds of outcomes are traced, and supervised rule induction methods (decision trees and association rules) are used to discover ADE detection rules, with respect to time constraints. The rules are then filtered, validated, and reorganized by a committee of experts. The rules are described in a rule repository, and several statistics are automatically computed in every medical department, such as the confidence, relative risk, and median delay of outcome appearance. 236 validated ADE-detection rules are discovered; they enable to detect 27 different kinds of outcomes. The rules use a various number of conditions related to laboratory results, diseases, drug administration, and demographics. Some rules involve innovative conditions, such as drug discontinuations.

Medication related computerized decision support system (CDSS): make it a clinicians' partner!

Medication related Computerized Decision Support System (CDSS) are known to have a positive impact on Adverse Drug Events (ADE) prevention but they face acceptance problems due to over alerting and usability issues. We present here a Human factors approach to the design of these Clinical Decision Support (CDS) functions and to their integration into different Electronic Health Record (EHR) / Computerized Physicians Order Entry (CPOE) systems, so that the resulting CDSS corresponds to the users needs and fits clinical workflows and cognitive processes. We used ethnographic observations completed with semi-structured interviews to analyse existing work situations and work processes. These were then described in detail using the SHEL (Software, Hardware, Environment & Liveware) formalism, which enables a structured description of the work system and provides an appropriate classification of human errors potentially leading to ADEs. We then propose a Unified Modelling Language (UML) model supporting the characterization by the CDSS of the drug monitoring and clinical context of patients at risk of ADE. This model combines the status of the lab test orders on the one hand with the validity and normality of the lab results on the other hand. This makes the system able to catch the context of the monitoring of the drugs through their corresponding lab tests and lab results (e.g. kalemia for potassium) and also part of the context of the clinical status of the patient (actual lab values, but also diseases and other pathologies that are identified as potential causes of the ADE e.g. renal insufficiency and potassium). We show that making the system able to catch the monitoring and clinical contexts opens interesting opportunities for the design of the CDS information content and display mode. Implementing this model would allow the CDSS to take into account the actions already engaged by the healthcare team and to adapt the information delivered to the monitoring and clinical context, thus making the CDSS a partner to the clinicians, nurses and pharmacists.

Scorecards: a new method to prevent adverse drug events? Preliminary results from a clinical field study.

In the field of the detection and prevention of preventable ADEs, several methods have been explored to decrease the rate of ADEs due to monitoring errors. This paper describes an innovative method that aims at improving patient safety by increasing ADEs' awareness of healthcare professionals. To this end, ADE-scorecards that provide healthcare professionals with retrospective data about ADEs' causes and rates have been developed. In order to evaluate the impact of this method on the ADE rate, in-field clinical tests have been set up. Data were collected by both qualitative (semi-structured interviews) and quantitative methods (log analysis and ADE rate calculation). Preliminary results reveal that ADE-scorecards are well-accepted by most of the healthcare professionals who intend to use them as discussion supports and/or learning tools. Thus, ADE-scorecards seem to be a relevant method to improve patient safety by increasing ADE-awareness of healthcare professionals.

Correlation between exposure to phthalates and concentrations of malondialdehyde in infants and children undergoing cyclic parenteral nutrition.

BACKGROUND: Plasticizers such as di(2-ethylhexyl) phthalate (DEHP) are added to polyvinyl chloride (PVC) to confer flexibility. However, DEHP is associated with reproductive disorders in humans. Because of its noncovalent bond to the PVC matrix, this plasticizer tends to leach easily. Infants and children undergoing cyclic, long-term parenteral nutrition (PN) could be particularly at risk of potential toxicity from DEHP due to regular exposure. Malondialdehyde (MDA) is one of the most commonly used markers of free radical activity. The purpose of this study was to investigate how long-term exposure to phthalate affects the plasmatic rate of MDA. METHODS: Studies were performed on 7 randomized infants and children on regular cyclic, long-term PN, and the results were compared with those of 5 nontreated infants. The circulating concentrations of DEHP in children and infants during the PN therapy were measured by high-performance liquid chromatography. The concentrations were assessed before and after the PN session. In the same way, plasma MDA concentrations were measured. RESULTS: The circulating concentrations of DEHP before and after a 10- to 11-hour cyclic PN treatment in 7 infants and children under regular perfusion ranged widely, showing a significant increase after the treatment among all the patients. The same phenomenon observed with the rate of MDA showed that the 2 events are closely dependent. Therefore, long-term exposure to DEHP during cyclic PN raised plasma MDA levels, indicating increased oxidative stress. CONCLUSION: Long-term exposure to DEHP during PN increased free radical activity in vivo.

Contribution of human factors for the review of automatically detected ADE.

The European project PSIP (Patient Safety through Intelligent Procedures in Medication) aims at semi-automatically identifying and preventing ADE. Automatically detected Adverse Drug Events have to be reviewed and validated by human experts. Existing methods usually have the experts review the cases and document their rating in a structured form. One of the limitations of these methods is their poor ability to analyze and clear the disagreements between the experts and the system. This paper presents an innovative Human Factors based method to support the review by clinicians and pharmacologists of these automatically detected ADE. We use think aloud methods and portable labs to track and record the experts reasoning and their reviewing cognitive procedures. We present preliminary results obtained with this method, which allows identifying the key data and information used to characterize the ADE. This method provides useful feedbacks allowing a continuous refinement and improvement of the automated detection system.