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Aims The incidence of clinical events related to medication errors and/or adverse drug reactions reported in the literature varies by a degree that cannot solely be explained by the clinical setting, the varying scrutiny of investigators or varying definitions of drug-related events. Our hypothesis was that the individual complexity of many clinical cases may pose relevant limitations for current definitions and algorithms used to identify, classify and count adverse drug-related events. Methods Based on clinical cases derived from an observational study we identified and classified common clinical problems that cannot be adequately characterized by the currently used definitions and algorithms. Results It appears that some key models currently used to describe the relation of medication errors (MEs), adverse drug reactions (ADRs) and adverse drug events (ADEs) can easily be misinterpreted or contain logical inconsistencies that limit their accurate use to all but the simplest clinical cases. A key limitation of current models is the inability to deal with complex interactions such as one drug causing two clinically distinct side effects or multiple drugs contributing to a single clinical event. Using a large set of clinical cases we developed a revised model of the interdependence between MEs, ADEs and ADRs and extended current event definitions when multiple medications cause multiple types of problems. We propose algorithms that may help to improve the identification, classification and counting of drug-related events. Conclusions The new model may help to overcome some of the limitations that complex clinical cases pose to current paper- or software-based drug therapy safety.

Aims The aim was to improve medication safety in an emergency department (ED) by enhancing the integration and presentation of safety information for drug therapy. Methods Based on an evaluation of safety of drug therapy issues in the ED and a review of computer-assisted intervention technologies we redesigned an electronic case sheet and implemented computer-assisted interventions into the routine work flow. We devised a four step system of alerts, and facilitated access to different levels of drug information. System use was analyzed over a period of 6 months. In addition, physicians answered a survey based on the technology acceptance model TAM2. Results The new application was implemented in an informal manner to avoid work flow disruption. Log files demonstrated that step I, ‘valid indication’ was utilized for 3% of the recorded drugs and step II ‘tooltip for well-known drug risks’ for 48% of the drugs. In the questionnaire, the computer-assisted interventions were rated better than previous paper based measures (checklists, posters) with regard to usefulness, support of work and information quality. Conclusion A stepwise assisting intervention received positive user acceptance. Some intervention steps have been seldom used, others quite often. We think that we were able to avoid over-alerting and work flow intrusion in a critical ED environment.

Bei der Versorgung von Patienten im Zeitablauf spielt das Wissen uber vor- und nachgelagerte Diagnose- und Therapieentscheidungen eine ausschlaggebende Rolle. Ein Musterbeispiel ist das Wissen uber den Medikationsstatus eines Patienten. Die Gefahr von unerwunschten Arzneimittelwirkungen (UAW) macht die Bedeutung der Informationsinfrastruktur und vor allem des Informationsmanagements hinsichtlich der patientenrelevanten Medikation sichtbar. Der Bundeseinheitliche Medikationsplan soll als Grundlage fur ein verbessertes AMTS-Management (Arzneimitteltherapiesicherheit, AMTS) dienen. In mehreren Testregionen wurden in Pilotprojekten Erfahrungen hinsichtlich der Akzeptanz dieses Instrumentariums gewonnen. Kombiniert mit organisationsokonomischen Uberlegungen zeigt sich die Bedeutung einer adaquaten institutionellen und anreiztheoretischen Einordnung eines derartigen Instrumentariums in die Gesundheitsversorgung, insbesondere im Hinblick auf Sektoren ubergreifender Prozesse. Dies kann mit praktischen Erfahrungen aus einer Testregion unterlegt werden.

Summary Background: Adverse drug events (ADE) involving or not involving medication errors (ME) are common, but frequently remain undetected as such. Presently, the majority of available clinical decision support systems (CDSS) relies mostly on coded medication data for the generation of drug alerts. It was the aim of our study to identify the key types of data required for the adequate detection and classification of adverse drug events (ADE) and medication errors (ME) in patients presenting at an emergency department (ED). Methods: As part of a prospective study, ADE and ME were identified in 1510 patients presenting at the ED of an university teaching hospital by an interdisciplinary panel of specialists in emergency medicine, clinical pharmacology and pharmacy. For each ADE and ME the required different clinical data sources (i.e. information items such as acute clinical symptoms, underlying diseases, laboratory values or ECG) for the detection and correct classification were evaluated. Results: Of all 739 ADE identified 387 (52.4%), 298 (40.3%), 54 (7.3%), respectively, required one, two, or three, more information items to be detected and correctly classified. Only 68 (10.2%) of the ME were simple drug-drug interactions that could be identified based on medication data alone while 381 (57.5%), 181 (27.3%) and 33 (5.0%) of the ME required one, two or three additional information items, respectively, for detection and clinical classification. Conclusions: Only 10% of all ME observed in emergency patients could be identified on the basis of medication data alone. Focusing electronic decisions support on more easily available drug data alone may lead to an under-detection of clinically relevant ADE and ME.

Background: Since the 1970s, studies have examined potential risk factors associated with adverse drug reactions (ADRs) in a variety of settings. However, no pharmacoepidemiological study exists that incorporates clinical and laboratory parameters in a multiple regression model in order to consider predictors for ADRs. Objectives: To characterize risk factors associated with ADRs in patients admitted to university hospital departments of internal medicine. Design and Setting: Intensive pharmacovigilance was carried out in departments of internal medicine of two university hospitals. All admissions were followed prospectively for the occurrence of ADRs by members of a pharmacoepidemiological team consisting of physicians, pharmacologists and pharmacists. To identify patients at high risk for experiencing ADRs, patient histories and several clinical and laboratory data, determined at the time of admission, were taken into consideration. In addition to the drug prescribed, 40 parameters defined vital status at admission. These included temperature, heart rate, blood pressure (systolic-diastolic), body mass index, nicotine and alcohol use, and first laboratory test results after admission on nutrition status, inflammation, liver, kidney, pancreas or thyroid status, electrolytes, blood count and coagulation. Results: 907 patients were observed during the study period. The mean age of the study population was 60 + 16 years. The median number of different drugs administered per patient during hospitalization was 9.6 + 7.7. In 345 patients, 592 ADRs were evaluated: 33.4% possible, 61.5% probable and 4.7% highly probable. Two ADR-related deaths were observed during the study period. Analysing ADR predictors, 17 of 40 parameters reached significance in univariate analysis, but only five in a multivariate binary regression model: raised temperature (odds ratio [OR] 1.609; 95% CI 1.133, 2.285), low erythrocyte levels (OR 0.386; 95% CI 0.194, 0.768), low thrombocyte levels (OR 0.788, 95% CI 0.627, 0.989), high number of drugs (OR 1.117; 95% CI 1.076, 1.159) and female sex (OR 1.562; 95% CI 0.785, 2.013) were independent predictors for ADRs. Conclusion: For the patients investigated, of the large number of clinical data available only five independent factors predict ADR occurrence. Taking these results into account, physicians will be able to focus early on patients at risk for ADRs. To minimize ADR occurrence, ADR predictors should be integrated into the clinical pathway.

The aim of the present study was to evaluate a computerised monitoring system (CMS) based on laboratory test results for the detection of adverse drug reactions (ADRs) on a paediatric ward.A prospective, 6-month pharmacoepidemiological survey was performed on a 22-bed paediatric isolation ward. ADRs were identified by intensive chart review. In addition to spontaneous reporting by the treating physician, automatic laboratory signals generated by a CMS were evaluated for their association with ADRs. ADRs were classified by the affected target organs according to the WHO-ART system organ classes.A total of 73 ADRs were identified in 439 admissions (396 patients) by chart review. The CMS alerted 31 (42.4%) ADRs while 23 (31.5%) ADRs were found solely by treating physicians. Eight ADRs were detected by both approaches resulting in a total detection rate of 74% (compared with intensive pharmacovigilance). Out of a total of 27,434 laboratory tests performed routinely, 1,563 were classified as abnormal by the predefined CMS and used as the basis of alerts. The sensitivity of the system with respect to patients alerted was 90.3% and the specificity only 19.6%.This study demonstrates that, using CMS, a different kind of mild adverse events were detected compared to the observation by the treating physician. The system presented appears to be sufficiently sensitive, but the specificity is too low to make it acceptable for physicians in daily practice. In children, clinically important ADRs can be detected best by intensified surveillance.

Summary Aim : To investigate the effectiveness of a computer monitoring system that detects adverse drug reactions (ADRs) by laboratory signals in gastroenterology. Methods : A prospective, 6-month, pharmacoepidemiological survey was carried out on a gastroenterological ward at the University Hospital Erlangen-Nuremberg. Two methods were used to identify ADRs. (i) All charts were reviewed daily by physicians and clinical pharmacists. (ii) A computer monitoring system generated a daily list of automatic laboratory signals and alerts of ADRs, including patient data and dates of events. Results : One hundred and nine ADRs were detected in 474 admissions (377 patients). The computer monitoring system generated 4454 automatic laboratory signals from 39 819 laboratory parameters tested, and issued 2328 alerts, 914 (39%) of which were associated with ADRs; 574 (25%) were associated with ADR-positive admissions. Of all the alerts generated, signals of hepatotoxicity (1255), followed by coagulation disorders (407) and haematological toxicity (207), were prevalent. Correspondingly, the prevailing ADRs were concerned with the metabolic and hepato-gastrointestinal system (61). The sensitivity was 91%: 69 of 76 ADR-positive patients were indicated by an alert. The specificity of alerts was increased from 23% to 76% after implementation of an automatic laboratory signal trend monitoring algorithm. Conclusion : This study shows that a computer monitoring system is a useful tool for the systematic and automated detection of ADRs in gastroenterological patients.

Background and objective: Many drugs that are used to treat children are either not licensed for use in paediatric patients (unlicensed) or prescribed outside the terms of the product licence (off label). The incidence of adverse drug reactions (ADRs) associated with the use of such drugs is yet to be established. This study investigates, for the first time in a German patient population, the impact of unlicensed and off-label drug use on ADRs in paediatric patients. Patients and methods: An 8-month prospective pharmacoepidemiological cohort-based survey was conducted on a ten-bed paediatric isolation ward at the University Hospital Erlangen-Nuremberg, Germany. All patients were intensively monitored for ADRs by a pharmacoepidemiological team. ADRs were characterised according to international classification methods. All drug prescriptions were evaluated retrospectively as to unlicensed or off-label use on the basis of the product information. Results: A total of 178 patients were included in the study and 740 drug prescriptions were given to 156 patients (median three prescriptions per patient). In 198 cases (27.7% of all prescriptions) drugs were used in either an unlicensed (n = 3) or off-label (n = 195) manner. A total of 46 ADRs were observed in 31 patients (17.4%). Patients receiving at least one unlicensed or off-label drug prescription during hospitalisation (n = 92) experienced an ADR significantly more frequently (n = 26 patients) than patients receiving only licensed drugs (n = 64 vs 5 patients). ADRs were associated with 29 (5.6%) of the 517 licensed drug prescriptions and with 12 (6.1%) of the 198 unlicensed or off-label drug prescriptions. The majority of ADRs caused by unlicensed and off-label drug use were recognised by the attending physician. However, statistical analysis revealed no significant difference in the number of licensed and unlicensed/off-label drug prescriptions causing ADRs. Conclusion: This study demonstrated that at a paediatric isolation ward the incidence of ADRs caused by unlicensed or off-label drug use was not significantly more than that caused by the licensed drug use. However, patients treated with unlicensed or off-label drugs were shown to possess a significantly increased risk for developing ADRs.

Serum immunoglobulin E (IgE) was investigated in patients with chronic pancreatitis in order to elucidate possible disease mechanisms linking pancreatitis, adverse reaction to foods and allergy.Serum IgE was analysed in 86 non-atopic patients with advanced chronic pancreatitis and 54 non-atopic controls. IgE detection was performed by enzyme-linked immunofluorescence.Mean IgE levels (+/- standard error of mean) in chronic pancreatitis patients (286.1+/-49 kU/l) were found to be significantly elevated compared to controls (67.7+/-11 kU/l; P0.0001). Normal IgE levels (100 kU/l) were present in 40/54 control patients (74.1%), but only 39/86 pancreatitis patients (45.3%). Of the patients with chronic pancreatitis, 47/86 (54.6%) had clearly elevated IgE levels of100 kU/l and their IgE values did not show a Gaussian distribution. However, nine-fold higher IgE levels were found in chronic pancreatitis patients with alcohol consumption of25 g/day and exocrine insufficiency (915.5+/-240 kU/l) than in pancreatitis patients with normal exocrine function and no alcohol consumption (103.4+/-43 kU/l; P0.001). Moreover, acute episodes of chronic pancreatitis were found to increase serum IgE levels.In patients with chronic pancreatitis, serum IgE production is markedly enhanced, especially during acute inflammatory episodes or when alcohol is consumed. Since abstinence from alcohol and pancreatic enzyme substitution are associated with clearly lower IgE levels, it may be concluded that pancreatic insufficiency with reduced nutrient digestion and alcohol consumption stimulate IgE production. This finding gives rise to the speculation that, apart from pancreatic inflammation, cross-linking of IgE with alimentary or other antigens might be involved in the pathophysiology of a sub-population of patients with chronic pancreatitis and manifest pancreatic insufficiency.

Adverse drug reactions (ADRs) are a well-known cause of hospital admission. Nevertheless a quantitative estimate of the preventability of and physicians' awareness of these reactions is lacking.Using intensive bedside and computer-assisted drug surveillance methods a 13-month prospective pharmacoepidemiological survey was carried out on patients admitted to two medical wards of the Erlangen-Nuremberg University Hospital in Erlangen, Germany. This study aimed to define the incidence of preventable and unavoidable ADRs. In addition we investigated the awareness of the physicians to ADRs at the time of admission and the rate of contraindicated pre-admission prescriptions.In 78 (8.5%) of 915 (10.9%) admissions a total of 102 (42 preventable) community-acquired ADRs were detected on admission. In 45 (3.8%) of the admissions ADRs led directly to hospitalisation. 56.9% of the ADRs were not recognised by the attending physician on admission. Marked correlation was found between the awareness of ADRs and their probability and severity scores (r = 0.85 and r = 0.94, respectively; p0.05). The most frequently detected ADRs were due to direct toxicity and secondary pharmacological effects. Idiosyncratic reactions were often missed and 18.6% of all drugs prescribed prior to admission were contraindicated. Leading the list were diuretics, analgesics/NSAIDs and antipsychotics/sedatives.Awareness of existing ADRs on hospital admission and appropriate prescribing prior to hospital admission require attention. Early detection of ADRs on hospital admission can be achieved by the use of computer support systems. Many ADRs could be prevented by adhering to indications and contraindications.

Geriatric patients with multiple comorbidities are at high risk of experiencing an adverse drug reaction (ADR) during hospitalisation. The aim of the study was to compare the rate of ADRs as predicted by a computerised pharmacological database to the actual rate determined by direct observation in a sample of geriatric patients.During a 4-month period, geriatric patients were monitored using prospective observation. Patients were intensively screened for ADRs by a pharmacoepidemiological team (PET), consisting of two pharmacists and a physician. Actual ADRs detected by the PET were compared with those predicted by a computerised drug database. Furthermore, the set of actual ADRs, which resulted from drug-drug interactions (DDIs), were contrasted with potential DDIs signalled by the database. The main outcome measures were the incidence of actual ADRs. For the detection rate of the database we focused on frequent ADRs (1% according to product information and database) and all DDIs indicated automatically by the database.163 patients (121 female), mean age 79.8 +/- 7.1 years (range 60-98), were included in the study which was conducted on a geriatric rehabilitation hospital ward. The mean duration of hospitalisation was 24.3 +/- 8.4 days. Elderly patients received an average of 14.0 drugs (range 2-35) during their hospital stay. Of all patients, 60.7% experienced at least one ADR. The PET detected a total of 153 ADRs, with a mean of 0.9 ADRs per patient (range 0-5). The computerised drug database predicted an average of 309 potential ADRs for each patient; however, only 21 ADRs per patient were of high frequency. In 48% of ADR-positive patients (defined by PET) at least one of these frequent ADRs occurred.DDIs were detected by the PET in 14.7% of patients. Our database indicated a mean of 12 potential DDIs per patient. In 14 out of 24 DDI-positive patients, at least one signal indicated a real DDI. The database sensitivity was consequently 58.3%.In geriatric patients the incidence of ADRs is high. Computerised drug databases are a useful tool for detecting and avoiding ADRs. Our software, however, also produced a large number of signals that did not relate to actual ADRs found by the PET. The sheer number of these 'false' signals shows the need for refinement and optimisation of databases for daily clinical use.

Many patients with chronic pancreatitis (CP) complain of several types of food intolerance despite elimination of fat and alcohol. Since there are no data on serum immunoglobulin E (IgE) concentrations in CP, IgE concentrations in serum were detected in 97 persons with CP and 50 controls. IgE was analyzed by the use of a highly sensitive fluoro-enzyme-immunoassay. In CP, a significantly raised IgE level (mean +/- SEM; 286.1 +/- 49 KU/L; p 25 g/day). Alcohol consuming patients with CP and normal pancreatic function had a mean serum IgE of 295.0 +/- 114 KU/L, while patients with alcohol consumption and sufficiently treated exocrine pancreatic insufficiency showed a serum IgE of 393.7 +/- 147 KU/L (p = 0.03). Non-enzyme supplemented patients with CP and exocrine pancreatic insufficiency were characterized by approximately 10-fold increased serum IgE (1080.0 +/- 313 KU/L; p = 0.001). Non-allergic, alcohol consuming patients with CP have significantly increased serum IgE values. Since patients without alcohol consumption and normal pancreatic function or sufficiently treated exocrine insufficiency showed clearly lower IgE values than non-compliant patients with manifest exocrine pancreatic insufficiency, these results are compatible with the assumption that a reduced rate of antigen digestion in exocrine pancreatic insufficiency may lead to an increased intestinal antigen load, stimulating an abnormal humoral immune response with IgE production. Alcohol may further contribute to this by damaging the mucosal barrier.

Background: It has been claimed that the risk of adverse drug reactions increases with age. However, only limited data exist for disease-group specific risks and none for patients with liver and gastrointestinal diseases. Aims: To determine the incidence and characteristics of adverse drug reactions and the physicians’ awareness of adverse drug reactions. Methods: During a 7-month period, a prospective survey of 532 male patients (158 aged 65 years or older; 30%) was conducted on a hepatogastroenterological ward of a tertiary-care university hospital, using intensive bedside and computer-assisted drug surveillance methods. Results: No difference was found in the overall rate of adverse drug reactions between older and younger patients (25.9% vs. 24.2%) during 6213 treatment days. However, a significantly higher risk for developing adverse drug reactions could be shown for the elderly with biliary tract diseases (P

To implement a computer-based adverse drug reaction monitoring system and compare its results with those of stimulated spontaneous reporting, and to assess the excess lengths of stay and costs of patients with verified adverse drug reactions.A prospective cohort study was used to assess the efficacy of computer-based monitoring, and case-matching was used to assess excess length of stay and costs.This was a study of all patients admitted to a medical ward of a university hospital in Germany between June and December 1997.379 patients were included, most of whom had infectious, gastrointestinal or liver diseases, or sleep apnoea syndrome. Patients admitted because of adverse drug reactions were excluded.All automatically generated laboratory signals and reports were evaluated by a team consisting of a clinical pharmacologist, a clinician and a pharmacist for their likelihood of being an adverse drug reaction. They were classified by severity and causality. For verified adverse drug reactions, control patients with similar primary diagnosis, age, gender and time of admission but without adverse drug reactions were matched to the cases in order to assess the excess length of hospitalisation caused by an adverse drug reaction.Adverse drug reactions were detected in 12% of patients by the computer-based monitoring system and stimulated spontaneous reporting together (46 adverse reactions in 45 patients) during 1718 treatment days. Computer-based monitoring identified adverse drug reactions in 34 cases, and stimulated spontaneous reporting in 17 cases. Only 5 adverse drug reactions were detected by both methods. The relative sensitivity of computer-based monitoring was 74% (relative specificity 75%), and that of stimulated spontaneous reporting was 37% (relative specificity 98%). All 3 serious adverse drug reactions were detected by computer-based monitoring, but only 2 out of the 3 were detected by stimulated spontaneous reporting. The percentage of automatically generated laboratory signals associated with an adverse drug reaction (positive predictive value) was 13%. The mean excess length of stay was 3.5 days per adverse drug reaction. 48% of adverse reactions were predictable and detected solely by computer-based monitoring. Therefore, the potential for savings on this ward from the introduction of computer-based monitoring can be calculated as EUR56 200/year ($US59 600/year) [ 1999 values].Computer monitoring is an effective method for improving the detection of adverse drug reactions in inpatients. The excess length of stay and costs caused by adverse drug reactions are substantial and might be considerably reduced by earlier detection.

The number and proportion of emergency admissions of elderly patients with multiple morbidities and correspondingly extensive medication plans has been increasing continuously in recent years (1, 2). Adverse drug events (ADEs) are common reasons for treatment, but are often not recognized as such (1, 3– 6). Adverse drug events are caused by either conventional adverse drug reactions (ADRs) (7) or medication errors (MEs) (6) that lead to clinical symptoms. Overall, greater attention to drug therapy safety seems to be necessary in elderly patients. To identify and prevent risks more easily, lists of potentially inappropriate medications (PIMs) for elderly patients have been developed on the basis of expert consensus. Well-known examples are the Beers list (8), the STOPP and START criteria (9), and, since 2010 in Germany, the PRISCUS list (10, 11). It is assumed that these potentially inappropriate medications are associated with an increased risk of ADEs in elderly patients. Current studies, however, indicate that PIMs are responsible for only a relatively small percentage of ADEs in elderly patients (1, 12, 13). Moreover, in the international literature on PIMs a substantial percentage of drugs and cases were excluded from analyses, and no distinction was made between MEs and ADRs (1, 14). This raises the question of the extent to which errors caused by methodological shortcomings when data on ADEs were collated led to database bias, causing the potential number of PIMs to be underestimated. There are currently no studies available on the occurrence of such events in acute clinical care for drugs on the PRISCUS list. This study therefore aimed to investigate the effects of PIMs on elderly patients admitted as emergency cases regarding ADEs, involving and not involving MEs.

Background/Aim: The female gender appears to suffer from more adverse drug reactions (ADRs) than the male gender. So far, there has been no epidemiologic study analyzing gender-based differences in drug prescribing and its ADR risks. The aim of the present study was to establish a drug risk stratification adjusted to age, number of prescriptions and drug classes with respect to gender differences based on intensive data acquisition methods. Method: A prospective multicenter study was conducted in several departments in Germany and Israel (pediatrics, medicine and geriatrics) enclosing 2,371 inpatients. Results: A total of 25,532 drug prescriptions during hospitalization were evaluated. At least 1 ADR was found in 774 patients (32.6%). Drugs for the cardiovascular system, nervous system, alimentary tract and musculoskeletal system were prescribed most often in females. The following drug classes led significantly more often to ADRs in women as compared to men: alimentary tract (OR 0.5; p = 0.0002), cardiovascular system (OR 0.72; p = 0.0140), musculoskeletal system (OR 0.31; p = 0.0004) and nervous system (OR 0.62; p = 0.0023). After adjustment to age, total number of prescriptions and drug class, only anti-infectives (antibacterials) and musculoskeletal system (anti-inflammatory) drugs stand out as causing more ADRs in women. Conclusion: Antibacterials and anti-inflammatory agents cause more ADRs in females as compared to males.

Computer-assisted signal generation is an important issue for the prevention of adverse drug reactions (ADRs). However, due to poor standardization of patients' medical data and a lack of computable medical drug knowledge the specificity of computerized decision support systems for early ADR detection is too low and thus those systems are not yet implemented in daily clinical practice. We report on a method to formalize knowledge about ADRs based on the Summary of Product Characteristics (SmPCs) and linking them with structured patient data to generate safety signals automatically and with high sensitivity and specificity.A computable ADR knowledge base (ADR-KB) that inherently contains standardized concepts for ADRs (WHO-ART), drugs (ATC) and laboratory test results (LOINC) was built. The system was evaluated in study populations of paediatric and internal medicine inpatients.A total of 262 different ADR concepts related to laboratory findings were linked to 212 LOINC terms. The ADR knowledge base was retrospectively applied to a study population of 970 admissions (474 internal and 496 paediatric patients), who underwent intensive ADR surveillance. The specificity increased from 7% without ADR-KB up to 73% in internal patients and from 19.6% up to 91% in paediatric inpatients, respectively.This study shows that contextual linkage of patients' medication data with laboratory test results is a useful and reasonable instrument for computer-assisted ADR detection and a valuable step towards a systematic drug safety process. The system enables automated detection of ADRs during clinical practice with a quality close to intensive chart review.

Several economic evaluations of adverse drug events (ADEs) exist, but the underlying methodology has not been standardized so far. The aim of the study was to combine prospective, intensive pharmacovigilance methods, and standardized accounting data to calculate direct costs of community-acquired ADEs (caADEs) contributing to emergency department (ED) admission and subsequent hospitalization.A prospective observational study with three phases extending over 2 years was implemented in a 749 bed tertiary care hospital with an annual ED census of approximately 45 000 patients. The patient records of all adult non-trauma ED admissions were systematically analyzed by a team of emergency physicians, clinical pharmacologists, and pharmacists for potential ADE. Associated diagnosis related group costs were extracted from standardized accounting data.Of 2262 patients attending the ED during the study periods, the hospitalization of 366 patients (16.2%) was related to one or more caADEs of which 97.5% were considered predictable and 62.0% were classified as preventable. The mean caADE-related diagnosis related group costs were €2743 (95% bias-corrected and accelerated CI: €2498 to €3018). Extrapolated to a national scale, this corresponds to caADE-related costs of €2.245bn for the German health insurance funds, annually. Costs of €1.310bn could be attributed to events classified as predictable and preventable.In an ED, caADEs are frequent, and a significant proportion of these events and their related costs appear to be predictable and preventable. The ED as a first-line provider for ADE cases appears to be an appropriate environment to implement strategic and operative improvements for enhanced patient safety.

The incidence of clinical events related to medication errors and/or adverse drug reactions reported in the literature varies by a degree that cannot solely be explained by the clinical setting, the varying scrutiny of investigators or varying definitions of drug-related events. Our hypothesis was that the individual complexity of many clinical cases may pose relevant limitations for current definitions and algorithms used to identify, classify and count adverse drug-related events.Based on clinical cases derived from an observational study we identified and classified common clinical problems that cannot be adequately characterized by the currently used definitions and algorithms.It appears that some key models currently used to describe the relation of medication errors (MEs), adverse drug reactions (ADRs) and adverse drug events (ADEs) can easily be misinterpreted or contain logical inconsistencies that limit their accurate use to all but the simplest clinical cases. A key limitation of current models is the inability to deal with complex interactions such as one drug causing two clinically distinct side effects or multiple drugs contributing to a single clinical event. Using a large set of clinical cases we developed a revised model of the interdependence between MEs, ADEs and ADRs and extended current event definitions when multiple medications cause multiple types of problems. We propose algorithms that may help to improve the identification, classification and counting of drug-related events.The new model may help to overcome some of the limitations that complex clinical cases pose to current paper- or software-based drug therapy safety.

Risperidone, a widely used atypical and potent neuroleptic drug, is assumed to induce fewer hepatic side-effects than phenothiazine anti-psychotics. Recently, we observed a case of risperidone-induced cholestatic hepatotoxicity. A 37-year-old male developed a rapid increase in liver enzymes and cholestatic parameters after starting treatment with risperidone for paranoid psychosis. Work-up for other potential aetiologies was negative. The results of a percutaneous liver biopsy were consistent with drug-induced liver injury and cholestasis. Over the course of one month after the discontinuance of all anti-psychotic agents, the liver function test results returned to near-normal values. This observation supports the need to monitor cholestatic parameters in addition to liver function enzymes during initiation and the first weeks of risperidone intake.

Endoscopic access to strictured biliodigestive anastomoses often is difficult and may require percutaneous transhepatic biliary drainage or reoperation. Push- or push-and-pull enteroscopy was used to diagnose disease and treat 24 postsurgical patients with suspected strictured biliodigestive anastomosis. Endoscopic retrograde cholangiography and biliary interventional procedures were used. Endoscopic accessibility, diagnosis of disease, therapeutic success, and complication rates were investigated at a single tertiary university gastroeneterology center. Push enteroscopy reached biliary enteroanastomoses in 5 of the 24 patients (20.8%), whereas push-and-pull enteroscopy found choledocho- or hepaticojejunostomies in 17 of the remaining 19 postsurgical patients (89.4%). In all, successful enteroscopic intervention was achieved for 21 of the 24 patients (87.5%), whereas only 3 patients had to undergo percutaneous cholangiodrainage (12.5%). Cicatricially changed biliodigestive anastomoses were found in 14 of 21 patients (66.6%) including a mucosal type stricture in 7 patients (50%), an intramural type stricture in 5 patients (35.7%), and a ductal type stricture in 2 patients (14.2%). The remaining seven patients (33.3%) were normal. Enteroscopic interventions at strictured biliodigestive anastomosis included ostium incision for 8 (57.1%) and endoprosthesis insertion for 13 (92.8%) of the 14 patients, with prompt resolution of cholestasis and cholangitis. The major complications for the 24 patients involving 68 double-balloon enteroscopy (DBE) examinations comprised 2 perforations (8.3% per patient), 1 mild peritonitis (4.1%), and 1 cholangitis (4.1%), whereas minor complications were experienced by up to 20.8% of the patients. Modern interventional enteroscopy yields a high rate of successful interventions for strictured biliodigestive anastomosis, requires ostium incision for mucosal and intramural types of strictures, and helps to reduce percutaneous approaches.

This study aims to describe the drug use on a Neonatal Intensive Care Unit (NICU) at a University Children’s Hospital in Germany, to investigate the licensing status of the drugs used and to conclude critical areas in neonatal intensive care to support prioritisation of future research. An 11-month, prospective cohort study was conducted on the NICU at the University Children’s Hospital Erlangen, Germany. All products prescribed during the study period were analysed whether or not the SPC contains information on term and preterm neonates. A total of 183 patients (102 male) with a mean gestational age of 33.6 weeks (minimum = 24, maximum = 42) were included. The mean length of hospitalisation was 19.4 days (minimum = 2, maximum = 167). On average, patients received 11.1 drugs (minimum = 0, maximum = 46). The majority of prescriptions were accounted for by antibiotics (n = 515), which were received by 90% of all patients, followed by CNS drugs (n = 448) and respiratory drugs (n = 306). Of all the different drugs prescribed (n = 102) only 38% had information regarding their use in patients aged less than 1 month in their SPC. Analgesics and cardiovascular drugs were prescribed frequently, but without having information for use in neonates. Seventy percent of all patients and 100% of very preterm infants received at least one of these drugs. Treatment strategies on a preterm intensive care unit are complex and little information is available for the drugs used. Analgesics and cardiovascular drugs are of major concern. Efforts will have to be made to conduct well-designed and powered studies in this vulnerable population.

Increasingly, patients are admitted to hospital as emergency cases beyond the remit of outpatient emergency care. The university medical center in Erlangen has registered annual increases of up to 10%. Thanks to the continuous availability of medical services, a large proportion of patients even present to hospitals independently (1, 2). The organizational structures of emergency departments vary widely, partly—but not entirely—owing to the links with rescue services and the general environment of the hospital. Different organizational approaches range from outpatient admission units with triage systems to special emergency outpatient clinics (“chest pain unit”) or admission units for emergencies where possible referrals/transfers to specialist wards or units are decided only after a time delay—for example, the next morning (1, 3– 6). Although triage instruments have become the quality standard in emergency departments, and time intervals—for example, from the patient’s arrival to initial contact with a doctor/nursing staff—can be measured in a replicable fashion, this does not allow any conclusions about the quality—in the sense of correctness/appropriateness of measures—or about the time it takes to reach a diagnosis. Ultimately, quality indicators are lacking in the heterogeneous area between outpatient care delivered by general practitioners and inpatient care (4, 7). The main requirements for an emergency department are, however, homogenous. They consist of recognizing the acutely life threatening condition of the patient, providing appropriate treatment, or referring the patient for such treatment. This process comprises primary diagnostics and risk stratification on the basis of lead symptoms, initial care, and organization of further specialist diagnostic tests and treatment (1, 2, 6, 8). The present study aims to investigate whether on the basis of data from the hospital information system—data whose documentation is mandatory and that are available in an electronic format—objectifiable numerical parameters of an emergency department can be calculated and used as potential quality indicators.

Several publications indicate that the female gender experiences a higher incidence of adverse drug reactions (ADRs) than does the male gender. The reasons, however, remain unclear. Gender-specific differences in the pharmacokinetic and pharmacodynamic behaviour of drugs could not be identified as an explanation. The aim of this study was to analyse ADR risk with respect to gender, age and number of prescribed drugs. A prospective multicenter study based on intensive pharmacovigilance was conducted. Information on patient characteristics and evaluated ADRs was stored in a pharmacovigilance database—KLASSE. In 2,371 patients (1,012 female subjects), 25,532 drugs were prescribed. In 782 patients, at least one ADR was found. A multivariate regression analysis adjusting for age, body mass index (BMI) and number of prescribed drugs showed a significant influence of female gender on the risk of encountering ADRs [odds ratio (OR) 1.596, confidence interval (CI) 1.31–1.94; p

We determined in vitro the potency of macrolides as P-glycoprotein inhibitors and tested in hospitalised patients whether coadministration of P-glycoprotein inhibitors leads to increased serum concentrations of the P-glycoprotein substrates digoxin and digitoxin. In vitro, the effect of macrolides on polarised P-glycoprotein-mediated digoxin transport was investigated in Caco-2 cells. In a pharmacoepidemiological study, we analysed the serum digoxin and digitoxin concentrations with and without coadministration of P-glycoprotein inhibitors in hospitalised patients. All macrolides inhibited P-glycoprotein-mediated digoxin transport, with concentrations producing 50% inhibition (IC50) values of 1.8, 4.1, 15.4, 21.8 and 22.7 μmol/L for telithromycin, clarithromycin, roxithromycin, azithromycin and erythromycin, respectively. Coadministration of P-glycoprotein inhibitors was associated with increased serum concentrations of digoxin (1.3 ± 0.6 vs 0.9 ± 0.5 ng/mL, p < 0.01). Moreover, patients receiving macrolides had higher serum concentrations of cardiac glycosides (p < 0.05). Macrolides are potent inhibitors of P-glycoprotein. Drug interactions between P-glycoprotein inhibitors and substrates are likely to occur during hospitalisation.

Objective Recent findings suggest that permanent blockade of cyclooxygenase 2 (COX-2) is one factor contributing to the cardiovascular side effects of selective COX-2 inhibitors (coxibs) and nonsteroidal antiinflammatory drugs (NSAIDs). The present study compared the extent and time course of COX-2 inhibition and the effects on cardiovascular parameters (changes in blood pressure and heart rate) between various antirheumatic doses of diclofenac, celecoxib, and rofecoxib in healthy elderly volunteers. Methods A randomized, parallel-group study was conducted in volunteers receiving 75 mg diclofenac twice daily, 200 mg celecoxib twice daily, or 25 mg rofecoxib once daily for 8 days. Blood samples were obtained predose and at specified time points postdose, on days 1 and 8, for assay of drug plasma concentrations and COX-2 inhibition. Lipopolysaccharide-induced prostaglandin E2 synthesis was measured ex vivo as an index of COX-2 activity in human whole blood. Results COX-2 inhibition was significantly less pronounced after treatment with celecoxib and rofecoxib than with diclofenac. Maximal inhibitions after a single dose and at steady state, respectively, were as follows: 99% and 99% with diclofenac, 70% and 81% with celecoxib, and 56% and 72% with rofecoxib. At steady state, only diclofenac caused virtually complete COX-2 inhibition over the whole dose interval, and this corresponded to the highest increase in systolic blood pressure and greatest reduction in heart rate. Conclusion Diclofenac elicited the most pronounced COX-2 inhibition, blood pressure elevation, and suppression of heart rate. It is assumed that the extent and time course of intravascular COX-2 inhibition may determine the differential profile of cardiovascular side effects associated with NSAIDs and coxibs, but this has to be proven in future studies.

Up to 23% of the population, depending on their ethnic background, has genetically determined differences in the metabolism of drugs by the cytochrome P450 (CYP) enzymes CYP2C9, CYP2C19 and CYP2D6. The aim of this survey was to determine the relationship between genetical polymorphisms in these CYP enzymes and adverse drug reactions (ADRs) in geriatric patients. In a prospective 6-month cohort study of 243 patients in a geriatric rehabilitation ward, mean age 80.2 ± 7.7 years, ADRs were identified by intensive monitoring by a pharmacoepidemiological team, consisting of pharmacists and physicians. 125 out of these 243 patients were genotyped cross-sectionally for polymorphisms of CYP2C9, CYP2C19 and CYP2D6 by the TaqMan-polymerase chain reaction. The main outcome measures were the prevalence of genetical polymorphisms and the patients’ risk for developing an ADR as related to the genotype. Patients received an average of 14.2 drugs during hospitalisation which led to 251 ADRs in the whole cohort and 149 ADRs in the cross-sectional genotyping study. Genotype frequencies of CYP2C9 enzyme were 25.9% (n = 29) intermediate metabolisers (IMs) and 2.7% (n = 3) poor metabolisers (PMs). For the enzyme CYP2C19, 26.8% (n = 33) IMs and 0.8% (n = 1) PMs were detected. For the enzyme CYP2D6, 24.1% (n = 26) IMs and 3.7% (n = 4) PMs were found in the analysed patient population. In total, 61.6% (n = 77) of genotyped patients experienced mutations in at least one of the three cytochrome enzymes. The ADR rate did not differ significantly between patients with genetic mutations and wild-type genotype patients. Moreover, only eight out of 40 ADRs which were associated with drugs metabolised by CYP2C9, CYP2C19 or CYP2D6 were detected in patients with IM genotype and none in patients with PM genotype. In this investigation geriatric patients showed a high rate of ADRs. However, no association between the ADR rate and the patients’ genotype could be detected, which most likely was a result of the small number of patient samples analysed. Although prophylactic genotyping would have not prevented ADRs in this pilot study, physicians nevertheless have to be aware of potential genetic mutations in patients with polypharmacy.

AIM: To evaluate double balloon enteroscopy (DBE) in post-surgical patients to perform endoscopic retrograde cholangiopancreatography (ERCP) and interventions. METHODS: In 37 post-surgical patients, a stepwise approach was performed to reach normal papilla or enteral anastomoses of the biliary tract/pancreas. When conventional endoscopy failed, DBE-based ERCP was performed and standard parameters for DBE, ERCP and interventions were recorded. RESULTS: Push-enteroscopy (overall, 16 procedures) reached enteral anastomoses only in six out of 37 post-surgical patients (16.2%). DBE achieved a high rate of luminal access to the biliary tract in 23 of the remaining 31 patients (74.1%) and to the pancreatic duct (three patients). Among all DBE-based ERCPs (86 procedures), 21/23 patients (91.3%) were successfully treated. Interventions included ostium incision or papillotomy in 6/23 (26%) and 7/23 patients (30.4%), respectively. Biliary endoprosthesis insertion and regular exchange was achieved in 17/23 (73.9%) and 7/23 patients (30.4%), respectively. Furthermore, bile duct stone extraction as well as ostium and papillary dilation were performed in 5/23 (21.7%) and 3/23 patients (13.0%), respectively. Complications during DBE-based procedures were bleeding (1.1%), perforation (2.3%) and pancreatitis (2.3%), and minor complications occurred in up to 19.1%. CONCLUSION: The appropriate use of DBE yields a high rate of luminal access to papilla or enteral anastomoses in more than two-thirds of post-surgical patients, allowing important successful endoscopic therapeutic interventions.