Adverse drug events caused by three high-risk drug-drug interactions in patients admitted to intensive care units: A multicentre retrospective observational study.

AIMS: Knowledge about adverse drug events caused by drug-drug interactions (DDI-ADEs) is limited. We aimed to provide detailed insights about DDI-ADEs related to three frequent, high-risk potential DDIs (pDDIs) in the critical care setting: pDDIs with international normalized ratio increase (INR+ ) potential, pDDIs with acute kidney injury (AKI) potential, and pDDIs with QTc prolongation potential. METHODS: We extracted routinely collected retrospective data from electronic health records of intensive care units (ICUs) patients (≥18 years), admitted to ten hospitals in the Netherlands between January 2010 and September 2019. We used computerized triggers (e-triggers) to preselect patients with potential DDI-ADEs. Between September 2020 and October 2021, clinical experts conducted a retrospective manual patient chart review on a subset of preselected patients, and assessed causality, severity, preventability, and contribution to ICU length of stay of DDI-ADEs using internationally prevailing standards. RESULTS: In total 85 422 patients with ≥1 pDDI were included. Of these patients, 32 820 (38.4%) have been exposed to one of the three pDDIs. In the exposed group, 1141 (3.5%) patients were preselected using e-triggers. Of 237 patients (21%) assessed, 155 (65.4%) experienced an actual DDI-ADE; 52.9% had severity level of serious or higher, 75.5% were preventable, and 19.3% contributed to a longer ICU length of stay. The positive predictive value was the highest for DDI-INR+ e-trigger (0.76), followed by DDI-AKI e-trigger (0.57). CONCLUSION: The highly preventable nature and severity of DDI-ADEs, calls for action to optimize ICU patient safety. Use of e-triggers proved to be a promising preselection strategy.

The effect of structured medication review followed by face-to-face feedback to prescribers on adverse drug events recognition and prevention in older inpatients - a multicenter interrupted time series study.

BACKGROUND: The effectiveness of interventions to improve medication safety in older inpatients is unclear, given a paucity of properly designed intervention studies applying clinically relevant endpoints such as hospital-acquired preventable Adverse Drug Events (pADEs) and unrecognized Adverse Drug Events (uADEs). Therefore, we conducted a quality improvement study and used hospital-acquired pADEs and uADEs as main outcomes to assess the effect of an intervention aimed to improve medication safety in older inpatients. METHOD: The study followed an interrupted time series design and consisted of three equally spaced sampling points during baseline and during intervention measurements. Each sampling point included between 80 to 90 patients. A total of 500 inpatients ≥65 years and admitted to internal medicine wards of three Dutch hospitals were included. An expert team retrospectively identified and assessed ADEs via a structured patient chart review. The findings from baseline measurement and meetings with the internal medicine and hospital pharmacy staff were used to design the intervention. The intervention consisted of a structured medication review by hospital pharmacists, followed by face-to-face feedback to prescribers, on average 3 days per week. RESULTS: The rate of hospital-acquired pADEs per 100 hospitalizations was reduced by 50.6% (difference 16.8, 95% confidence interval (CI): 9.0 to 24.6, P <  0.001), serious hospital-acquired pADEs by 62.7% (difference 12.8, 95% CI: 6.4 to 19.2, P <  0.001), and uADEs by 51.8% (difference 11.2, 95% CI: 4.4 to 18.0, P <  0.001). Additional analyses confirmed the robustness of the intervention effect, but residual bias cannot be excluded. CONCLUSIONS: The intervention significantly decreased the overall and serious hospital-acquired pADE occurrence in older inpatients, and significantly improved overall ADE recognition by prescribers. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number Register, trial registration number: ISRCTN64974377 , registration date (date assigned): 07/02/2011.

Adverse drug events in older hospitalized patients: results and reliability of a comprehensive and structured identification strategy.

BACKGROUND: Older patients are at high risk for experiencing Adverse Drug Events (ADEs) during hospitalization. To be able to reduce ADEs in these vulnerable patients, hospitals first need to measure the occurrence of ADEs, especially those that are preventable. However, data on preventable ADEs (pADEs) occurring during hospitalization in older patients are scarce, and no 'gold standard' for the identification of ADEs exists. METHODOLOGY: The study was conducted in three hospitals in the Netherlands in 2007. ADEs were retrospectively identified by a team of experts using a comprehensive and structured patient chart review (PCR) combined with a trigger-tool as an aid. This ADE identification strategy was applied to a cohort of 250 older hospitalized patients. To estimate the intra- and inter-rater reliabilities, Cohen's kappa values were calculated. PRINCIPAL FINDINGS: In total, 118 ADEs were detected which occurred in 62 patients. This ADE yield was 1.1 to 2.7 times higher in comparison to other ADE studies in older hospitalized patients. Of the 118 ADEs, 83 (70.3%) were pADEs; 51 pADEs (43.2% of all ADEs identified) caused serious patient harm. Patient harm caused by ADEs resulted in various events. The overall intra-rater agreement of the developed strategy was substantial (κ = 0.74); the overall inter-rater agreement was only fair (κ = 0.24). CONCLUSIONS/SIGNIFICANCE: The ADE identification strategy provided a detailed insight into the scope of ADEs occurring in older hospitalized patients, and showed that the majority of (serious) ADEs can be prevented. Several strategy related aspects, as well as setting/study specific aspects, may have contributed to the results gained. These aspects should be considered whenever ADE measurements need to be conducted. The results regarding pADEs can be used to design tailored interventions to effectively reduce harm caused by medication errors. Improvement of the inter-rater reliability of a PCR remains challenging.

Frequency and nature of drug-drug interactions in the intensive care unit.

PURPOSE: Drug-drug interactions (DDIs) may compromise patient safety. However, there are no good estimates of their frequency or understanding of their nature in the intensive care unit (ICU). The objective of this study was to determine the frequency and nature of potential DDIs (pDDIs) in the ICU when assessed in light of documented and perceived clinical relevance. METHODS: We developed a computerized algorithm to identify pDDI occurrence in ICU admissions with medication administration, on the basis of the Dutch national drug database. A panel of nine local pharmacists and intensivists completed questionnaires to classify the perceived relevance of the identified pDDI types for the ICU. A focus group discussed the conflicting classifications of relevance to reach consensus. For the pDDI types classified as relevant, we calculated their number and frequency per admission days. RESULTS: Out of 9644 admissions, 3892 had at least one pDDI. The pDDIs corresponded to 85 types, 36 of which were deemed relevant on the basis of the survey and focus group. These 36 types corresponded to 16,122 pDDIs (rate: 33.6 per 100 admission days) and 1084 unique admissions. PDDIs occurred in 11% of admissions to the general ICU, after limiting analysis to severe and relevant DDI types. The most frequently encountered drug classes were antithrombotic agents and antibacterials for systemic use. CONCLUSIONS: There are many potential DDIs with high perceived relevance in the ICU that appear to require attention and follow-up. Computerized decision support may help reduce the number of pDDIs but needs to be tailored to the environment in which it operates.

Recognition of adverse drug events in older hospitalized medical patients.

OBJECTIVE: To assess medical teams' ability to recognize adverse drug events (ADEs) in older inpatients. METHODS: The study cohort comprised 250 patients aged 65 years or older consecutively admitted to Internal Medicine wards of three hospitals in the Netherlands between April and November 2007. An independent expert team identified ADEs present upon admission or occurring during hospitalization by a structured retrospective patient chart review. For all ADEs identified, the expert team assessed causality, severity, preventability, and recognition by medical teams. RESULTS: The medical teams did not recognize 19.9 % of all ADEs present upon admission {60.4 ADEs [95 % confidence interval (CI) 51.5-70.8] per 100 hospitalizations} and 20.3 % of all ADEs occurring during the hospital stay [47.2 ADEs (95 % CI 39.4-56.5) per 100 hospitalizations]. Unrecognized ADEs were significantly more often ADEs with possible causality (p=0.014, df=1), ADEs caused by medication errors (p<0.001, df=1), and ADEs not manifesting as new symptoms (p<0.001, df=1). The medical teams did not recognize 23.2 % of mild to moderately severe ADEs and 16.5 % of severe, life-threatening, or fatal ADEs. The recognition of ADEs varied with event type. CONCLUSIONS: The recognition of ADEs by medical teams was substantial for those ADEs with evident causality and with clinically apparent and severe consequences. ADEs mimicking underlying pathologies with a lower severity went unrecognized much more often, as did those resulting only in abnormal laboratory values. Tools to improve the recognition of ADEs by medical teams should, therefore, focus on those ADEs that are more challenging to detect.

Association between acute geriatric syndromes and medication-related hospital admissions.

BACKGROUND: Elderly patients are at a 4-fold higher risk of adverse drug events (ADEs) and drug-related hospitalization. Hospitalization of an elderly patient is often preceded by geriatric syndromes, like falls or delirium. OBJECTIVES: The primary aim of this study was to investigate whether geriatric syndromes were associated with ADEs in acutely admitted elderly patients. METHODS: Consecutive medical patients, aged 65 years or more, who were acutely admitted, were enrolled. An initial multidisciplinary evaluation was completed and baseline characteristics were collected. A fall before admission was retrieved from medical charts. Delirium was determined by the Confusion Assessment Method. RESULTS: A total of 641 patients were included. Over 25% had an ADE present at admission, 26% presented with delirium and 12% with a fall. Delirium was associated with the use of antidepressants, antipsychotics and antiepileptics. In all ADEs (n = 167), ADEs were associated with a fall, with non-steroidal anti-inflammatory drugs or diuretics, but not with pre-existing functioning, delirium or older age. For ADEs involving psychoactive medication (n = 35), an association was found between delirium, falls, opioids and antipsychotics in bivariate analyses. A fall just before hospitalization (odds ratio [OR] 3.69 [95% CI 1.41, 9.67]), antipsychotics (OR 3.70 [95% CI 1.19, 11.60]) and opioids (OR 14.57 [95% CI 2.02, 105.30]) remained independently associated with an ADE involving psychoactive medication. CONCLUSION: This prospective study demonstrated that, in a cohort of elderly hospital patients, a fall before admission and prevalent delirium are associated with several pharmacological groups and/or with ADE-related hospital admission.

Pleconaril revisited: clinical course of chronic enteroviral meningoencephalitis after treatment correlates with in vitro susceptibility.

BACKGROUND: Human enteroviruses (HEVs) can cause severe infections, especially in patients with a deficient humoral immune response, such as X-linked agammaglobulinemia. In this patient group, chronic enteroviral meningitis (CEMA) is feared because of extensive morbidity and high fatality rate. Treatment options consist of intravenous immunoglobulin (IVIG), with various outcomes. Pleconaril is an antiviral agent with in vitro activity against HEVs that has been used in the treatment of HEV infections. METHODS: The efficacy of pleconaril and IVIG against HEV isolated from the patients was assessed in vitro in two patients with CEMA. RESULTS: Echovirus 11 was found in the cerebrospinal fluid (CSF) of case 1. Treatment with high-dose IVIG and pleconaril did not provide any clinical improvement and HEV PCR in CSF remained positive. Case 2 (echovirus 13 positive in CSF) was also treated with IVIG and pleconaril. The patient recovered completely and HEV PCR in CSF became negative. Recent IVIG batches contained low titres of neutralizing antibodies against the patient strains. Echovirus 11 (case 1) was resistant to pleconaril in vitro, whereas echovirus 13 (case 2) was susceptible, in accordance with virological response after treatment and subsequent clinical results. CONCLUSIONS: This is the first report that evaluates efficacy of antiviral treatment in CEMA patients in relation to in vitro susceptibility of clinical virus isolates. Since pleconaril is no longer available for compassionate use we strongly propagate that new drugs should be developed against these potential life threatening HEV infections.

Studies pertaining to the ACOVE quality criteria: a systematic review.

PURPOSE: To identify and uniformly describe studies employing the Assessing Care Of Vulnerable Elders (ACOVE) quality indicators within a comprehensive thematic model that reflects how the indicators were used. DATA SOURCES: A systematic search of MEDLINE, EMBASE and CINAHL was conducted. STUDY SELECTION: English-language studies meeting our criteria published prior to January 2010. Data extraction Included studies were analyzed and described by two independent researchers. RESULTS OF DATA SYNTHESIS: A total of 41 articles met our selection criteria. Studies were classified into the themes 'Application of indicators' (32 studies) and ' ANALYSIS: and development of indicators' (13 studies). 'Application' studies included assessing quality of care, influencing behavior of health professionals and examining the association of quality of care with other factors. 'Analysis and development' included studies developing new indicator sets, and those adapting and validating the original quality indicators to new settings. CONCLUSIONS: The indicators were used in a wide range of applications with two main foci: the assessment of quality of care for elderly patients, and investigating the feasibility of similar indicators and their adaptation to new settings. Very few of the studies published to date have addressed the goal of care improvement. We foresee an important role for application of indicators that proactively help health-care professionals to deliver the right care at the right time, for example by resorting to decision support systems.

Assessing quality of care of elderly patients using the ACOVE quality indicator set: a systematic review.

BACKGROUND: Care of the elderly is recognized as an increasingly important segment of health care. The Assessing Care Of Vulnerable Elderly (ACOVE) quality indicators (QIs) were developed to assess and improve the care of elderly patients. OBJECTIVES: The purpose of this review is to summarize studies that assess the quality of care using QIs from or based on ACOVE, in order to evaluate the state of quality of care for the reported conditions. METHODS: We systematically searched MEDLINE, EMBASE and CINAHL for English-language studies indexed by February 2010. Articles were included if they used any ACOVE QIs, or adaptations thereof, for assessing the quality of care. Included studies were analyzed and relevant information was extracted. We summarized the results of these studies, and when possible generated an overall conclusion about the quality of care as measured by ACOVE for each condition, in various settings, and for each QI. RESULTS: Seventeen studies were included with 278 QIs (original, adapted or newly developed). The quality scores showed large variation between and within conditions. Only a few conditions showed a stable pass rate range over multiple studies. Overall, pass rates for dementia (interquartile range (IQR): 11%-35%), depression (IQR: 27%-41%), osteoporosis (IQR: 34%-43%) and osteoarthritis (IQR: 29-41%) were notably low. Medication management and use (range: 81%-90%), hearing loss (77%-79%) and continuity of care (76%-80%) scored higher than other conditions. Out of the 278 QIs, 141 (50%) had mean pass rates below 50% and 121 QIs (44%) had pass rates above 50%. Twenty-three percent of the QIs scored above 75%, and 16% scored below 25%. CONCLUSIONS: Quality of care per condition varies markedly across studies. Although there has been much effort in improving the care for elderly patients in the last years, the reported quality of care according to the ACOVE indicators is still relatively low.

The effect of an active on-ward participation of hospital pharmacists in Internal Medicine teams on preventable Adverse Drug Events in elderly inpatients: protocol of the WINGS study (Ward-oriented pharmacy in newly admitted geriatric seniors).

BACKGROUND: The potential of clinical interventions, aiming at reduction of preventable Adverse Drug Events (preventable ADEs) during hospital stay, have been studied extensively. Clinical Pharmacy is a well-established and effective service, usually consisting of full-time on-ward participation of clinical pharmacists in medical teams. Within the current Hospital Pharmacy organisation in the Netherlands, such on-ward service is less feasible and therefore not yet established. However, given the substantial incidence of preventable ADEs in Dutch hospitals found in recent studies, appears warranted. Therefore, "Ward-Oriented Pharmacy", an on-ward service tailored to the Dutch hospital setting, will be developed. This service will consist of multifaceted interventions implemented in the Internal Medicine wards by hospital pharmacists. The effect of this service on preventable ADEs in elderly inpatients will be measured. Elderly patients are at high risk for ADEs due to multi-morbidity, concomitant disabilities and polypharmacy. Most studies on the incidence and preventability of ADEs in elderly patients have been conducted in the outpatient setting or on admission to a hospital, and fewer in the inpatient setting. Moreover, recognition of ADEs by the treating physicians is challenging in elderly patients because their disease presentation is often atypical and complex. Detailed information about the performance of the treating physicians in ADE recognition is scarce. METHODS/DESIGN: The design is a multi-centre, interrupted time series study. Patients of 65 years or older, consecutively admitted to Internal Medicine wards will be included. After a pre-measurement, a Ward-Oriented Pharmacy service will be introduced and the effect of this service will be assessed during a post-measurement. The primary outcome measures are the ADE prevalence on admission and ADE incidence during hospital stay. These outcomes will be assessed using structured retrospective chart review by an independent expert panel. This assessment will include determination of causality, severity and preventability of ADEs. In addition, the extent to which ADEs are recognised and managed by the treating physicians will be considered. DISCUSSION: The primary goal of the WINGS study is to assess whether a significant reduction in preventable ADEs in elderly inpatients can be achieved by a Ward-Oriented Pharmacy service offered. A comprehensive ADE detection method will be used based on expert opinion and retrospective, trigger-tool enhanced, chart review.

Quality indicators for in-hospital pharmaceutical care of Dutch elderly patients: development and validation of an ACOVE-based quality indicator set.

BACKGROUND: In 2001, the ACOVE (Assessing Care Of Vulnerable Elders) quality indicators (QIs) were developed in the US to measure the quality of care of vulnerable elderly patients. However, the ACOVE QI set was developed mainly to assess the overall quality of care of community-dwelling vulnerable elders (as opposed to hospitalized elderly). Therefore, they need to be adapted when used in a non-US hospital setting. In addition, the ACOVE QIs depend on patient and caretaker interviews to assess the quality of care. OBJECTIVE: The aim of this study was to develop and validate a set of explicitly phrased QIs to measure (without the need for interviews) the quality of pharmaceutical care of elderly hospitalized patients in the Netherlands. STUDY DESIGN: The QI set was developed based on the ACOVE QIs, Dutch national guidelines, evidence from the literature and expert opinion. The QI set focused on in-hospital pharmaceutical care and was evaluated in terms of whether the QIs were able to assess the quality of care using medical records and a hospital information system. In three review rounds, the QI set was adapted and judged on face and content validity. The feasibility of implementation of the QI set and inter-rater reliability were determined. SETTING: The study was conducted between September 2007 and August 2008 in a tertiary 1002-bed university hospital. RESEARCH TEAM: Two pharmacists were responsible for the selection and adaptation of QIs. An internist-geriatrician, a physician with experience in quality assurance and internal medicine and a senior hospital pharmacist formed the expert panel responsible for reviewing the QIs. MEASUREMENTS: Fleiss' κ values and the intraclass correlation coefficient were calculated for inter-rater reliability. RESULTS: An 87-item QI set was accepted by the expert panel. Of this set, 49 QIs were based on ACOVE QIs and 38 QIs were newly added. The QI set demonstrated excellent inter-rater reliability and good feasibility. CONCLUSIONS: We developed a valid and reliable set of QIs to efficiently assess the quality of the in-hospital pharmaceutical care provided to elderly Dutch patients.

Towards evidence-based pharmacotherapy in children.

In daily practice, it is difficult to find a registered drug for children, because about 70% of the drugs prescribed in children are not studied, off-label or unlicensed in this age group. Clinical trials have usually been performed in adults, and then in daily practice dosages are adjusted for children without proper studies in that age group. In some countries, national formularies are being established to overcome the existing variance in prescribing between physicians. Complicating factors in finding the correct dosage for children include the heterogeneity between different age groups in the developmental stages of the organs influencing the absorption, distribution, metabolism, and excretion as well as differences in body composition during growth. Growth may also influence the effects and adverse effects of a drug used in a child. For oral administration of drugs in children, the bioavailability, the taste, the composition, and the absence of toxic ingredients for that age group are additional important factors. The EU has recently introduced legislation to stimulate the pharmaceutical industry to investigate the pharmacological effect and safety of new medicines in children. In response to this legislation, research networks are being established to provide the optimal infrastructure for pediatric drug investigation. The goals of this paper are to review the current problems in daily practice and to address the needs for evidence based pharmacotherapy in children.

Application of the Bow-Tie model in medication safety risk analysis: consecutive experience in two hospitals in the Netherlands.

BACKGROUND: To improve medication safety effectively, one should systematically analyse and assess the risks for medication errors and determine the possible causes. So far, no risk-analysis instrument exists in healthcare that can be used to analyse and visualize risks, causes and consequences of potential adverse events in a prospective manner. In high-risk industries such as petrochemistry and aviation, the Bow-Tie model is frequently used. This model combines causes, errors, preventive and recovery measures, and consequences in one model and gives insight into the magnitude and causes of existing safety risks. The aim of our project was to study the usefulness of the Bow-Tie model in the hospital setting for prospective analysis of risks in the medication process in order to develop a practicable method. METHODS: The model was first adapted to the clinical setting. Thereafter, the risk-analysis model was applied in a large tertiary teaching hospital in multidisciplinary sessions. The sessions and risk-analysis method were evaluated on the following aspects: applicability, comprehensibility, creation of awareness in and motivation of participants, and the capability of the 'system approach' (the approach taken by the Bow-Tie model, which focuses on the conditions under which individuals work and tries to build defences to avert errors or mitigate their effects, in contrast to a 'person approach', which focuses on errors of individuals, blaming them for forgetfulness, inattention etc.). Based on this evaluation, the risk analysis method was adjusted and consecutively applied in a general teaching hospital. After evaluation of the sessions in the second hospital a recommended method for risk analysis with the Bow-Tie model was defined. RESULTS: The risk-analysis method with the Bow-Tie model in the first hospital gave insight into many medication safety-related risks. However, the method was insufficient on comprehensibility and on the creation of awareness and motivation owing to a great number of determined risks which made thorough analysis, drawing of Bow-Ties and prioritizing difficult. The adjusted method in the second hospital focused more on the in-depth analysis of a small number of important safety issues of a department with specific attention for underlying causes. This approach was considered better in applicability, comprehensibility and the creation of awareness. Furthermore, by analyzing underlying causes, more attention could be paid to latent conditions (which can translate into error-provoking conditions) within the system. CONCLUSION: We found the Bow-Tie to be an appropriate model for prospective risk analysis of medication safety in a hospital. By applying the model in two hospitals consecutively we developed a feasible method for risk-analysis sessions. Key factors of this recommended method are a focus on the prioritized selection of safety issues and specific attention to latent conditions within the system by analysing these safety issues in depth to the root causes with the help of the Bow-Tie model.