The effect of computerised decision support alerts tailored to intensive care on the administration of high-risk drug combinations, and their monitoring: a cluster randomised stepped-wedge trial.

BACKGROUND: Drug-drug interactions (DDIs) can harm patients admitted to the intensive care unit (ICU). Yet, clinical decision support systems (CDSSs) aimed at helping physicians prevent DDIs are plagued by low-yield alerts, causing alert fatigue and compromising patient safety. The aim of this multicentre study was to evaluate the effect of tailoring potential DDI alerts to the ICU setting on the frequency of administered high-risk drug combinations. METHODS: We implemented a cluster randomised stepped-wedge trial in nine ICUs in the Netherlands. Five ICUs already used potential DDI alerts. Patients aged 18 years or older admitted to the ICU with at least two drugs administered were included. Our intervention was an adapted CDSS, only providing alerts for potential DDIs considered as high risk. The intervention was delivered at the ICU level and targeted physicians. We hypothesised that showing only relevant alerts would improve CDSS effectiveness and lead to a decreased number of administered high-risk drug combinations. The order in which the intervention was implemented in the ICUs was randomised by an independent researcher. The primary outcome was the number of administered high-risk drug combinations per 1000 drug administrations per patient and was assessed in all included patients. This trial was registered in the Netherlands Trial Register (identifier NL6762) on Nov 26, 2018, and is now closed. FINDINGS: In total, 10 423 patients admitted to the ICU between Sept 1, 2018, and Sept 1, 2019, were assessed and 9887 patients were included. The mean number of administered high-risk drug combinations per 1000 drug administrations per patient was 26·2 (SD 53·4) in the intervention group (n=5534), compared with 35·6 (65·0) in the control group (n=4353). Tailoring potential DDI alerts to the ICU led to a 12% decrease (95% CI 5-18%; p=0·0008) in the number of administered high-risk drug combinations per 1000 drug administrations per patient, after adjusting for clustering and prognostic factors. INTERPRETATION: This cluster randomised stepped-wedge trial showed that tailoring potential DDI alerts to the ICU setting significantly reduced the number of administered high-risk drug combinations. Our list of high-risk drug combinations can be used in other ICUs, and our strategy of tailoring alerts based on clinical relevance could be applied to other clinical settings. FUNDING: ZonMw.

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.

Heterogeneity in the Identification of Potential Drug-Drug Interactions in the Intensive Care Unit: A Systematic Review, Critical Appraisal, and Reporting Recommendations.

Patients admitted to the intensive care unit (ICU) are frequently exposed to potential drug-drug interactions (pDDIs). However, reported frequencies of pDDIs in the ICU vary widely between studies. This can be partly explained by significant variation in their methodological approach. Insight into methodological choices affecting pDDI frequency would allow for improved comparison and synthesis of reported pDDI frequencies. This study aimed to evaluate the association between methodological choices and pDDI frequency and formulate reporting recommendations for pDDI frequency studies in the ICU. The MEDLINE database was searched to identify papers reporting pDDI frequency in ICU patients. For each paper, the pDDI frequency and methodological choices such as pDDI definition and pDDI knowledge base were extracted, and the risk of bias was assessed. Each paper was categorized as reporting a low, medium, or high pDDI frequency. We sought associations between methodological choices and pDDI frequency group. Based on this comparison, reporting recommendations were formulated. Analysis of methodological choices showed significant heterogeneity between studies, and 65% of the studies had a medium to high risk of bias. High risk of bias, small sample size, and use of drug prescriptions instead of administrations were related to a higher pDDI frequency. The findings of this review may support researchers in designing a reliable methodology assessing pDDI frequency in ICU patients. The reporting recommendations may contribute to standardization, comparison, and synthesis of pDDI frequency studies, ultimately improving knowledge about pDDIs in and outside the ICU setting.

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

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

Improving medication safety in the Intensive Care by identifying relevant drug-drug interactions - Results of a multicenter Delphi study.

PURPOSE: Drug-drug interactions (DDIs) may cause adverse outcomes in patients admitted to the Intensive Care Unit (ICU). Computerized decision support systems (CDSSs) may help prevent DDIs by timely showing relevant warning alerts, but knowledge on which DDIs are clinically relevant in the ICU setting is limited. Therefore, the purpose of this study was to identify DDIs relevant for the ICU. MATERIALS AND METHODS: We conducted a modified Delphi procedure with a Dutch multidisciplinary expert panel consisting of intensivists and hospital pharmacists to assess the clinical relevance of DDIs for the ICU. The procedure consisted of two rounds, each included a questionnaire followed by a live consensus meeting. RESULTS: In total the clinical relevance of 148 DDIs was assessed, of which agreement regarding the relevance was reached for 139 DDIs (94%). Of these 139 DDIs, 53 (38%) were considered not clinically relevant for the ICU setting. CONCLUSIONS: A list of clinically relevant DDIs for the ICU setting was established on a national level. The clinical value of CDSSs for medication safety could be improved by focusing on the identified clinically relevant DDIs, thereby avoiding alert fatigue.

ß-Blocker use is associated with a higher relapse risk of inflammatory bowel disease: a Dutch retrospective case-control study.

OBJECTIVE: Inflammatory bowel disease (IBD) is a multifactorial disease and many factors may influence the disease course, like the concomitant use of medication. An example thereof is the use of ß-blockers, antagonizing ß-adrenergic receptors. ß-adrenergic receptor activation has potent anti-inflammatory effects on the immune system. We addressed whether an association exists between the use of beta-blockers and the course of IBD, defined by the risk of a disease relapse in patients with IBD. PATIENTS AND METHODS: In this retrospective case-control study, we used a population-based cohort of patients with IBD. We identified colitis relapses using IBD medication prescriptions as a proxy. We calculated the number of relapses per 100 person-years and compared this between patients with IBD using ß-blockers and patients with IBD not using ß-blockers. We used Cox proportional hazards models with shared frailty to compare the relative relapse risk between both groups. RESULTS: A total of 250 patients with IBD were included, of which 30 patients used a ß-blocker for at least 3 months. With the Cox proportional hazards model with shared frailty, adjusted for age and sex, we observed a 54% (hazard ratio: 1.54; 95% confidence interval: 1.05-2.25; P=0.03) higher risk of a relapse in the group of patients with IBD using ß-blockers versus the group not using ß-blockers. CONCLUSION: Even in this limited cohort study, we show that patients with IBD using ß-blockers have an increased relapse risk. Indeed, concomitant medication use seems to be a factor that can influence the course of IBD, and this should be acknowledged while making decisions about treatment of IBD and follow-up.