The effect of medication related clinical decision support at the time of physician order entry.

Background In advanced clinical decision support systems, patient characteristics and laboratory values are included in the algorithms that generate alerts. These alerts have a higher specificity than basic medication surveillance alerts. The alerts of advanced clinical decision support systems can be shown directly to the prescriber during order entry, without the risk of generating an overload of irrelevant alerts. We implemented five advanced algorithms that are shown directly to the prescriber. These algorithms are for gastrointestinal prophylaxis, folic or folinic acid prescribed with orally or subcutaneously administered methotrexate, vitamin D prescribed with bisphosphonates, hyponatremia and measuring plasma levels for vancomycin and gentamicin. Objective We evaluated the effect of the implementation of the algorithms. Setting We performed prospective intervention studies with a historical group for comparison in both inpatients and outpatients at a teaching hospital in the Netherlands. Methods We compared the time period after implementation of the algorithm with the time period before implementation, using data from the hospital information system Epic. Difference in guideline adherence were analyzed using Chi square tests. Main outcome measure The outcome measures were the number of alerts, the acceptance rate of the advice in the alert, and for the algorithm measuring plasma levels for vancomycin and gentamicin the time to the correct dose. Results For all algorithms, the implementation resulted in a significant increase in guideline adherence, varying from 11 to 36%. The acceptance rate varied from 14% for hyponatremia to 90% for methotrexate. For gastrointestinal prophylaxis the acceptance rate was 4.4% for basic drug-drug interaction alerts when no gastrointestinal prophylaxis was prescribed and increased to 44.7% after implementation of the advanced algorithm. This algorithm substantially decreased the number of alerts from 812 before implementation to 217 after implementation. After implementation of the algorithm for measuring plasma levels for vancomycin and gentamicin, the proportion of patients receiving the correct dose after 48 h increased from 73 to 84% (p = 0.03). Conclusion Implementation of advanced algorithms that take patient characteristics into account and are shown directly to the physician during order entry, result in an increased guideline adherence.

A clinical decision support system to improve adequate dosing of gentamicin and vancomycin.

OBJECTIVE: Gentamicin and vancomycin meet the criteria for measuring plasma concentrations during therapy. However, compliance with the accompanying guidelines remains low. The primary objective of this study was to determine whether the implementation of a clinical decision support system, which displays an alert if a plasma concentration should be measured and a daily reviewed patient list resulted in improved compliance. MATERIALS AND METHODS: This intervention study was performed at the Spaarne Gasthuis, Haarlem/Hoofddorp, the Netherlands. The authors included 261 treatments with either gentamicin or vancomycin intravenously for at least 48 h in the year before and after implementation of the clinical decision support system in May 2015. The authors analyzed whether plasma concentrations were measured sooner and more frequently after the implementation, and determined whether the time until the correct dosage, with adequate drug concentrations, was reduced after implementation. RESULTS: Before implementation, plasma concentrations were measured within 72 h in 47% of the treatments. After implementation, this percentage increased to 80% (p < 0.01). After implementation, the time was significantly shorter until the correct dosage was given. CONCLUSION: The implementation of a clinical decision support system and a patient list resulted in improved compliance with the guidelines and optimized the treatment with gentamicin and vancomycin.

Development of a risk model for predicting QTc interval prolongation in patients using QTc-prolonging drugs.

Background Numerous drugs prolong the QTc interval on the ECG and potentially increase the risk of cardiac arrhythmia. This risk is clinically relevant in patients with additional risk factors. Objective The objective was to develop and validate a risk model to predict QTc interval prolongation of eligible ECGs. Setting Spaarne Gasthuis (Haarlem/Hoofddorp, The Netherlands). Method A dataset was created from ECGs recorded in patients using one or more QTc prolonging drugs, in the period January 2013 and October 2016. In the development set, independent risk factors for QTc interval prolongation were determined using binary logistic regression. Risk scores were assigned based on the beta coefficient. In the risk-score validation set, the area under the ROC-curve, sensitivity and specificity were calculated. Main outcome measure QTc interval prolongation, defined as a QTc interval > 500 ms. Results In the development set 12,949 ECGs were included and in the risk-score validation set 6391 ECGs. The proportion of ECGs with a prolonged QTc interval in patients with no risk factors in the risk-score validation set was 2.7%, while in patients with a high risk score the proportion was 26.1%. The area under the ROC curve was 0.71 (95% CI 0.68-0.73). The sensitivity and specificity were 0.81 and 0.48, respectively. Conclusion A risk model was developed and validated for the prediction of QTc interval prolongation. This risk model can be implemented in a clinical decision support system, supporting the management of the risks involved with QTc interval prolonging drugs.

Risk factors for QTc interval prolongation.

PURPOSE: Prolongation of the QTc interval may result in Torsade de Pointes, a ventricular arrhythmia. Numerous risk factors for QTc interval prolongation have been described, including the use of certain drugs. In clinical practice, there is much debate about the management of the risks involved. In this study, we quantified the effect of these risk factors on the length of the QTc interval. METHODS: We analyzed all ECGs that were taken during routine practice between January 2013 and October 2016 in the Spaarne Gasthuis, a general teaching hospital in the Netherlands. We collected laboratory values in the week before the ECG recording and the drugs prescribed. For the identification of risk factors, we used multilevel linear regression analysis to correct for multiple ECG recordings per patient. RESULTS: We included 133,359 ECGs in our study, taken in 40,037 patients. Patients using one QT-prolonging drug had a 11.08 ms (95% CI 10.63-11.52; p < 0.001) longer QTc interval. Patients using two QT-prolonging drugs had a 3.04 ms (95% CI 2.06-4.02; p < 0.001) increase in the QTc interval compared to patients using one QT-prolonging drug. Women had a longer QTc interval compared to men (16.30 ms 95% CI 14.59-18.01; p < 0.001). The QTc interval increased with increasing age, but the difference between men and women diminished. Other independent risk factors that significantly prolonged the QTc interval with at least 10 ms were hypokalemia, hypocalcemia, and the use of loop diuretics. CONCLUSION: We identified and quantified various risk factors for QTc interval prolongation.

Ciprofloxacin does not Prolong the QTc Interval: A Clinical Study in ICU Patients and Review of the Literature.

PURPOSE: Ciprofloxacin may prolong the QT interval and increase the risk of Torsade de Pointes (TdP). Intravenous administration of ciprofloxacin in patients with additional risks may elevate the risk of QTc interval prolongation. We prospectively assessed whether intravenous ciprofloxacin prolongs the QT interval in patients with additional co-morbidities and risk factors. We also reviewed the literature on the QT prolonging effect or TdP inducing effect of ciprofloxacin. METHODS: ICU Patients who were treated with intravenous ciprofloxacin as part of their therapy were recruited. ECG was recorded within 60 min before start and in the last 30 min of 1 h infusion, or within 30 min after the end of ciprofloxacin infusion. QT interval was corrected for the heart rate using both Bazett's and Fridericia's formula. The changes were analyzed using the paired Student's t-test. RESULTS: Ten patients were included in the study (average age 74-y, 6 males). The average baseline QTc interval corrected with Bazett's formula was 448 ms that was shortened during or after ciprofloxacin infusion by 3 ms and 2 ms based on Bazett's  (p=0.67) and Fridericia's (p=0.68) formula, respectively. No observational study  or cohort study thus far has shown that ciprofloxacin has a QT prolonging effect or increases the risk of TdP or (cardiovascular) mortality.  Conclusion. Based on our results and the results of previous studies, it is unlikely that ciprofloxacin has a clinically relevant QT prolonging effect or an increased risk of TdP. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Physicians' Compliance with a Clinical Decision Support System Alerting during the Prescribing Process.

Clinical decision support systems have been shown to improve practitioner performance. Most systems designed to prevent medication errors generate lists with patients who fulfill the criteria of the algorithm. These lists are reviewed by a pharmacist and physicians are contacted by telephone. Presenting pop-up alerts as part of the workflow with a clear recommendation is a feature critical to success. Therefore we implemented three algorithms in a clinical decision support system alerting during the medication ordering process. We analyzed whether the recommendations in these alerts were followed. We evaluated 1. whether folic or folinic acid was co-prescribed more frequently within 48 h after ordering methotrexate, 2. whether vitamin D or analogues were co-prescribed more frequently within 48 h after ordering bisphophonates and 3. whether sodium lowering drugs were stopped more frequently within one hour in patients with hyponatremia. We analyzed the difference in the 48 days before implementation and the 43 days after implementation, using Pearson's Chi2 test. Co-prescription of folic or folinic acid increased from 54 to 91% (p = 0.014), co-prescription of vitamin D or analogues increased from 11 to 40% (p = 0.001) and the number of stopped orders for sodium lowering drugs increased from 3 to 14% (p = 0.002). This clinical decision support system that alerts physicians for preventable medication errors during the medication ordering process is an effective approach to improve prescribing behavior.

Improving the effectiveness of drug safety alerts to increase adherence to the guideline for gastrointestinal prophylaxis.

OBJECTIVE: Gastrointestinal bleedings are the most frequently occurring reason for medication-related hospital admissions, which are potentially preventable. We implemented a clinical decision support system that recommends to prescribe gastrointestinal prophylaxis in patients with an increased risk according to the Dutch guideline. Our primary objective was to determine whether the implementation resulted in improved compliance with this guideline for gastrointestinal prophylaxis. A secondary objective was to determine whether implementation resulted in a reduction of the number of drug safety alerts. MATERIALS AND METHODS: This intervention study was performed at the Spaarne Gasthuis, a teaching hospital, using Epic as hospital information system. We selected prescriptions with an indication for gastrointestinal prophylaxis according to the guideline, in the three months before and after implementation of the clinical decision support in November 2014. We analyzed whether gastrointestinal prophylaxis was prescribed more frequently after implementation using the Pearson's Chi-square test and the change in the number of drug safety alerts. RESULTS: Before implementation in 84.0% of the included 2064 prescriptions gastrointestinal prophylaxis was co-prescribed. After implementation this percentage increased to 94.5% of the 2269 prescriptions (p<0.001). The number of drug safety alerts decreased by 78.2% from 980 to 217 alerts. CONCLUSION: The introduction of a clinical decision support system for gastrointestinal prophylaxis improved adherence to the Dutch guideline. This was most likely due to a reduction in the number of irrelevant drug safety alerts.

The effect of intratympanic gentamicin for treatment of Ménière's disease on lower frequency hearing.

Background The intratympanic application of the ototoxic aminoglycoside gentamicin has shown promising results as an ablative treatment for vertigo associated with Ménière's disease. Objective To evaluate the efficacy and safety of intratympanic gentamicin and to specifically analyse the effect of this treatment on high and low hearing frequencies in patients with unilateral definite Ménière's disease. Method Subjects were treated with intratympanic gentamicin and were evaluated on vertigo, tinnitus, mean pure tone audiometry threshold and speech discrimination score. Subjects were followed for evaluation for up to 2 years after treatment. Results The number of vertigo spells per month decreased and subjects experienced less tinnitus. During follow up there was an increase of hearing loss in the low (0.25-, 0.5-, 1-kHz) frequency range (13.3 dB; p = 0.03). There was no significant increase of hearing loss in the high (2-, 4-, 8-kHz) frequency range. A clinically significant change in speech discrimination score was found in 50 % of the subjects. Conclusion Our results indicate that intratympanic gentamicin especially affects the mean pure tone audiometry threshold in the low frequency range, which may have clinical implications. Though many of our results are (statistically) substantial the study was limited by the small cohort size.

Stability assessment of repackaged bevacizumab for intravitreal administration.

Intravitreal bevacizumab is frequently used off-label for the treatment of neovascular age-related macular degeneration, but there are concerns about the safety of intravitreal administered bevacizumab. It is suggested that repackaging bevacizumab in plastic syringes could affect the safety due to the unknown shelf life of the syringes. In this study, we analyzed the shelf life of the repackaged bevacizumab syringes, stored at 4 degrees C, at certain time intervals. Over the 32 days tested, bevacizumab concentration and the pH were stable. However, the number of particles in the repackaged bevacizumab syringes increased during storage at 4 degrees C and had exceeded the limits for intravitreal injections after 7 days. Since the number of particles seems to be the limitation of the shelf life of repackaged bevacizumab, it is necessary to quantify the number of particles in repackaged bevacizumab. Based on our results the maximum shelf life of repackaged bevacizumab should be 3 days.

Effect of administration route on the pharmacokinetics of cobalamin in elderly patients: a randomized controlled trial.

BACKGROUND: The gold standard for cobalamin deficiency treatment is administration of cobalamin by intramuscular injection. The injection is painful and inconvenient, particularly for elderly persons. Cobalamin might also be administered intranasally. Previous studies do not provide insight into the pharmacokinetics of intranasal cobalamin administration in comparison with cobalamin injection. AIM: To quantify the pharmacokinetics of intranasally and intramuscularly administered cobalamin to determine if intranasal administration might be an alternative for intramuscular administration. METHODS: Ten inpatients and outpatients of a geriatrics unit were recruited and randomly assigned to receive a single dose of 1000 µg cobalamin administered either by intranasal spray or intramuscular injection (5 per group). Inclusion criteria were written informed consent, age >65 years, and a cobalamin serum concentration <200 pmol/L. Total cobalamin serum concentrations were determined 10 times within 48 hours after administration. The differences in Cmax, Tmax, and AUC0-48 h per administration route were statistically compared using ANOVA. RESULTS: The average Cmax was 1 nmol/L after intranasal and 38.5 nmol/L after intramuscular administration. The average Tmax for intranasal and intramuscular administration was 42 minutes versus 342 minutes, respectively, and the AUC0-48 h was 1.3 µmol/L/min versus 45.4 µmol/L/min, respectively. These values also differed significantly (P<0.05). The estimated bioavailability of the intranasal administration was 2%. CONCLUSIONS: The pharmacokinetics of intranasal and intramuscular cobalamin administration in elderly, cobalamin-deficient patients differ significantly. However, the estimated 2% bioavailability of cobalamin after intranasal administration makes intranasal cobalamin administration a potentially interesting administration route for elderly patients. Netherlands Trial Registry identifier: NTR 3005.