Description of a clinical decision support tool with integrated dose calculator for paediatrics.

Medication errors, especially dosing errors are a leading cause of preventable harm in paediatric patients. The paediatric patient population is particularly vulnerable to dosing errors due to immaturity of metabolising organs and developmental changes. Moreover, the lack of clinical trial data or suitable drug forms, and the need for weight-based dosing, does not simplify drug dosing in paediatric or neonatal patients. Consequently, paediatric pharmacotherapy often requires unlicensed and off-label use including manipulation of adult dosage forms. In practice, this results in the need to calculate individual dosages which in turn increases the likelihood of dosing errors. In the age of digitalisation, clinical decision support (CDS) tools can support healthcare professionals in their daily work. CDS tools are currently amongst the gold standards in reducing preventable errors. In this publication, we describe the development and core functionalities of the CDS tool PEDeDose, a Class IIa medical device software certified according to the European Medical Device Regulation. The CDS tool provides a drug dosing formulary with an integrated calculator to determine individual dosages for paediatric, neonatal, and preterm patients. Even a technical interface is part of the CDS tool to facilitate integration into primary systems. This enables the support of the paediatrician directly during the prescribing process without changing the user interface.Conclusion: PEDeDose is a state-of-the-art CDS tool for individualised paediatric drug dosing that includes a certified calculator. What is Known: • Dosing errors are the most common type of medication errors in paediatric patients. • Clinical decision support tools can reduce medication errors effectively. Integration into the practitioner's workflow improves usability and user acceptance. What is New: • A clinical decision support tool with a certified integrated dosing calculator for paediatric drug dosing. • The tool was designed to facilitate integration into clinical information systems to directly support the prescribing process. Any clinical information system available can interoperate with the PEDeDose web service.

Drugs as risk factors of acute kidney injury in critically ill children.

BACKGROUND: Acute kidney injury (AKI) is a serious condition in critically ill children. Nephrotoxic medication exposure is a common contributing factor to AKI, but little literature is available in pediatrics. The aim of the present study was to assess potential associations between drugs and the risk of developing AKI. METHODS: We performed a retrospective case-control study in a pediatric intensive care unit (PICU). Cases were patients who developed AKI during PICU stay. Patients without AKI served as controls and were matched to cases by age and gender in a one-to-one ratio. RESULTS: One hundred case-control pairs were included. Cases were not statistically different from controls with regard to median weight and main diagnoses, but differed with regard to the need for mechanical ventilation, severity of illness, and median length of PICU stay. Multivariate models revealed a statistically significant higher risk of developing AKI for patients treated with metamizole, morphine, paracetamol, and tropisetron. A similar risk could be shown for medication groups, namely glucocorticoids, betalactam antibiotics, opioids, and non-steroidal anti-inflammatory drugs. CONCLUSIONS: The results suggest that drugs are associated with acute renal dysfunction in critically ill children, but the multifactorial causes of AKI should be kept in mind.

Analysis of medication prescribing errors in critically ill children.

UNLABELLED: Medication prescribing errors (MPE) can result in serious consequences for patients. In order to reduce errors, we need to know more about the frequency, the type and the severity of such errors. We therefore performed a prospective observational study to determine the number and type of medication prescribing errors in critically ill children in a paediatric intensive care unit (PICU). Prescribing errors were prospectively identified by a clinical pharmacist. A total of 1129 medication orders were analysed. There were 151 prescribing errors, giving an overall error rate of 14 % (95 % CI 11 to 16). The medication groups with the highest proportion of MPEs were antihypertensives, antimycotics and drugs for nasal preparation with error rates of each 50 %, followed by antiasthmatic drugs (25 %), antibiotics (15 %) and analgesics (14 %). One hundred four errors (70 %) were classified as MPEs which required interventions and/or resulted in patient harm equivalent to 9 % of all medication orders (95 % CI 6.5 to 14.4). Forty-five MPEs (30 %) did not result in patient harm. CONCLUSION: With a view to reduce MPEs and to improve patient safety, our data may help to prevent errors before they occur. WHAT IS KNOWN: • Prescribing errors may be the most frequent medication errors. • In paediatric populations, the incidence of prescribing errors is higher than in adults. What is New: • Several risk factors for medication prescribing errors, such as medication groups, long PICU stay, and mechanical ventilation could be presented. • Analysing the combination of the most frequent prescribing errors and the severity of these errors.

Pharmacokinetics and tolerability of intranasal or intravenous administration of nalbuphine in infants.

OBJECTIVES: Intranasal nalbuphine could be a safe, efficacious and non-invasive alternative to parenteral pain medication in infants. We aimed to assess pharmacokinetics (PK) and tolerability of intranasal and intravenous nalbuphine administration in infants. METHODS: Prospective open-label study including infants 1-3 months of age admitted to the emergency department, receiving nalbuphine for procedural pain management. Patients were alternately allocated to a single nalbuphine dose of 0.05 mg/kg intravenously or 0.1 mg/kg intranasally. Nalbuphine PK samples were collected 15, 30 and 120-180 min after dosing. Area under the concentration time curve (AUC0-Tlast) was calculated by non-compartmental analysis (NCA) and compared by Wilcoxon test. Neonatal Infant Pain Score was assessed during nalbuphine administration and the following interventions: venous access, urinary catheterisation, lumbar puncture. RESULTS: Out of 52 study subjects receiving nalbuphine, 31 were eligible for NCA (11 intravenous, 20 intranasal). Median AUC0-Tlast after 0.05 mg/kg intravenously was 8.7 (IQR: 8.0-18.6) µg×L/hour vs 7.6 (5.4-10.4) µg×L/hour after intranasal administration of 0.1 mg/kg (p=0.091). Maximum serum concentration (Cmax) was observed 30 min after intranasal administration (3.5-5.6 µg/L). During intravenous and intranasal nalbuphine administration, mild to no pain was recorded in 71% and 67% of study subjects, respectively. CONCLUSION: This is the first study investigating intranasal administration of nalbuphine in infants suggesting an intranasal bioavailability close to 50%. Non-invasive intranasal application was well tolerated. Additional studies are warranted to optimise dosing and timing of interventions as Cmax is delayed by half an hour after intranasal administration. TRIAL REGISTRATION NUMBER: NCT03059511.

Impact of a clinical decision support system on paediatric drug dose prescribing: a randomised within-subject simulation trial.

BACKGROUND: Drug dosing errors are among the most frequent causes of preventable harm in paediatrics. Due to the complexity of paediatric pharmacotherapy and the working conditions in healthcare, it is not surprising that human factor is a well-described source of error. Thus, a clinical decision support system (CDSS) that supports healthcare professionals (HCP) during the dose prescribing step provides a promising strategy for error prevention. METHODS: The aim of the trial was to simulate the dose derivation step during the prescribing process. HCPs were asked to derive dosages for 18 hypothetical patient cases. We compared the CDSS PEDeDose, which provides a built-in dose calculator to the Summary of Product Characteristics (SmPC) used together with a pocket calculator in a randomised within-subject trial. We assessed the number of dose calculation errors and the time needed for calculation. Additionally, the effect of PEDeDose without using the built-in calculator but with a pocket calculator instead was assessed. RESULTS: A total of 52 HCPs participated in the trial. The OR for an erroneous dosage using the CDSS as compared with the SmPC with pocket calculator was 0.08 (95% CI 0.02 to 0.36, p<0.001). Thus, the odds of an error were 12 times higher while using the SmPC. Furthermore, there was a 45% (95% CI 39% to 51%, p<0.001) time reduction when the dosage was derived using the CDSS. The exploratory analysis revealed that using only PEDeDose but without the built-in calculator did not substantially reduce errors. CONCLUSION: Our results provide robust evidence that the use of the CDSS is safer and more efficient than manual dose derivation in paediatrics. Interestingly, only consulting a dosing database was not sufficient to substantially reduce errors. We are confident the CDSS PEDeDose ensures a higher safety and speeds up the prescribing process in practice.

Automation of the medication process in Swiss hospitals: results of a survey.

OBJECTIVES: Medication management is a core process in hospital administration. The safety, timeliness and efficiency of medication distribution may be improved by automating logistical and administrative aspects of the process. Forming an accurate high-level picture of current practices may help decision-makers to better advance the state of automation. This study aims to identify which systems for automating the medication process are currently in use in Swiss hospitals, and to what extent each system is used. METHODS: A 27-question survey was developed and distributed to Swiss Association of Public Health Administration and Hospital Pharmacists (GSASA) members. The survey focused on enterprise resource planning (ERP) systems, automation of in-hospital distribution and dispensing of pharmaceutical goods, bedside scanning, and the management of drug master data. RESULTS: The response rate was 98% (58/59 hospital pharmacies). All institutions had an ERP system in use, most frequently SAP (n=23, 39%). Electronic invoices from suppliers were fully processed by 37% and partially processed by 17% of respondents. Twenty-five percent of respondents reported performing bedside scanning for the purpose of medication administration. Automated medication distribution systems were available in 20 hospitals (34%), of which 13 were central robots and seven were decentralised systems. CONCLUSION: A considerable gap remains to achieve closed loop processes between multiple systems. The present results provide an inventory of existing systems and current trends for use by decision-makers in hospitals and hospital pharmacies.

Digitalisation of the drug prescribing process in Swiss hospitals - results of a survey.

BACKGROUND: The state of digitalisation in the healthcare sector in Switzerland is lagging, even as the national electronic health record (EHR) is being gradually implemented. Little is known about the implementation of electronic prescribing systems, their auxiliary features or drug datasets in Swiss hospitals.The aim of this study was to understand which electronic systems are implemented to support doctors in Swiss hospitals during the medication prescribing process. METHODS: The survey was sent in spring 2021 to the chief pharmacists of the main Swiss hospitals. The survey focused on the introduction of the EHR, the clinical information system (CIS) and its prescribing module, as well as drug information data and clinical decision support systems (CDSS). RESULTS: The response rate was 98% (58/59 hospitals). Almost half of the hospitals (47%) were connected to the national EHR, almost all hospitals (86%) used a CIS and a vast majority of the hospitals (84%) had implemented electronic prescribing systems in their CIS. 10 years ago, around 63% of hospitals used a CIS and 40% were equipped with an electronic prescribing system. Today, CDSS of any kind were implemented in 50% of the hospitals, predominantly for drug-drug interactions. Drug master data were maintained in most hospitals (76%) via an automated interface, but mostly supplemented manually. Clinical drug information data were maintained in 74% of hospitals. In 67% of hospitals, datasets were imported via an automated interface. CONCLUSIONS: The digitalisation of the medical prescribing process in Swiss hospitals has progressed over the last decade. Drug prescriptions via electronic prescribing systems were introduced in most hospitals. However, this survey suggests that the current use of CDSS is far from exhausted, and that clinical drug information data could be maintained more efficiently. Optimising electronic support for healthcare professionals during the prescribing process still has considerable potential.

Pharmacometric Analysis of Intranasal and Intravenous Nalbuphine to Optimize Pain Management in Infants.

Objectives: The objective of this pharmacometric (PMX) study was to (i) characterize population pharmacokinetics (PPK) and exposure-pain response associations following intranasal (0.1 mg/kg) or intravenous (IV, 0.05 mg/kg) administration of nalbuphine, with the goal to (ii) evaluate strategies for optimized dosing and timing of painful interventions in infants 1-3 months old. Methods: PPK analysis of nalbuphine serum concentrations, prospectively collected 15, 30, and between 120 and 180 min post-dose, utilizing the software package Monolix. The final PPK model was applied to derive individual time-matched concentration predictions for each pain assessment (Neonatal Infant Pain Score, NIPS) after establishment of venous access and urinary catheterization or lumbar puncture. Drug exposure-pain response simulations were performed to evaluate potential benefits of higher doses with respect to a previously proposed target concentration of 12 mcg/L (efficacy threshold). Results: Thirty-eight of 52 study subjects receiving nalbuphine had at least one concentration measurement and were included in the pharmacometric analysis. A two-compartment model with allometric scaling was applied to describe population PK data, with intranasal bioavailability estimated to be 41% (95%CI: 26-56%). Model-based simulations showed that the proposed efficacy threshold (12 mcg/L) is expected to be exceeded with an IV dose of 0.05 mg/kg for 6 min, with 0.1 mg/kg for 30 min and with 0.2 mg/kg for 80 min. This efficacy threshold is not achieved with intranasal doses of 0.1 and 0.2 mg/kg, whereas an intranasal dose of 0.4 mg/kg is expected to exceed such threshold for 30 to 100 min. Conclusion: This PMX study confirmed that bioavailability of intranasal nalbuphine is close to 50%. Exposure-pain response simulations indicated that an intranasal dose of 0.4 mg/kg is required to provide a comparable pain control as achieved with an IV dose of 0.1-0.2 mg/kg. The optimal time window for painful procedures appears to be within the first 30 min after IV administration of 0.1 mg/kg nalbuphine, whereas such procedures should be scheduled 30 min after an intranasal dose of 0.4 mg/kg nalbuphine. Additional clinical studies are warranted to confirm these PMX based recommendations and to further optimize pain management in this vulnerable infant population.

Too much of too little: xylitol, an unusual trigger of a chronic metabolic hyperchloremic acidosis.

Homeopathic globules are frequently used in children as a first-line treatment. Most of these globules are coated with sugar substitutes like xylitol; these substitutes are known for their laxative effect. Our patient shows that consumption of globules coated with xylitol does not have only laxative effects. It may cause indeed considerable weight loss and life-threatening enteral bicarbonate loss by diarrhea when overdosed in an infant.

Evaluation of Incompatible Coadministration of Continuous Intravenous Infusions in a Pediatric/Neonatal Intensive Care Unit.

OBJECTIVES: We aimed to evaluate and quantify incompatible coadministrations of continuous intravenous medication in the daily clinical practice of a PICU/NICU. METHODS: We conducted a retrospective, observational study in the setting of an 18-bed PICU/NICU. All concurrently administered continuous infusions, including blood products and parenteral nutrition, were analyzed for 2 months. Raw electronic data were retrieved and subjected to quality controls. Infusion combinations were classified as compatible, incompatible, no data, or variable according to the internal hospital charts, Trissel's database, and the Swiss summary of product characteristics. For situations with incompatible coadministrations, we assessed alternative distributions of infusions among the currently available lumen. RESULTS: Data for 100 patients were analyzed. Patients were exposed to a mean of 6.9 ± 3.6 individual continuous infusions administered through 3.8 ± 1.8 lumina. Among the 1447 coadministered continuous infusions, we detected 146 incompatible combinations (10%), resulting in 105 individually relevant incompatible situations. Furthermore, 185 combinations (13%) were not covered by internal compatibility charts, and for 207 combinations (15%) no data on compatibility were available. We found that 58% of the incompatible situations could have been avoided by a redistribution of the infusions among the available lumina. CONCLUSIONS: Most infusion combinations in the studied PICU/NICU were compatible and covered by the internal compatibility charts. However, we also identified concurrent administrations of incompatible infusions or for which compatibility data are not available. A significant reduction of coadministrations of incompatible infusions could be achieved through optimal use of available lumina.

Risk factors for gastrointestinal bleeding: a hospital-based case-control study.

QUESTIONS UNDER STUDY/PRINCIPLES: Gastrointestinal (GI) bleeding is a frequent serious adverse drug reaction, potentially causing hospital admission and death. We investigated risk factors for a first-time GI bleeding leading to hospital admission with a focus on drugs and drug-drug interactions (DDIs). METHODS: We conducted a hospital-based case-control study at the Kantonsspital Winterthur, encompassing 74 patients with a first-time GI bleeding in the year 2005 and 148 controls, matched to cases on age, sex and calendar time. RESULTS: Multivariate models including various drugs and comorbidities revealed a significant risk for GI bleeding for treatment with nonsteroidal antiinflammatory drugs (NSAIDs) (odds ratio [OR] 8.6, 95% confidence interval [CI] 3.1-23) and thrombocyte aggregation inhibitors (OR 2.2, 95% CI 1.1-4.6). Anticoagulation alone in the therapeutic international normal ratio (INR) range was not associated with bleedings (OR 0.9, 95% CI 0.4-2.3), but INR values > or = 4 were associated with an increased bleeding risk (OR 13, 95% CI 1.2-150). DDI models yielded increased risk estimates for combined use of NSAID and glucocorticoids (OR 20, 95% CI 1.6-257), and for combined use of oral anticoagulants and NSAIDs (8 cases, 0 controls, crude OR approx. 20). CONCLUSION: The findings of this small hospital-based case-control analysis suggest that a first-time GI bleeding is associated with INR values above the therapeutic range, but not with well-controlled oral anticoagulation in the absence of other risk factors such as DDIs. The combinations of glucocorticoids or oral anticoagulants with NSAIDs carry a high risk for GI bleeding.

Prevalence of drug-drug interactions at hospital entry and during hospital stay of patients in internal medicine.

OBJECTIVE: The aim of this study was to assess potential drug-drug interactions (pDDIs) at hospital admission, during hospitalization and at discharge and to evaluate the number of pDDIs created during hospitalization. METHODS: The medication of 851 patients was screened for pDDIs (major and moderate severity) using the screening program Pharmavista. The frequency of pDDIs per patient, per number of drugs and drug pairs was estimated. RESULTS: During hospitalization, the frequency of major and moderate pDDIs per patient was 1.11, which was higher compared to hospital admission (0.59) or to hospital discharge (0.60). The frequency of major and moderate pDDIs per drug prescribed (13.7% vs. 9.1%) or per drug pairs analyzed (4.5% vs. 2.3%) was higher at hospital admission compared to hospital discharge. 47% of all major and moderate pDDIs at discharge were due to a medication change during hospitalization. CONCLUSIONS: Although the number of major and moderate pDDIs per patient did not increase from hospital admission to discharge, it is important to realize that 47% of all major and moderate DDIs at hospital discharge were created during hospitalization. Prescribing drugs with a low risk for pDDIs as well as careful monitoring for adverse drug reactions are important measures to minimize harm associated with DDIs.

Evaluation of frequently used drug interaction screening programs.

OBJECTIVE: Drug-drug interaction (DDI) screening programs are an important tool to check prescriptions of multiple drugs. The objective of the current study was to critically appraise several DDI screening programs. METHODS: A DDI screening program had to fulfil minimal requirements (information on effect, severity rating, clinical management, mechanism and literature) to be included into the final evaluation. The 100 most frequently used drugs in the State Hospital of Baden, Switzerland, were used to test the comprehensiveness of the programs. Qualitative criteria were used for the assessment of the DDI monographs. In a precision analysis, 30 drugs with and 30 drugs without DDIs of clinical importance were tested. In addition, 16 medical patient profiles were checked for DDIs, using Stockley's Drug Interactions as a reference. MAIN OUTCOME MEASURE: Suitability of DDI screening program (quality of monographs, comprehensiveness of drug list, statistical evaluation). RESULTS: Out of nine programs included, the following four fulfilled the above mentioned criteria: Drug Interaction Facts, Drug-Reax, Lexi-Interact and Pharmavista. Drug Interaction Facts contained the smallest number of drugs and was therefore the least qualified program. Lexi-Interact condenses many DDIs into one group, resulting in less specific information. Pharmavista and Drug-Reax offer excellent DDI monographs. In the precision analysis, Lexi-Interact showed the best sensitivity (1.00), followed by Drug-Reax and Pharmavista (0.83 each) and Drug Interaction Facts (0.63). The analysis of patient profiles revealed that out of 157 DDIs found by all programs, only 18 (11%) were detected by all of them. No program found more than 50% of the total number of DDIs. A further evaluation using Stockley's Drug interactions as the gold standard revealed that Pharmavista achieved a sensitivity of 0.86 (vs Drug Interaction Facts, Lexi-Interact and Drug-Reax with a sensitivity of 0.71 each) and a positive predictive value of 0.67. CONCLUSION: None of the four DDI screening programs tested is ideal, every program has its strengths and weaknesses, which are important to know. Pharmavista offers the highest sensitivity of the programs evaluated with a specificity and positive predictive value in an acceptable range.

Recognition and management of potential drug-drug interactions in patients on internal medicine wards.

INTRODUCTION: Our aim was to study and possibly improve the clinical management of potential drug-drug interactions (pDDIs) in hospitalized patients by specific interventions. METHODS: During the initial period, inpatients on three medical wards were screened for major and moderate pDDIs using the interaction screening program Pharmavista. During the second period, patients at discharge were screened similarly. After assessment of the detected pDDIs for clinical relevance, written recommendations and/or information about the pDDIs were sent to the treating physicians. Feedback from the physicians and implementation of the recommendations were analyzed. RESULTS: During the initial period, 502 inpatients were exposed to 567 pDDIs, of which 419 (74%) were judged to be clinically relevant. Three hundred and forty-nine substantiated recommendations and 70 simple information leaflets were handed out to the physicians. Eighty percent (278 of 349) of the recommendations were accepted and implemented. During the second period, 792 patients at hospital discharge were exposed to 392 pDDIs, of which 258 (66%) were judged to be clinically relevant. Two hundred and forty-seven substantiated recommendations and 11 simple information leaflets were sent to the physicians. Seventy-three percent (180 of 247) of the recommendations were accepted. At hospital discharge, 47 of 71 interventions recommending checkable medication changes were implemented. One year after hospital discharge, 11 of 13 checked medication changes were still in place. CONCLUSIONS: Clinically relevant pDDIs are common in patients on medical wards, and their management can be influenced by providing substantiated recommendations to physicians. Most changes in medication following such recommendations are still in place 1 year after discharge.

The use of an hydrogen peroxide multipurpose isolator for inhouse preparation of human embryo culture media: a unique successful Swiss randomized prospective study.

PURPOSE: To develop inhouse made (IHM) embryo culture medium with a Multipurpose Isolator and compare the embryo development in a prospective randomized study with commercial media. METHODS: Fertilization by intracytoplasmic single sperm injection (ICSI) of Metaphase II oocytes obtained after 96 controlled ovarian hyperstimulation cycles in patients not older than 37 years. Transfer of zygotes to IHM or commercial Cook Sydney IVF Cleavage medium (SIC) immediately after pronucleus observation. Evaluation of embryo cleavage and score, pregnancy, and implantation rate. RESULTS: From 100 zygotes cultured in SIC, 61% were at the 4 cell stage 45 h after ICSI compared to 77% (78/101) in the IHM, P < 0.05. The mean embryo score with IHM was 3.9 +/- 0.9 compared to 3.5 +/- 1.2 with SIC, P < 0.05. The clinical pregnancy rate per transfer was 38.9% (37/95), the implantation rate was 23% (46/200), and no differences were observed between the groups.