Galunisertib downregulates mutant type I collagen expression and promotes MSCs osteogenesis in pediatric osteogenesis imperfecta.

Qualitative alterations in type I collagen due to pathogenic variants in the COL1A1 or COL1A2 genes, result in moderate and severe Osteogenesis Imperfecta (OI), a rare disease characterized by bone fragility. The TGF-ß signaling pathway is overactive in OI patients and certain OI mouse models, and inhibition of TGF-ß through anti-TGF-ß monoclonal antibody therapy in phase I clinical trials in OI adults is rendering encouraging results. However, the impact of TGF-ß inhibition on osteogenic differentiation of mesenchymal stem cells from OI patients (OI-MSCs) is unknown. The following study demonstrates that pediatric skeletal OI-MSCs have imbalanced osteogenesis favoring the osteogenic commitment. Galunisertib, a small molecule inhibitor (SMI) that targets the TGF-ß receptor I (TßRI), favored the final osteogenic maturation of OI-MSCs. Mechanistically, galunisertib downregulated type I collagen expression in OI-MSCs, with greater impact on mutant type I collagen, and concomitantly, modulated the expression of unfolded protein response (UPR) and autophagy markers. In vivo, galunisertib improved trabecular bone parameters only in female oim/oim mice. These results further suggest that type I collagen is a tunable target within the bone ECM that deserves investigation and that the SMI, galunisertib, is a promising new candidate for the anti-TGF-ß targeting for the treatment of OI.

Analysis of standard concentrations of continuous infusions in nine Spanish neonatal intensive care units.

OBJECTIVES: The aim of this study was to describe the use of standard concentrations for continuous infusion drugs in Spanish neonatal intensive care units (NICUs). METHODS: We conducted an observational multicentre study based on a survey sent by email to 9 Spanish NICUs during January and February 2018. We collected data on intravenous drugs frequently used in neonates, and their preparation. Continuous infusion drugs with a standard concentration implemented in ≥2 NICUs were selected. An analysis of the concentrations reported was performed, and the rate of adherence to international recommendations of the Institute of Safe Medication Practice (ISMP) and Vermont Oxford Network (VON) was calculated. RESULTS: From 69 drugs mentioned in the survey, 14 were included in the study, with all but one (furosemide) being considered high-alert medications by the ISMP. From the 9 participating NICUs, 3 had no established standard concentrations for any of the 14 drugs selected. In the other participating NICUs, dexmedetomidine was used with a standard concentration in the 3 NICUs which used the drug, whereas furosemide showed the lowest implementation rate (a standard concentration was implemented in 2 of the 7 NICUs which used the drug). In regard to concentrations adopted in the different NICUs, 80 variations were identified for the 14 drugs. The mean number of different standard concentrations for each drug per NICU was 2 (range 1-5). Adherence to ISMP/VON recommendations varied considerably depending on the drugs, from high adherence for heparin (2/3) and fentanyl (2/3) to low adherence for norepinephrine (0/4). CONCLUSIONS: The establishment of standard concentrations is highly recommended for continuous infusion medications as an effective error-prevention strategy. Nevertheless, we detected a low implementation rate in our NICUs and a lack of consistency in the concentrations selected.

Intravenous drug use in neonatal intensive care units.

OBJECTIVES: Intravenous drug use in neonates is frequent and prone to medication errors. The aim of this study was to describe the intravenous drugs most frequently used in Spanish Neonatal Intensive Care Units (NICU), their preparation and the implementation rate of standardised concentration infusions. METHODS: We conducted an observational multicentre study based on a survey sent by email to nine Spanish NICUs during January and February 2018. We collected data describing the intravenous drugs frequently used in neonates and their preparation. A descriptive analysis of the medicines reported (and their preparation) was performed, to assess how frequently standard concentrations were used and how medications were prepared in central pharmacies. RESULTS: Overall, 69 different drugs were reported by participating NICUs. Of these, 33% (n=23) were not approved for use in neonates and 38% (n=26) corresponded to high-alert medications, according to the Institute for Safe Medication Practices. A mean of only 63.5% of intravenous medicines were standardised. The standard-concentration implementation rate was somewhat higher for intermittent (mean 74.1%) than continuous (mean 42.9%) infusions. Notably, infusions were more commonly prepared on wards than in hospital pharmacies. CONCLUSIONS: Intravenous drug use in NICUs has been identified as a high-risk process, and error-reduction strategies (such as concentration standardisation) have been recommended. Further data are necessary to design the most suitable intervention in our country (Spain), but institutional initiatives are needed to achieve this.

Drug compatibility in neonatal intensive care units: gaps in knowledge and discordances.

In this work, we reviewed the compatibility data of drug combinations frequently administrated in nine Spanish neonatal intensive care units (NICUs) and analyzed the degree of agreement among three highly used databases (Micromedex, King Guide to Parenteral Admixtures, and Stabilis) through Cohen's kappa coefficient statistical analysis. Among 1945 drug combinations analyzed, 283 were compatible, 421 were potentially compatible, 216 were incompatible, 139 were controversial, and there was no data for 886 combinations. In general, the three databases showed a strong degree of agreement: Micromedex vs. King Guide (κ = 0.746; p < 0.001), King Guide vs. Stabilis (κ = 0.743; p < 0.001), and Micromedex vs. Stabilis (κ = 0.691; p < 0.001). However, in 6 of 648 (Micromedex vs. King Guide), 3 of 357 (King Guide vs. Stabilis), and 32 of 606 (Micromedex vs. Stabilis) comparisons, drug pairs were compatible according to the first database and incompatible according to the second, indicating discordances among databases.Conclusion: There is a gap in knowledge about physical compatibility of a great number of drug combinations commonly used in NICUs. Although the three databases showed strong concordance, for some drug combinations, important discrepancies were found. Thus, there is a need for further studies on drug compatibility to increase safety of intravenous administration. What is Known: • Y site-administration in NICUs is very common and some administration errors are related to the lack of information on the compatibility of intravenous drugs. • Physical compatibility data of drugs frequently used in NICUs is still very limited. What is New: • Physical compatibility data of drug combinations commonly used in Spanish NICUs was reviewed in three highly used admixture databases: Micromedex, King Guide to Parenteral Admixtures and Stabilis, and our results showed a strong degree of agreement between them, however for some drug combinations, important discrepancies were found. • Our results indicated that there is still a large gap in knowledge about physical compatibility of a great number of drug combinations commonly used in NICUs..

Physical compatibility of alprostadil with selected drugs commonly used in the neonatal intensive care units.

This study aimed to determine the physical compatibility of alprostadil with 17 continuous infusion drugs commonly administered in neonatal intensive care units. Test samples were prepared in a laminar airflow hood. Alprostadil 20 mcg/ml was mixed with each drug in a 1:1 ratio, in two orders of mixing. Physical stability of the admixtures was assessed by visual examination and by measuring turbidity. Visual examination was conducted by two observers by two methods: visual examination against a black and white background under normal fluorescent light and using a high-intensity monodirectional light. pH was measured as chemical stability predictor. Evaluations were performed immediately and 4 h after mixing. An additional visual control was performed at 24 h. Visual examination was positive or doubtful for the four drug combinations not considered compatible. Turbidity values were under 0.5 NTU throughout the study in all samples. No modifications of one pH unit or more was detected in any drug pair over time.Conclusion: Alprostadil was considered physical compatible with 13 drugs (adrenalin, amiodarone, calcium gluconate, dobutamine, dopamine, fentanyl, flecainide, furosemide, heparin, ketamine, midazolam, milrinone and morphine). Incompatibility could not be ruled out for 3 drugs (cisatracurium, dexmedetomidine and noradrenalin), and insulin was considered incompatible with alprostadil. What is Known: • Y-site administration is common in neonatal intensive care units, and volume of diluents and rate of infusions in newborns were lower than in adults which might result in high concentrations and prolonged contact time at Y-site administration. • Available data about compatibility of alprostadil with other drugs was scarce. What is New: • Alprostadil was compatible with 13 drugs commonly used in neonatal intensive care units. • Insulin was considered incompatible with alprostadil, and incompatibility cannot be ruled out for cisatracurium, dexmedetomidine and noradrenalin with alprostadil.

Intravenous medicine preparation technique training programme for nurses in clinical areas.

OBJECTIVE: The key objective of this study was to highlight the weak points in the medicine use process. METHOD: We collected 15 videos from eight neonatal intensive care units where staff nurses showed how medicine preparation was performed. Recorded medicines were: vancomycin (6), gentamicin (5), caffeine citrate (2) and phenobarbital (2). RESULTS: We did not review any video without errors. In 8/15 (53.3%) videos, the same syringe was used to measure the medicine and the diluent. In 8/15 (53.3%) videos, the syringes used were not the correct size for the volume being measured. In 4/15 (26.6%) videos, the volume measured into the syringes was not checked after it was measured from vials or ampoules. In just one vancomycin preparation could the reconstitution process be described as a correct process; in the other five videos, mixing after diluent addition to the vancomycin vial was almost non-existent (less than 10 s). Mixing after the medicine and diluent were in the same syringe was also non-existent in all of the videos. CONCLUSIONS: Hospitals should provide training programmes outlining the correct preparation technique.

Medicine preparation errors in ten Spanish neonatal intensive care units.

This study assessed the rate of errors in intravenous medicine preparation at the bedside in neonatal intensive care units vs the preparation error rate in a hospital pharmacy service. We conducted a prospective observational study between June and September 2013. Ten Spanish neonatal intensive care units and one hospital pharmacy service participated in the study. Two types of preparation errors were considered: calculation errors and accuracy errors. A total of 522 samples were collected: 238 of vancomycin, 139 of gentamicin, 39 of phenobarbital and 88 of caffeine citrate preparations. Of these, 444 samples were collected by nurses in neonatal intensive care units, and 60 were provided by the hospital pharmacy service. Overall, 18 samples were excluded from the analysis. We detected calculation errors in 6/444 (1.35%) and accuracy errors in 243/444 (54.7%) samples from the neonatal intensive care units. In contrast, in samples from the hospital pharmacy service, no calculation errors were detected, but there were accuracy errors in 23/60 (38.3%) samples. CONCLUSION: While calculation errors can be eliminated using protocols based on standard drug concentrations, accuracy error rates depend on several variables that affect both neonatal intensive care units and hospital pharmacy services. WHAT IS KNOWN: Medication use is associated with a risk of errors and adverse events. Medication errors are more frequent and have more severe consequences in paediatric patients. Lack of knowledge of drug pharmacokinetics and pharmacodynamics in relation to physiological immaturity makes neonates more vulnerable to medication errors. WHAT IS NEW: Calculation errors are avoided using concentration standard preparation protocols. Accuracy in the preparation process depends mainly on the degree to which commercial drug preparations meet current legal requirements and the syringes and preparation techniques used.

Strategies implementation to reduce medicine preparation error rate in neonatal intensive care units.

UNLABELLED: This study assessed the rate of errors in intravenous medicine preparation at bedside in neonatal intensive care units versus preparation error rate in a hospital pharmacy service before and after several strategies were implemented. We performed a prospective observational study during 2013-2015. Ten Spanish neonatal intensive care units and one hospital pharmacy service participated in the study. Two types of preparation errors were considered, calculation errors and accuracy errors. The study was carried out over three consecutive phases: (1) pre-intervention phase, when medicine preparation samples were collected from neonatal intensive care units and hospital pharmacy service according to their normal clinical practice; (2) intervention phase, when protocol standardisation and educational strategy took place; and (3) post-intervention phase, when new medicine samples were collected after strategy implementation. In neonatal intensive care units, 1.35 % of samples registered calculation errors in pre-intervention phase; no calculation errors were registered in hospital pharmacy service samples. In post-intervention phase, no calculation errors were registered in either group. Accuracy error rate decreased both in neonatal intensive care units (54.7 vs 23 %) and hospital pharmacy service (38.3 vs 14.6 %). CONCLUSION: Calculation errors can disappear with good standardisation protocols. Decrease in accuracy error depends on good preparation technique and environmental factors. WHAT IS KNOWN: • Medication use is associated with a risk of errors and adverse events. Medication errors are more frequent and have more severe consequences in paediatric patients. • Lack of commercial drug formulations adapted to newborn infants makes medicine preparation process more prone to error. What is New: • Calculation errors are minimising using concentration standard protocols. Preparation rules are essential to ensure the accuracy process. • Environmental conditions affect the accuracy process.

Educational strategy to reduce medication errors in a neonatal intensive care unit.

OBJECTIVE: We aimed to evaluate the effect of a comprehensive preventive educational strategy on the number and type of drug errors in the prescription process in a regional neonatal intensive care unit (NICU). DESIGN: Medication errors during prescription were recorded in a 41 bed, level III regional neonatal unit by a pharmacist. Data were retrieved from handwritten doctor's orders and introduced at bedsite into an e-database. Each prescription, not related to enteral and parenteral nutrition and blood products, was evaluated for dosage, units, route and dosing interval. The study was developed in three phases: pilot phase to know the baseline drug error rate and estimate sample size; pre-intervention (4182 drug orders reviewed); and post-intervention seven months after a comprehensive preventive educational intervention consisting sessions about drug errors and study's aims was implemented. RESULTS: After the preventive educational intervention was implemented, the prescription error rate and the percentage of registers with one or more incident decreased significantly from 20.7 to 3% (p < 0.001) and from 19.2 to 2.9% (p < 0.001), respectively. Simultaneously, an improvement in correct identification of the prescribing physician was registered (from 1.3 to 78.2%). The rest of items analysed were similar in both periods. CONCLUSION: The implementation of a structured preventive educational intervention for health professionals in a regional NICU reduced the medication error rate, possibly by the dissemination of a patient safety culture.

Medication errors in a neonatal intensive care unit. Influence of observation on the error rate.

AIM: To study if medication error rate decreased as a consequence of a simple observation process of registering its occurrence. METHODS: Prescription and transcription processes were prospectively registered along two different period of time in a level III regional Neonatal Intensive Care Unit: a pilot phase, aimed to know the baseline drug error rate and a phase I, a pre-intervention phase, both part of a study designed to determinate the effect of a preventive strategy in drug error rate. Random drug prescriptions by physicians and their transcriptions by nurses were reviewed and registered by a hospital pharmacist. A drug error episode was registered if dosage, units, route and administration interval were incorrect, illegible or not indicated. RESULTS: A significant reduction in the prescription error rate from 32.8% in the pilot phase to 19.2% in the pre-intervention study phase was observed (p< 0.001). Rates of incorrect dosing (13.6% vs. 5%) and lack of dose specification in the medical prescriptions (3.3% vs. 0.5%) dropped significantly but transcription errors did not. CONCLUSION: The presence of a person reviewing and registering the drug records apparently had by itself a substantial positive effect on the overall drug error rate. This phenomenon known as the Hawthorne effect should be taken in consideration when evaluating the efficacy of any preventive intervention aimed at improving patient safety.