Trough anti-Xa activity after intermediate dose nadroparin for thrombosis prophylaxis in critically ill patients with COVID-19 and acute kidney injury.

Our objective was to assess the incidence of drug bioaccumulation in critically ill COVID-19 patients with AKI receiving intermediate dose nadroparin for thrombosis prophylaxis. We conducted a Prospective cohort study of critically ill COVID-19 patients. In patients on intermediate dose nadroparin (5700 IU once daily) we assessed the incidence of bioaccumulation (trough anti-Xa level > 0.2 IU/mL) stratified according to presence of AKI. We quantified this association using multilevel analyses. To assess robustness of our observations, we explored the association between AKI and anti-Xa activity in patients receiving high dose nadroparin (> 5700 IU). 108 patients received intermediate dose nadroparin, of whom 24 had AKI during 36 anti-Xa measurements. One patient with AKI (4.2% [95%CI 0.1-21%]) and 1 without (1.2% [95%CI 0.03-6.5%]) developed bioaccumulation (p = 0.39). Development of AKI was associated with a mean increase of 0.04 (95%CI 0.02-0.05) IU/ml anti-Xa activity. There was no statistically significant association between anti-Xa activity and AKI in 51 patients on high dose nadroparin. There were four major bleeding events, all in patients on high dose nadroparin. In conclusion, Bioaccumulation of an intermediate dose nadroparin did not occur to a significant extent in critically ill patients with COVID-19 complicated by AKI. Dose adjustment in AKI may be unnecessary.

Voluntarily reported prescribing, monitoring and medication transfer errors in intensive care units in The Netherlands.

Background Medication errors occur frequently in intensive care units (ICU). Voluntarily reported medication errors form an easily available source of information. Objective This study aimed to characterize prescribing, monitoring and medication transfer errors that were voluntarily reported in the ICU, in order to reveal medication safety issues. Setting This retrospective data analysis study included reports of medication errors from eleven Dutch ICU's from January 2016 to December 2017. Method We used data extractions from the incident reporting systems of the participating ICU's. The reports were transferred into one database and categorized into type of error, cause, medication (groups), and patient harm. Descriptive statistics were used to calculate the proportion of medication errors and the distribution of subcategories. Based on the analysis, ICU medication safety issues were revealed. Main outcome measure The main outcome measure was the proportion of prescribing, monitoring and medication transfer error reports. Results Prescribing errors were reported most frequently (n = 233, 33%), followed by medication transfer errors (n = 85, 12%) and monitoring errors (n = 27, 4%). Other findings were: medication transfer errors frequently caused serious harm, especially the omission of home medication involving the central nervous system and proton pump inhibitors; omissions and dosing errors occurred most frequently; protocol problems caused a quarter of the medication errors; and medications needing blood level monitoring (e.g. tacrolimus, vancomycin, heparin and insulin) were frequently involved. Conclusion This analysis of voluntarily reported prescribing, monitoring and medication transfer errors warrants several improvement measures in these processes, which may help to increase medication safety in the ICU.

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.

Holmium-166 poly(L-lactic acid) microsphere radioembolisation of the liver: technical aspects studied in a large animal model.

OBJECTIVE: To assess the accuracy of a scout dose of holmium-166 poly(L-lactic acid) microspheres ((166)Ho-PLLA-MS) in predicting the distribution of a treatment dose of (166)Ho-PLLA-MS, using single photon emission tomography (SPECT). METHODS: A scout dose (60 mg) was injected into the hepatic artery of five pigs and SPECT acquired. Subsequently, a 'treatment dose' was administered (540 mg) and SPECT, computed tomography (CT) and magnetic resonance imaging (MRI) of the total dose performed. The two SPECT images of each animal were compared. To validate quantitative SPECT an ex vivo liver was instilled with (166)Ho-PLLA-MS and SPECT acquired. The liver was cut into slices and planar images were acquired, which were registered to the SPECT image. RESULTS: Qualitatively, the scout dose and total dose images were similar, except in one animal because of catheter displacement. Quantitative analysis, feasible in two animals, tended to confirm this similarity (r(2) = 0.34); in the other animal the relation was significantly better (r(2) = 0.66). The relation between the SPECT and planar images acquired from the ex vivo liver was strong (r(2) = 0.90). CONCLUSION: In the porcine model a scout dose of (166)Ho-PLLA-MS can accurately predict the biodistribution of a treatment dose. Quantitative (166)Ho SPECT was validated for clinical application.

Microspheres with ultrahigh holmium content for radioablation of malignancies.

PURPOSE: The aim of this study was to develop microspheres with an ultra high holmium content which can be neutron activated for radioablation of malignancies. These microspheres are proposed to be delivered selectively through either intratumoral injections into solid tumors or administered via an intravascularly placed catheter. METHODS: Microspheres were prepared by solvent evaporation, using holmium acetylacetonate (HoAcAc) crystals as the sole ingredient. Microspheres were characterized using light and scanning electron microscopy, coulter counter, titrimetry, infrared and Raman spectroscopy, differential scanning calorimetry, X-ray powder diffraction, magnetic resonance imaging (MRI), and X-ray computed tomography (CT). RESULTS: Microspheres, thus prepared displayed a smooth surface. The holmium content of the HoAcAc microspheres (44% (w/w)) was higher than the holmium content of the starting material, HoAcAc crystals (33% (w/w)). This was attributed to the loss of acetylacetonate from the HoAcAc complex, during rearrangement of acetylacetonate around the holmium ion. The increase of the holmium content allows for the detection of (sub)microgram amounts of microspheres using MRI and CT. CONCLUSIONS: HoAcAc microspheres with an ultra-high holmium content were prepared. These microspheres are suitable for radioablation of tumors by intratumoral injections or treatment of liver tumors through transcatheter administration.

Microsphere radioembolization of liver malignancies: current developments.

The worldwide incidence of hepatic malignancies, both primary and secondary, exceeds 1 000 000 new cases each year. The poor prognosis of patients suffering from hepatic malignancies has lead to the development of a liver directed therapy which consists of intra-arterial administration of radioactive particles through a catheter. Yttrium-90 ((90)Y) microspheres are increasingly applied for this purpose, and up to now nearly all clinical experience with radioembolization has been obtained with these microspheres. The response rate is very promising in both patients with primary and metastatic liver malignancies. Currently, two commercially available (90)Y microsphere devices are in use clinically, both as a first-line treatment and in a salvage setting. Unfortunately, the use of a pure beta-emitter like (90)Y hampers acquisition of high quality nuclear images for pre-treatment work-up and follow-up. This issue was addressed by the development of holmium-166 ((166)Ho) and rhenium-188 ((188)Re) microspheres, which emit both beta-particles for therapeutic purposes and gamma-photons for nuclear imaging. Moreover, since holmium is paramagnetic it allows for magnetic resonance imaging. (166)Ho loaded poly(L-lactic acid) microspheres have been thoroughly investigated in a preclinical setting, and recently the first clinical results for (188)Re microspheres were reported. This review provides an overview of the current status and (pre-)clinical developments of radioactive microspheres for treatment of liver malignancies.