Assessment of drug delivery devices working at microflow rates.

Almost every medical department in hospitals around the world uses infusion devices to administer fluids, nutrition, and medications to patients to treat many different diseases and ailments. There have been several reports on adverse incidents caused by medication errors associated with infusion equipment. Such errors can result from malfunction or improper use, or even inaccuracy of the equipment, and can cause harm to patients' health. Depending on the intended use of the equipment, e.g. if it is used for anaesthesia of adults or for medical treatment of premature infants, the accuracy of the equipment may be more or less important. A well-defined metrological infrastructure can help to ensure that infusion devices function properly and are as accurate as needed for their use. However, establishing a metrological infrastructure requires adequate knowledge of the performance of infusion devices in use. This paper presents the results of various tests conducted with two types of devices.

Calibration of insulin pumps based on discrete doses at given cycle times.

One application in the medical treatment at very small flow rates is the usage of an Insulin pump that delivers doses of insulin at constant cycle times for a specific basal rate as quasi-continuous insulin delivery, which is an important cornerstone in diabetes management. The calibration of these basal rates are performed by either gravimetric or optical methods, which have been developed within the European Metrology Program for Innovation and Research (EMPIR) Joint Research Project (JRP) 18HLT08 Metrology for drug delivery II (MeDDII). These measurement techniques are described in this paper, and an improved approach of the analytical procedure given in the standard IEC 60601-2-24:2012 for determining the discrete doses and the corresponding basal rates is discussed in detail. These improvements allow detailed follow up of dose cycle time and delivered doses as a function of time to identify some artefacts of the measurement method or malfunctioning of the insulin pump. Moreover, the calibration results of different basal rates and bolus deliveries for the gravimetric and the optical methods are also presented. Some analysis issues that should be addressed to prevent misinterpreting of the calibration results are discussed. One of the main issues is the average over a period of time which is an integer multiple of the cycle time to determine the basal rate with the analytical methods described in this paper.

Calibration methods for flow rates down to 5 nL/min and validation methodology.

Improving the accuracy and enabling traceable measurements of volume, flow, and pressure in existing drug delivery devices and in-line sensors operating at very low flow rates is essential in several fields of activities and specially in medical applications. This can only be achieved through the development of new calibrationmethods and by expanding the existing metrological infrastructure to perform micro-flow and nano-flow measurements. In this paper, we will investigate new traceable techniques for measuring flow rate, from 5 nL/min to 1,500 nL/min and present the results of an inter-comparison between nine laboratories for the calibration of two different flow meters and a syringe pump.

Primary standards for measuring flow rates from 100 nl/min to 1 ml/min - gravimetric principle.

Microflow and nanoflow rate calibrations are important in several applications such as liquid chromatography, (scaled-down) process technology, and special health-care applications. However, traceability in the microflow and nanoflow range does not go below 16 µl/min in Europe. Furthermore, the European metrology organization EURAMET did not yet validate this traceability by means of an intercomparison between different National Metrology Institutes (NMIs). The NMIs METAS, Centre Technique des Industries Aérauliques et Thermiques, IPQ, Danish Technological Institute, and VSL have therefore developed and validated primary standards to cover the flow rate range from 0.1 µl/min to at least 1 ml/min. In this article, we describe the different designs and methods of the primary standards of the gravimetric principle and the results obtained at the intercomparison for the upper flow rate range for the various NMIs and Bronkhorst High-Tech, the manufacturer of the transfer standards used.

Computational fluid dynamics simulation of a-v fistulas: from MRI and ultrasound scans to numeric evaluation of hemodynamics.

PURPOSE: A-v anastomosis entails dramatic changes in hemodynamic conditions, which may lead to major alterations to the vessels involved; primarily dilatations and devastating stenoses. Wall shear stress is thought to play a key role in the remodeling of the vessels exposed to abnormal levels and oscillating wall shear stress. In this study we sought to develop a framework suitable for thorough in vivo analyses of wall shear stress and vessel morphology of a-v fistulas in patients. METHODS: Using ultrasound and magnetic resonance imaging (MRI) transverse image stacks from six patient a-v fistulas were obtained. From the image stacks three-dimensional geometries of the patient fistulas were created using dedicated segmentation software. Geometries of three a-v fistulas were imported into finite element software in order to perform fluid flow simulations of blood flows and frictional forces on the vessel walls in the a-v fistulas. Boundary conditions for the simulations were obtained using both a MRI phase contrast and an ultrasound Doppler technique. RESULTS: The segmentation of the six fistulas of very different age and morphology (two end-to-side and four side-to-side) showed the ability of the approach to create geometries of various fistula morphologies. Simulations of the three fistulas showed an instant picture of the present status of the exposure to different levels of wall shear stress and the morphological status in the vessel remodeling process. CONCLUSION: The study demonstrated the capability of the CFD framework to analyze patient a-v fistulas on a regular basis using both MRI and ultrasound-based approaches.

Wall shear stress and local plaque development in stenosed carotid arteries of hypercholesterolemic minipigs.

BACKGROUND: Wall shear stress is thought to play a critical role in the local development of atherosclerotic plaque and to affect plaque vulnerability. However, current models and hypotheses do not fully explain the link between wall shear stress and local plaque development. We aimed to investigate the relation between wall shear stress and local plaque development in surgically induced common carotid artery stenoses of hypercholesterolemic minipigs. MATERIALS, METHODS AND RESULTS: We created a surgically induced stenosis of the common carotid artery in 10 minipigs using a perivascular collar. We documented the flow and shear stress changes by ultrasound, magnetic resonance imaging, and computational fluid dynamics. Carotid plaques were documented by microscopy. Atherosclerotic lesions, in both pre-stenotic and post-stenotic segments, were associated with thrombus in the stenosed segment. In patent carotid arteries, atherosclerotic lesions were found in the post-stenotic segments only. Atherosclerotic lesions developed where low and oscillatory shear stress were present simultaneously, whereas low or oscillatory shear stress alone did not lead to lesion formation. CONCLUSIONS: Low and oscillatory shear stress in combination promoted plaque development, including plaques with necrotic cores that are the key and dangerous characteristic of vulnerable plaques.