Infusion therapy is medically and technically challenging and frequently associated with medical errors. When administering pharmaceuticals by means of infusion, dosing errors can occur due to flow rate variability. These dosing errors may lead to adverse effects. We aimed to systematically review the available biomedical literature for in vitro measurement and modeling studies that investigated the physical causes of flow rate variability. Special focus was given to syringe pump setups, which are typically used if very accurate drug delivery is required. We aimed to extract from literature the component with the highest mechanical compliance in syringe pump setups. We included 53 studies, six of which were theoretical models, two articles were earlier reviews of infusion literature, and 45 were in vitro measurement studies. Mechanical compliance, flow resistance, and dead volume of infusion systems were stated as the most important and frequently identified physical causes of flow rate variability. The syringe was indicated as the most important source of mechanical compliance in syringe pump setups (9.0×10-9 to 2.1×10-8 l/Pa). Mechanical compliance caused longer flow rate start-up times (from several minutes up to approximately 70 min) and delayed occlusion alarm times (up to 117 min).
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.
For critical drug delivery, it is important to have a constant and well-known infusion rate delivered by the complete infusion set-up (pump, tubing, and accessories). Therefore, various drug delivery devices and accessories were tested in this article in terms of their infusion accuracy, start-up delay, response time, and dependency on the viscosity. These measurements were performed as part of the European funded research project MeDD. The obtained results show that the infusion accuracy of the devices is flow rate and accessory depended, especially for low flow rates. Viscosity does not have a significant impact on the flow rate accuracy.
Multi-infusion therapy, in which multiple pumps are connected to one access point, is frequently used in patient treatments. This practice is known to cause dosing errors following setpoint changes in the drug concentrations that actually enter the patients. Within the Metrology for Drug Delivery Project, we analyzed and quantified the two main physical phenomena leading to these errors: the "push-out" effect and the system mechanical compliance. We compared the dosing errors of a three-pump system with two infusion sets, both with and without anti-reflux valves, using in vitro spectrophotometric experiments. Additionally, computer simulations were used to study the compliance effect separately. We found a start-up time of more than 1 h, and a dosing error following a setpoint increase of another pump for the low flow rate pump, corresponding to 0.5 μg noradrenaline delivered in 8 min. We showed that the dead volume inside the tubes and syringe compliance produce opposite deviations from the setpoint values in the actual drug output concentrations, making the net result hard to predict and often counterintuitive. We conclude that metrology on compliance and push-out effects could be used by infusion device manufacturers to successfully improve drug delivery performance and relevant standards for high-risk multi-infusion applications.
The number of primary rays in the labral fan of filter-feeding black fly (Diptera: Simuliidae) larvae has been used by some authors to aid in species identification. We examined the number of primary labral fan rays in field-collected last-instar larvae of Simulium rostratum and Simulium decorum. Significant inter- and intra-specific differences were found both spatially and temporally. Simulium rostratum and S. decorum larvae were also reared to last instar (from eggs or first- or second-instar larvae) under three feeding regimes to test the effect of seston load on the number of primary labral fan rays. In both species the fan-ray number decreased when the food supply was increased. We conclude that the primary fan ray number should be used cautiously in species diagnosis because it is a phenotypically plastic trait that varies with seston load. A potential feedback mechanism to explain the observed differences in fan-ray number is hypothesised.
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