Biomedical Engineering / Biomedizinische Technik

Published by De Gruyter

Volume 60 Issue 4 - Special Issue: Low Liquid Flows in Medical Technology / Guest Editors: Stephan Klein and Peter Lucas

Issue of Biomedical Engineering / Biomedizinische Technik

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Contents
Journal Overview

Publicly Available August 5, 2015

Editorial

Publicly Available August 5, 2015

Low liquid flows – an important aspect in medical technology

Stephan Klein, Peter Lucas

Page range: 269-270

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Special issue articles

April 16, 2015

Metrology for drug delivery

Peter Lucas, Stephan Klein

Page range: 271-275

Abstract

In various recently published studies, it is argued that there are underestimated risks with infusion technology, i.e., adverse incidents believed to be caused by inadequate administration of the drugs. This is particularly the case for applications involving very low-flow rates, i.e., <1 ml/h and applications involving drug delivery by means of multiple pumps. The risks in infusing are caused by a lack of awareness, incompletely understood properties of the complete drug delivery system and a lack of a proper metrological infrastructure for low-flow rates. Technical challenges such as these were the reason a European research project “Metrology for Drug Delivery” was started in 2011. In this special issue of Biomedical Engineering , the results of that project are discussed.

Publicly Available August 5, 2015

Flow variability and its physical causes in infusion technology: a systematic review of in vitro measurement and modeling studies

Roland A. Snijder, Maurits K. Konings, Peter Lucas, Toine C. Egberts, Annemoon D. Timmerman

Page range: 277-300

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Abstract

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).

Publicly Available August 5, 2015

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

Hugo Bissig, Harm Tido Petter, Peter Lucas, Elsa Batista, Eduarda Filipe, Nelson Almeida, Luis Filipe Ribeiro, João Gala, Rui Martins, Benoit Savanier, Florestan Ogheard, Anders Koustrup Niemann, Joost Lötters, Wouter Sparreboom

Page range: 301-316

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Abstract

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.

August 5, 2015

Primary standard for liquid flow rates between 30 and 1500 nl/min based on volume expansion

Peter Lucas, Martin Ahrens, Jan Geršl, Wouter Sparreboom, Joost Lötters

Page range: 317-335

Abstract

An increasing number of microfluidic systems operate at flow rates below 1 μl/min. Applications include (implanted) micropumps for drug delivery, liquid chromatography, and microreactors. For the applications where the absolute accuracy is important, a proper calibration is required. However, with standard calibration facilities, flow rate calibrations below ~1 μl/min are not feasible because of a too large calibration uncertainty. In the current research, a traceable flow rate using a certain temperature increase rate is proposed. When the fluid properties, starting mass, and temperature increase rate are known, this principle yields a direct link to SI units, which makes it a primary standard. In this article, it will be shown that this principle enables flow rate uncertainties in the order of 2–3% for flow rates from 30 to 1500 nl/min.

July 8, 2015

An experimental setup for traceable measurement and calibration of liquid flow rates down to 5 nl/min

Martin Ahrens, Bodo Nestler, Stephan Klein, Peter Lucas, Harm Tido Petter, Christian Damiani

Page range: 337-345

Abstract

This work presents the improvements of an experimental setup for measuring ultra-low flow rates down to 5 nl/min. The system uses a telecentric CCD imaging system mounted on a high-precision, computer-controlled linear stage to track a moving liquid meniscus inside a glass capillary. Compared to the original setup, the lowest attainable expanded uncertainty at any flow rate has been reduced from 5.4% to 2%. In addition, the conformity with specification of three commercial micro-fluidic devices was evaluated using the new setup: one syringe pump, one implantable infusion pump and one thermal flow sensor. The flow sensor and the implantable infusion pump met the compliance criteria (coverage probability 95%). The syringe pump however, failed to meet the specifications at 5 nl/min and 10 nl/min. No assessment could be made at higher flow rates.

Publicly Available May 6, 2015

Assessment of drug delivery devices

Elsa Batista, Nelson Almeida, Andreia Furtado, Eduarda Filipe, Luis Sousa, Rui Martins, Peter Lucas, Harm Tido Petter, Roland Snijder, Annemoon Timmerman

Page range: 347-357

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Abstract

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.

July 29, 2015

An adjustable flow restrictor for implantable infusion pumps based on porous ceramics

Holger Jannsen, Stephan Klein, Bodo Nestler

Page range: 359-364

Abstract

This paper describes an adjustable flow restrictor for use in gas-driven implantable infusion pumps, which is based on the resistance of a flow through a porous ceramic material. The flow inside the walls of a ceramic tube can be adjusted between 270 nl/min and 1260 nl/min by changing the flow path length in the ceramic over a distance of 14 mm. The long-term stability of the flow restrictor has been analyzed. A drift of -8% from the nominal value was observed, which lies within the required tolerance of ±10% after 30 days. The average time needed to change the flow rate is 40 s. In addition, the maximum adjustment time was 110 s, which also lies within the specification.

Publicly Available July 4, 2015

How physical infusion system parameters cause clinically relevant dose deviations after setpoint changes

Annemoon M. Timmerman, Roland A. Snijder, Peter Lucas, Martine C. Lagerweij, Joris H. Radermacher, Maurits K. Konings

Page range: 365-376

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Abstract

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.

August 1, 2015

In vitro comparison of two changeover methods for vasoactive drug infusion pumps: quick-change versus automated relay

Stéphanie Genay, Bertrand Décaudin, Sébastien Lédé, Frédéric Feutry, Christine Barthélémy, Gilles Lebuffe, Pascal Odou

Page range: 377-380

Abstract

This study aimed to compare in vitro two syringe changeover techniques to determine which was better at minimising variations in norepinephrine (NE) delivery: the manual quick-change or automated technique. NE concentration was measured continuously using a UV spectrophotometer, and infusion flow rate was monitored by an infusion pump tester. Syringe changeovers were made with either of the two techniques studied. Relays induced disturbances in drug delivery. The temporary increase in NE mass flow rate was significantly higher with manual relays than with automated ones. The automated relay offered a better control of the amounts of NE administered than the quick-change technique.

August 5, 2015

How to use current practice, risk analysis and standards to define hospital-wide policies on the safe use of infusion technology

Annemoon M. Timmerman, Suzanne M. Oliveira-Martens, Roland A. Snijder, Anders K. Nieman, Toine C. Egberts

Page range: 381-387

Abstract

Infusion therapy is widely used in hospitals. It is well known that medication errors constitute one of the highest risks to patient safety, leading to numerous adverse events concerning incorrect application of infusion technology. Both clinical practice and in vitro studies show that infusion of multiple medications via one access point induces unwanted phenomena such as backflow and an incorrect system response to interventions. Within the Metrology for Drug Delivery project, we addressed the role of infusion devices in drug delivery. We surveyed current practices for application in hospitals to provide input to standards and quality norms for the materials used in infusion technology. Furthermore, we organized meetings with clinicians and other relevant stakeholders to set up a risk analysis-based infusion policy, accompanied by easy to access operating procedures on infusion technology. It was found difficult to establish clear-cut infusion safety guidelines based on quantitative data because of the many different application areas and stakeholders. However, both the expert team and the survey indicated the value of multidisciplinary qualitative discussion for defining best practices. We advise to incorporate specific requirements on infusion devices in protocols and standards, adjusted to specific applications, to ensure safe use of infusion technology.

About this journal

Objective
Biomedical Engineering / Biomedizinische Technik (BMT) is a high-quality forum for the exchange of knowledge in the fields of biomedical engineering, medical information technology and biotechnology/bioengineering. As an established journal with a tradition of more than 60 years, BMT addresses engineers, natural scientists, and clinicians working in research, industry, or clinical practice. All articles are peer-reviewed. All manuscripts must be submitted in English.

Topics

diagnostic imaging
image processing
biosignal processing
modelling and simulation
biomechanics
information and communication in medicine
telemedicine and e-health
surgery
minimum invasive interventions
endoscopy and image-guided therapy
diagnostic and therapeutic instrumentation
clinical engineering
micro- and nanosystems in medicine
active implants
biosensors
neuro-engineering
neural systems
rehabilitation and prosthetics
biomaterials
cellular and tissue engineering
artificial organs
biomedical engineering for audiology, ophthalmology, emergency and dental medicine
general subjects (e.g., education and training, health technology assessment)
special topics (e.g., linking proteomics and genomics with biomedical engineering, emergency medicine)

Article formats
Reviews, Research Articles, Short Communications

Volume 60 Issue 4 - Special Issue: Low Liquid Flows in Medical Technology / Guest Editors: Stephan Klein and Peter Lucas

Issue of Biomedical Engineering / Biomedizinische Technik

Frontmatter

Low liquid flows – an important aspect in medical technology

Metrology for drug delivery

Abstract

Flow variability and its physical causes in infusion technology: a systematic review of in vitro measurement and modeling studies

Abstract

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

Abstract

Primary standard for liquid flow rates between 30 and 1500 nl/min based on volume expansion

Abstract

An experimental setup for traceable measurement and calibration of liquid flow rates down to 5 nl/min

Abstract

Assessment of drug delivery devices

Abstract

An adjustable flow restrictor for implantable infusion pumps based on porous ceramics

Abstract

How physical infusion system parameters cause clinically relevant dose deviations after setpoint changes

Abstract

In vitro comparison of two changeover methods for vasoactive drug infusion pumps: quick-change versus automated relay

Abstract

How to use current practice, risk analysis and standards to define hospital-wide policies on the safe use of infusion technology

Abstract