The hemodynamic cardiac profiler volume-time curves and related parameters: an MRI validation study.

Background.The hemodynamic cardiac profiler (HCP) is a new, non-invasive, operator-independent screening tool that uses six independent electrode pairs on the frontal thoracic skin, and a low-intensity, patient-safe, high-frequency applied alternating current to measure ventricular volume dynamics during the cardiac cycle for producing ventricular volume-time curves (VTCs).Objective.To validate VTCs from HCP against VTCs from MRI in healthy volunteers.Approach.Left- and right-ventricular VTCs were obtained by HCP and MRI in six healthy participants in supine position. Since HCP is not compatible with MRI, HCP measurements were performed within 20 min before and immediately after MRI, without intermittent fluid intake or release by participants. Intraclass correlation coefficients (ICCs) were calculated to validate HCP-VTC against MRI-VTC and to assess repeatability of HCP measurements before and after MRI. Bland-Altman plots were used to assess agreement between relevant HCP- and MRI-VTC-derived parameters. Precision of HCP's measurement of VTC-derived parameters was determined for each study participant by calculating the coefficients of variation and repeatability coefficients.Main results.Left- and right-ventricular VTC ICCs between HCP and MRI were >0.8 for all study participants, indicating excellent agreement between HCP-VTCs and MRI-VTCs. Mean (range) ICC of HCP right-ventricular VTC versus MRI right-ventricular VTC was 0.94 (0.88-0.99) and seemed to be slightly higher than the mean ICC of HCP left-ventricular VTC versus MRI-VTC (0.91 (0.80-0.96)). The repeatability coefficient for HCP's measurement of systolic time (tSys) was 45.0 ms at a mean value of 282.9 ± 26.3 ms. Repeatability of biventricular HCP-VTCs was excellent (ICC 0.96 (0.907-0.995)).Significance.Ventricular volume dynamics measured by HCP-VTCs show excellent agreement with VTCs measured by MRI. Since abnormal tSys is a sign of numerous cardiac diseases, the HCP may potentially be used as a diagnostic screening tool.

Bedside visualisation tool for prediction of deviation from intended dosage in multi-infusion therapy.

BACKGROUND: In multi-infusion therapy, multiple infusion pumps are connected to one single vascular access point. Interaction between pressure changes from different pumps may result in temporary dosing errors, which can be very harmful to the patient. It is known that these dosing errors occur. However, clinicians tend to find it hard to estimate the order of magnitude of these errors. METHODS: This research uses an existing mathematical model to create a bedside prediction tool that is able to provide clinicians with the dosing errors that will occur after flow rate changes in multi-infusion therapy. A panel of clinicians, consisting of both nurses and doctors, was formed, and, in order to assess the level of knowledge about dosing errors in multi-infusion, the panel was presented with four medication schedules in which a syringe exchange or change in flow rate took place. The panel was asked to predict the resulting dosing errors. RESULTS: A prediction tool was developed that describes a two pump multi-infusion system and predicts dosing errors resulting from changing the flow rate at one pump. 44% of the panel members wrongly predicted the impact of changing the set flow of liquid A on the flow of liquid B that reaches the patient. Nobody was able to correctly predict the dosing deviation if a very small catheter was used. After the prediction tool was shown, the clinicians indicated they had a improved understanding of what deviations to expect and that the tool would be useful in understanding multi-infusion dosing errors. CONCLUSIONS: Using the predictive tool to visualise the deviations from the set flow rate is an effective method to allow clinicians to gain insight in dosing errors in multi-infusion therapy. This knowledge can be used to better anticipate future dosing errors in clinical situations.

Effect of non-return valves on the time-of-arrival of new medication in a patient after syringe exchange in an infusion set-up.

The presence of a non-return valve in an infusion set-up is expected to affect the time-of-arrival of new medication in a patient after syringe exchange. Using Computational Fluid Dynamics (CFD) we have studied the flow through a typical non-return valve, focusing on two separate effects: (A) the overall delay in the time-of-arrival, and (B) timing effects due to the distortion of the Poiseuille flow profile in the non-return valve. The results show that (A) the additional delay in time-of-arrival of new medication, caused by the non-return valve alone, corresponds to the delay that would be caused by 11.2 cm of extra infusion line instead of the valve, and that (B) the non-Poiseuille flow profile inside the non-return valve gives rise to an extra slow wash-out of the last portion of the remnant fluid of the old medication. We conclude that awareness of these extra delays may be important for clinicians in certain time-critical situations.

Unexpected dosing errors due to air bubbles in infusion lines with and without air filters.

The effect of the presence of an air bubble, inside an infusion line, on the time (Tnew) needed for a new medication to reach the patient after a syringe exchange was studied in this paper. If an air bubble escapes through an air filter, then a sudden drop in pressure occurs, causing a relaxation of the compressible part of the syringe, followed by a gradual restoration of the flow rate in the line. We modeled this phenomenon mathematically and measured it experimentally in vitro. In an example with a pump flow rate of 5 mL/h and an air bubble of 1 cm length inside an infusion line (diameter 1 mm) with an air filter, both theory and experiment yield an additional increase of at least 600% in delay time if a naive estimate (based on the size of the bubble alone) is replaced by a more realistic estimate incorporating compressibility. Furthermore, we show that an air bubble in a line without air filter may increase Tnew by a factor 2, depending on the initial position of the air bubble. We conclude that an air bubble in an infusion line causes delays that may not be expected by health care professionals.

High-frequency irreversible electroporation for cardiac ablation using an asymmetrical waveform.

BACKGROUND: Irreversible electroporation (IRE) using direct current (DC) is an effective method for the ablation of cardiac tissue. A major drawback of the use of DC-IRE, however, are two problems: requirement of general anesthesia due to severe muscle contractions and the formation of bubbles containing gaseous products from electrolysis. The use of high-frequency alternating current (HF-IRE) is expected to solve both problems, because HF-IRE produces little to no muscle spasms and does not cause electrolysis. METHODS: In the present study, we introduce a novel asymmetric, high-frequency (aHF) waveform for HF-IRE and present the results of a first, small, animal study to test its efficacy. RESULTS: The data of the experiments suggest that the aHF waveform creates significantly deeper lesions than a symmetric HF waveform of the same energy and frequency (p = 0.003). CONCLUSION: We therefore conclude that the use of the aHF enhances the feasibility of the HF-IRE method.

Analytical method for calculation of deviations from intended dosages during multi-infusion.

BACKGROUND: In this paper, a new method is presented that combines mechanical compliance effects with Poiseuille flow and push-out effects ("dead volume") in one single mathematical framework for calculating dosing errors in multi-infusion set-ups. In contrast to existing numerical methods, our method produces explicit expressions that illustrate the mathematical dependencies of the dosing errors on hardware parameters and pump flow rate settings. METHODS: Our new approach uses the Z-transform to model the contents of the catheter, and after implementation in Mathematica (Wolfram), explicit expressions are produced automatically. Consistency of the resulting analytical expressions has been examined for limiting cases, and three types of in-vitro measurements have been performed to obtain a first experimental test of the validity of the theoretical results. RESULTS: The relative contribution of various factors affecting the dosing errors, such as the Poiseuille flow profile, resistance and internal volume of the catheter, mechanical compliance of the syringes and the various pump flow rate settings, can now be discerned clearly in the structure of the expressions generated by our method. The in-vitro experiments showed a standard deviation between theory and experiment of 14% for the delay time in the catheter, and of 13% for the time duration of the dosing error bolus. CONCLUSIONS: Our method provides insight and predictability in a large range of possible situations involving many variables and dependencies, which is potentially very useful for e.g. the development of a fast, bed-side tool ("calculator") that provides the clinician with a precise prediction of dosing errors and delay times interactively for many scenario's. The interactive nature of such a device has now been made feasible by the fact that, using our method, explicit expressions are available for these situations, as opposed to conventional time-consuming numerical simulations.

Non-invasive measurement of volume-time curves in patients with mitral regurgitation and in healthy volunteers, using a new operator-independent screening tool.

Left ventricular volume-time curves (VTCs) provide hemodynamic data, and may help clinical decision making. The generation of VTCs using echocardiography, however, is time-consuming and prone to inter-operator variability. In this study, we used a new non-invasive, operator-independent technique, the hemodynamic cardiac profiler (HCP), to generate VTCs. The HCP, which uses a low-intensity, patient-safe, high-frequency applied AC current, and 12 standard ECG electrodes attached on the thorax in a pre-defined pattern, was applied to five young healthy volunteers, five older healthy volunteers, and five patients with severe mitral regurgitation. From the VTCs generated by the HCP, the presence or absence of an isovolumetric contraction phase (ICP) was assessed, as well as the left ventricular ejection time (LVET), time of the pre-ejection period (tPEP), and ratio of the volumes of the early (E) and late (A) diastolic filling (E V/A V ratio), and compared to 2D transthoracic echocardiography (2D TTE) at rest. The reproducibility by two different operators showed good results (RMS = 5.2%). For intra-patient measurement RMS was 2.8%. Both LVET and the E V/A V ratio showed a strong significant correlation between HCP and 2D TTE derived parameters (p < 0.05). For tPEP, the correlation was still weak (p = 0.32). In all five patients with mitral regurgitation, the ICP was absent in the VTC from the HCP, whereas it was present in the 10 healthy volunteers, which is in accordance with pathophysiology. We conclude that the HCP seems to be a method for reproducible VTC generation, and may become a useful early screening tool for cardiac dysfunction in the future.

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

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).

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

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.

Correct positioning of central venous catheters using a new electric method.

PURPOSE: In order to find the correct final position of the tip of a central venous catheter, we have developed a new electric method (the Proximity of Cardiac Motion (PCM) method), designed to work in tandem with the existing ECG-based method. METHODS: A small, patient-safe, high-frequency current is fed through the catheter (via the saline-filled lumen of the catheter, or a stylet). Simultaneously, the resulting voltage is measured by two electrodes on the frontal thoracic skin. The catheter tip hence functions as a current source inside the vasculature. The cardiac motion produces a variation in the amplitude of the measured voltage in the rhythm of the cardiac cycle, and the strength of this oscillatory variation is proportional to the strength of the incident current field on the heart, which is a rapidly decaying function of the distance between the catheter tip and the cavoatrial junction (CAJ). Hence the strength of this oscillatory variation is a strong indicator for the proximity of the catheter tip with respect to the CAJ. RESULTS: The new method has been tested in an animal model, yielding an average final position of the catheter tip of 2.1 cm above the CAJ, with a maximum deviation of 0.5 cm. CONCLUSIONS: We conclude that the new PCM method can be combined with the existing ECG method, and may potentially have significant added value when the ECG method cannot be applied, for example, in patients with atrial fibrillation or a pacemaker.

A new electric method for non-invasive continuous monitoring of stroke volume and ventricular volume-time curves.

BACKGROUND: In this paper a new non-invasive, operator-free, continuous ventricular stroke volume monitoring device (Hemodynamic Cardiac Profiler, HCP) is presented, that measures the average stroke volume (SV) for each period of 20 seconds, as well as ventricular volume-time curves for each cardiac cycle, using a new electric method (Ventricular Field Recognition) with six independent electrode pairs distributed over the frontal thoracic skin. In contrast to existing non-invasive electric methods, our method does not use the algorithms of impedance or bioreactance cardiography. Instead, our method is based on specific 2D spatial patterns on the thoracic skin, representing the distribution, over the thorax, of changes in the applied current field caused by cardiac volume changes during the cardiac cycle. Since total heart volume variation during the cardiac cycle is a poor indicator for ventricular stroke volume, our HCP separates atrial filling effects from ventricular filling effects, and retrieves the volume changes of only the ventricles. METHODS: ex-vivo experiments on a post-mortem human heart have been performed to measure the effects of increasing the blood volume inside the ventricles in isolation, leaving the atrial volume invariant (which can not be done in-vivo). These effects have been measured as a specific 2D pattern of voltage changes on the thoracic skin. Furthermore, a working prototype of the HCP has been developed that uses these ex-vivo results in an algorithm to decompose voltage changes, that were measured in-vivo by the HCP on the thoracic skin of a human volunteer, into an atrial component and a ventricular component, in almost real-time (with a delay of maximally 39 seconds). The HCP prototype has been tested in-vivo on 7 human volunteers, using G-suit inflation and deflation to provoke stroke volume changes, and LVot Doppler as a reference technique. RESULTS: The ex-vivo measurements showed that ventricular filling caused a pattern over the thorax quite distinct from that of atrial filling. The in-vivo tests of the HCP with LVot Doppler resulted in a Pearson's correlation of R = 0.892, and Bland-Altman plotting of SV yielded a mean bias of -1.6 ml and 2SD =14.8 ml. CONCLUSIONS: The results indicate that the HCP was able to track the changes in ventricular stroke volume reliably. Furthermore, the HCP produced ventricular volume-time curves that were consistent with the literature, and may be a diagnostic tool as well.

In-vivo validation of a new non-invasive continuous ventricular stroke volume monitoring system in an animal model.

INTRODUCTION: Recently, a non-invasive, continuous ventricular stroke volume monitoring system using skin electrodes has been developed. In contrast to impedance-based methods, the new technique (ventricular field recognition) enables measurement of changes in ventricular volume. A prototype using this new method was built (the hemologic cardiac profiler, HCP) and validated against a reference method in a pig model during variations in cardiac output. METHODS: In six Dalland pigs, cardiac output was simultaneously measured with the HCP (CO-HCP), and an invasive ultrasonic flow-probe around the ascending aorta (CO-FP). Variations in CO were achieved by change in ventricular loading conditions, cardiac pacing, and dobutamine administration. Data were analysed according to Bland-Altman analysis and Pearson's correlation. RESULTS: Pearson's correlation between the CO-HCP and the CO-FP was r = 0.978. Bland-Altman analysis showed a bias of - 0.114 L/minute, and a variability of the bias (2 standard deviations, 2SD) of 0.55 L/minute. CONCLUSIONS: The results of the present study demonstrate that CO-HCP is comparable to CO-FP in an animal model of cardiac output measurements during a wide variation of CO. Therefore, the HCP has the potential to become a clinical applicable cardiac output monitor.

Temperature-induced tissue susceptibility changes lead to significant temperature errors in PRFS-based MR thermometry during thermal interventions.

Proton resonance frequency shift-based MR thermometry (MRT) is hampered by temporal magnetic field changes. Temporal changes in the magnetic susceptibility distribution lead to nonlocal field changes and are, therefore, a possible source of errors. The magnetic volume susceptibility of tissue is temperature dependent. For water-like tissues, this dependency is in the order of 0.002 ppm/°C. For fat, it is in the same order of magnitude as the temperature dependence of the proton electron screening constant of water (0.01 ppm/°C). For this reason, proton resonance frequency shift-based MR thermometry in fatty tissues, like the human breast, is expected to be prone to errors. We aimed to quantify the influence of the temperature dependence of the susceptibility on proton resonance frequency shift-based MR thermometry. Heating experiments were performed in a controlled phantom set-up to show the impact of temperature-induced susceptibility changes on actual proton resonance frequency shift-based temperature maps. To study the implications for a clinical case, simulations were performed in a 3D breast model. Temperature errors were quantified by computation of magnetic field changes in the glandular tissue, resulting from susceptibility changes in a thermally heated region. The results of the experiments and simulations showed that the temperature-induced susceptibility changes of water and fat lead to significant errors in proton resonance frequency shift-based MR thermometry.

Assessment of stroke volume index with three different bioimpedance algorithms: lack of agreement compared to thermodilution.

OBJECTIVE: The accuracy of bioimpedance stroke volume index (SVI) is questionable as studies report inconsistent results. It remains unclear whether the algorithms alone are responsible for these findings. We analyzed the raw impedance data with three algorithms and compared bioimpedance SVI to transpulmonary thermodilution (SVI(TD)). DESIGN AND SETTING: Prospective observational clinical study in a university hospital. PATIENTS: Twenty adult patients scheduled for coronary artery bypass grafting (CABG). INTERVENTIONS: SVI(TD) and bioimpedance parameters were simultaneously obtained before surgery (t1), after bypass (t2), after sternal closure (t3), at the intensive care unit (t4), at normothermia (t5), after extubation (t6) and before discharge (t7). Bioimpedance data were analyzed off-line using cylinder (Kubicek: SVI(K); Wang: SVI(W)) and truncated cone based algorithms (Sramek-Bernstein: SVI(SB)). MEASUREMENTS AND RESULTS: Bias and precision between the SVI(TD) and SVI(K), SVI(SB), and SVI(W) was 1.0+/-10.8, 9.8+/-11.4, and -15.7+/-8.2 ml/m2 respectively, while the mean error was abundantly above 30%. Analysis of data per time moment resulted in a mean error above 30%, except for SVI(W) at t2 (28%). CONCLUSIONS: Estimation of SVI by cylinder or truncated cone based algorithms is not reliable for clinical decision making in patients undergoing CABG surgery. A more robust approach for estimating bioimpedance based SVI may exclude inconsistencies in the underlying algorithms in existing thoracic bioimpedance cardiography devices.

Modeling friction, intrinsic curvature, and rotation of guide wires for simulation of minimally invasive vascular interventions.

Obtaining the expertise to perform minimally invasive vascular interventions requires thorough training. In this paper, an algorithm for simulating minimally invasive vascular interventions for training purposes is presented and evaluated. The algorithm enables the simulation of completely straight guide wires as well as intrinsically curved ones based on applied translations and rotations. Friction between the guide wire and the vasculature is incorporated in the model. Quantitative validation is performed by comparing the simulated guide-wire position with the actual position as assessed by 3-D rotational X-ray imaging in physical experiments on a variety of vascular phantoms that truthfully represent human anatomy. The results show that for proper settings of the model's parameters, accurate simulations of guide-wire motion can be obtained, with an average precision of the guide-wire position of around 1.0 mm.

A new method for spatially selective, non-invasive activation of neurons: concept and computer simulation.

Currently available non-invasive neurostimulation devices, using skin electrodes or externally applied magnetic coils, are not capable of producing a local stimulation maximum deep inside a homogeneous conductor, because of a fundamental limitation inherent to the Laplace equation. In this paper, a new neurostimulation method (the DeepFocus method) is presented, which avoids this limitation by using an indirect method of producing electric currents inside tissues: First, cylinder-shaped ferromagnetic rotating disks of non-permanent magnetic material are placed near the skin and magnetized by a non-rotating magnetic coil. Each of the disks rotates at high speed around its own axis of symmetry, thus producing a purely electric Lorentz force field having a non-zero divergence outside the disk, and therefore giving rise to charge accumulations inside the tissues. Subsequently, the magnetic field is switched off suddenly, causing a re-distribution of charge, and hence short-lived electrical currents, which can be used to activate neurons. Two magnet configurations are presented in this paper, and analyzed by computer simulation, showing that the DeepFocus method produces a maximum current density (the 'focus') deep inside the conducting body. The field strength thus created in the focus (7.9 V/m) is strong enough to activate thick myelinated fibers, but can be kept below the threshold for C-fibers, which makes the new method a possible tool for pain mitigation by targeted neurostimulation.

Robustness and complexity of a minimally invasive vascular intervention simulation system.

Minimally invasive vascular interventions offer advantages over open surgery. Thorough training is needed to master the skills required to correctly perform these minimally invasive interventions. Simulation is becoming a potential alternative for training. We have developed the foundation, i.e., the algorithmics and models, for a minimally invasive vascular intervention simulation system focusing on guide-wire manipulations. In this article we address the robustness, accuracy, and complexity of this foundation using a phantom. To this end the theory on which the simulation is based is used to formulate constraints on the simulation parameters. Furthermore, the parameter space has been explored in order to optimize the trade-off we are facing: accuracy versus speed of the simulation. A physical experiment setup has been designed that allows us to obtain ground-truth data. The accuracy of the simulation has been determined by comparing physical experimental results with various simulations. For multiple combinations of parameter settings the simulation supplies a guide-wire configuration with a root-mean-square error around 1 mm. The results show that the speed of the simulation is still an issue and needs to be improved. Nevertheless, the results also indicate that the developed algorithms and models are a robust foundation to build a simulation system on.

Simulation of minimally invasive vascular interventions for training purposes.

OBJECTIVE: To master the skills required to perform minimally invasive vascular interventions, proper training is essential. A computer simulation environment has been developed to provide such training. The simulation is based on an algorithm specifically developed to simulate the motion of a guide wire--the main instrument used during these interventions--in the human vasculature. In this paper, the design and model of the computer simulation environment is described and first results obtained with phantom and patient data are presented. MATERIALS AND METHODS: To simulate minimally invasive vascular interventions, a discrete representation of a guide wire is used which allows modeling of guide wires with different physical properties. An algorithm for simulating the propagation of a guide wire within a vascular system, on the basis of the principle of minimization of energy, has been developed. Both longitudinal translation and rotation are incorporated as possibilities for manipulating the guide wire. The simulation is based on quasi-static mechanics. Two types of energy are introduced: internal energy related to the bending of the guide wire, and external energy resulting from the elastic deformation of the vessel wall. RESULTS: A series of experiments were performed on phantom and patient data. Simulation results are qualitatively compared with 3D rotational angiography data. CONCLUSIONS: The results indicate plausible behavior of the simulation.