Continuous non-invasive blood pressure monitoring using concentrically interlocking control loops.

A new method and apparatus for non-disruptive blood pressure (BP) recording in the finger based on the vascular unloading technique is introduced. The instrument, in contrast to intermittent set point readjustments of the conventional vascular unloading technique, delivers BP without interruptions, thus refining the Penáz' principle. The method is based on concentrically interlocking control loops for correct long-term tracing of finger BP, including automatic set point adaptation, light control and separate inlet and outlet valves for electro-pneumatic control. Examples of long-term BP recordings at rest and during autonomic function tests illustrate the potential of the new instrument.

On-line adaptive algorithm with glucose prediction capacity for subcutaneous closed loop control of glucose: evaluation under fasting conditions in patients with Type 1 diabetes.

AIMS: To evaluate an algorithm with glucose prediction capacity and continuous adaptation of patient parameters-a model predictive control (MPC) algorithm-to control blood glucose concentration during fasting conditions in patients with Type 1 diabetes. In the subcutaneous (sc) route within a closed loop system. METHODS: Paired experiments were performed in six patients. Over 8 h the MPC algorithm was used to control glucose with s.c. insulin administration and two different glucose monitoring protocols: first, the algorithm was provided with intravenous (i.v.) glucose values for insulin dosage calculation directly (i.v.-s.c. route). Then, in the second experiment, i.v. glucose values were fed to the MPC with a delay of 30 min to simulate s.c. glucose measurements ('s.c.'-s.c. route). In both experiments plasma glucose, insulin dosage, and serum insulin levels were analysed. RESULTS: Glucose concentration was brought from hyper- to normoglycaemia and kept in the physiological range (6-7 mmol/l) with both routes in all subjects. Mean glucose concentration reached the threshold of 7 mmol/l approximately 2 (i.v.-s.c. route) and 3 ('s.c.'-s.c. route) hours after the start of glucose control with the MPC. During the last 2 h of automated glucose control, mean glucose concentration was 6.3 +/- 0.2 mmol/l and 6.6 +/- 0.3 mmol/l for i.v.-s.c. and 's.c.'-s.c. route, respectively. Glucose concentration, insulin doses, and serum insulin levels did not differ significantly between routes (P > 0.05). CONCLUSIONS: The MPC algorithm is suitable for glucose control during fasting within an extracorporeal artificial beta-cell in the subcutaneous route Type 1 diabetic patients.

Non-invasive beat-to-beat cardiac output monitoring by an improved method of transthoracic bioimpedance measurement.

The report describes a method of impedance cardiography using an improved estimate of thoracic volume. The formulas and their implementation in hardware and software are explained and new shortband electrodes are described which generate a good homogeneous thoracic field. Examples of stroke volume and cardiac output curves underline the capabilities of the monitoring system "Task Force Monitor". In several experiments, results are compared to thermodilution as well as to BioZ measurements: the new method excels in comparison with thermodilution and is comparable to the BioZ device. Compared to traditional electrodes, the new shortband electrodes are shown to provide better reproducibility.

An iterative algorithm for myocardial activation time imaging.

An iterative algorithm based on a general regularization scheme for nonlinear ill-posed problems in Hilbert scales (method A) is applied to the magnetocardiographic inverse problem imaging the surface myocardial activation time map. This approach is compared to an algorithm using an optimization routine for nonlinear ill-posed problems based on Tikhonov's approach of second order (method B). Method A showed good computational performance and the scheme for determining the proper regularization parameter lambda was found to be easier than in case of method B. The formulation is applied to magnetocardiographic recordings from a patient suffering from idiopathic ventricular tachycardia in which a sinus rhythm sequence was followed by a ventricular extrasystolic beat.

Measurement of interstitial albumin in human skeletal muscle and adipose tissue by open-flow microperfusion.

The absolute concentration of albumin was measured in the interstitial fluid of subcutaneous adipose tissue and skeletal muscle in six healthy volunteers by combining the method of open-flow microperfusion and the no-net-flux calibration technique. By use of open-flow microperfusion, four macroscopically perforated double lumen catheters were inserted into the tissue regions of interest and constantly perfused. Across the macroscopic perforations of the catheters interstitial fluid was partially recovered in the perfusion fluid. Catheters were perfused with five solutions, each containing different concentrations of albumin. Absolute interstitial albumin concentrations were calculated by applying linear regression analysis to perfusate vs. sampled albumin concentration (no-net-flux calibration technique). Interstitial albumin concentrations were significantly lower (P < 0.0001) in adipose tissue (7.36 g/l; r = 0.99, P < 0.0003; range: 4.3-10.7 g/l) and in skeletal muscle (13.25 g/l; r = 0.99, P < 0.0012; range: 9.7 to 15.7 g/l) compared with the serum concentration (48.9 +/- 0.7 g/l, mean +/- SE, n = 6; range: 46.4-50.4 g/l). Furthermore, interstitial albumin concentrations were significantly higher in skeletal muscle compared with adipose tissue (P < 0.01). The study indicates that open-flow microperfusion allows stable sampling of macromolecules from the interstitial space of peripheral tissue compartments. Moreover, the present data report for the first time in healthy humans in vivo the true albumin concentrations of interstitial fluid of adipose tissue and skeletal muscle.

A bidomain model based BEM-FEM coupling formulation for anisotropic cardiac tissue.

A hybrid boundary element method (BEM)/finite element method (FEM) approach is proposed in order to properly consider the anisotropic properties of the cardiac muscle in the magneto- and electrocardiographic forward problem. Within the anisotropic myocardium a bidomain model based FEM formulation is applied. In the surrounding isotropic volume conductor the BEM is adopted. Coupling is enabled by requesting continuity of the electric potential and the normal of the current density across the boundary of the heart. Here, the BEM part is coupled as an equivalent finite element to the finite element stiffness matrix, thus preserving in part its sparse property. First, continuous convergence of the coupling scheme is shown for a spherical model comparing the computed results to an analytic reference solution. Then, the method is extended to the depolarization phase in a fibrous model of a dog ventricle. A precomputed activation sequence obtained using a fine mesh of the heart was downsampled and used to calculate body surface potentials and extracorporal magnetic fields considering the anisotropic bidomain conductivities. Results are compared to those obtained by neglecting in part or totally (oblique or uniform dipole layer model) anisotropic properties. The relatively large errors computed indicate that the cardiac muscle is one of the major torso inhomogeneities.

Two-dimensional Fourier representation used in the bioelectric forward problem.

The objective of this paper is the application of two-dimensional discrete Fourier transformation for solving the integral equation of the bioelectric forward problem. Therefore, the potential, the source term, and the integral equation kernel are assumed to be sampled at evenly spaced intervals. Thus the continuous functions of the problem domain can be expressed by their two-dimensional discrete Fourier transform in the spatial frequency domain. The method is applied to compute the surface potential generated by an eccentric dipole in a homogeneous spherical conducting medium. The integral equation for the potential is solved in the spatial frequency domain and the value of the potential at the sampling points is obtained from inverse Fourier transformation. The solution of the presented method is compared to both, an analytic solution and a solution gained from applying the boundary element method. Isoparametric quadrilateral boundary elements are used for modeling the spherical volume conductor in the boundary element solution, while in the two-dimensional Fourier transformation method the volume conductor is represented by a parametric boundary surface approximation.

Diffusion-weighted imaging with navigated interleaved echo-planar imaging and a conventional gradient system.

PURPOSE: To demonstrate the technical feasibility and precision of a navigated diffusion-weighted (DW) MR imaging method with interleaved echo-planar imaging and test its diagnostic sensitivity for detection of ischemic stroke. MATERIALS AND METHODS: Apparent diffusion coefficient (ADC) measurements were performed in phantoms, and six healthy adult volunteers were examined to determine intrasubject (precision) and intersubject (reference range) variations in absolute ADC and relative ADC (rADC) measurements. DW imaging maps and lesion rADC values were also obtained in 34 consecutive stroke patients to evaluate the sensitivity and reliability of DW-interleaved echo-planar imaging for detection of ischemic brain damage. RESULTS: Phantom and volunteer ADC values were in excellent agreement with published data. The intrasubject variation of rADC was 6.2%. The ADC precision ranged from 6.5% in the subcortical white matter in the frontal lobe to 12.9% in the head of the caudate nucleus. Interleaved echo-planar imaging enabled rapid acquisition of high-quality images of the entire brain without substantial artifacts. Within the 1st week, the sensitivity of DW-interleaved echo-planar imaging for detection of acute infarction was 90% (18 of 20 true-positive studies) and independent of lesion location. CONCLUSION: DW-interleaved echo-planar imaging with phase navigation and cardiac triggering is robust, reliable, and fast. With high sensitivity for detection of early ischemic infarction, it is useful for examining stroke patients by using MR systems with conventional gradient hardware.

Plasma and interstitial glucose dynamics after intravenous glucose injection: evaluation of the single-compartment glucose distribution assumption in the minimal models.

Recent experimental evidence suggests that estimates of glucose effectiveness (S(G)) from the minimal model of unlabeled glucose disappearance (Cold-MM) are in error. The single-compartment glucose distribution assumption embedded in the model has been indicated as a possible source of error. In this study, to directly examine the single-compartment assumption, we measured plasma and interstitial glucose concentrations after intravenous glucose injection. Additionally, we compared the accuracy of the estimates of glucose effectiveness from the Cold-MM and the single-compartment tracer minimal model (Hot-MM). Paired labeled intravenous glucose tolerance tests (IVGTTs) were performed in each of six C-peptide-negative type 1 diabetic subjects. Two different insulin infusion protocols were used: an infusion at constant basal rates and an infusion at variable rates to mimic a normal insulin response. During the labeled IVGTT with basal insulin infusion, the microperfusion technique was employed to sample adipose tissue interstitial fluid. Marked differences between the plasma and interstitial dynamics of (cold) glucose were observed during the first 22 min after glucose injection. These results suggest that the requirements for a single-compartment representation of glucose kinetics are not satisfied during at least the first 22 min of an IVGTT. Data from the labeled IVGTT with normal insulin response were used to identify the minimal-model parameters. The measure of S(G) derived using the Cold-MM was 3.44-fold higher than the direct measure obtained from the labeled IVGTT with basal insulin infusion (0.0179+/-0.0027 vs. 0.0052+/-0.0010 min(-1), P<0.01). The measure of glucose effectiveness (S(G)*) derived by the Hot-MM was 1.36-fold higher than the direct measure available from the labeled IVGTT with basal insulin infusion (0.0079+/-0.0013 vs. 0.0058+/-0.0004 min(-1), P>0.26). These results suggest that the Hot-MM is more appropriate for the evaluation of glucose effectiveness than the Cold-MM.

Application of high-order boundary elements to the electrocardiographic inverse problem.

Eight-noded quadrilateral boundary elements are applied to the electrocardiographic inverse problem as an example for high-order boundary elements. It is shown that the choice of the shape functions used for approximation of the potentials has a remarkable influence on the solution obtained if the number of electrodes is smaller than the number of primary source points (under-determined equation system). Three different formulations are investigated considering a concentric spheres problem where an analytic solution is available: (a) the isoparametric formulation; (b) the quasi-first-order formulation; and (c) the pseudo-subparametric formulation as a new method. In a second step the pseudo-subparametric formulation (which provided the best results in the test problem) is applied to real word data. The transmembrane potential pattern of a 40 years old female suffering from severe heart failure and ventricular tachycardia after large anterior wall myocardial infarction is reconstructed for one time instant. Furthermore, an algorithm for the calculation of the transfer matrix is presented which avoids restrictions to the boundary element mesh caused by the placement of the electrodes.

Direct access to interstitial fluid in adipose tissue in humans by use of open-flow microperfusion.

To gain direct access to the interstitial fluid (ISF), a new technique called open-flow microperfusion has been evaluated. This method is based on a double-lumen catheter with macroscopic (0.3-0.5 mm diameter) perforations that is inserted into the subcutaneous adipose tissue and constantly perfused. Thus partial equilibration between the ISF and the perfusion fluid occurs. The glucose concentration of the ISF was determined by established (zero flow rate, no net flux, and recirculation procedures) and new (ionic reference and suction technique) calibration methods by use of open-flow microperfusion. The data show that 1) the glucose concentration in the ISF is significantly lower than the corresponding arterialized venous plasma values during basal steady-state conditions (adipose tissue 3.2 +/- 0.10 mM, plasma 5.27 +/- 0.12 mM) as well as during hyperglycemic clamp experiments (adipose tissue 7.3 +/- 0.13 mM, plasma 9.91 +/- 0.16 mM), and 2) it is possible to determine the recovery continuously by using the ion concentration of the ISF as an internal standard (ionic reference).

Lactate metabolism of subcutaneous adipose tissue studied by open flow microperfusion.

Open flow microperfusion and a novel calibration technique (ionic reference technique) were evaluated for the frequent measurement of the absolute lactate concentration in sc adipose tissue. Furthermore, the influence of the plasma insulin concentration on the lactate concentration of sc adipose tissue was investigated during hyperglycemia. Sixteen lean healthy young men participated in the studies. In the postabsorbtive state the mean sc lactate concentrations were 1.29 and 1.36 mmol/L for the ionic reference technique and the no net flux protocol, respectively (not significant, P > 0.05). The simultaneously measured arterialized plasma lactate concentration was significantly lower at 0.77 mmol/L (P < 0.05). Both the sc lactate concentration (1.8+/-0.33 mmol/L) and the plasma lactate concentration (0.96+/-0.03 mmol/L) were significantly elevated during a hyperinsulinemic euglycemic clamp experiment. During a hyperglycemic clamp experiment the sc lactate concentration reached a significantly elevated plateau (2.15+/-0.27 mmol/L) that was not influenced by the increasing plasma insulin concentration. It is concluded that 1) open flow microperfusion combined with the ionic reference technique enables frequent measurement of the sc lactate concentration; 2) sc adipose tissue is a significant source of lactate release in the postabsorbtive state as well as during hyperinsulinemic clamp conditions; and 3) insulin concentrations greater than 180 pmol/L have no further influence on adipocyte stimulation of sc adipose tissue with respect to lactate release.

Continuous measurement of subcutaneous lactate concentration during exercise by combining open-flow microperfusion and thin-film lactate sensors.

The present study was carried out to investigate in vivo in healthy humans the method of open-flow microperfusion for monitoring of the subcutaneous (s.c.) lactate concentration during rest and cycle ergometer exercise. Using open-flow microperfusion, a perforated double lumen catheter with an inflow and an outflow connection is inserted into the s.c. adipose tissue and perfused with a sterile, isotonic, ionfree fluid. Due to the low flow rate, the fluid partially equilibrates with the surrounding tissue. The equilibrated perfusate passes a sensor flow chamber where the substance of interest and the rate of recovery (i.e. the ratio of sampled concentration to interstitial concentration) are continuously monitored. Within this study, the method was evaluated in four healthy volunteers during cycle ergometer exercise. The relative increase of the lactate concentration was approximately a third in the s.c. tissue compared to the capillary blood and the peak time was delayed on average by 10 min. The correlation coefficient between blood and s.c. tissue lactate concentration ranged from r = 0.41 to r = 0.90 (n = 29) in the individual experiments. The combination of open-flow microperfusion and lactate and conductivity sensors enables on-line monitoring of the s.c. lactate concentration without in vivo calibration during steady-state and cycle ergometer exercise.

Neural predictive controller for insulin delivery using the subcutaneous route.

A neural predictive controller for closed-loop control of glucose using subcutaneous (s.c.) tissue glucose measurement and s.c. infusion of monomeric insulin analogs was developed and evaluated in a simulation study. The proposed control strategy is based on off-line system identification using neural networks (NN's) and nonlinear model predictive controller design. The system identification framework combines the concept of nonlinear autoregressive model with exogenous inputs (NARX) system representation, regularization approach for constructing radial basis function NN's, and validation methods for nonlinear systems. Numerical studies on system identification and closed-loop control of glucose were carried out using a comprehensive model of glucose regulation and a pharmacokinetic model for the absorption of monomeric insulin analogs from the s.c. depot. The system identification procedure enabled construction of a parsimonious network from the simulated data, and consequently, design of a controller using multiple-step-ahead predictions of the previously identified model. According to the simulation results, stable control is achievable in the presence of large noise levels, for unknown or variable time delays as well as for slow time variations of the controlled process. However, the control limitations due to the s.c. insulin administration makes additional action from the patient at meal time necessary.

Simulation studies on neural predictive control of glucose using the subcutaneous route.

A novel strategy for closed-loop control of glucose using subcutaneous (s.c.) tissue glucose measurement and s.c. infusion of monomeric insulin analogues was developed and evaluated in a simulation study. The proposed control strategy is an amalgamation of a neural network and nonlinear model predictive control (NPC) technique. A radial basis function neural network was used for off-line system identification of Nonlinear Auto Regressive model with eXogenous inputs (NARX) model of the glucoregulatory system. The explicit NARX model obtained from the off-line identification procedure was then used to predict the effects of future control actions. Numerical studies were carried out using a comprehensive model of glucose regulation. The system identification procedure enabled construction of a parsimonious network from the stimulated data, and consequently, design of a controller using multiple-step-ahead predictions of the previously identified model. According to the simulation results, stable control is achievable in the presence of large noise levels and for unknown or variable physiological or technical time delays. In conclusion, the simulation results suggest that closed-loop control of glucose will be achievable using s.c. glucose measurement and s.c. insulin administration. However, the control limitations due to the s.c. insulin administration makes additional action of the patient at meal time necessary.

A software package for non-invasive, real-time beat-to-beat monitoring of stroke volume, blood pressure, total peripheral resistance and for assessment of autonomic function.

The goal of the present study was to develop and evaluate algorithms for non-invasive, real-time, beat-to-beat monitoring of stroke index (SI), blood pressure (BP) and total peripheral resistance index (TPRI) which has a menu-driven interface, suitable for routine use by unskilled staff. In addition, it was our aim to include a meta-analysis for the evaluation of autonomic function derived from the above haemodynamic data. This includes spectral analysis of heart rate (HR), BP, SI and TPRI and the automatic calculation of baroreceptor reflex sensitivity. Impedance cardiography was used for beat-to-beat SI determination, Finapres corrected by an oscillometric blood pressure measurement (Dinamap) on the upper arm for beat-to-beat BP measurement. We demonstrate noise free recordings during physiological (head up tilt) and pharmacological intervention (alpha 1-, beta 2-adrenoreceptor agonists, insulin induced hypoglycemia). The newly developed software should prove valuable for physiological, pharmacological and clinical studies.

On the realization of an analytic high-resolution EEG.

The analytic solution of the harmonic downward continuation of the scalp potential field in an N-shell heterogeneous, but isotropic, spherical volume conductor model has been derived. The objective of this paper was to investigate the realization of a so-called "high-resolution electroencephalogram (EEG)": by enhancing the poor spatial resolution of EEG recordings. To this end, the forward problem for a dipolar source arbitrarily located at the source point Q = Q(rs, phi s, theta s) has been determined in a compact matrix notation. It is possible to transfer the potential field given on the outer surface of a spherically shaped volume conductor to an arbitrary inner surface (e.g., to the cortical surface) under consideration of the electrical and geometrical properties of the model. For the application of the proposed method to real-world problems, the coefficients of the series expansion describing the cortical potential distribution are determined by minimizing the squared curvature of the scalp potential field integrated over the scalp surface. Simulation results for distributed sources show that the proposed method is superior to the surface Laplacian method for interelectrode distances below 2.5 cm.

Validation of home blood glucose meters with respect to clinical and analytical approaches.

OBJECTIVE: To evaluate the clinical and analytical accuracy of home blood glucose meters. RESEARCH DESIGN AND METHODS: Six blood glucose meters--Reflolux S (Boehringer Mannheim, Mannheim, Germany), One Touch II (LifeScan, Milpitas, CA), Glucocard Memory (Menarini, Florence, Italy), Precision QID (Medisense, Cambridge, U.K.), HaemoCue (HaemoCue, Angelholm, Sweden), and Accutrend alpha (Boehringer Mannheim, Mannheim, Germany)--were compared with a reference method (Beckman Glucose Analyzer II) under controlled conditions (glucose clamp technique). Validation of the blood glucose meters was accomplished by clinically oriented approaches (error grid analysis), statistical approaches (variance components analysis), and by the criteria of the American Diabetes Association (ADA), which recommend a target variability of < 5%. RESULTS: A total of 1,794 blood glucose monitor readings and 299 reference values ranging from 2.2 to 18.2 mmol/l were analyzed (705 readings < 3.89 mmol/l, 839 readings between 3.89 and 9.99 mmol/l, and 250 readings > 9.99 mmol/l). According to error grid analysis, only Reflolux S and Glucocard M had 100% of estimations within the clinically acceptable zones A and B. Assessment of analytical accuracy revealed substantial differences between the glucose meters after separation of the data into defined glycemic ranges. None of the devices met the ADA criteria. CONCLUSIONS: To evaluate accuracy of blood glucose meters, error grid analysis, as well as statistical models, are helpful means and should be performed together. Analytical performance of currently available home blood glucose meters differs substantially within defined glycemic ranges.

Analytical validation of the BEM--application of the BEM to the electrocardiographic forward and inverse problem.

The objective of this study is to analytically validate a boundary element (BE) formulation for the relationship between the transmembrane potential on the heart's surface and the potential on the body surface applying a concentric spherical test geometry. The relative difference (reldif) between the potential on the outer sphere of the test geometry computed analytically and numerically is determined by 3.59% for the coarse discretization (48 BEs) and by 0.46% in the case of the finer subdivision (192 BEs). In the inverse problem, the transmembrane potential on the inner sphere is estimated numerically from the electric potential on the outer sphere by using a minimum-norm least-square approach. The relative differences found are 20.2% when no measurement noise is added and 26.4% in the presence of 2% additional Gaussian noise. The BE formulation is also applied to real world data for solving the electrocardiographic inverse problem. A normal volunteer's inhomogeneous thorax (outer thorax surface, surfaces of the lungs, epicardial heart surface) is modelled by 424 BEs. The same inverse method is then applied in order to reconstruct the transmembrane potential on the epicardium from the measured body surface potential (BSP) data during normal ventricular depolarisation.

Novel system for real-time ex vivo lactate monitoring in human whole blood.

The objective of the study was to evaluate the performance of an amperometric enzyme based lactate sensor and to investigate the possibility of replacing a double lumen catheter based blood withdrawal system with a heparin coated single lumen system. The inner lumen of a double lumen catheter which was placed in a peripheral vein was perfused with heparin solution. The outer lumen was used to collect heparinized blood samples at a defined flow rate. The single lumen system was attached to a heparinized catheter which was also placed in a peripheral vein. The undiluted blood samples were collected at a specified flow rate. A sensor flow chamber incorporating an amperometric thin-film lactate microbiosensor was placed in the sampling line for real-time lactate monitoring. Plasma lactate concentrations were measured during frequently performed hyperlactatemia bicycle ergometer experiments in six healthy volunteers (age 25.8 +/- 2.8 years, BMI 22.7 +/- 1 kg/m2). Additionally, plasma lactate was measured in real-time using the lactate sensors. The first three experiments were performed with a double lumen based catheter system whereas the following three experiments were performed with a heparin coated catheter system. The correlation coefficients of sensor readings and laboratory analyzer results in all six experiments were between 0.93 and 0.99, respectively (P < 0.001). The miniaturized lactate sensors showed a linear range up to 25 mmol/l lactate concentration and 95% response times < 30 s in undiluted serum. During the experiments maximum lactate concentrations of 14 mmol/l were achieved. Improvements of system performance using heparin coated catheter systems could be shown. The overall SD of the sensor readings compared to laboratory results using three double lumen catheter based systems was 0.91 mmol/l whereas the SD using three heparin coated systems was 0.65 mmol/l. In summary, real-time monitoring of lactate in human whole blood is feasible with such a device and can be improved by using heparin coated catheter systems.