HK1225263A1 - A method of and a system for determining a cardiovascular quantity of a mammal - Google Patents

Abstract

The subject application is directed to a method of and a system for determining a cardiovascular quantity of a mammal. The method comprises selecting a measuring site of a vessel; determining or estimating a mean diameter of the vessel at the measuring site; determining a pulse wave velocity and/or another elasticity related quantity of the vessel at the measuring site; determining a distension of the vessel at the measuring site; and calculating the at least one cardiovascular quantity from the determined mean diameter, elasticity related quantity and distension of the vessel. The system comprises a plurality of sets of electrodes where each set of electrodes comprising at least two electrodes can be attached to a skin surface of the mammal; electrical devices for applying an electric oscillating signal over the respective sets of electrodes; at least one processor and memory unit arranged to receive signals from the respective sets of electrodes; wherein said at least one processor is designed and programmed to calculate the at least one cardiovascular quantity according to the method using signals from the respective sets of electrodes.

Description

Method and system for determining cardiovascular quantity of mammal

Related information of divisional application

The scheme is a divisional application. The parent of this division is the invention patent application with application date of 2012, 2/17, application number 201280018884.2 entitled "method and system for determining cardiovascular quantity in a mammal".

Technical Field

The present invention relates to a method for determining at least one cardiovascular quantity, such as blood pressure and/or vascular compliance, of a mammal.

Background

Most types of prior art methods of measuring cardiovascular properties suffer from the problem that the performance of the measurement and the measurement itself are significantly affected by the patient's condition, which can lead to inaccurate results.

Furthermore, it is well recognized that blood pressure often exhibits considerable variation over time. Due to these factors and the fact that diurnal differences are very important for the correct diagnosis of hypertension, the uk health authority has newly published guidelines (NICE clinical guideline 127, 8 months 2011). It has also recently been shown that performing ambulatory blood pressure measurements is generally Cost-effective (Lovibond K et al, Cost-effective for a protocol for diagnosis of hypertension in primary care: modeling studies (Cost-effectiveness of the diagnosis of high blood pressure in primary care) Lancet, 2011, month 1; 378 (9798): 1219-30).

Many prior art methods for blood pressure measurement require the application of a back pressure from an external pressure device, such as an occlusive cuff or other pressure generating device. These interfering methods that generate external pressure can have a great impact on humans and blood pressure. Blood pressure may be measured, for example, by an invasive pressure sensor, oscillometry, or auscultatory tonometry. The blood pressure can also be obtained from auxiliary parameters like the pulse wave velocity. However, these methods require calibration against known standards. These methods inevitably affect the patient's condition, for example, requiring surgery or the application of external pressure to an artery using an occlusive cuff or requiring that the patient be in a particular location. Furthermore, it is well known that cardiovascular quantity measurements made in a doctor's office or hospital are often quite inaccurate and often always higher than measurements when the patient is at home. This is commonly referred to as "white gown syndrome". However, the mere fact that the patient is able to feel that the measurement is being made generally has a psychological impact, which can lead to changes in the patient's state.

The imaging method provides information about the structure and dimensions of the measured limb, i.e. the constituent organs and their respective tissues. NMR or X-ray based methods typically have spatial and temporal resolution, which is insufficient to measure time variations on a time scale comparable to or smaller than a single pulse time, and accordingly arterial dilation cannot be reliably determined based on such methods. Ultrasound may provide sufficient spatial and temporal resolution, but this approach is often affected by the patient's condition and thus provides unreliable results. Optical coherence tomography can provide the necessary spatial and temporal resolution, but the penetration depth is very small. Thus, all imaging modalities are not suitable for continuous dynamic measurements and they are also very expensive. However, these methods may provide relevant a priori information about the anatomy.

The stiffness (or elasticity) of an artery can be evaluated by pulse wave velocity method, in which the pulse propagation velocity along the artery is estimated. The basic phenomenon is acoustic in nature. Propagation delay from, for example, the heart to the thigh, wrist, or foot is typically measured. However, the propagation length depends on the individual anatomy, which may show considerable differences in both the actual length and the vessel diameter. In addition, the pulse wave propagation velocity depends on the artery diameter and the stiffness of the artery wall. These properties vary along the path from the heart to, for example, the wrist.

US6443906 describes a method and apparatus for continuous monitoring of blood pressure. This method requires the device to be placed close to the wrist and includes a sensor with a protrusion-a piston that is pressed into the user's body to apply force to the artery. The reaction force on the opposite side of the artery is provided by the radius. The device will only function correctly in such a position and the device exerts a force on the artery, so that the method will disturb the patient's condition.

US5309916 describes a device for measuring blood pressure, wherein the device comprises a sensor arrangement attached to the outside of the body and in electrically conductive connection with an electronic circuit. The sensor arrangement and circuit are configured to determine, in at least one body measurement area, values of variable measurements of the pulse beat rhythm periodically varying over time, such as flow velocity, flow, volume, cross-sectional size and/or cross-sectional flow area of arterial blood. The sensor and circuitry also determine a measure of the pulse wave velocity. By linking these two values together and including at least one calibration value, at least one value characterizing the blood pressure can be determined. Many different measurement principles are involved, for example measurement by light or ultrasound radiation.

As is clearly indicated in US5309916, this method requires individual calibration, i.e. the blood pressure of a particular patient needs to be measured by direct measurement, e.g. using an inflatable cuff. Such individual calibration is both complex and produces inaccurate results. Furthermore, it is not described how and which parameters should be associated with the calibration measurements. Calibration measurements using a patient's blood pressure state are likely to be unreliable for relevant determinations of other blood pressure states, which means that a reliable calibration requires calibration measurements of a large number of different blood pressure states of the same patient.

WO2007/000164 discloses a method and apparatus for non-interventional blood pressure measurement. The method and apparatus are based on capacitive sensing, where the tissue cross section constitutes the majority of the dielectric of the capacitance and the capacitor forms part of the resonant circuit. However, since the conductivity of blood is usually very high, electrodes that are electrically isolated from the body are required and calibration is required. It should be noted that this method only utilizes the imaginary part of the impedance formed by the electrode and the material isolated from the electrode.

Based on the capacitive sensing method disclosed in WO2007/000164, WO2010/057495 discloses a method for combined measurement of distension and pulse wave velocity to obtain a calibrated blood pressure. This application does not disclose a direct method for obtaining blood pressure variability and absolute blood pressure.

US2005/0283088 discloses a method for determining stroke volume from bioimpedance measurements including the brachial artery, but does not include determining the following components: blood pressure, vascular stiffness, or vascular compliance.

It is an object of the present invention to devise a method which allows a non-invasive determination of one or more cardiovascular quantities, such as blood pressure, wherein the determination does not require individual calibration and which at the same time yields highly reliable determinations.

Another object of the invention is that the method can be implemented in a simple form, for example by a patient or an assistant that does not require special training but merely as a simple operating guide.

These and other objects are achieved by the invention and its embodiments as defined in the claims and described hereinafter.

Disclosure of Invention

The method of the invention relates to determining at least one cardiovascular quantity of a mammal and comprises

Selecting a measurement site of a blood vessel;

(ii) determining or estimating the mean diameter of the blood vessel at the measurement site;

(iii) determining the pulse wave velocity and/or the elasticity and/or a further elasticity-related component of the blood vessel at the measurement site;

(iv) determining the vasodilation at the measurement site; and

(v) calculating at least one cardiovascular quantity from the determined average diameter, the elasticity-related quantity and the vessel dilation at the measurement site.

According to the present invention, it has been found that by calculating the cardiovascular quantity from data comprising the average diameter of the blood vessel at the measurement site, the elasticity-related component of the blood vessel at the measurement site and the dilatation of the blood vessel at the measurement site, a more accurate determination can be obtained, which determination also does not require any individual calibration or any other type of calibration procedure before or after the measurement. An accurate determination in this context means a determination with very low measurement uncertainty, e.g. about 10% or less, preferably about 5% or less.

The method of the present invention thus provides an alternative to the methods described in the prior art discussed above, but it also provides a method of determining a cardiovascular quantity invasively or non-invasively which has an unexpectedly high degree of reliability with respect to the determination of a similar cardiovascular quantity using prior art non-invasive prior art methods.

As used herein, the term "non-invasive" means that the method does not require complete penetration of the epidermis of the mammalian skin, and "invasive" means that the method does require complete penetration of the epidermis.

Step (ii) determining or estimating the mean diameter of the blood vessel at the measurement site; step (iii) determining an elasticity-related component of the vessel at the measurement site; and step (iv) determining the vasodilation at the measurement site may be performed in any order, or even-preferably-these determinations may be made simultaneously. One or more of these determinations may be reused for other determinations. For example, in one embodiment, the determination or estimation of the mean diameter of the blood vessel at the measurement site may be reused for other or subsequent determinations of the cardiovascular quantity at the selected measurement site. In one embodiment, the determination of the elasticity-related component of the blood vessel at the measurement site can be reused for other or subsequent determinations of the cardiovascular quantity at the selected measurement site.

In one embodiment, the determination or estimation of the mean diameter of the blood vessel at the measurement site and/or the determination of the elasticity-related component of the blood vessel at the measurement site is performed less frequently than the determination of the dilatation of the blood vessel at the measurement site, and the determination or estimation of the mean diameter of the blood vessel at the measurement site and/or the determination of the elasticity-related component of the blood vessel at the measurement site may be used again, for example in the form of a previously determined mean value. Thus, the method can provide a plurality of successive determinations of the desired cardiovascular quantity, and in practice the method can provide a continuous or semi-continuous determination of the desired cardiovascular quantity. Due to the simplicity of the method, in one embodiment the method provides a continuous or semi-continuous determination of the desired cardiovascular quantity, even without the use of the aforementioned determination.

The mammal may be any mammal and in particular a human. In one embodiment, the mammal is a pet, such as a cat, dog, or horse.

The term "patient" refers to a mammal whose cardiovascular quantity or quantities are determined, while the term "user" or "assistant" refers to a person who takes a measurement or assists the patient in taking a measurement. In general, the method of the invention is simple to perform and preferably may comprise using the cardiovascular system of the invention programmed to perform the necessary calculations, and in many cases the patient himself/herself is able to make the measurements.

The blood vessel may be any blood vessel, but is preferably one of the major blood vessels in the mammalian body. The blood vessel is preferably an artery, such as a brachial, radial, ulnar, femoral, finger, or carotid artery.

The measurement site of the blood vessel, also referred to simply as measurement site, refers to a site comprising a length segment of the blood vessel which is long enough to perform the determination and at the same time not too long, so that the average diameter does not vary much, for example about 10% or more within the length of the measurement site. Preferably, the length of the measurement site is selected such that the time-averaged diameter of the blood vessel varies by about 5% or less, for example about 3% or less, within or along the length of the measurement site. The length of the measurement site is selected according to the type and size of the mammal and according to the average diameter and position of the blood vessels to be measured. Generally, it is desirable for the measurement site to have a length of about 30cm or less, for example about 15cm or less, for example about 5cm or less. The minimum length of the measurement site depends on the accuracy and quality of the equipment to be or required for the determination and, optionally, any disturbances not related to the measurement object. In one embodiment, the measurement site has a length of about 5mm or more, for example about 1cm or more, for example about 2cm or more.

The actual length of the measurement site is determined by a combination of electrode size and tissue distribution, and when one or more sets of pure excitation electrode sets are used, it is also determined by the mutual electrode distance. The field lines that run through subcutaneous fat have a very small extent, since fat has a lower electrical conductivity than muscle and blood. In the muscle the field lines stretch substantially by the amount produced by the muscle cross section. Due to the low electrical conductivity and permittivity of the bone, the field lines will tend to avoid the bone and thus be able to eliminate contributions from the bone. The calculation of the field distribution can be carried out using, for example, maxwell's equation-based finite element programs for the alignment static conditions. The detailed equivalent circuit diagram can also be designed in such a way that: the conductivity and permittivity of the lumped impedance elements are given by the electrical properties of the tissue and the physical dimensions of the limb or tissue segment, respectively, as represented by an equivalent impedance circuit, see further below.

In one embodiment, the measurement site for the blood vessel is selected as a blood vessel site in a limb, arm, leg, hand, foot, finger, neck or heart region, thorax, abdominal cavity, pelvic cavity of the mammal. The blood vessels at these locations appear to be relatively easy to measure. Of course, the choice of measurement site can also be made with respect to the desired diagnostic application.

The particular device used, such as the cardiovascular system of the invention, is typically adapted to one or more specific measurement sites, for example 2, 3, 4 or 5 different specific measurement sites.

In one embodiment, the measurement site is selected such that the measurement site is substantially free of other blood vessels that would interfere with the determination.

The method according to the invention makes at least three determinations at the measurement site, i.e. determinations of the mean diameter, the elasticity-related component and the vasodilation of the blood vessel, and preferably calculates one or more cardiovascular components using all three determinations.

The individual determination of the mean diameter, the elasticity-related component and the vasodilation of the blood vessel at the measurement site can in principle be carried out by any non-invasive method, but preferably one or more of the methods described below are used.

In one embodiment, the separate determination of at least one and preferably all of the mean diameter, the elasticity-related component and the vasodilation of the blood vessel at the measurement site is performed by a method comprising: applying at least one set of electrodes within a selected distance from the measurement site, applying an electrical signal to the electrodes, and arranging the electric field lines to traverse the blood vessel at the measurement site. The electric field lines show the direction of the electric field vector, while the field line density indicates the field strength.

A set of electrodes includes at least two electrodes. In one embodiment, a set of electrodes includes 3, 4, or more electrodes. In case several sets of electrodes are used, one electrode may for example be part of a first set of electrodes for a one time determination and part of a second set of electrodes for a second time determination. Similar electrode configurations are well known to those skilled in the art.

Each electrode used may have a size adjusted according to the measurement site. Preferably, the electrode size should be chosen so small that its size has a negligible effect on the measured dilatation pulse, but also so large that the current density anywhere does not have any effect on the tissue. The term "electrode size" refers to the contact area of the electrode and the skin. An example of an electrode size is about 10mm²To about 16cm²E.g. about 1cm². In the case of electrodes having a circular contact area, the contact area may, for example, have a diameter of about 5mm or more, such as about 1cm or more, for example about 2cm or more. Other electrode shapes than rectangular or circular are also possible, such as elliptical, triangular, or according to the shape of the particular tissue anatomy within the field lines. The mutual spacing between the electrodes may be, for example, 5mm or more, for example about 1cm or more, or even about 10cm or more. The relative displacement of the electrodes is preferably perpendicular to the blood vessel, which constitutes the object of measurement.

In order to provide a good electrical contact, the electrodes are preferably arranged in close contact with the skin, preferably using a suitable adhesive and/or gel that reduces the contact resistance.

In one embodiment, each electrode of the at least one set of electrodes is attached to the skin surface of the mammal, preferably by an adhesive. The electrodes are applied at a selected distance or distances from each other, either directly on the skin or preferably on or in one or more substrates, respectively. The distance or distances of the selected electrodes from each other can vary depending on the predetermined point on the body to be applied and is preferably a set of parameters as a basis for determining and calculating the cardiovascular quantity.

An oscillating voltage or an oscillating current is preferably applied to at least one set of electrodes such that at least some electric field lines between the electrodes traverse the blood vessel, which constitutes the measurement object. The oscillating voltage or oscillating current is also referred to as the excitation signal.

In one embodiment, the excitation signal includes a plurality of frequencies in a range of about 100Hz to about 10MHz or higher. These frequencies may be applied simultaneously in parallel or they may be applied sequentially. The relationship between voltage and current is given by the impedance of the limb tissue between the electrodes, which is also given by the anatomy of the limb tissue, the specific conductivity and permittivity of the different limb tissues, and the physical dimensions of the tissues. The conductivity and permittivity of different types of tissue vary with frequency.

In one embodiment, the method includes applying at least one set of electrodes within a selected distance from a measurement site, applying an electrical oscillation signal to the set of electrodes, and determining at least one impedance parameter on the set of electrodes.

By the present invention it has been found that by establishing the determination of at least one and preferably all of the mean diameter, the elasticity-related component or/and the vasodilation of the blood vessel at the measurement site on the basis of the determination of the one or more impedance parameters, an undisturbed determination of the desired cardiovascular quantity can be obtained. By introducing impedance sensing as a measurement parameter to determine one or more physical quantities: mean diameter, elasticity, or/and distension, which provides better predictive and diagnostic values more representative of the subject's blood pressure without affecting the subject's condition and thus ultimately its outcome.

By means of the invention, the determination of the cardiovascular quantity can be carried out with sensors arranged on a smaller body area than what can be achieved with the methods of the prior art, in particular, for example, when previously using pressure cuffs. In fact, when only one set of electrodes is used, the use of body area can be significantly minimized. Furthermore, by a reasonable choice of patches, and/or electrodes and/or wiring and/or processor and transmitter/receiver technology, the electrode area and the size of the measurement site can advantageously be significantly reduced, as is well known to the person skilled in the art. By laying the electrodes on the substrate, for example, the discomfort of the subject is reduced.

The change in impedance can generally be converted to a dilation Δ A (or Δ d) by a formula that is derived based on an impedance model of the limb (in which the tissue is present)

l is the length of the vessel portion under the field lines of a set of electrodes and σ is the poisson's ratio.

At least one impedance parameter may be measured using a bridge, such as a wheatstone bridge or a variant thereof; the method preferably includes automatically balancing the bridge. These types of bridges are well known in the art.

In one embodiment, the real and imaginary parts of the measured impedance are used to determine one or more cardiovascular components.

In one embodiment, the mean diameter of the blood vessel at the measurement site is the estimated mean diameter. For example, the estimated average diameter may be estimated for a particular patient based on the type, size, gender, age, and/or condition of the patient and/or based on previous determinations of average diameter at the site of measurement or at other sites of the patient's blood vessels.

The vessel size can vary significantly from person to person. Thus, estimating the mean diameter only for the population may result in an undesirably low accuracy of the measurement of the cardiovascular quantity.

In one embodiment, the mean diameter of the blood vessel at the measurement site is the determined mean diameter, e.g. based on the measurement. So that a more accurate average diameter can be obtained.

In one embodiment, an electrical equivalent circuit comprising a resistor and a capacitor is established for the impedance. The resistance of the resistor and the capacitance of the capacitor of the equivalent circuit depend on the conductivity, permittivity and geometry. Measuring the mean value of the complex impedance over time at a plurality of frequencies and using a priori knowledge about the electrical properties of the tissue makes it possible to establish a set of equations from which a time-averaged mean size can be deduced and used as the determined mean diameter.

Different types and combinations of tissue and ex vivo electrical properties are explicitly listed in the published literature. However, the conditions to which a living body is exposed are not generally described and do not generally allow for a clear division into different limb tissues. This is particularly the case for measurements on the skin, on subcutaneous fat where vascularization of the living body can significantly alter the electrical properties.

The applicant has carried out measurements in its upper arm of a living human having a subcutaneous fat thickness in the range of less than 1mm to more than 3cm, and the measurements have confirmed this fact. It may also prove possible to apply a very simple model for the condition of the living body and thus to determine the cardiovascular quantity on the basis thereof.

In the frequency range of 1kHz to 1MHz one can utilize an equivalent circuit comprising a resistor and a capacitor in series and parallel combination, where the fat permittivity has a weak exponential dependence with frequency, with an index of about 0.1, and has a nearly constant resistance over the area, where the impedance is mainly the resistance.

In one embodiment, the impedance of at least one electrode set is determined to obtain an average diameter.

In one embodiment, one set of electrodes is used for excitation, while the other set of electrodes is used for determination. Detecting, i.e. measuring, with a single set of electrodes can reduce the effect from skin impedance, but at the cost of introducing a four-terminal equivalent circuit complexity.

In one embodiment, determining the average diameter of the blood vessel at the measurement site comprises: providing an electrical circuit comprising a set of electrodes positioned such that electric field lines between the set of electrodes intersect a blood vessel at a measurement site; applying a plurality of electrical oscillating signals to the set of electrodes, wherein the plurality of electrical oscillating signals comprises at least two different excitation frequencies; and determining an impedance between the set of electrodes for each excitation frequency.

The plurality of impedance determinations may be measured at different frequencies ranging from 1kHz to about 100 MHz. Frequencies greater than about 100MHz are not suitable because they do not penetrate sufficiently into the measurement site. In one embodiment, the first frequency (f1) is selected to be in the range of about 1kHz to about 1MHz, the second frequency (f2) is selected to be in the range of about 1kHz to about 100MHz, such as in the range of about 100kHz to about 100MHz, the third frequency is selected to be in the range of about 100kHz to 1MHz, and the optional fourth frequency is selected to be in the range of about 10kHz to about 10 MHz.

In one embodiment, the different excitation frequencies include a first frequency selected from about 1kHz, about 12kHz and about 400kHz, a second frequency selected from about 12kHz, about 400kHz, about 1.6MHz and about 10MHz, a third frequency selected from about 1kHz, about 12kHz, about 400kHz, about 1.6MHz and about 10MHz, and optionally a fourth frequency selected from about 1kHz, about 12kHz, about 400kHz, about 1.6MHz and about 10 MHz. Alternatively, pulsed excitation can be applied. The temporal width of the pulse should be equal to or less than the reciprocal value of the spectral range that should be covered. One or more frequencies may be applied simultaneously or sequentially.

In one embodiment, the method includes determining an impedance of each set of electrodes for each excitation frequency.

The method of determining the mean diameter with different excitation frequencies is based on the fact that the electrical properties of each of fat, muscle and blood are significantly different. At about 400kHz, the permitivity of blood and muscle are nearly equal; while the electrical characteristics are not the same at about 1 MHz. Other excitation frequencies may be selected depending on the configuration of the selected limb.

In one embodiment, the method includes at least one electrode for excitation and at least one set of electrodes for detection. In one embodiment, the set of excitation electrodes may be disposed upstream or downstream of the blood vessel relative to the detection electrodes.

Alternatively, and preferably, one electrode of the excitation set and one electrode of the detection set are arranged upstream or downstream of the blood vessel with respect to the other electrode of the detection set and the other electrode of the excitation set in a crossed configuration, in which configuration only the overlap between the excitation field lines and the virtual detection field lines will contribute to the measurement signal. Thus, the influence from subcutaneous fat can be completely eliminated from the signal. The cross electrode configuration is as follows: for each set of electrodes, the electrodes are moved in the direction of the artery and in a direction perpendicular to the artery so that the connecting lines of the respective excitation and detection electrodes cross each other. In this case, the measured admittance, i.e. the reciprocal impedance, is given by the sum of the muscle admittance and the vessel admittance in the direction of the field lines. This configuration facilitates a simpler estimation of static and dynamic vessel characteristics, e.g. relative to a configuration with just two electrodes, since the influence from subcutaneous fat is removed from the calculation. Given that muscle and blood are incompressible, this means that in this configuration, expansion can be quantitatively correlated with impedance changes.

According to the present invention, it has been found that a better determination of the mean diameter of the vessel can be obtained using the real and imaginary parts of the impedance than when only the real or imaginary parts are used to determine the mean diameter of the vessel.

In order to perform the inverse operation to obtain an estimate of the mean diameter of the blood vessel at the measurement site, it is preferred to provide an a priori estimate of the anatomy at the measurement site and in the vicinity intersected by the field lines or subsets of field lines, to establish a set of mathematical formulas for detecting the impedance between the sets of electrodes based on this pre-model for an equivalent lumped parameter equivalent circuit, wherein the mathematical formulas represent the combined effect of the impedance along the electric field lines, and wherein at least one length part of the field lines passes through the skin, one length part of at least one subset of field lines passes through the fat layer, one length part of the subset of field lines passes through the muscle, and one length part of the subset of field lines passes through the blood vessel, and to determine the actual length part of the field lines passing through the blood vessel based on the measured impedance between the sets of electrodes at least two different excitation frequencies and the set of mathematical formulas. For using separate sets of electrodes for excitation and detection, respectively, it has to be taken into account that the field lines of the two sets of electrodes overlap.

The set of mathematical formulas may, for example, include an equation for each length portion of the field line, with the length portion of the field line as one unknown parameter.

In practice, an estimate of the mean diameter of the vessel at the measurement site can be obtained by performing an inverse operation using such a structural model: the structural model is based on a cross-section of the anatomical structure, including the measurement site and the adjacent regions intersected by the set of field lines, and is specified by the type of tissue under the measurement device, their effective cross-sectional dimensions, the effective intersection area of the field lines, and the values of permittivity and conductivity with respect to the excitation frequency. Such a structural model can be built based on NMR images, on images obtained by ultrasound, or images obtained with X-rays. Of course, such NMR, ultrasound, or X-ray images are not necessary for each individual making an impedance measurement, since only one overall structural model is required for each measurement site in question.

In one embodiment, the expression for determining the average diameter from the measured impedance can be obtained, for example, by a "solving" process using the "Mathematica" program of wolfrom Research (Wolfram Research), although other equation solvers known to those skilled in the art can also be employed. A particularly preferred method of determining the average diameter from the measured impedance is shown in the examples below.

In yet another embodiment, the artery size is estimated based on a prior image of the patient, e.g., obtained from an NMR image, ultrasound, X-ray, multi-frequency excitation, or a combination of two or more of the methods.

The vasodilation (also called vessel dilation) Δ a or Δ d is obtained from the time change of the impedance.

In one embodiment of the invention, the expansion is obtained using a commercially available impedance analyzer, by using which the impedance variation (optionally high-pass filtered by low frequency variations) and the average impedance can be determined. However, such devices are generally not suitable for dynamic measurements and are often too bulky to be positioned on a patient. Thus, these methods are not preferred, but can be used in the general concept of the method of the invention.

The method for determining the vasodilation at the measurement site comprises: providing an electrical circuit comprising a set of electrodes such that electric field lines between the set of electrodes intersect a blood vessel at a measurement site; and determining a temporal change in impedance between the set of electrodes.

For the determination of the mean diameter, when determining the dilation, it is also preferred here to determine based on the real and imaginary parts of the impedance measurements obtained from the one or more detection electrodes.

In one embodiment, the determination of the vasodilation at the measurement site comprises determining the maximum and minimum impedance between the set of electrodes, preferably the method comprises determining the change in impedance over time, determining the time change in impedance, and calculating the vasodilation at the measurement site.

In one embodiment, the method comprises applying at least one set of electrodes within a selected distance from a measurement site, applying an electrical oscillation signal to the set of electrodes, and determining at least one impedance parameter selected from the group consisting of average impedance, minimum impedance, maximum impedance, temporal variation of impedance, variation of impedance over time, or a combination of two or more of the aforementioned with respect to the set of electrodes.

In one embodiment, at least one sensor is provided, the sensor comprising a set of electrodes electrically connected in an electrical circuit such that electric field lines between the electrodes intersect a blood vessel at a measurement site, the method comprising applying an electrical oscillation signal across the set of electrodes and determining a change in at least one impedance parameter of the set of electrodes over time.

In one embodiment, a voltage is applied to a set of electrodes and the associated current is measured, for example, using the same set of electrodes.

In one embodiment, the current is introduced through a set of electrodes and the associated voltage is measured, for example, using the same set of electrodes.

In one embodiment, the method comprises applying at least one set of electrodes within a selected distance from the measurement site, applying an electrical signal of at least one excitation frequency, such as an oscillating current and/or an oscillating voltage, to the at least one set of electrodes, i.e. the set of excitation electrodes, and determining at least one impedance parameter by measuring on the at least one set of electrodes, i.e. the set of detection electrodes, wherein the set of excitation electrodes and the set of detection electrodes constitute the same set of electrodes.

In one embodiment, the current is introduced through one set of electrodes and one or more voltages are measured using a different set of electrodes.

In order to obtain the vasodilation at the measurement site, a time-resolved signal measurement is preferably used. However, if the time-averaged diameter is known, it is sufficient to measure the impedance time-variation at one frequency.

One embodiment utilizes the impedance of one electrode set and an excitation frequency of about 1 MHz. Other excitation frequencies are possible. However, it is preferred to utilize relatively high frequencies, such as about 100kHz or higher, to minimize the impedance effects of the skin. Since the skin has a very small thickness, capacitive coupling through the skin can be utilized. The effectiveness of this coupling increases with increasing frequency.

Another embodiment utilizes two sets of electrodes, one for excitation and one for detection.

The elasticity-related component may be, for example, the elasticity of the vessel, the stiffness of the vessel, the pulse wave velocity, or another elasticity-related component from which the elasticity can be calculated, preferably with an average diameter and/or optionally with dilation.

The determination of the elasticity-related component of the blood vessel at the measurement site preferably comprises determining the velocity of the pulse wave in the blood vessel at the measurement site. The terms "rate of pulse wave" and "pulse wave velocity" or simply "pulse rate" are used interchangeably and refer to the rate at which a blood pressure pulse travels along a blood vessel.

The propagation of a pulse along a blood vessel is essentially an acoustic phenomenon. The pulse wave velocity is much greater than the flow velocity and is, for example, about 5-15m/s for the brachial artery. The rate is determined by the Moens-Korteweg equation. A modification of this equation takes into account the Poisson ratio as follows

Where E is the elastic modulus of the vessel wall, h is the wall thickness,if v is measured, the term E × h/(1- σ) can be determined²) And r is obtained by estimating the impedance at several different frequencies if the term E × h/(1- σ)²) It is known that a transition from expansion to pressure change can then be achieved.

Methods for inferring blood pressure from auxiliary parameters like pulse wave velocity and flow velocity are well known in the art, for example, the method described in US5,309,916, the method described by thomas in Continuous pulse wave velocity recording (Continuous pulse wave velocity recording for indicating monitored blood pressure) for indirectly monitoring human blood pressure, Medical and biological Engineering and Computing, vol 3, page 321 and 322, 1964. These measurements typically require calibration against known standard blood pressure measurement devices.

In one embodiment, the method comprises applying at least two sets of electrodes, a first set of electrodes and a second set of electrodes, within a selected distance from the measurement site, applying an electrical signal of at least one excitation frequency, such as an oscillating current and/or voltage, to the first set of electrodes, the set of excitation electrodes, and determining at least one impedance parameter by measuring on said second set of electrodes, the set of detection electrodes, whereby the set of excitation electrodes and the set of detection electrodes constitute different sets of electrodes.

In one embodiment, the determination of the pulse wave velocity in the blood vessel at the measurement site comprises: positioning at least two sensors such that there is a selected spacing between electrodes of the sensors and the two sensors are separated by a vessel direction that covers a vessel length segment L containing at least a portion of the measurement site; and determining by each sensor the variation of the pulse with time and thus the pulse wave velocity. The sensor may be any type of sensor capable of detecting a pulse. In order to have a high accuracy, the sensor is preferably chosen such that it does not substantially affect the detected pulse.

In the present application, a sensor is defined as a substrate comprising at least one excitation element and/or detection element, e.g. one or more electrodes.

In a preferred embodiment, at least two sensors are provided, wherein each sensor comprises a set of electrodes. The excitation frequencies of the two sets of electrodes may preferably be slightly different, so as to avoid undesired cross-coupling between the two sets of electrodes. The first frequency may be about 1MHz or higher and the second frequency may be about 900kHz or lower. At least two sets of electrodes are provided, each covering a portion of the vessel under test, which provides a record of the time of pulse propagation along the vessel. The spacing between the electrodes may be, for example, about 1cm to about 50cm, such as about 30cm, about 10cm or about 3 cm. Small intervals are preferred to conform to the consistency required for the mean diameter of the artery, but the determination of the temporal pulse interval becomes more affected by noise, undesirable cross-coupling, and inaccuracies when approaching smaller intervals.

In the literature, the mean blood density of humans has been estimated to be 1060kg/m³. For other mammals, one skilled in the art will be able to find similar mean blood densities.

In one embodiment, the pulse wave velocity is determined by using three sets of electrodes. One set is placed between the other two sets, also on the vessel and used for stimulation. The other two groups are used for pulse detection. The electrode sets are spaced apart along the blood vessel. The electrodes of the electrode set are located on each side of the electrodes, perpendicular to the extended length of the blood vessel.

In yet another embodiment, only one set of electrodes is utilized. The delay used to determine the component is derived by using the reflection from the vessel branch. Reflections in the arterial system are well known to those skilled in the medical arts.

For the determination of the mean diameter and/or the expansion, when determining the elasticity-related component, it is also desirable here to base the determination on the real and imaginary parts of the impedance measurement, however in most cases the expansion may be based entirely on the real or absolute value of the impedance.

Determining the impedance from the electrode signal would typically require specialized signal processing. Here, the key issue is that the dynamic part of the impedance associated with the average impedance is very small. High performance universal impedance measurement devices can be employed and their application falls within the scope of the present invention. However, prior art high performance universal impedance measurement devices are generally bulky, expensive, and often do not provide sufficient time resolution, so other approaches are preferred as described below.

In a preferred embodiment, a wheatstone bridge adapted to measure complex impedance is used. Generally, such bridges appear to be beneficial for use in situations where the mean impedance is determined, for example for the determination of the mean diameter of a blood vessel, and where the time variation of the impedance is determined, for example for the determination of the dilatation.

The bridge is preferably balanced with a feedback circuit and is designed as a servo controlled PID loop as is well known to those skilled in the art. The loop response time is set to be greater than the expected time, also referred to as the time interval, between successive pulses. A simple adaptive algorithm adapted to the minimum rms signal of the bridge can also be used.

In a preferred embodiment, the signals from the electrodes are applied to an integrating detector, as is well known to those skilled in the art.

In an embodiment, a first set of detection electrodes, a second set of detection electrodes, and a third set of excitation electrodes located between the first set of electrodes and the second set of electrodes are provided, the latter being positioned such that at least electric field lines excited by the third set of electrodes intersect the blood vessel at the measurement site, wherein preferably the third set of electrodes is positioned between the first set of electrodes and the second set of electrodes.

In one embodiment of the method, the determination of the at least one impedance parameter is accomplished with signal processing by using at least one voltage follower and/or instrumentation amplifier for sensing and amplifying the input signal, and at least one mixer for demodulating the impedance parameter for integral detection of the impedance value of the amplified signal, and an analog-to-digital converter for digitizing the analog signal into a digital value.

1. An oscillating current is applied to the two electrodes. The electrodes may be the middle set of electrodes in a six electrode configuration. The frequency is in the range of 10kHz to 10MHz, preferably in the range of 100kHz to 1 MHz.

2. The voltages of a set of electrodes are calculated in such a way

a. Bandpass filtering is performed centered around the excitation frequency.

b. The measured signal is mixed (multiplied) with an in-phase signal and a quadrature signal, both obtained from the oscillator. This provides the real and imaginary parts of the impedance of the signal.

c. The mixer output is low pass filtered. Mixing and low-pass filtering essentially provide additional and very efficient band-pass filtering that is automatically centered on the excitation frequency (ensured by the reference signal from the oscillator). The low-pass filter has a corner frequency much larger than the pulse frequency (e.g. 100 Hz). A transversal filter (finite impulse response filter) is preferably used to ensure a constant delay over the frequency range.

3. A normalized correlation function is calculated to record a length of, for example, 2 to 20 seconds.

4. A reference correlation function is defined which may be the correlation function of the skewed sawtooth signal intercepted by a gaussian function.

5. A reference function is fitted to the correlation function of the signal. A time scale is obtained. (Note that both the reference and correlation functions are normalized, making axial scaling a unique fitting parameter.)

6. A reference function is calculated for each fit. The covariance of the correlation function and the reference function is calculated for each fit, as well as the correlation function corresponding to the given fit. An acceptance threshold is set. A typical value is 0.7 times the maximum covariance. The initial covariance is obtained when the person is at rest.

7. The time locations of acceptable correlation functions are identified, and the average of the maximum and minimum values of the signal over the time interval corresponding to the interval in which each correlation function is evaluated. The difference yields the impedance change.

In general, the impedance change can be converted to a dilation Δ A (or Δ d) by a formula that is derived based on an impedance model of the limb (with tissue therein)

l is the length of the portion of the vessel subject to the field lines of a set of electrodes and σ is the poisson's ratio.

In another embodiment, the signal processing is performed by a combination of threshold and zero crossings. It can be carried out as follows:

1. the steady state was obtained by letting the subject sit and rest for about 1 minute.

2. The signal is band pass filtered (as described previously). The response time of the filter is about 1/3 of the expected pulse interval.

3. The average of the individual maxima recorded over a period of time, given by the bandwidth of the inverse filter, is estimated.

4. If the signal at time 1/3 of the filter response time (reciprocal bandwidth) exceeds 50% of the average peak value, the zero crossing is detected and the number of occurrences of the zero crossing is recorded.

5. For the number of accepts recorded at 4, the subsequent zero crossing should not occur before 2/3 times the filter response time.

6. For the differential impedance and thus the pulse pressure, the maximum and minimum values of the signal that meet the previous requirements are recorded.

7. The transit time is estimated using the zero crossings of the acceptance of the signals from the two channels (pulse wave velocity).

If two sets of electrodes are positioned on the same limb, the impedance loads of the two sets of electrodes may interfere with each other. This can be avoided, for example, by time multiplexing of the excitation signals.

In one embodiment of bridge detection, balancing is provided by simultaneously balancing the bridges, preferably in combination with slightly different excitation frequencies. The preferred excitation frequency is a compromise involving sensitivity and cross-coupling: the relatively low conductivity of blood means that the field lines extend less along the length of the limb for which the measurement is taken, which in turn means that the contribution to the impedance change caused by the change in vessel diameter is relatively small. An excitation frequency of about 100kHz seems to provide a good compromise.

It is possible to determine or estimate the time interval between pulses associated with the patient's heartbeat and in fact a rough estimate is sufficient. For humans, the time interval may be estimated to be about 1 second, for example. For other mammals, the time interval can be estimated, for example, to be about 0.1 seconds to about 10 seconds. The feedback circuit means that the bridge will be balanced. In one embodiment, only the resistive component is adjusted. Simple impedance calculations show how any change in the complex impedance of the test object can be compensated by a pure resistive component. This embodiment facilitates the application of an electronically positionable resistor. In an alternative embodiment, a varactor can be used as the variable capacitor. They can be based on reverse biased diodes or MOS devices, for example.

In one embodiment, the method includes determining or estimating the time interval between mammalian pulses, preferably at the measurement site, determining an average impedance with a bridge, and automatically balancing the bridge with a feedback loop having a loop response time approximately equal to or greater than the time interval between pulses. The method preferably includes adjusting at least two resistive components of the bridge.

In one embodiment, the method includes determining or estimating a time interval between mammalian pulses, preferably at a measurement site, determining a time variation of impedance with a bridge, and automatically balancing the bridge with a feedback loop having a loop response time approximately equal to or greater than the time interval between pulses, the method including determining the time variation of bridge imbalance.

In one embodiment, for delay estimation in a configuration with three sets of electrodes, it is achieved by processing the signals from each set of detection electrodes as previously described and cross-correlating the two demodulated signals. The resulting normalized cross-correlation function can then be verified using the reference function as previously described. The delay is then estimated from the displacement of the first peak of the validated cross-correlation function. The peak may be inferred by fitting a reference function to the measurement function. The reference function may be approximated by a parabola. The excitation is applied to a set of excitation electrodes placed between the detection electrodes.

In one embodiment, for delay estimation, it is done by zero crossing detection and verification as previously described. The delay can be inferred from the difference in zero crossings of the signals from the two detection electrodes.

A single forward propagating pulse at the radial artery can be modeled by the following expression:

d(t)＝a[sin(2πt/t₁)exp(-(t/t₂)²)+(1-t)(1-exp(-t/t₃))]×[unitstep(t)-unitstep(t-1)]

(2a)

in one embodiment, a fitting process is utilized to provide estimates of t1, t2, and t 3. Other mathematical expressions can be utilized and they can be adapted to the specific location on the body where the measurement is to be made.

In one embodiment, the delay is estimated in a relatively simple manner. The spacing between the sets of electrodes is selected to be so small that the temporal width of the pulse is significantly less than the pulse delay from the first set of electrodes to the second set of electrodes. For humans this will typically mean a separation of about 15cm or less.

The estimator is defined by the following expression:

in another embodiment, where the spacing between sets of electrodes is greater than about 15cm, errors may become unacceptable using the above estimates. The estimates are modified to incorporate an iterative process similar to that in a delay locked loop, where the delay of the delay line is continuously updated through the control loop to match the delay of one signal with respect to the other.

It is worth noting that those parts of the signal that are steepest with respect to the temporal gradient generally provide the best determination of the temporal localization. It should also be noted that the first part of the pulse is considered to be preferable for pulse wave velocity measurement. These facts indicate that for pulse wave velocity measurement, a high-pass filtered signal should preferably be used. The degree to which the high-pass filtering can be applied is determined by the possible appearance of small characteristic differences of the signal and by the noise. In one embodiment, a high pass filter up to 1Hz is employed. In another embodiment, a high pass filtering up to 100Hz is performed.

In yet another embodiment, a general procedure is employed: calculating a cross-correlation function based on the measured values and fitting a model cross-correlation function to the calculated cross-correlation function with a delay as a fitting parameter.

The measured pulses for different subjects will usually have different shapes because of the influence of reflections and variations of the vascular structures and because of the different distances from the heart to the measurement site. This reflection is generally undesirable. This effect can be minimized by filtering the observed pulse with a filter that matches the expected forward propagating pulse.

In some cases, some of the fluctuations may be within the same general bandwidth as the desired signal. Thus, it is not possible to remove these unwanted fluctuations by simple filtering. However, fluctuations are typically not synchronized with the heartbeat, meaning that they are removed in other ways.

This fact can be applied in various ways and in particular by:

conditional averaging, in which a large set of measured pulses is shifted to a given pulse by an amount given by the sum of the pulses from a defined reference pulse. These pulses are then averaged. Fluctuations that are not synchronized with the heartbeat will tend to disappear during the averaging process. If the pulse characteristics interfere with a preset value that is adjusted according to an identified quasi-periodic sequence of the first measurement sequence, the sequence is discarded. The reference pulse can be obtained from an ECG signal, which is typically well defined over time, or from selected pulses of an impedance signal. It should be noted that this process works even if the pulse phase exhibits little (less than about 10%) variation.

A mechanism similar to a phase locked loop. The oscillator of the loop will typically generate quadrature signals. The quadrature signal is multiplied with the input signal for generating an error signal, which facilitates the locking of the loop. The in-phase signal multiplied by the input signal is used to lock the indicator. However, in the present case, the signal corresponding to the in-phase signal should not be a sinusoidal signal but a quasi-periodic signal having a signal form given by the desired pulse shape. The signal corresponding to the quadrature signal may be the derivative of the input signal, the phase shifted version of which has a zero mean. The hilbert transform of the signal has also been shown to provide a good error signal in the loop.

In an embodiment of the method of the present invention, calculating the at least one cardiovascular quantity from the mean diameter of the blood vessel, the elasticity-related quantity and the vasodilation determined at the measurement site comprises calculating a systolic pressure, calculating a diastolic pressure and/or calculating a vascular compliance.

To obtain the differential pressure (difference between systolic and diastolic pressure) and the absolute pressure (diastolic pressure), the relationship between pressure and vessel radius will be used. Blood vessels exhibit a non-linear relationship between pressure and radius. At low pressures, the blood vessels are very elastic due to the predominance of elastin fibers. At higher pressures, the blood vessels appear stiffer; collagen fibers dominate in their properties. It should also be noted that zero transmural pressure (pressure differential across the wall) does not imply a zero radius. Negative transmural pressure is required for complete deflation of the blood vessel.

In the calculation of one embodiment, the wall may be assumed to be incompressible, so that the cross-sectional area and average diameter of the wall are constant. For positive transmural pressure, the following relationship is used:

the expression is selected from: gary Drzewiecki, Shawn Field, Issam Moubaak and John K. -J.Li, "relationship of vascular growth and collapsible pressure regions" (Vessel growth and collapsible compression-area relationship), "Am J Physiol Heart Physiol273: H2030-H2043,1997, equation (7 a); the area A of the cross-sectional tube cavity is formed by pi r²And (4) determining. Component P₁、b、A_bAnd P₀Is a constant that is specific to the subject, e.g., patient, and to the location of the mammalian measurement site.

It should be noted that the estimates of differential pressure and absolute pressure can be based on other assumed functional relationships of pressure to vessel radius, which means that the gradient does not change sign, as long as the relationship is monotonic and non-linear.

The relationship between pressure and radius given above is only for rA ≧ A_bThe method is effective; a. the_bIs the value at which deformation would occur if the pressure were lower. The extrapolation based on experimental data actually shows that P is given by equation (4)_sWhen r is 0, it must be 0. This fact indicates that equation (4) can be simplified as the following expression:

it should be noted that an exponential relationship can generally be assumed for the relationship between pressure and vessel cross-section. For very large pressures close to the pressure at which a blood vessel may burst, such a relationship is no longer valid.

The pulse wave velocity can be expressed by combining the terms of equations (1) and (5)To thereby obtain

Equation (6) is essentially the Bramwell-Hill formula, assuming that the longitudinal expansion of the vessel is negligible. As can be seen in equation (1), the pulse wave velocity depends on the radius of the blood vessel. For relative expansions that are much smaller than unity, the actual value of r can be replaced by the average value of r. The change in expansion is typically less than about 10%. For larger variations, non-linear effects may be considered. The non-linear effect means that the pulse is broadened because the wave speed decreases with increasing radius. Such an effect is contrary to the fact that tapering of the arteries implies a sharp pulse.

Measuring v, A, Δ A and deriving the density ρ from the tabulated values facilitates calculating Δ P according to equation (6).

In one embodiment, the absolute pressure can be obtained according to equation (5). To achieve this, two parameters P' and r are estimated_b'. From steps ii and iii, two values of r are known, namely { r, r + Δ r }. In fact, the entire range of values of the vessel radius between r and r + Δ r is generally available from steps ii and iii, and only two values are required to determine { P', r_b′}。

Vascular compliance is defined by the change in vessel volume divided by the change in pressure, i.e.

Wherein

l is the length of the portion of the blood vessel being measured by a set of electrodes,

r_sis the systolic pressure P_sRadius of inferior blood vessel, and

r_dis the diastolic pressure P_dThe lower vessel radius.

The method of the invention further comprises determining one or more other dimensions of the blood vessel at the measurement site, such as the thickness of the vessel wall, the maximum diameter of the blood vessel, the minimum diameter of the blood vessel, the temporal change in the diameter of the blood vessel and/or the change in the diameter of the blood vessel over time. Other dimensions may be determined using methods similar to those used in determining the average diameter.

The method also includes determining a pulse rate.

It is generally desirable that the method be non-invasive. Preferably, the method does not include applying pressure to the blood vessel. More preferably, the method is non-disruptive in nature, preferably such that the patient does not feel when making a particular determination. The method may be performed as a continuous, semi-continuous or stepwise determination of the selected cardiovascular quantity/quantities.

The invention also relates to a cardiovascular quantity system for determining at least one cardiovascular quantity in a blood vessel of a mammal. The cardiovascular quantity system comprises

A plurality of sets of electrodes, wherein each set of electrodes is attachable to the skin surface of the mammal such that when an electrical signal, such as a current or voltage, is applied to the electrodes at the measurement site, a capacitive coupling is provided through the skin surface and between the individual electrodes of the set of electrodes;

an electrical element for applying an electrical signal, for example an oscillating signal, on each set of electrodes;

at least one processor and memory unit arranged to receive electrical response signals from the sets of electrodes; wherein the processor is designed and programmed to calculate at least one cardiovascular quantity based on the electrical response signals from the sets of electrodes according to the method of the present invention as described previously.

The electrode set may be as described above. In one embodiment, one or more sets of electrodes are applied to a flexible housing, e.g. a patch, e.g. as described in WO2007/000164 and/or WO 2010/057495.

The housing/patch, optionally in combination with the electrodes, may be reusable or disposable. A voltage from any electrical element, such as a battery, may be applied. The power source is releasably connected to the electrodes, which makes the disposable housing/patch easier to apply to the electrodes. The electrodes may be secured to the patch at preselected locations.

The cardiovascular quantity system may comprise one or more processors and one or more memory units, wherein the memory unit and the processor or several of them may be combined into one single unit or they may be in the form of several separate units. The one or more processors are together designed and programmed to calculate at least one cardiovascular quantity based on the signals from the sets of electrodes.

In one embodiment, the one or more processors are programmed together to calculate an average diameter, an elasticity-related component, and a vessel dilation of the vessel at the measurement site based on the signals from the sets of electrodes.

In one embodiment, the one or more processors are programmed together to calculate the at least one cardiovascular quantity based on a determination of an average diameter of the vessel at the measurement site, the elasticity-related quantity, and the vessel dilation.

In one embodiment, the one or more processors are programmed together to calculate systolic pressure, diastolic pressure and/or calculate vascular compliance based on the determination of the mean diameter of the blood vessel, the elasticity-related component and the vasodilation at the measurement site.

In one embodiment, at least one memory cell is directly coupled to each set of electrodes for storing the determined value of the impedance.

In one embodiment, at least one processor unit is coupled directly or wirelessly to the sets of electrodes for preprocessing the impedance values but not performing a final calculation of the systolic pressure, the diastolic pressure and/or calculating the vascular compliance.

The pre-processing preferably comprises determining at least one of the at least one impedance parameter selected from the group consisting of average impedance over a set of electrodes, minimum impedance, maximum impedance, time variation of impedance, variation of impedance over time, or a combination of two or more of the foregoing impedance parameters. In one embodiment, the pre-processing includes determining an average diameter, an elasticity-related component, and a vessel dilation of the vessel at the measurement site based on the signals from the sets of electrodes.

In one embodiment, the at least one memory unit and the at least one preprocessing processor are incorporated in a local patient unit, which may be in direct or wireless data connection with the sets of electrodes. The local patient unit may for example be adapted to be carried by the patient or to be placed in the patient's home or in an environment in which the patient is expected to be. In one embodiment, the local patient unit is incorporated in a PC or mobile phone.

In one embodiment, at least one processor is incorporated in the main processor unit, the one or more processors programmed to calculate systolic pressure, diastolic pressure and/or calculate vascular compliance based on data obtained from the local patient unit. The local patient unit and the main processor unit may be adapted to provide data communication via a direct connection or a wireless connection. In one embodiment, data from the local patient unit can be transmitted to the host processor over the internet.

It should be noted that although one advantage of the method of the present invention is that it is now possible to provide accurate measurements of blood vessels without having to apply a back pressure to the limb containing the blood vessel, it has been realised that the method of the present invention can also be carried out when a back pressure is actually being applied. A back pressure of about 40mmHg has a negligible effect on the measurements made on the artery, but this essentially squeezes the vein so that there is no blood present, which simplifies the determination of the arterial cross-section. Measuring the change in distension with applied external pressure can also have diagnostic or prognostic value in itself.

It should be emphasized that the term "comprises/comprising" when used herein is to be interpreted as an open-ended term, i.e. it should be interpreted to specify the presence of stated features, such as elements, units, integers, steps, components, and combinations thereof, but does not preclude the presence or addition of one or more other stated features.

All features and embodiments of the invention, including all ranges and preferred ranges, can be combined in various ways within the scope of the invention, unless there is a particular reason why such features cannot be combined.

Further scope of applicability of the present invention will become apparent from the detailed description of the examples and embodiments given hereinafter. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

Drawings

The present invention will now be explained more fully with reference to the accompanying drawings in conjunction with a number of examples.

FIG. 1 is a schematic diagram of a cardiovascular quantity system of the present invention.

Figure 2 illustrates one electrode configuration that can be used in the method of the invention.

Figure 2a illustrates another electrode configuration that can be used in the method of the invention.

Figure 3 shows a cross-sectional view of the upper arm.

Figure 3a shows a longitudinal sectional view of the upper arm in one electrode configuration of the method of the invention.

Fig. 4a and 4b show some values of permittivity (a) and conductivity (b) as a function of excitation frequency for different types of tissue, respectively.

Fig. 5a is a schematic illustration of a first electrical schematic equivalent to a section of tissue based on a prior model of the anatomical structure.

Fig. 5b is a schematic illustration of a second electrical schematic corresponding to a section of tissue based on a prior model of the anatomical structure.

Fig. 6 is a schematic diagram of determining the time variation of impedance using a bridge circuit.

Fig. 7a and 7b are schematic diagrams of determining the average impedance and the impedance fluctuations using a bridge.

Fig. 8a and 8b are schematic diagrams of the calculated changes in the real (a) and imaginary (b) parts of the impedance associated with the heartbeat, respectively.

Fig. 9a is a time variation diagram of the absolute value of the measured impedance for one electrode configuration.

Fig. 9b is a time variation diagram of the absolute values of the measured impedances for three different objects.

Fig. 10a shows the measured (solid line) and fitted average impedance versus excitation frequency for two electrodes.

Fig. 10b shows the absolute values of the impedance measured with two electrodes (solid line) and a function fitted to the measured values.

Fig. 11 shows a single pulse measured and fitted.

Detailed Description

Fig. 1 shows a system arrangement according to one embodiment of the system of the invention, wherein the sensor patch 1 comprises at least one set of not shown electrodes on a substrate, which are applied to the skin of the patient near the brachial artery 2 of the patient. The patch 1 is positioned at a distance from the radial artery 3, the ulnar artery 4 and the carotid artery 5, respectively. The system further comprises a voltage or current generator (not shown) which provides an electrical excitation signal to the electrodes on the sensor patch 1. The system comprises a reading and processing unit 6, optionally a storage unit, for reading, processing and optionally storing the measured responses from the electrodes. The system may also include a computer 6 a. The reading and processing unit 6 is connected to the sensor patch 1 and/or the computer 6a wirelessly and/or by wires 7, 8. The computer 6a is programmed to perform the desired calculations of the method of the invention and may, for example, calculate medically relevant key parameters and provide a graphical interface. In a variant of the system, the one or more calculations are performed in the reading and processing unit 6, the reading and processing unit 6 being able to be positioned in the vicinity on the patch, and/or on the object shown, and/or remote overall, and being able to be provided by one or more processing units here.

Fig. 2 shows a typical electrode configuration for measuring impedance at two locations. The electrodes 11a, 11b, 11c, 11d are attached to the patch 10, the patch 10 being attachable to the skin 9 of the patient, for example by means of an adhesive. The electrodes 11a, 11b, 11c, 11d are grouped into two sets of electrodes 12, 13. The electrodes 11a, 11b, 11c, 11d are connected to the electronic unit 14 by electrically shielded conductive elements 15, the conductive elements 15 being, for example, polymer-insulated metal wires. Each of the two sets of electrodes 12, 13 comprises two electrodes 11a, 11b and 11c, 11d, respectively. When four electrodes are applied as shown, two electrodes of the first set may be used for excitation and the other two electrodes of the second set may be used for measurement.

An oscillating current generator (not shown), such as a Howland generator or other type of constant current generator, is used for excitation of at least two electrodes in the first set. It may be beneficial for the generator to exhibit nearly infinite self-impedance with the current generator. However, a voltage generator or other generator may be applied instead if the self-impedance is subsequently eliminated in the calculation. Preferably, oscillating electrical energy is used for the electrical excitation.

In fig. 2, a first set of electrodes 12 may be used for excitation, while a second set of electrodes 13 may be used for detection. Alternatively, a cross-coupling configuration may be used, with an excitation current or voltage applied across electrodes 11a and 11d and measured across electrodes 11c and 11b, or vice versa.

Fig. 2a shows one electrode configuration, a six electrode configuration, with one electrode set for excitation and two electrode sets for detection. The electrodes 11a, 11b, 11c, 11d, 11e, 11f are attached to or provided in a patch 10a, which patch 10a can be attached to the skin 9 of the patient, for example by means of an adhesive. The electrodes 11a, 11b, 11c, 11d, 11e, 11f are grouped into three groups of electrodes 12a, 12b, 13a, the first group 12a comprising the electrodes 11a, 11b, the second group 12b comprising the electrodes 11c, 11d and the third group comprising the electrodes 11e, 11 f. Each of the electrodes 11a, 11b, 11c, 11d, 11e, 11f is connected to an electronic unit 14a through an electrically shielded conductive element 15 a. Fig. 3 shows a simple reconstruction of a transverse section of the upper arm for a healthy young male, as can be obtained for example with MR imaging. It can be seen that in the cross-section shown, the upper arm comprises the brachial artery 16, the vein 17, the nerve 18, the bone 19, the fat layer 20, the muscle 20a, and the skin 21.

Fig. 3a shows a longitudinal section of an arm to which two sets of electrodes are applied as shown in fig. 3, for example the two outer electrode sets 12a, 12b in fig. 2 a. Here, the excitation by the electrodes 11a and 11d is shown as excitation from, for example, a current or voltage generator positioned on or remote from the patch. Thus, here electrodes 11a from the first set of electrodes 12a and electrodes 11d from the second set of electrodes 12b are utilized in a crossed field line configuration. When an oscillating current is used, a current may be applied to the electrode 11a and the electrode 11 d. The field lines generated by this type of excitation are shown by dashed lines 11 fe.

Detection is performed using the electrodes 11b and 11c accordingly, for example by providing suitable detection means 11cc on both electrodes, measuring the response to electrical excitation given by the arm characteristics. Virtual "field lines" 11gd are shown in fig. 3a, which are interpreted as field lines associated with the electrodes 11b and 11c, if they have been excited.

This crossed configuration of the electrodes for excitation/detection facilitates a determination method in which the influence of e.g. skin and/or subcutaneous fat is negligible, since this has surprisingly been confirmed by the applicant through detailed analysis and through a series of measurements that only the "overlapping" field line region, i.e. the inner region of the arm, will contribute to the impedance measurement, which effectively "cuts off" the contribution from the outer subcutaneous fat.

Fig. 4a and 4b show typical values of permittivity (a) and conductivity (b) as a function of excitation frequency for different types of tissue and for blood, respectively, which can be found in the open literature and provided by models used today. It has been found that in these test measurements these model values taken ex vivo are not used for vascularized tissue, but are clearly correlated with model values of live blood.

Fig. 5a shows an equivalent electrical circuit for the impedance between any two electrodes. The equivalent electrical circuit is interpreted to comprise a plurality of sub-circuits 22, 23, 24 and 25 arranged in parallel and/or in series according to an a priori estimation of the anatomical structure at the measurement site and in the vicinity of the region intersected by the field lines of the set of detection electrodes being analyzed. Subcircuits 22, 23, 24, and 25 are shown as: sub-circuit 22 is equivalent to skin, sub-circuit 23 is equivalent to the outer fat layer, sub-circuit 24 is equivalent to muscle, and sub-circuit 25 is equivalent to one or more blood vessels. In this representation, the muscle 24 is disposed parallel to one or more blood vessels 25. By establishing a set of mathematical formulas for impedance using such a representation, the mean diameter of the vessel can be determined based on impedance measurements at a plurality of different oscillation frequencies.

Fig. 5b shows another equivalent electrical circuit, the representation of which is further detailed. The subcircuit 24b in series with the one or more blood vessels 25 represents a portion of the muscle in the arm that is accessed through the field lines of a set of electrodes in line of sight with the one or more blood vessels 25 being measured, i.e. primarily the brachial artery 16. The remaining muscle portion contributions are provided as sub-circuits 24a parallel to the "seen" muscle portion 24b and one or more blood vessels 25.

Fig. 6 illustrates the concept of a signal processing loop for tracking the phase of a signal, verifying its consistency with the heartbeat and estimating the impedance change synchronized with the heartbeat. The signal processing and correlation loops include first and second multipliers 27a, 27b, an integrating and low pass filter 28, a waveform generator 29 providing quadrature outputs, an averaging circuit 30, a maximum and minimum detection circuit 31, a threshold verifier 32 and a squaring and averaging unit 33.

The input signal 26 is, for example, an impedance signal detected at the detection electrode groups 11b, 11c, and is supplied to the circuit system. The waveform generator 29 generates two signals whose repetition frequency is controlled by the output of the integrating and low pass filter 28. The signal to the second multiplier 27b, which is not part of the loop, is the desired pulse signal with a stable amplitude; the signal entering first multiplier 27a, which is part of the loop, is in quadrature with signal 26, so that the average multiplier output of first multiplier 27a provides the error signal: the error signal is negative if the repetition rate is higher than the pulse rate, and positive if the repetition rate is lower than the pulse rate. If there is a suitable, i.e. acceptable, input signal, the waveform generator 29 will generate a signal of the same repetition frequency. The harmonic is eliminated by multiplying the in-phase signal of the waveform generator by the input signal 26 and averaging it by the averaging circuit 30, and the correlation between the input signal 26 and the signal of the waveform generator is obtained as the output signal of the averaging circuit 30. The maximum/minimum detector 31 will then provide outputs 34 representing the maximum and minimum measured impedances, corresponding to the systolic and diastolic pressures, respectively. The output signal from the averaging circuit 30 is also verified in a threshold verifier 32 and is accepted only when the averaged output of the second multiplier 27b normalized with the input signal power exceeds a preset threshold. The input signal power is derived from the squaring and averaging unit 33, which indicates the squaring and averaging of the input signal 26.

Fig. 7a and 7b illustrate impedance fluctuations using an impedance bridge to extract the average impedance and the detected value. Fig. 7a shows a bridge with one fixed impedance 37 and two adjustable impedances 38, 39 and a target impedance 36, i.e. the object impedance. The excitation signal is provided by a generator 40. The balance of the bridge is measured at the measurement location 41. The adjustment during the measurement period can be performed manually, but is preferably performed automatically, for example by a processing unit.

Fig. 7b shows an alternative type of bridge implementation that provides the advantage of automatically adjusting the impedance so that the output signal has a higher resolution and interference in the output signal is eliminated. The adjustable impedances 43, 45 are preferably purely resistors. The fixed impedance 42 is also preferably a pure resistor. Any impedance 47 can be compensated for by means of the capacitor 46. The excitation signal is provided by the current generator 44 and the bridge balance is measured at the measurement location 48. The control device or processor 48a provides settings for each of the adjustable impedances 43, 45 based on the bridge balancing signal measurements at the measurement locations 48.

Those skilled in the art are also familiar with other types of bridge and non-bridge signal measurement methods known in the art that can be used to measure or indicate the impedance at the measuring electrode. Any suitable one of these methods may be used in or in conjunction with the present invention.

Fig. 8a and 8b show the calculated change in the real (a) and imaginary (b) parts of the impedance associated with the heartbeat, respectively.

Fig. 9a shows a time-varying trace of the absolute value of the impedance measured with electrodes placed between the biceps and the triceps. Each electrode area is about 100mm²And the spacing between the electrode centers is about 30 mm.

Fig. 9b shows three traces of the temporal variation of the pulse pressure with respect to the mean arterial pressure, expressed in mmHg, each corresponding to one of three different subjects measured with electrodes placed between the biceps and the triceps. Each electrode area is about 400mm²And the spacing between the electrode centers is about 30 mm. The uppermost trace is the result for healthy young men; the middle trace is for very high systolic pressure andelderly women with low body mass index; the lowest trajectory is for middle-aged males with very high blood pressure and very high body mass index.

Fig. 10a shows the mean impedance as a function of the excitation frequency, characterized by absolute value and phase, measured for electrodes placed on patches placed on the inside of the upper arm. The electrode area is 400mm²And the spacing between the centers of the electrodes perpendicular to the artery is 50 mm.

Fig. 10b shows the absolute value in ohms (solid line) of the impedance measured on the upper arm with the electrode as in fig. 10a as a function of frequency in the range between 1kHz to 1MHz, and also shows the function fitted to the measured impedance (dashed line), thus demonstrating an excellent fit to the established model.

Fig. 11 shows a single pulse measured and fitted. The pulse is measured at the radial artery.

Claims (64)

1. A method of determining at least one cardiovascular quantity of a mammal, the method comprising

Estimating an average diameter of the blood vessel at the measurement site based on at least one impedance parameter measured by at least one set of electrodes applied at the measurement site of the blood vessel;

determining a vessel dilation at the measurement site based on the at least one impedance parameter; and

determining an elasticity-related component of the blood vessel at the measurement site based on the average diameter of the blood vessel, the dilation of the blood vessel or a combination thereof.

2. The method of claim 1, further comprising determining at least one cardiovascular quantity from the determined mean diameter, elasticity-related quantity and vasodilation at the measurement site.

3. The method of claim 1, wherein the blood vessel is an artery selected from the group consisting of brachial, radial, ulnar, femoral, finger, and carotid arteries.

4. The method of claim 1, wherein the at least one set of electrodes comprises at least two electrodes applied within a selected distance from the measurement site, and wherein the method further comprises applying an electrical signal to the electrodes and disposing electric field lines from the electrodes to intersect the blood vessel at the measurement site.

5. The method of claim 4, wherein each electrode of the at least one set of electrodes is attached to a skin surface of the mammal.

6. The method of claim 5, wherein at least one sensor is provided comprising the at least one set of electrodes electrically connected in an electrical circuit such that electric field lines between the electrodes intersect the blood vessel at the measurement site, the method further comprising applying an electrical oscillation signal across the set of electrodes and determining a change in at least one impedance parameter of the set of electrodes over time.

7. The method of claim 6, further comprising: applying the at least one set of electrodes within a selected distance from the measurement site, applying an electrical signal selected from the group consisting of oscillating current and oscillating voltage of at least one excitation frequency to the at least one set of electrodes, and determining the at least one impedance parameter by measuring on the at least one set of electrodes.

8. The method of claim 7, wherein the at least one set of electrodes consists of an excitation electrode set and a detection electrode set.

9. The method of claim 6, wherein the method further comprises applying at least two sets of electrodes, a first set of electrodes and a second set of electrodes, within a selected distance from the measurement site, applying an electrical signal selected from oscillating current and oscillating voltage of at least one excitation frequency to the first set of electrodes, and determining the at least one impedance parameter by measuring on said second set of electrodes.

10. The method of claim 9, wherein the first electrode set is an excitation electrode set and the second electrode set is a detection electrode set.

11. The method according to any of claims 6-10, wherein the measurement of the at least one impedance parameter is performed with signal processing by: at least one of a voltage follower and an instrumentation amplifier for sensing and amplifying the signal from the detection electrode, and at least one set of mixers for demodulating the signal by quadrature detection, and wherein the method further comprises amplifying the demodulated signal comprising the in-phase signal and the quadrature signal at a known value.

12. The method of claim 1, wherein estimating an average diameter comprises determining an average diameter using a multi-frequency excitation.

13. The method of claim 1, wherein estimating the average diameter of the blood vessel at the measurement site comprises: providing an electrical circuit comprising: at least one set of electrodes such that electric field lines between the set of electrodes intersect the blood vessel at the measurement site; applying a plurality of electrical oscillating signals selected from an oscillating current and an oscillating voltage to the set of electrodes, wherein the plurality of electrical oscillating signals comprises at least two different excitation frequencies; and determining an impedance between the set of electrodes for each excitation frequency.

14. The method of claim 13, wherein estimating the average diameter of the blood vessel at the measurement site comprises: providing an a priori estimate of the cross-sectional anatomy at the measurement site and in the vicinity of the region intersected by the field lines of the set of electrodes; establishing, by an equivalent circuit, a set of mathematical formulas based on the a priori estimates for the impedances between the sets of electrodes, wherein the mathematical formulas divide the electric field lines into at least a length portion of the field lines that cross the skin, a length portion of the field lines that cross the fat layer, a length portion of the field lines that cross the muscle, and a length portion of the field lines that cross the blood vessel; and determining an actual length portion of the field lines traversing the blood vessel based on the determined impedances between the set of electrodes at the at least two different excitation frequencies and the set of mathematical formulas.

15. The method according to claim 13 or 14, wherein at the measurement site at least four electrodes are applied and an excitation current is applied to at least a first set of electrodes, the first set of electrodes comprising at least two electrodes which are moved in the direction of the artery and in the direction perpendicular to the artery and the voltage is measured on at least a second set of electrodes comprising at least two electrodes which are moved in the direction of the artery and in the direction perpendicular to the artery and configured such that the diagonals of the first set of electrodes and the second set of electrodes intersect.

16. The method of claim 1, wherein determining the elasticity-related component of the blood vessel at the measurement site comprises determining a pulse wave velocity in the blood vessel at the measurement site, wherein determining the pulse wave velocity in the blood vessel at the measurement site comprises placing at least two sensors at a selected mutual distance along a length segment L of the blood vessel comprising at least a part of the measurement site, and determining the change in the pulse over time by each sensor to determine the pulse wave velocity.

17. The method of claim 16, wherein at least two sensors are provided, a first sensor comprising a first set of electrodes and a second sensor comprising a second set of electrodes, the sets of electrodes being electrically connected in an electrical circuit such that electric field lines between the sets of electrodes traverse the blood vessel at the first pulse wave sensing site and the second pulse wave sensing site, respectively.

18. The method of claim 1, wherein at least three electrode sets are provided, a first electrode set being a detection electrode, a second electrode set being a detection electrode, and a third electrode set being an excitation electrode, the third electrode set being positioned such that at least electric field lines excited by the third electrode set intersect the blood vessel at the measurement site.

19. The method of claim 18, wherein the third set of electrodes is positioned between the first set of electrodes and the second set of electrodes.

20. The method of claim 1, further comprising applying an electrical oscillating signal selected from an oscillating current and an oscillating voltage across the at least one set of electrodes, determining a change in impedance of each of the at least one set of electrodes over time and a time shift of one impedance signal relative to another impedance signal.

21. The method according to claim 1, wherein the determined cardiovascular quantity is a blood pressure difference, which is the difference between the systolic and diastolic blood pressure, wherein the blood pressure difference is determined from the pulse wave velocity v in the blood vessel at the measurement site by using the following equation

Where Δ P is the blood pressure differential, Δ A is the dilation of the blood vessel, ρ is the blood density, and A is the mean cross-sectional area of the blood vessel.

22. The method of claim 1, wherein determining the dilation of the blood vessel at the measurement site comprises: providing an electrical circuit comprising a set of electrodes such that electric field lines between the set of electrodes intersect a blood vessel at a measurement site; and determining a time variation of the impedance of the set of electrodes.

23. The method of claim 1, comprising applying the at least one set of electrodes within a selected distance from a measurement site, applying an electrical oscillation signal to the at least one set of electrodes, and determining at least one impedance parameter selected from an average impedance, a minimum impedance, a maximum impedance, a time variation of impedance, a variation of impedance over time, or any combination thereof, across the at least one set of electrodes.

24. A method as in claim 22, wherein the method comprises estimating a time interval between mammalian pulses, determining an average impedance using a bridge, and automatically balancing the bridge via a feedback loop having a loop response time at least as large as the time interval between pulses by adjusting at least two resistive components of the bridge.

25. A method as in claim 22, wherein the method comprises estimating a time interval between mammalian pulses, determining a time variation of said impedance using a bridge, auto-balancing the bridge with a feedback loop having a loop response time at least as large as the time interval between pulses, and determining a time variation of bridge imbalance.

26. The method of claim 1, wherein one or more of the average diameter, the elasticity-related component, and the vessel dilation of the blood vessel is determined based on a determination of at least one impedance parameter selected from the group consisting of average impedance, minimum impedance, maximum impedance, temporal change in impedance, change in impedance over time, or any combination thereof across a set of electrodes.

27. The method of claim 1, wherein calculating at least one cardiovascular component from the mean diameter of the blood vessel, the elasticity-related component, and the vasodilation determined at the measurement site comprises calculating one or more of a blood pressure difference, a systolic pressure, a diastolic pressure, and a vascular compliance.

28. The method of claim 1, further comprising determining at least one other dimension of the blood vessel at the measurement site, the dimension selected from the group consisting of vessel wall thickness, maximum diameter of the blood vessel, minimum diameter of the blood vessel, temporal change in diameter of the blood vessel, and change in diameter of the blood vessel over time.

29. The method of claim 1, wherein the method further comprises determining a pulse rate.

30. The method of claim 1, wherein the method is non-invasive.

31. The method of claim 1, comprising not applying pressure to the blood vessel.

32. The method of claim 1, further comprising determining one or more selected from pulse magnitude, pulse pressure, and pulse rate by applying a back pressure for calibration purposes.

33. A system for determining at least one cardiovascular quantity of a mammal, comprising:

means for estimating an average diameter of the blood vessel at the measurement site based on at least one impedance parameter measured by at least one set of electrodes applied at the measurement site of the blood vessel;

means for determining a vessel dilation at the measurement site based on the at least one impedance parameter; and

means for determining an elasticity-related component of the blood vessel at the measurement site based on the average diameter of the blood vessel, the expansion of the blood vessel or a combination thereof.

34. The system of claim 33, further comprising means for determining at least one cardiovascular quantity from the determined mean diameter, elasticity-related quantity and vasodilation at the measurement site.

35. The system of claim 33, wherein the blood vessel is an artery selected from the group consisting of brachial, radial, ulnar, femoral, finger, and carotid arteries.

36. The system of claim 33, wherein the at least one set of electrodes comprises at least two electrodes applied within a selected distance from the measurement site, and wherein the system further comprises means for applying an electrical signal to the electrodes, and means for disposing electric field lines from the electrodes to intersect the blood vessel at the measurement site.

37. The system of claim 36, wherein each electrode of the at least one set of electrodes is attached to a skin surface of the mammal.

38. The system of claim 37, wherein at least one sensor is provided comprising the at least one set of electrodes electrically connected in an electrical circuit such that electric field lines between the electrodes intersect the blood vessel at the measurement site, the system further comprising means for applying an electrical oscillation signal across the set of electrodes and determining a change in at least one impedance parameter of the set of electrodes over time.

39. The system of claim 38, further comprising: applying the at least one set of electrodes within a selected distance from the measurement site, applying an electrical signal selected from the group consisting of oscillating current and oscillating voltage of at least one excitation frequency to the at least one set of electrodes, and determining the at least one impedance parameter by measuring on the at least one set of electrodes.

40. The system of claim 39, wherein the at least one set of electrodes consists of an excitation electrode set and a detection electrode set.

41. The system of claim 38, wherein the system further comprises means for applying at least two sets of electrodes, a first set of electrodes and a second set of electrodes, within a selected distance from the measurement site, means for applying an electrical signal selected from oscillating current and oscillating voltage at least one excitation frequency to the first set of electrodes, and means for determining the at least one impedance parameter by measuring on said second set of electrodes.

42. The system of claim 40, wherein the first electrode set is an excitation electrode set and the second electrode set is a detection electrode set.

43. The system according to any of claims 38-42, wherein the measurement of the at least one impedance parameter is made with signal processing by: at least one of a voltage follower and an instrumentation amplifier for sensing and amplifying the signal from the detection electrode, and at least one set of mixers for demodulating the signal by quadrature detection, and wherein the system further comprises means for amplifying the demodulated signal comprising the in-phase signal and the quadrature signal at a known value.

44. The system of claim 33, wherein estimating an average diameter comprises determining an average diameter using a multi-frequency excitation.

45. The system of claim 33, wherein estimating the average diameter of the blood vessel at the measurement site comprises: providing an electrical circuit comprising: at least one set of electrodes such that electric field lines between the set of electrodes intersect the blood vessel at the measurement site; applying a plurality of electrical oscillating signals selected from an oscillating current and an oscillating voltage to the set of electrodes, wherein the plurality of electrical oscillating signals comprises at least two different excitation frequencies; and determining an impedance between the set of electrodes for each excitation frequency.

46. The system of claim 45, wherein estimating the average diameter of the blood vessel at the measurement site comprises: providing an a priori estimate of the cross-sectional anatomy at the measurement site and in the vicinity of the region intersected by the field lines of the set of electrodes; establishing, by an equivalent circuit, a set of mathematical formulas based on the a priori estimates for the impedances between the sets of electrodes, wherein the mathematical formulas divide the electric field lines into at least a length portion of the field lines that cross the skin, a length portion of the field lines that cross the fat layer, a length portion of the field lines that cross the muscle, and a length portion of the field lines that cross the blood vessel; and determining an actual length portion of the field lines traversing the blood vessel based on the determined impedances between the set of electrodes at the at least two different excitation frequencies and the set of mathematical formulas.

47. The system of claim 45 or 46, wherein at least four electrodes are applied at the measurement site and an excitation current is applied to at least a first set of electrodes, the first set of electrodes comprising at least two electrodes which are moved in the direction of the artery and in the direction perpendicular to the artery and a voltage is measured on at least a second set of electrodes comprising at least two electrodes which are moved in the direction of the artery and in the direction perpendicular to the artery and configured such that diagonals of the first set of electrodes and the second set of electrodes intersect.

48. The system of claim 33, wherein determining the elasticity-related component of the blood vessel at the measurement site comprises determining a pulse wave velocity in the blood vessel at the measurement site, wherein determining the pulse wave velocity in the blood vessel at the measurement site comprises placing at least two sensors at selected mutual distances along a length segment L of the blood vessel comprising at least a portion of the measurement site, and determining the change in pulse with time by each sensor to determine the pulse wave velocity.

49. The system of claim 48, wherein at least two sensors are provided, a first sensor comprising a first set of electrodes and a second sensor comprising a second set of electrodes, the sets of electrodes being electrically connected in an electrical circuit such that electric field lines between the sets of electrodes traverse the blood vessel at the first pulse wave sensing site and the second pulse wave sensing site, respectively.

50. The system of claim 33, wherein at least three electrode sets are provided, a first electrode set being a detection electrode, a second electrode set being a detection electrode, and a third electrode set being an excitation electrode, the third electrode set being positioned such that at least electric field lines excited by the third electrode set intersect the blood vessel at the measurement site.

51. The system of claim 50, wherein the third set of electrodes is positioned between the first set of electrodes and the second set of electrodes.

52. The system of claim 33, further comprising applying an electrical oscillating signal selected from an oscillating current and an oscillating voltage across the at least one set of electrodes, determining a change in impedance of each of the at least one set of electrodes over time and a time shift of one impedance signal relative to another impedance signal.

53. The system of claim 33, wherein the determined cardiovascular quantity is a blood pressure difference, which is the difference between the systolic and diastolic blood pressure, wherein the blood pressure difference is determined from the pulse wave velocity v in the blood vessel at the measurement site by using the following equation

Where Δ P is the blood pressure differential, Δ A is the dilation of the blood vessel, ρ is the blood density, and A is the mean cross-sectional area of the blood vessel.

54. The system of claim 33, wherein determining the dilation of the blood vessel at the measurement site comprises: providing an electrical circuit comprising a set of electrodes such that electric field lines between the set of electrodes intersect a blood vessel at a measurement site; and determining a time variation of the impedance of the set of electrodes.

55. The system of claim 33, comprising applying the at least one set of electrodes within a selected distance from a measurement site, applying an electrical oscillation signal to the at least one set of electrodes, and determining at least one impedance parameter selected from an average impedance, a minimum impedance, a maximum impedance, a time variation of impedance, a variation of impedance over time, or any combination thereof, across the at least one set of electrodes.

56. A system as in claim 55, wherein the system comprises means for estimating a time interval between mammalian pulses, means for determining an average impedance using the bridge, and means for automatically balancing the bridge via a feedback loop by adjusting at least two resistive components of the bridge, the feedback loop having a loop response time at least as large as the time interval between pulses.

57. The system according to claim 55, wherein the system further comprises means for estimating a time interval between mammalian pulses, means for determining a time variation of said impedance using a bridge, means for auto-balancing the bridge through a feedback loop having a loop response time at least as large as the time interval between pulses, and means for determining a time variation of bridge imbalance.

58. The system of claim 33, wherein one or more of the average diameter, the elasticity-related component, and the vessel dilation of the blood vessel is determined based on a determination of at least one impedance parameter selected from the group consisting of average impedance, minimum impedance, maximum impedance, temporal change in impedance, change in impedance over time, or any combination thereof across a set of electrodes.

59. The system of claim 33, wherein calculating at least one cardiovascular component from the mean diameter of the blood vessel, the elasticity-related component, and the vasodilation determined at the measurement site comprises calculating one or more of a blood pressure differential, a systolic pressure, a diastolic pressure, and a vascular compliance.

60. The system of claim 33, further comprising means for determining at least one other dimension of the blood vessel at the measurement site, the dimension selected from the group consisting of vessel wall thickness, maximum diameter of the blood vessel, minimum diameter of the blood vessel, temporal change in diameter of the blood vessel, and change in diameter of the blood vessel over time.

61. The system of claim 33, wherein the system further comprises means for determining a pulse rate.

62. The system of claim 33, wherein the system is non-invasive.

63. The system of claim 33, wherein the system does not apply pressure to the blood vessel.

64. The system of claim 33, further comprising means for determining one or more selected from pulse magnitude, pulse pressure, and pulse rate by applying a back pressure for calibration purposes.