Estimation of hemodynamic parameters

Abstract

Apparatus and methods for estimating one or more hemodynamic parameters, such as cardiac output or stroke volume. Embodiments are based on the concept of incorporating information about vascular tone into the estimation of the hemodynamic parameters to improve accuracy. More specifically, embodiments use a measurement of the time it takes a blood pulse to travel from the heart along a specific length of an arterial pathway as a surrogate measure of vascular tone and incorporate this into the estimation of the hemodynamic parameters. Embodiments are also based on incorporating surrogate measurements of vascular tone for multiple different arterial pathways to account for variations in vascular tone between different parts of the circulatory system.

Description

[Technical Field]

[0001] The present invention relates to an apparatus and method for estimating one or more hemodynamic parameters. [Background technology]

[0002] To assess hemodynamic stability, it is important to measure and monitor various hemodynamic parameters, including central hemodynamic parameters such as cardiac output (CO), stroke volume (SV), and their changes over time.

[0003] Cardiac output (CO) is defined as the volume of blood pumped by the heart per minute [liters / min] and is therefore influenced by two factors: heart rate (HR) [beats / min] and stroke volume (SV), where stroke volume is the volume of blood pumped from the left ventricle of the heart into the aorta with each beat [L / beat].

[0004] Central hemodynamic parameters such as those listed above can be measured invasively or non-invasively. Typically, this involves obtaining a measure of blood flow in one or more arteries. Blood flow (blood flow), Q, is defined as the amount of blood flowing through a blood vessel per unit time. This can be expressed mathematically as Q=vA, where Q is the blood flow rate (ml / s) at a location along an arterial pathway, v is the blood flow velocity (cm / s) at that location, and A is the cross-sectional area of the blood vessel at that location (cm 2 )

[0005] A variety of non-invasive measurement methods exist, including the use of ultrasound sensing means to measure blood flow through major arteries using, for example, Doppler ultrasound. Other methods of measuring blood flow are also known, such as using blood pressure measurements to indirectly determine blood flow.

[0006] As shown schematically in Figure 1, in known methods, blood flow is typically measured (in one artery) in one of the branches 14a-14n of the vascular tree, and this blood flow measurement can then be used to estimate one or more hemodynamic parameters. This can be done, for example, by using a predetermined algorithm or transfer function that takes the blood flow measurement as an input and provides a hemodynamic parameter estimate as an output. Figure 1 schematically illustrates blood flow from a heart 12 through various arterial branches 14a-14n of the circulatory system. The volumetric blood output from the heart at each heartbeat is the stroke volume (SV), and the volumetric output per minute is the cardiac output (CO). Summary of the Invention [Problem to be solved by the invention]

[0007] Although such methods are simple and fast, they are known to lack accuracy. Obtaining blood flow measurements only in a single branch of the arterial system can lead to inaccurate estimation of hemodynamic parameters, since flow rates may differ in different arterial branches. Furthermore, known estimation methods cannot take into account differences in autoregulation and vasoconstriction properties that exist for different arterial branches.

[0008] Therefore, improved methods for obtaining non-invasive estimates of hemodynamic parameters would be of value in this field. [Means for solving the problem]

[0009] The invention is defined by the claims.

[0010] According to an example according to an aspect of the present invention, there is provided a controller configured to determine an estimate of at least one hemodynamic parameter of a subject, the controller comprising: - receiving an input indicative of an arterial blood flow measurement in at least one arterial pathway of the subject, wherein the arterial pathway is a central arterial pathway or a peripheral arterial pathway; - obtaining, for each of the central and peripheral arterial pathways, a measure indicative of the time difference T between a cardiac ejection event and the arrival of a corresponding pulse wave at a predetermined location along each arterial pathway as a result of blood flow from the heart to that location; - determining an estimate of the hemodynamic parameter based on a combination of the blood flow measurements from the at least one arterial pathway and the time difference measure ΔT for each of the central and peripheral arterial pathways; It is configured as follows.

[0011] Embodiments of the present invention are based on the insight that known approaches to estimating hemodynamic parameters, such as cardiac output or stroke volume, can be improved by considering vascular tone in different branches of the arterial system. Vascular tone refers to the degree of constriction a blood vessel undergoes relative to its maximally dilated state at a given time. All arterial and venous blood vessels (under normal conditions) exhibit a degree of smooth muscle contraction, which determines the vessel's diameter and therefore tone. Vascular tone in any given local region can change at any time depending on the hemodynamic state and is regulated by competing vasoconstrictor and vasodilator nerve influences. The function of changes in vascular tone is twofold: to globally regulate arterial blood pressure in the body and to regulate local vascular flow within an organ. Thus, vascular tone in an arterial pathway at any given time affects measurable hemodynamic parameters, such as cardiac output and stroke volume. Furthermore, vascular tone varies in different arterial pathways, and accurate estimation of hemodynamic parameters should take this variation into account.

[0012] Vascular tone is difficult to measure directly. Embodiments of the present invention are based on the understanding that the time it takes for blood to travel from the heart along a predetermined length of an arterial pathway depends on the vascular tone of that pathway. The two are correlated. In light of this, it is the inventors' understanding that this duration can be used as a surrogate measure for vascular tone in a given arterial pathway.

[0013] There are two standard clinical measurements that provide an indication of this duration: pulse arrival time (PAT) and pulse transit time (PTT), and certain embodiments of the present invention utilize these clinical measurements to derive a ΔT measurement. However, the use of these standard measurements is not required to derive a ΔT measurement.

[0014] Thus, in summary, embodiments of the present invention are based on integrating information about vascular tone of different arterial pathways in the circulatory system into the determination of central hemodynamic parameters to improve the accuracy of these parameters. A surrogate measure of vascular tone is estimated by calculating the time it takes blood to travel along a length of one or more arterial pathways (e.g., pulse arrival time (PAT) or pulse transit time (PTT)). This measure can then be combined with arterial blood flow measurements for at least one arterial pathway (preferably the central arterial pathway) and integrated into an algorithm or calculation or transfer function to determine one or more hemodynamic parameters.

[0015] This allows the calculation to be sensitive to different autoregulation in different arterial pathways, including dynamic changes in vascular tone, resulting in more accurate estimates of central hemodynamic parameters, which allows for improved clinical decision-making and medical intervention, and therefore improved medical outcomes for patients.

[0016] The blood flow measurement is a measure of the volumetric blood flow per unit time at a measurement location in the arterial pathway. In other words, the blood flow measurement is a measure of the amount of blood flowing through the arterial pathway (e.g., flowing past a measurement location in the arterial pathway) per unit time. This can be expressed mathematically as Q=vA, where Q is the blood flow rate (ml / s) at a location along the arterial pathway, v is the blood velocity (cm / s) at that location, and A is the cross-sectional area of the blood vessel at that location (cm 2 )

[0017] The controller can be configured to provide the blood flow measurements for the at least one arterial pathway and a measure indicative of the time difference T for both the central arterial pathway and the peripheral arterial pathway, or a parameter derived from the measure, as inputs to a predetermined transfer function, the transfer function configured to generate an estimate of the at least one hemodynamic parameter based on the inputs.

[0018] In other words, the controller is configured to process the blood flow measurements for the at least one arterial pathway and the time difference measures T, or parameters derived therefrom, for both the central and peripheral arterial pathways using the transfer function to generate an estimate of the at least one hemodynamic parameter.

[0019] The transfer function can define or embody a predetermined functional relationship between the input and the at least one hemodynamic parameter, and the transfer function can generate the hemodynamic parameter based on the predetermined functional relationship and the input.

[0020] The transfer function may be a classical algorithmic function and / or a machine learning model in some examples. The transfer function may have a linear function of the inputs. In some examples, the transfer function may be a multi-parametric linear regression model that models the target hemodynamic parameter as a linear sum of each of the input parameters, with each input parameter weighted by a corresponding weighting factor.

[0021] The controller is preferably configured to generate a data output indicative of the estimated value of the at least one hemodynamic parameter. This data output may be a data packet containing data representative of the estimate, or a series of values of the estimate derived over a period of time, ready for export of data, for example, to a data store or a user interface, or along a network communication channel. The method may include transmitting the data output to another module or device, for example a user interface.

[0022] In an advantageous embodiment, ultrasound monitoring techniques can be used to detect the blood flow and / or ΔT parameters, for example, Doppler ultrasound can be used to obtain blood flow measurements.

[0023] The inputs of the at least one blood flow measurement and the ΔT measurement can be combined using a predetermined function, equation, or algorithm to determine at least one hemodynamic parameter. A machine learning engine can also be used to derive the hemodynamic parameter from the above inputs. These various approaches will be broadly referred to herein as transfer functions.

[0024] For example, a predetermined or pre-stored function (transfer function) can be used that embodies a predetermined functional relationship between the above inputs and is capable of calculating at least one hemodynamic parameter based on these inputs. The transfer function can simply be a mathematical relationship between some input parameters and a central hemodynamic parameter that serves as an output.

[0025] To derive such a transfer function, machine learning and / or statistical methods can be applied to, for example, a labeled data set. For example, multiparametric regression has been successfully used in studies to estimate such transfer functions using clinical data sets. With sufficient data, the transfer function can also be improved using patient metadata, such as gender, BMI, and other patient personal information.

[0026] An arterial pathway refers, for example, to a longitudinal section of a particular length along one or more arteries of the circulatory system.

[0027] Peripheral arterial access refers to arterial access in the peripheral vascular system, ie, in the portion of the circulatory system consisting of arteries other than those in the head, chest, or abdomen (eg, in the arms, hands, legs, and feet).

[0028] By central arterial pathway is meant a pathway in the central vascular system, ie, an artery in the head, chest, abdomen or neck, for example.

[0029] Preferably, the blood flow measurements may be derived from at least a central arterial pathway, such as a carotid artery. However, the measurements may also be derived from other arterial pathways, including peripheral arterial pathways. In some instances, blood flow measurements may be derived from both peripheral and central arterial pathways. The at least one arterial pathway from which the blood flow measurements are derived is preferably one of the same two arterial pathways (central and peripheral) from which the ΔT measurements are derived.

[0030] Cardiac ejection event (cardiac ejection event) refers to an event corresponding to the ejection of blood from the heart, i.e., a cardiac event (i.e., cardiac systole). This event may be a defined reference point in the process of blood ejection, for example, during the systole of the cardiac cycle, such as the end of the pre-ejection period when the aorta opens and blood begins to be ejected from the left ventricle. In another example, the event may be the beginning of the pre-ejection period when the heart is first electrically activated and begins to contract.

[0031] The act of obtaining the measure indicative of the time difference, ΔT, may include receiving, at the controller, an input indicative of the time difference for each of two arterial pathways. In other examples, the act may include a processing or calculating step. For example, the controller may be configured to receive, for each arterial pathway, a signal input indicative of the detection of a pulse wave arrival at a predetermined location along the arterial pathway and an input indicative of the detection of an ejection event, and to determine a time, ΔT, for each arterial pathway.

[0032] Although the above description and examples herein refer to two arterial pathways, in other embodiments, ΔT time differences may be determined for more than two arterial pathways. Blood flow measurements may be obtained for more than two arterial pathways, or even for more than two arterial pathways. In this case, the controller may be configured to determine at least one hemodynamic parameter based on a combination of the ΔT values and blood flow measurements for all arterial pathways.

[0033] The act of determining the hemodynamic parameter may be based on the use of a predetermined transfer function or algorithm. By transfer function, we mean a function that takes as input at least one blood flow measurement and ΔT measurement for two or more arterial pathways and calculates as output an estimate of at least one hemodynamic parameter. The transfer function may simply be a mathematical relationship between some input parameters and a central hemodynamic parameter that serves as an output. This has been explained above and will be further explained below.

[0034] The transfer function may include a machine learning algorithm. Various implementation options in this regard will be described in detail below.

[0035] The transfer function may be stored, for example, locally on a memory included in the controller or operably coupled to the controller, and in some instances may be implemented by programming the controller itself.

[0036] According to one set of examples, obtaining the time difference measure for each arterial pathway may include obtaining a pulse arrival time (PAT) measurement for each arterial pathway.

[0037] The ejection event in this case may correspond to the point of electrical activation of the heart, which corresponds to the beginning of the pre-ejection period when the heartbeat first begins.

[0038] By way of example, the event can be detected as the time of occurrence of a QRS complex in an ECG signal. The event may correspond to the time of occurrence of a particular reference point within the QRS complex, such as one of the Q, R, and S peaks (e.g., the R peak, which is the largest peak). This may correspond to the time of occurrence of the start of the QRS complex.

[0039] However, the use of an ECG to detect this event is not essential and other means such as the use of an accelerometer, inductive sensing means or radar sensing means could be used instead.

[0040] In some approaches, PAT can be measured using ECG (electrocardiography) and PPG (photoplethysmography) sensor measurements. ECG can be used to detect the onset of the QRS complex as the start of the heart's electrical activation, and PPG can be used to detect the onset of the pulse wave at a downstream location along the arterial pathway via optical measurement of blood volume. Both measurements are standard in clinical practice.

[0041] According to one or more embodiments, obtaining a time difference measure ΔT for each arterial pathway may include obtaining a pulse transit time (PTT) measurement for each arterial pathway. Pulse transit time is the time between ejection of blood into the aorta and the arrival of a corresponding pulse wave at a downstream measurement location. In other words, it is the time between the end of the pre-ejection period (PEP) and the arrival of a pulse wave at a predetermined location along the arterial pathway.

[0042] In some embodiments, obtaining the PTT measurement for each arterial line may include obtaining a PAT measurement for each arterial line, obtaining an estimate of a pre-ejection period (PEP) duration, and determining the PTT measurement for each arterial line by subtracting the PEP duration from the PAT measurement for each arterial line.

[0043] Pre-ejection period (PEP) is a term in the art that refers to the period measured from the electrical activation of the heart (e.g., indicated by the QRS complex in an ECG signal) to the ejection of blood from the heart into the aorta. This is the time between the electrical activation of the heart and the opening of the aortic valve.

[0044] Thus, the pulse arrival time (PAT) is related to the PEP by PAT=PEP+PTT, where PTT is the pulse propagation time.

[0045] There are various ways to obtain an estimate of PEP.

[0046] According to one set of examples, an estimate of PEP duration can be derived based on the use of inputs from phonocardiogram (PCG) sensing means and / or impedance cardiogram (ICG) measuring means. For example, the opening of the aortic valve and the ejection of blood each produce a characteristic high-pitched sound: a snap for opening and a click for ejection. One or both of these can be identified in PCG measurements occurring after the first heart sound. This can be used, for example, to detect the time of the ejection event.

[0047] Furthermore, ICG and ECG can additionally or alternatively be used together to directly identify PEP. A method for doing this is described in detail in the article "Estimated Preejection Period (PEP) Based on the Detection of the R-wave and dZ / dt-min Peaks in ECG and ICG" by Ren Y. van Lien, Nienke M. Schutte, Jan H. Meijer, and Eco J.C. de Geus, 18 April 2013, IOP Publishing Ltd.

[0048] Measurements from these sensing modalities can be used to identify the moment the aortic valve opens. From this, the time between the electrical activation of the heart (e.g., the onset of the QRS complex or other reference point in an ECG measurement) and the opening of the aortic valve (at which point the pressure wave begins to travel along the arterial system) can be determined. This period corresponds to the pre-ejection period.

[0049] In another example, the controller may use a predetermined estimate or reference value for the pre-ejection period, which may be stored, for example, in local memory or retrieved from a remote data source such as a remote server.

[0050] According to one or more embodiments, the hemodynamic parameter may be determined based on the variation of a time difference value ΔT over time for each arterial pathway. For this set of embodiments, the controller may be configured to obtain multiple time difference measurements ΔT for each of the arterial pathways corresponding to different cardiac cycles, determine a measure indicative of the variation of the ΔT values over time for each arterial pathway, and determine an estimate of the hemodynamic parameter based on the variation of the ΔT values.

[0051] According to one or more embodiments, determining the estimate of the hemodynamic parameter includes determining a quotient between the ΔT values for the peripheral and central pathways. In other words, the estimate of the hemodynamic parameter can be based on the quotient ΔT_cen / ΔT_peri, where ΔT_cen is the value of the time difference ΔT for the central arterial pathway and ΔT_peri is the value of the time difference ΔT for the peripheral arterial pathway. The quotient can be calculated in the opposite manner in other examples, i.e., ΔT_peri / ΔT_cen.

[0052] Detection of changes or fluctuations in vascular tone surrogate measures (ΔT values) and / or their ratios (in the case of multiple surrogate measures) indicates changes in the (relative) tone of the measured branch of the vascular tree. These changes may indicate both local and more systemic changes in vascular tone of the arterial system. Incorporating these measurements into the calculation of hemodynamic parameters provides more accurate estimates.

[0053] The at least one hemodynamic parameter calculated by the controller may include at least one of cardiac output, stroke volume, and stroke volume variation (SVV). Other examples of hemodynamic parameters that may be derived include blood flow velocity, stroke volume variation, systolic velocity, diastolic velocity, and blood pressure.

[0054] The details of the transfer function may vary depending on the hemodynamic parameter to be derived. The transfer function may embody a mathematical relationship between input parameters and an output hemodynamic parameter. Thus, for different target hemodynamic parameters, this relationship, e.g., the weights applied to different inputs in the calculation, and possibly the inputs used to calculate it (e.g., if there are additional inputs in addition to blood flow and T measurements), may be different.

[0055] The controller may be configured to obtain at least one metric indicative of the blood flow measurement using ultrasound sensing means, which may comprise one or more ultrasound transducers, for example an ultrasound transducer unit or probe configured to generate ultrasound pulse emissions and detect reflected ultrasound echo signals.

[0056] The ultrasound sensing means may output ultrasound data to the controller or may output calculated blood flow measurements directly to the controller. The ultrasound sensing means may acquire Doppler ultrasound data. The ultrasound sensing means may in some instances further comprise a dedicated ultrasound processing unit to extract one or more blood flow measurements from the acquired ultrasound data and provide these to the controller to estimate hemodynamic parameters.

[0057] Advantageously, to monitor blood flow in an artery, a wearable ultrasound sensor can be used that is placed on at least one arterial pathway, such as the carotid artery, thereby measuring the blood flow through the arterial pathway.

[0058] It should be noted that the use of ultrasound in the context of the present invention is particularly advantageous because ultrasound sensing has the versatility to obtain a wide range of different information and is completely non-invasive. Furthermore, these ultrasound-based features can be combined in several ways in accordance with one or more embodiments to provide meaningful information, such as blood flow waveforms, which are the product of cross-sectional area and velocity waveforms.

[0059] For example, in the context of embodiments of the present invention, ultrasound-based measurements can be obtained using pulse wave Doppler ultrasound measurements, which can be used to generate a (blood flow) velocity waveform from which useful features can be extracted, such as peak systolic velocity, maximum velocity, and many others.

[0060] Relevant information can also be derived from B-mode ultrasound data or measurements, which can be used, for example, to derive waveforms of vessel diameter.

[0061] However, the use of ultrasound is not required, for example an alternative to the use of ultrasound is to obtain blood flow measurements indirectly using blood pressure measurements, as will be explained in more detail below.

[0062] According to one or more embodiments, the controller may be configured to obtain, for at least one of the arterial pathways, both a measure of arterial flow and a measure of pulse wave arrival time at predetermined locations along the arterial pathway using the same single ultrasound sensing means. In this way, the same components can be used for the dual functions of detecting pulse wave arrival and measuring blood flow. This therefore limits the total number of parts.

[0063] The controller can be configured to detect, for at least one of the arterial pathways, the arrival time of a pulse wave at a predetermined location along the arterial pathway using a PPG sensor. For example, the peripheral arterial pathway can be an arterial pathway extending along the subject's arm, and a PPG sensor attached to the subject's finger can be used to detect the arrival of a pulse wave at the subject's finger. This is merely an example, provided for illustrative purposes only and is not intended to be limiting.

[0064] According to some examples, the aforementioned ejection event may be the moment of electrical activation of the heart corresponding to the onset of the pre-ejection period.

[0065] In some alternatives, the ejection event may correspond to the end of the pre-ejection period.

[0066] The controller may be configured to detect the occurrence of an ejection event using an ECG sensor input.

[0067] For example, if the ejection event is at a time corresponding to the beginning of the pre-ejection period, detecting the occurrence of the ejection event may include detecting the time at the beginning of the QRS complex in the ECG signal.

[0068] The use of an ECG is just one exemplary means. Alternative means for detecting the occurrence of an ejection event include the use of an inductive sensor, a radar sensor, an accelerometer, or a heart rate sensor such as a chest heart rate sensor band.

[0069] An example according to one or more embodiments further provides an apparatus for deriving an estimate of at least one hemodynamic parameter, the apparatus comprising: - first sensor means for detecting a cardiac ejection event; - second sensor means coupled to a location along the subject's arterial pathway for detecting the arrival time of a blood pulse wave from the heart at said location; - third sensor means for detecting blood flow through said arterial pathway; and - a controller according to any example or embodiment described above or below or according to any claim of the present application, operatively coupled to said first, second and third sensor means; It has.

[0070] The first, second and third sensor means may correspond to different sensor devices, or one or more of the sensor means may correspond to the same sensor device. The first sensor means may in some instances be an ECG sensor device. The second sensor means may comprise a PPG sensor for optically coupling to said location. The third sensor means may be an ultrasonic sensing means.

[0071] Thus, at least one group of embodiments comprises: - ECG sensor device for detecting cardiac ejection events; - at least one PPG sensor for optically coupling to a location along the arterial pathway of the subject and detecting the arrival time of a blood pulse wave from the heart at said location; - ultrasonic sensing means for detecting blood flow through at least one arterial pathway; and - a controller according to any example or embodiment described above or below or according to any claim of the present application, operatively coupled to said ECG sensor device, at least one PPG sensor and ultrasound sensing means; The device may include an apparatus for deriving an estimate of at least one hemodynamic parameter having:

[0072] As mentioned above and further explained below, there are alternative sensor means to these.

[0073] The ultrasound sensing means may comprise an ultrasound transducer arrangement, may be configured to detect blood flow using Doppler ultrasound measurements, and may include a dedicated ultrasound processing unit to extract one or more blood flow measurements from the acquired ultrasound data and provide these to the controller for use in estimating hemodynamic parameters.

[0074] An example according to another aspect of the present invention provides a computer-implemented method for determining an estimate of at least one hemodynamic parameter, the method comprising: - receiving an input indicative of an arterial flow measurement for at least one arterial pathway of the subject, the arterial pathway being a central arterial pathway or a peripheral arterial pathway; - obtaining, for each of the central and peripheral arterial pathways, a measure indicative of the time difference T between a cardiac ejection event and the arrival of a corresponding pulse wave at a predetermined location along each arterial pathway as a result of blood flow from the heart to that location; and - determining an estimate of the hemodynamic parameter based on a combination of blood flow measurements of the at least one arterial pathway and a time difference measure ΔT for each arterial pathway; It has.

[0075] The determining step may include, for example, providing the blood flow measurements for the at least one arterial pathway and a measure indicative of the time difference ΔT for both the central and peripheral arterial pathways, or a parameter derived from the measure, as inputs to a predetermined transfer function configured to generate an estimate of the at least one hemodynamic parameter based on the inputs and a predetermined functional relationship between the inputs and the at least one hemodynamic parameter.

[0076] The method preferably further comprises generating a data output indicative of an estimate of said at least one hemodynamic parameter.

[0077] The present invention also provides a computer program product including a computer-readable medium having computer-readable code embodied therein that is configured, when executed by a suitable computer or processor, to cause the computer or processor to perform a method according to any example or embodiment described above or below, or according to any claim of the present application.

[0078] These and other aspects of the invention will be apparent from and elucidated with reference to the embodiments described hereinafter.

[0079] For a better understanding of the present invention, and to show more clearly how the same may be carried into effect, reference will now be made, by way of example only, to the accompanying drawings in which: [Brief explanation of the drawings]

[0080] [Figure 1] FIG. 1 shows a schematic representation of blood flow through different branches of the arterial system. [Figure 2] FIG. 2 shows a schematic diagram of the general concept of the present invention. [Figure 3]FIG. 3 illustrates a schematic diagram of an exemplary controller processing workflow in accordance with one or more embodiments. [Figure 4] FIG. 4 illustrates a schematic processing workflow according to another exemplary embodiment. [Figure 5] FIG. 5 illustrates a schematic processing workflow according to another exemplary embodiment. [Figure 6] FIG. 6 illustrates a schematic processing workflow according to another exemplary embodiment. [Figure 7] FIG. 7 illustrates a schematic diagram of an exemplary apparatus according to one exemplary embodiment. [Figure 8] FIG. 8 illustrates, in block diagram form, an exemplary method according to one or more embodiments. DETAILED DESCRIPTION OF THE INVENTION

[0081] The present invention will now be described with reference to the drawings.

[0082] It should be understood that the detailed description and specific examples, while indicating exemplary embodiments of the devices, systems, and methods, are for purposes of illustration only and are not intended to limit the scope of the invention. These and other features, aspects, and advantages of the devices, systems, and methods of the present invention will become better understood from the following description, appended claims, and accompanying drawings. It should be understood that the figures are schematic only and are not drawn to scale. It should also be understood that the same reference numerals are used throughout the figures to indicate the same or similar parts.

[0083] The present invention provides devices and methods for noninvasively estimating one or more hemodynamic parameters, such as cardiac output or stroke volume. Embodiments are based on incorporating information about vascular tone into the estimation of the hemodynamic parameters to improve accuracy. More specifically, embodiments use a measurement of the time (duration) ΔT of a blood pulse wave traveling from the heart along a specific length of arterial pathway as a surrogate measure of vascular tone and incorporate this into the estimation of the hemodynamic parameters. Embodiments are also based on incorporating surrogate measurements of vascular tone for multiple different arterial pathways to account for vascular tone variations between different parts of the circulatory system.

[0084] Known methods for estimating hemodynamic parameters are typically based on obtaining arterial flow measurements in a single artery, such as the neck, and deriving an estimate of a central hemodynamic parameter (such as cardiac output or stroke volume) using a transfer function incorporating an algorithm or formula that can calculate the hemodynamic parameter estimate from the flow measurement input.

[0085] However, such estimation methods typically assume that arterial flow at a single location represents the total arterial flow in the entire vascular tree. However, this assumption is inaccurate. As a result, currently known methods for estimating hemodynamic parameters fail to take into account different autoregulatory states in different parts of the circulatory system. For example, variations in vascular tone arise from both systemic global factors (e.g., blood pressure regulation) that affect the entire circulatory system and local factors, such as local regulation of blood flow in specific organs. Therefore, a more accurate estimation of hemodynamic parameters preferably takes into account possible changes in factors such as vascular tone in different parts of the circulatory system. For example, differences in these factors can be expected to exist between the central and peripheral parts of the circulatory system.

[0086] To illustrate this, consider the case where a measure of blood flow in the carotid arteries (central arterial system) is obtained and used to estimate total cardiac output (CO). The body regulates blood flow through the carotid arteries to provide the brain with sufficient oxygen and nutrients. However, at the same time, blood flow to peripheral regions, such as the arm, may also increase or decrease due to certain events, such as arm movement or strain. This causes total CO to increase or decrease accordingly. However, this cannot be detected by any change in blood flow through the carotid arteries, because blood flow through the carotid arteries is regulated according to cerebral demand. Thus, an accurate estimate of total CO cannot be obtained from central (carotid) arterial flow measurements alone.

[0087] However, by also taking into account peripheral measurements (such as peripheral PAT or PTT), variations in blood output to peripheral regions can be detected and combined with central arterial flow measurements to improve the estimation of total CO. It is this principle on which embodiments of the present invention are based.

[0088] According to an example according to an aspect of the present invention, there is provided a controller adapted to derive an estimate of at least one hemodynamic parameter of a subject, the controller comprising: - receiving an input indicative of an arterial flow measurement in at least one arterial pathway of the subject, wherein the arterial pathway is a central arterial pathway or a peripheral arterial pathway; - for each of the central and peripheral arterial pathways, obtaining a measure indicative of the time difference ΔT between a cardiac ejection event as a result of blood flow from the heart to a given location along each arterial pathway and the arrival of a corresponding pulse wave at that location; and - determining an estimate of a hemodynamic parameter based on a combination of the blood flow measurement of the at least one arterial pathway and the time difference measure ΔT for each arterial pathway; It is configured as follows.

[0089] The embodiments aim to correct the inaccurate assumption that flow through one branch of the vascular tree represents flow through all other branches. The embodiments are based on obtaining longitudinal surrogate measures of vascular tone in at least two branches of the vascular tree. By incorporating these measurements into the calculation of hemodynamic parameters, more accurate estimates can be obtained.

[0090] Vascular tone is difficult to measure directly. Embodiments of the present invention are based on the understanding that the time it takes for blood to travel from the heart along a predetermined length of an arterial pathway (in other words, how quickly the heart beats through the branches of the vascular tree) is closely dependent on the vascular tone of that arterial pathway. The two are correlated. In this regard, this travel time can be used as a surrogate measure of vascular tone in the arterial pathway.

[0091] Thus, in summary, embodiments of the present invention are based on integrating information about the vascular tone of different arterial pathways in the circulatory system into the determination of central hemodynamic parameters to improve the accuracy of these parameters. This information is combined with blood flow information and provided as input to a transfer function that generates as output an estimate of the hemodynamic parameter, such as cardiac output.

[0092] This general principle is illustrated diagrammatically in Figure 2. Embodiments of the present invention are based on combining information related to vascular tone (or indirectly indicative of vascular tone) with information related to blood flow and feeding it into, for example, a hemodynamic transfer function that is configured to generate as output, an estimate of one or more hemodynamic parameters based on the input information.

[0093] According to one or more embodiments, a surrogate measure of vascular tone can be estimated by calculating the time it takes blood to travel along the length of one or more arterial pathways (e.g., pulse arrival time (PAT) or pulse transit time (PTT)). This measure can then be combined with at least arterial blood flow measurements (preferably for at least the central arterial pathways, but optionally for the peripheral pathways instead) and integrated into an algorithm or calculation (transfer function) to determine one or more hemodynamic parameters.

[0094] This allows the calculation to be sensitive to differential autoregulation in different arterial pathways, including dynamic changes in vascular tone, resulting in more accurate estimates of central hemodynamic parameters, which allows for improved clinical decisions and medical interventions, and therefore improved medical outcomes for patients.

[0095] An arterial pathway refers to a longitudinal section of a particular length, for example along one or more arteries of the circulatory system.

[0096] Peripheral arterial pathway refers to the arterial pathway in the peripheral vasculature, ie, the portion of the circulatory system consisting of arteries not in the head, chest, or abdomen (eg, in the arms, hands, legs, and feet).

[0097] By central arterial pathway is meant a pathway in the central vascular system, ie, an artery in the head, chest, abdomen or neck, for example.

[0098] A cardiac ejection event (event) refers to an event corresponding to the ejection of blood from the heart, i.e., a cardiac event (i.e., cardiac systole). The event may be a defined reference point during the blood ejection process, such as the end of the pre-ejection period when the aorta opens and blood begins to be ejected from the left ventricle. In another example, the event may be the beginning of the pre-ejection period when the heart is first electrically activated and begins to contract.

[0099] Although two arterial pathways are mentioned in the above description and examples herein, in other embodiments, ΔT time differences can be determined for more than two arterial pathways. Blood flow measurements can be obtained for more than two arterial pathways, or even more than three arterial pathways. In this case, the controller can be configured to determine at least one hemodynamic parameter based on a combination of the blood flow measurements and ΔT values for all of these arterial pathways.

[0100] The general principles of the present invention are illustrated diagrammatically in FIG. 3 , which schematically illustrates an exemplary controller 22 that receives a set of inputs 23, performs computations using the inputs, and generates at least one output corresponding to an estimate of at least one hemodynamic parameter 24. In particular, the controller 22 receives a set of inputs related to a central arterial pathway, a set of inputs related to a peripheral arterial pathway, and at least one blood flow measurement input corresponding to blood flow through at least one of the central arterial pathway and the peripheral arterial pathway. Preferably, the measurements are central arterial pathway measurements. In other examples, blood flow measurements related to both the central arterial pathway and the peripheral arterial pathway may be received as inputs. Furthermore, in other embodiments, inputs related to both the central arterial pathway and two or more peripheral arterial pathways may be received. Furthermore, in some embodiments, inputs related to two or more central arterial pathways may be received.

[0101] The inputs for the central arterial pathway include an input indicating the arrival time of a pulse wave at a predetermined location along the central arterial pathway and an input indicating the occurrence time of a cardiac ejection event, which can be used to calculate the time difference ΔT_centr between these two events.

[0102] A similar set of inputs is received for the peripheral arterial pathway. Using the pulse wave arrival time and the time of the cardiac ejection event, the time difference ΔT_peri between these two events can also be calculated for the peripheral arterial pathway.

[0103] Although FIG. 3 shows the controller 22 receiving separate inputs for each of the central and peripheral arterial pathways corresponding to a cardiac ejection event, a single input indicating the occurrence of a cardiac ejection event may also be received by the controller.

[0104] The at least one blood flow measurement (e.g., for the central arterial pathway) and the time difference values ΔT_centr and ΔT_peri are then used by controller 22 in deriving hemodynamic parameter 24. Illustratively, the hemodynamic parameter may be, by way of non-limiting example, the subject's cardiac output (CO), the subject's stroke volume (SV), the subject's stroke volume variability (SVV), or the subject's stroke volume index (SVI).

[0105] Determining the estimate of the hemodynamic parameter 24 may be based on the application of a predetermined algorithm or calculation function by the controller. For example, the controller 22 may apply a predetermined transfer function 21 configured to receive as input at least one flow measurement and a time difference value ΔT of two or more arterial pathways and to generate an output indicative of one or more hemodynamic parameter estimates based on these inputs. By way of example, the transfer function 21 is shown schematically in FIG. 3. As previously mentioned, the ΔT values provide surrogate measures of vascular tone in each of the two arterial pathways, which may enable the algorithm or calculation or transfer function applied by the controller 22 to derive a more accurate hemodynamic parameter estimate 24.

[0106] For example, a predetermined or pre-stored function (transfer function) 21 can be used that embodies a predetermined functional relationship between inputs and can calculate at least one hemodynamic parameter based on the inputs. The transfer function can simply be a mathematical relationship between some input parameters and a central hemodynamic parameter that serves as an output. The transfer function can comprise a machine learning algorithm or engine trained using labeled data to derive a particular hemodynamic parameter based on input blood flow and T measurements.

[0107] To derive a transfer function, machine learning and / or statistical methods can be applied to, for example, a labeled data set. For example, multiparametric regression has been successfully used in tests to estimate such transfer functions based on clinical data sets. With sufficient data, the transfer function can also be improved using patient metadata, such as gender, BMI, and other patient personal information. Other approaches to providing a transfer function can include, for example, using support vector machines or naive Bayes models.

[0108] By way of example, the transfer function, according to one or more embodiments, can include any type of machine learning algorithm, such as a logistic regression model, a decision tree algorithm, an artificial neural network, a support vector machine, or a naive Bayesian model, or any other type of machine learning algorithm that is trained using a training dataset that includes previously acquired data for one or more patients.

[0109] Methods for training machine learning algorithms are well known. Typically, such methods involve acquiring a training data set including training input data entries and corresponding training output data entries. The training input data entries in this case would be acquired inputs for the transfer function, i.e., ΔT, PAT, PTT, or ΔPAT values measured for each of at least two arterial pathways and at least one blood flow measurement. In some embodiments, additional inputs may also be included. The training output data entries would correspond to the desired hemodynamic parameters, such as cardiac output, stroke volume, and / or stroke volume variation. To construct the training data, the hemodynamic parameters are measured manually, e.g., using invasive methods, to ensure accuracy when acquiring the training data entries.

[0110] An initialized machine learning algorithm is applied to each input data entry to generate a predicted output data entry. The error between the predicted output data entry and the corresponding training output data entry is used to modify the machine learning algorithm. This process can be repeated until the error converges and the predicted output data entry is sufficiently similar to the training output data entry (e.g., within 1%). This is typically known as a supervised learning approach.

[0111] The resulting trained algorithm can provide the required transfer function according to one or more embodiments.

[0112] There are various ways to obtain a set of inputs for two or more arterial pathways. In particular, there are various ways to obtain arterial flow measurements for at least one arterial pathway of a subject and to obtain a measure indicative of the time difference ΔT between a cardiac ejection event and the arrival of a corresponding pulse wave at a predetermined location along each of the two arterial pathways. For example, various sensor modalities can be used to derive these measurement inputs.

[0113] Various possible means or approaches for obtaining these measurement inputs will be briefly outlined in general terms, followed by a series of more detailed embodiments.

[0114] By way of example, obtaining a time difference measure for each arterial pathway may include obtaining a pulse arrival time (PAT) measurement for each arterial pathway.

[0115] The ejection event in this case may correspond to the time of electrical activation of the heart, which corresponds to the start of the pre-ejection period when the heartbeat first begins.

[0116] The ejection event can be detected using an ECG sensor. By way of example, this can be detected as the time of occurrence of the onset of the QRS complex in the ECG signal. However, the use of an electrocardiogram to detect this event is not required, and other means can be used instead. Alternatives include the use of an inductive sensor, a radar sensor, an accelerometer, or a heart rate sensor such as a chest heart rate sensor band.

[0117] The arrival time of a pulse wave at a predetermined location along the arterial pathway can in some instances be detected using a PPG sensor. Alternatively, to detect pulse wave arrival, an ultrasound sensing means, for example an ultrasound transducer unit configured to acquire Doppler ultrasound data at a predetermined pulse arrival location, can be used.

[0118] According to one or more embodiments, obtaining the time difference measure ΔT for each arterial pathway may include obtaining a pulse transit time (PTT) measurement for each arterial pathway. Pulse transit time is the time between ejection of blood into the aorta and the arrival of a corresponding pulse wave at a downstream measurement location. In other words, it is the time between the end of the pre-ejection period (PEP) and the arrival of a pulse wave at a predetermined location along the arterial pathway.

[0119] In some embodiments, obtaining a PTT measurement for each arterial line may include: obtaining a PAT measurement for each arterial line; obtaining an estimate of the duration of the pre-ejection period (PEP); and determining a PTT measurement for each arterial line by subtracting the PEP duration from the PAT measurement for each arterial line.

[0120] Pre-ejection period (PEP) is a term of the art that refers to the period measured from the electrical activation of the heart (e.g., indicated by the QRS complex in an ECG signal) to the ejection of blood from the heart into the aorta. This is the time between the electrical activation of the heart and the opening of the aortic valve.

[0121] Thus, pulse arrival time (PAT) is related to PEP by PAT=PEP+PTT, where PTT is the pulse transit time.

[0122] There are various ways to obtain an estimate of PEP.

[0123] According to one set of examples, an estimate of PEP duration may be derived based on the use of inputs from phonocardiogram (PCG) sensing means and / or impedance cardiogram (ICG) measuring means.

[0124] Measurements from these sensing modalities can be used to identify the point in time when the aortic valve opens. From this, the time between the electrical activation of the heart (e.g., the onset of the QRS complex in an ECG measurement) and the opening of the aortic valve (the point at which the pressure wave begins to travel along the arterial system) can be determined. This period corresponds to the pre-ejection period.

[0125] For example, the opening of the aortic valve and the ejection of blood each produce a high-pitched sound: a snap for opening and a click for ejection, either or both of which occur after the first heart sound and can be identified in PCG measurements, which can be used to detect when an ejection event is occurring.

[0126] Furthermore, ICG and ECG can additionally or alternatively be used together to directly identify PEP. A method for doing this is described in detail in the article "Estimated Preejection Period (PEP) Based on the Detection of the R-wave and dZ / dt-min Peaks in ECG and ICG" by Ren Y. van Lien, Nienke M. Schutte, Jan H. Meijer, and Eco J.C. de Geus, April 18, 2013, IOP Publishing Ltd.

[0127] In another example, the controller may use a predetermined estimate of PEP, which may be stored in local memory, for example, or retrieved from a remote data source, such as a remote server.

[0128] The controller may be configured to obtain a measure indicative of at least one blood flow measurement in the arterial pathway using ultrasound sensing means, which may comprise one or more ultrasound transducers, and which may include, for example, an ultrasound transducer unit or probe.

[0129] The ultrasound sensing means may output ultrasound data to a controller or may output calculated blood flow measurements directly to the controller. The ultrasound sensing means may acquire Doppler ultrasound data. The ultrasound sensing means may in some instances further comprise a dedicated ultrasound processing unit for extracting one or more flow measurements from the acquired ultrasound data and providing these to the controller to estimate hemodynamic parameters.

[0130] The use of ultrasound sensing is just one exemplary means for detecting blood flow; one other alternative is to obtain blood flow measurements indirectly, for example, using blood pressure measurements.

[0131] For example, an estimate of cardiac output can be derived from non-invasive blood pressure measurements. First, a continuous arterial blood pressure waveform is obtained non-invasively from the finger by applying a cuff around the middle phalanx of the finger and applying the well-known volume clamp technique. Using a model, a brachial artery blood pressure waveform can be derived from the measured finger arterial blood pressure waveform. Finally, an estimate of cardiac output can be obtained by applying pulse contour analysis to the brachial artery blood pressure waveform, which can be used to obtain an estimate of blood flow.

[0132] The pulse contour method described above uses, for example, the area under the systolic portion of the blood pressure curve in combination with, for example, the Windkessel model, and optionally, specific patient data such as age, sex, height, and weight, to obtain an estimate of stroke volume. This estimate, when combined with heart rate, provides an indication of cardiac output, from which blood flow information can be derived. This is described, for example, in Truijen et al., "Noninvasive continuous hemodynamic monitoring," J Clin Monit Comput (2012) 26:267-278.

[0133] A series of specific embodiments of the present invention will now be outlined in order to further describe and illustrate the principles of the inventive concepts.

[0134] FIG. 4 shows a schematic processing workflow of a first exemplary set of embodiments.

[0135] According to this set of embodiments, pulse arrival time (PAT) is used as a surrogate measure of vascular tone. In other words, a measure of the time difference ΔT between the cardiac ejection event and the arrival of the pulse wave is obtained by taking PAT measurements for each of the peripheral and central arterial pathways.

[0136] For example, the peripheral arterial pathway may be an arterial pathway extending from the heart down the arm to the fingers, and the central arterial pathway may be an arterial pathway extending from the heart toward the head via a passageway along the neck.

[0137] In operation, a PPG sensor can be placed at a stable location along a peripheral arterial pathway. For example, a finger clip PPG sensor can be used and coupled to a subject's finger. The PPG sensor can be used to detect the arrival time of each pulse wave from the heart to the finger following each ejection event ("Pulse arrival_peri"). This can correspond, for example, to a peak or other characteristic reference point in the PPG sensor output. Exemplary reference points for detection in the raw PPG pulse waveform include, for example, the time of systolic minimum, diastolic maximum, time of maximum systolic slope, or some other characteristic point.

[0138] As another example, pulse arrival at distal locations in the peripheral arterial pathway may be measured by other sensing modalities, such as ultrasound (US) sensors, accelerometers (ACC), or ballistocardiogram measurements.

[0139] An ECG sensing device can be used to detect the time of a cardiac ejection event ("heart ejection"). For example, a set of at least two ECG electrodes can be placed on a subject's chest to sense the heart's electrical activity. These can be attached to a dedicated ECG sensing processor configured to detect electrical signals using the electrodes. Each time the heart contracts (systole) to eject blood from the left ventricle and pump it through the arterial tree, a characteristic electrical signal can be detected in the ECG output. This signal pattern is known as the QRS complex and consists of a characteristic pattern of three peaks: a Q peak, an R peak, and an S peak. Thus, an ejection event can be detected by detecting the QRS complex in the ECG signal, e.g., by detecting the onset of the QRS complex or the time of a particular peak in the QRS complex, such as the R peak (typically the largest peak).

[0140] In some examples, an ultrasound sensing means may also be used and configured to perform ultrasound sensing, for example, in the subject's neck, at a location along the central arterial pathway (e.g., on the carotid artery). The ultrasound sensing means may include one or more ultrasound transducers and a dedicated ultrasound processing unit for processing acquired ultrasound data. The ultrasound data may be Doppler ultrasound data. The arrival time of a pulse wave at a predetermined location along the central arterial pathway ("Pulse arrival_cen") may be detected using the ultrasound sensing means. For example, Doppler ultrasound data provides an indication of blood flow through the arterial pathway, and thus, the arrival of a pulse wave at a predetermined location may be detected by a sudden increase in flow rate or the onset of an upward gradient in flow rate.

[0141] The same ultrasound sensing means can also be used to derive measures of arterial flow through central arterial pathways, for example, by acquiring and processing Doppler ultrasound data.

[0142] As another example, as described in detail above, measures of blood flow may be obtained using different sensing modalities. A measure of blood flow is required from at least one arterial pathway, which is preferably a central arterial pathway, but may alternatively be a peripheral arterial pathway. Optionally, blood flow measurements from both central and peripheral arterial pathways may be obtained and used in deriving estimates of hemodynamic parameters.

[0143] It should be noted that in an alternative example, other PPG sensors, for example placed on the nose, forehead or concha, could be used instead of ultrasound sensors to detect the arrival of pulses at locations along the central arterial pathway.

[0144] Using these acquired measurements, measures of pulse arrival time (PAT) for the central and peripheral arterial pathways are derived. PAT is defined as the time difference between the time of the QRS complex in an electrocardiogram (ECG) signal and the arrival time of the corresponding pulse at a distal location. Thus, the PAT for the central arterial pathway ("PAT_cen") can be derived by calculating the difference between the time of the cardiac ejection event and the time of pulse arrival at a distal point along the central arterial pathway (Pulse arrival_cen). Similarly, the PAT for the peripheral arterial pathway ("PAT_peri") can be derived by calculating the difference between the time of the cardiac ejection event and the pulse arrival time at a distal point along the peripheral arterial pathway (Pulse arrival_peri).

[0145] In some examples, PAT_cen, PAT_peri, and at least one arterial blood flow measurement are provided by the controller to a processing algorithm or calculation or transfer function 21 and used to derive an estimate of a hemodynamic parameter 24 (e.g., cardiac output or stroke volume).

[0146] According to another example, a quotient or ratio between the PAT_cen and PAT_peri measurements can optionally be calculated, and this quotient can then be used in calculating the estimated hemodynamic parameter 24. This value can be used instead of or in addition to the individual PAT_cen and PAT_peri values in calculating the estimated hemodynamic parameter.

[0147] Fluctuations in the PAT_cen measurement indicate changes in vascular tone in the central branches, while fluctuations in the PAT_peri measurement indicate changes in vascular tone in the peripheral branches. Furthermore, the ratio PAT_peri / PAT_cen indicates differential changes in vascular tone. Note that the quotient may alternatively be calculated in its inverse form: PAT_cen / PAT_peri.

[0148] It should be noted that when acquiring the various measurement inputs mentioned above (PPG, ECG, ultrasound), it is assumed that all measurement or sensor devices are synchronized in time with millisecond accuracy and that the calculation of time differences is sufficiently accurate.

[0149] In various examples, different combinations of measurements or parameters can be used as inputs to calculate the final estimated hemodynamic parameter, including, for example, a combination of two or more PAT measurements for each different central arterial pathway; a combination of two or more PAT measurements for each different peripheral arterial pathway; a combination of at least one PAT measurement for a central arterial pathway with at least one PAT measurement for a peripheral arterial pathway; a single quotient of PAT_cen and PAT_peri, or multiple quotients for multiple different pairs of central and peripheral arterial pathways.

[0150] In the above example, an ECG sensing device is used to identify the ejection event (the start of cardiac contraction), but other measurement or detection means are possible. A non-limiting set of other possible means for detecting an ejection event includes, for example, one or more accelerometers on the sternum (ballistocardiogram); one or more inductive sensors placed near the heart; a radar sensor placed near the heart; a transesophageal ultrasound probe; or a chest heart rate sensor, such as a chest band heart rate sensor.

[0151] FIG. 5 illustrates schematically the processing workflow of the second exemplary set of embodiments.

[0152] This set of embodiments differs from that of FIG. 4 only in that, instead of pulse arrival time (PAT), a pulse transit time (PTT) measurement is used as a surrogate measure of vascular tone. In other words, a measure of the time difference ΔT between the cardiac ejection event and the pulse arrival is obtained by obtaining PTT measurements for each of the peripheral and central arterial pathways. In all other respects, the features and workflow of this set of embodiments may be the same as those described above for the example of FIG. 4. Therefore, for the sake of brevity, the common features will not be described again in detail here.

[0153] To obtain a PTT measurement for each arterial pathway, the PAT value must be corrected for the pre-ejection period (PEP), the time during which the heart builds up pressure above the aortic pressure until the aortic valve opens. Excluding the PEP leads to a more accurate surrogate measure of vascular tone, since the pulse wave does not travel through the arterial pathway during this period.

[0154] Thus, obtaining a PTT measurement for each arterial route may include obtaining a PAT measurement for each arterial route, obtaining an estimate of the duration of the pre-ejection period (PEP), and determining a PTT measurement for each arterial route by subtracting the PEP duration from the PAT measurement for each arterial route. This is illustrated in Figure 5, which shows how each PTT value is obtained for each of the central arterial route (PTT_cen) and the peripheral arterial route (PTT_peri) by subtracting the PEP duration from each PAT value for these two arterial routes.

[0155] There are various ways to obtain an estimate of the PEP duration.

[0156] In some examples, the PEP duration can be derived based on the use of input from a phonocardiogram (PCG) sensing means and / or an impedance cardiogram (ICG) measuring means.

[0157] Measurements from these sensing modalities can be used to identify the point in time when the aortic valve opens. From this, the time between the electrical activation of the heart (the onset of the QRS complex as measured on an ECG) and the opening of the aortic valve (the point at which the pressure wave begins to travel along the arterial system) can be determined. This period corresponds to the pre-ejection period (PEP).

[0158] As previously mentioned, the opening of the aortic valve produces distinctive high-pitched sounds: a snap for opening and a click for ejection. One or both of these can be identified in PCG measurements that occur after the first heart sound. This can be used to detect the time of occurrence of aortic valve opening, which can then be used to determine PEP.

[0159] In another example, the controller 22 may use a predetermined estimate for the pre-ejection period, which may be stored, for example, in local memory or retrieved from a remote data source, such as a remote server.

[0160] In some examples, PTT_cen, PTT_peri, and blood flow measurements for at least one arterial pathway are provided by the controller to a processing algorithm or calculation or transfer function 21 and used to derive an estimate of a hemodynamic parameter 24 (e.g., cardiac output or stroke volume).

[0161] According to another example, a quotient or ratio can optionally be calculated between the PTT_cen and PTT_peri measurements, and this quotient can then be further used in calculating the estimated hemodynamic parameter 24. This value can be used instead of or in addition to the individual PTT_cen and PTT_peri values when calculating the estimated hemodynamic parameter 24.

[0162] It should be noted that, again, when acquiring the various measurement inputs mentioned above (PPG, ECG, ultrasound), it is assumed that all measurement or sensor devices are synchronized in time with millisecond accuracy, so that calculation of time differences is sufficiently accurate.

[0163] FIG. 6 shows a schematic processing workflow of the third set of embodiments.

[0164] In this set of embodiments, the controller is configured to detect changes or variations in vascular tone surrogate measures for each arterial pathway over time. This configuration provides an indication of changes in the (relative) tone of the measured branches of the vascular tree. These changes can indicate both local and more systemic changes in the vascular tree, which can further improve the accuracy of hemodynamic parameter estimation at any given time point.

[0165] Illustratively, the controller may be configured to obtain multiple time difference measurements ΔT for each of the arterial pathways corresponding to different cardiac cycles, determine a measure indicative of the variation in ΔT values over time for each arterial pathway, and determine an estimate of the hemodynamic parameter 24 based on the variation in ΔT values. The controller may continuously or repeatedly reacquire the ΔT values for each arterial pathway, thereby monitoring the variation in ΔT values as a function of time.

[0166] By way of example, and as shown in Figure 6, the controller may be configured to monitor fluctuations or changes in PAT values for each of the central and peripheral arterial pathways. For example, with each new heartbeat, the controller may obtain a new PAT measurement for each of the arterial pathways and calculate the difference ΔPAT between the new PAT value and the previous PAT value for the corresponding arterial pathway. These PAT change values for the central (ΔPAT_cen) and peripheral (ΔPAT_peri) arterial pathways are then provided by the controller to transfer function 21, which, in combination with blood flow measurement information, calculates hemodynamic parameters.

[0167] In other words, the controller uses the value of the beat-to-beat increase or decrease in PAT as a parameter for calculating hemodynamic parameters, rather than the absolute PAT value.

[0168] Optionally, a quotient or ratio can be calculated between the ΔPAT_cen and ΔPAT_peri measurements, and this quotient can be used in calculating the estimated hemodynamic parameter. This value can be used instead of or in addition to the individual ΔPAT_cen and ΔPAT_peri values in calculating the estimated hemodynamic parameter.

[0169] Although the example above uses changes in PAT values, the same principles can be applied to changes in PTT values, for example.

[0170] The means for obtaining each of the measurement inputs for calculating the PAT value and for obtaining the blood flow measurement values may be the same as those described above for the exemplary embodiment of Figures 4 and 5 and therefore will not be described in detail again here.

[0171] In contrast to the previously described embodiments of Figures 4 and 5, the set of embodiments according to Figure 6 does not require that all measurement devices be synchronized in time when acquiring the various measurement inputs (PPG, ECG, ultrasound) described above. For example, if two or more measurement devices are used to acquire inputs (ultrasound, PPG, ECG, etc.), it may be possible that the devices are not perfectly time synchronized. One way to solve this is to artificially force or impose synchronization by aligning a common reference point in the time series data acquired from the two or more measurement devices.

[0172] This process can be accomplished, for example, by first identifying predetermined reference points (characteristic anchor points) in the signal from each measurement device. These points can be physiological in nature or induced by the user, for example, by movement or by electromagnetic means. In either case, these points correspond to events known to leave a mark or imprint on the signal from each measurement device.

[0173] Once these common reference points have been identified in each signal, the signals can be time-aligned according to these points, i.e., such that the corresponding reference points in each of the signals are aligned in the time domain.

[0174] Discussed above are several embodiments that utilize transfer functions or algorithms to determine an estimate of a hemodynamic parameter based on two or more input parameters. Various options for implementing the transfer function are also briefly described.

[0175] One particular exemplary approach is to use a parametric regression model to map a set of input parameters to a set of output parameters. The principles of applying such an exemplary transfer function will be outlined in more detail for purposes of further explanation and illustration. The same principles can be applied according to any of the previously described embodiments to combine the specific sets of inputs outlined in each embodiment to derive estimated hemodynamic parameters.

[0176] This following example transfer function uses multi-parametric regression modeling employing three input parameters. By way of example, cardiac output (CO) is expressed as the following input parameters (independent variables): - arterial blood flow rate ("Flow") in the carotid artery (e.g., based on pulse wave Doppler ultrasound measurements); and - Cardiac ejection events and central arterial pathways (T centr ) and peripheral arterial pathway (ΔT peria measure indicating the time difference between the arrival of corresponding pulse waves at predetermined locations along the corresponding arterial pathways at each of the is estimated using a transfer function with

[0177] The transfer function can be estimated based on the following formula:

number

[0178] As previously mentioned, a training data set containing historical patient data for multiple patients can be used to train the model. Particularly with regard to multiparametric linear regression models, the model is established by first constructing a model or algorithm that incorporates each desired input parameter as a parameter (independent variable) of the model with a corresponding coefficient or weighting, and then training the constructed model based on the training data set, thereby fitting the model coefficients or weightings to provide an optimal fit between the input parameters of the training data set and the corresponding output parameters of the training data set. The desired input parameters form the independent variables of the model, while the target hemodynamic parameters are the dependent variables of the model. The model represents the estimated relevant hemodynamic parameters as a linear sum of a constant term (intercept) and each of the dependent variables multiplied by a corresponding weight or coefficient.

[0179] The training data set will have training input data entries and corresponding training output data entries, where the training input data entries correspond to example values of blood flow measurements for at least one arterial pathway and time difference measures ΔT for the central and peripheral arterial pathways for a given patient, and the training output data entries correspond to one or more predetermined hemodynamic parameters.

[0180] An initialized machine learning algorithm is applied to each input data entry to generate a predicted output data entry. The error between the predicted output data entry and the corresponding training output data entry is used to modify the machine learning algorithm. This process can be repeated until the error converges and the predicted output data entry is sufficiently similar to the training output data entry (e.g., within 1%). This is commonly known as a supervised learning approach.

[0181] For multiparametric regression models, the training process is the process of fitting the weights / coefficients of the model to the training dataset. Once the training or fitting process is complete, the model can be developed using the weights or coefficients obtained in the training or fitting process to map input parameters (independent variables) to output hemodynamic parameters.

[0182] The performance or accuracy of a generated machine learning model can be evaluated by running the model on a test dataset after training and evaluating the error between the output predictions generated by the model and the actual ground truth values. For example, in the case of a linear regression model, a measure of performance is the goodness of fit of the linear regression (R 2 ), standard error (SE), t-test of the estimate (tStat), p-value, root mean square error (RMSE) obtained from a correlation scatter plot, and / or reproducibility coefficient (rpc) obtained from a Bland-Altman plot.

[0183] Although the exemplary transfer functions described above use as input parameters a blood flow measurement for at least one arterial pathway and a time difference measure ΔT for both the central and peripheral arterial pathways, in other examples, the inputs to the transfer function may be different. For example, the transfer function may be adapted to accept as input one or more parameters derived from processing of the ΔT measure and / or the blood flow measure. Various examples have been described above, e.g., with reference to Figures 4-6.

[0184] In some examples, as described above with reference to FIG. 4, the input parameters of the transfer function may be the PAT_cen and PAT_peri values, or a function thereof (e.g., a quotient) in combination with a blood flow measure (see above for details). In some examples, as described above with reference to FIG. 5, the transfer function may be adapted to accept as input parameters the PPT_cen and PPT_peri values, or a function thereof (e.g., a quotient) in combination with a blood flow measure (see above for details). In some examples, as described above with reference to FIG. 6, the transfer function may be adapted to accept as input parameters a ΔPAT_cen and ΔPAT_peri value, or a function thereof (e.g., a quotient) in combination with a blood flow measure (see above for details). In some examples, the transfer function may be adapted to accept as input parameters a measure of pulse arrival time, a measure of cardiac ejection time, and a measure of blood flow at predetermined locations along each of the peripheral and arterial pathways.

[0185] Furthermore, while the above example of a transfer function is based on only three input parameters, it should be noted that in other examples, the transfer function can accept more input parameters, i.e., have more independent variables with corresponding weights for each. Additional input parameters may include, for example, parameters derived from blood flow and / or ΔT measurements, and / or patient metadata such as gender and body mass index.

[0186] It should be noted that although examples are given above in which the derived hemodynamic parameter is stroke volume or cardiac output, the same inventive concepts can be applied to derive any desired hemodynamic parameter. Other examples of hemodynamic parameters that can be derived include blood flow velocity, stroke volume variation, systolic velocity, diastolic velocity, and blood pressure.

[0187] An example according to another aspect of the present invention provides an apparatus for deriving an estimate of at least one hemodynamic parameter.

[0188] FIG. 7 illustrates a schematic diagram of an exemplary apparatus according to one or more embodiments.

[0189] The device includes an ECG sensor device 44 for detecting cardiac ejection events.

[0190] The device further comprises at least one PPG sensor 46 optically coupled to a location along the subject's arterial pathway for detecting the arrival time at that location of a blood pulse wave from the heart.

[0191] The device further comprises an ultrasonic sensing means 42 for detecting blood flow through the arterial pathway.

[0192] The device further comprises a controller 22 according to any example or embodiment described above or below or according to any claim of the present application, operably coupled to the ECG sensor device, at least one PPG sensor and ultrasound sensing means.

[0193] The ultrasound sensing means may comprise an ultrasound transducer arrangement. The ultrasound sensing means may be configured to detect blood flow using Doppler ultrasound measurements. The ultrasound sensing means may include a dedicated ultrasound processing unit for extracting one or more flow measurements from acquired ultrasound data and providing these to the controller for estimating hemodynamic parameters.

[0194] The set of measurement devices and sensors provided for this apparatus represents only one example, and other exemplary means for obtaining various input measurements for the controller are possible and are outlined in more detail in the description above.

[0195] An example according to another aspect of the present invention provides a computer-implemented method for deriving an estimate of at least one hemodynamic parameter.

[0196] The steps of an exemplary computer-implemented method 60 according to one or more embodiments are illustrated in block diagram form in FIG.

[0197] The method 60 comprises: - receiving 62 an input indicative of an arterial flow measurement for at least one arterial pathway of the subject, the arterial pathway being a central arterial pathway or a peripheral arterial pathway; - obtaining, for each of the central and peripheral arterial pathways, a measure indicative of the time difference ΔT between a cardiac ejection event and the arrival of a corresponding pulse wave as a result of blood flow from the heart to the predetermined location along each arterial pathway; and - determining 66 an estimate of a hemodynamic parameter based on a combination of blood flow measurements from said at least one arterial pathway and a time difference measure ΔT for each arterial pathway; It has.

[0198] Implementation options and details for each of the above steps can be understood and interpreted from the above description and discussion of the apparatus aspects (ie, controller aspects) of the present invention.

[0199] Any of the examples, options, or embodiment features or details described above with respect to the apparatus aspect of the invention (with respect to the controller) may be applied to, combined with, or incorporated into the method aspect of the invention, mutatis mutandis.

[0200] Examples according to another aspect of the present invention also provide a computer program product, which comprises code means configured to, when executed on a processor, cause the processor to perform a method according to any example or embodiment described above or below, or according to any claim of the present application.

[0201] As previously mentioned, embodiments utilize a controller 22. The controller can be implemented in numerous ways using software and / or hardware to perform the various functions required. The processor is one example of a controller employing one or more microprocessors that can be programmed using software (e.g., microcode) to perform the necessary functions. However, the controller can be implemented with or without a processor, and can also be implemented as a combination of dedicated hardware to perform some functions and a processor (e.g., one or more programmed microprocessors and associated circuitry) to perform other functions.

[0202] Examples of controller components that may be used in various embodiments of the present disclosure include, but are not limited to, conventional microprocessors, application specific integrated circuits (ASICs), and field programmable gate arrays (FPGAs).

[0203] In various configurations, a processor or controller may be associated with one or more storage media, such as volatile and non-volatile computer memory, such as RAM, PROM, EPROM, and EEPROM. The storage media may be coded with one or more programs that, when executed on the one or more processors and / or controllers, perform the necessary functions. The various storage media may be fixed within the processor or controller, or may be portable so that the stored one or more programs can be loaded into the processor or controller.

[0204] Variations to the disclosed embodiments can be understood and effected by those skilled in the art in practicing the claimed invention, from a study of the drawings, the disclosure and the appended claims. In the claims, the word "comprising" does not exclude other elements or steps, and the singular does not exclude a plurality.

[0205] A single processor or other unit may fulfill the functions of several items recited in the claims.

[0206] The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage.

[0207] The computer program may be stored / distributed on a suitable medium, such as an optical storage medium or a solid-state medium, supplied together with or as part of other hardware, but may also be distributed in other forms, such as via the Internet or other wired or wireless communication systems.

[0208] It should be noted that when the term "adapted" is used in the claims or description, the term "adapted" is intended to be equivalent to the term "configured."

[0209] Any reference signs in the claims should not be construed as limiting the scope.

Claims

1. 1. A controller for determining an estimate of at least one hemodynamic parameter of a subject, the controller comprising: receiving a data input indicative of an arterial blood flow measurement in at least one arterial pathway of the subject, wherein the arterial pathway is a peripheral arterial pathway or a central arterial pathway; obtaining, for each of the peripheral and central arterial pathways, a time difference measurement ΔT between a cardiac blood ejection event and the arrival of a corresponding pulse wave at a predetermined location along each arterial pathway as a result of blood flow from the heart to that location; providing the arterial blood flow measurements for the at least one arterial pathway and the time difference measurements ΔT for both the central arterial pathway and the peripheral arterial pathway, or a parameter derived from the arterial blood flow measurements and the time difference measurements ΔT, as inputs to a predetermined transfer function, wherein the transfer function generates an estimate of the at least one hemodynamic parameter based on the inputs and a predetermined functional relationship between the inputs and the at least one hemodynamic parameter; and generating a data output indicative of the estimate of the at least one hemodynamic parameter; controller.

2. The controller of claim 1 , wherein obtaining the time difference measurement ΔT for each arterial path comprises obtaining a pulse arrival time (PAT) measurement for each arterial path.

3. The controller of claim 1 or 2, wherein obtaining the time difference measurement ΔT for each arterial line comprises obtaining a pulse transit time (PTT) measurement for each arterial line.

4. 4. The controller of claim 3, wherein the act of obtaining the PTT measurement for each arterial line includes acts of obtaining a pulse arrival time (PAT) measurement for each arterial line, deriving an estimate of a pre-ejection period (PEP) duration, and determining the PTT measurement for each arterial line by subtracting the PEP duration from the PAT measurement for each arterial line.

5. 5. The controller of claim 1, wherein the controller obtains a plurality of time difference measurements ΔT for each of the arterial pathways corresponding to different cardiac cycles, determines a measure indicative of variation in the time difference measurements ΔT over time for each arterial pathway, and determines an estimate of the hemodynamic parameter based on the variation in the time difference measurements ΔT.

6. 6. The controller of claim 1, wherein determining the estimate of the hemodynamic parameter comprises determining a quotient of the time difference measurement ΔT for the peripheral arterial pathway and the central arterial pathway.

7. The controller of claim 1 , wherein the at least one hemodynamic parameter comprises at least one of cardiac output, stroke volume, and stroke volume variation.

8. A controller as claimed in any preceding claim, wherein the controller obtains the arterial blood flow measurements for at least one of the arterial lines using ultrasound sensing means.

9. 9. A controller as claimed in any one of claims 1 to 8, wherein the controller obtains, for at least one of the arterial pathways, both arterial blood flow measurements and arrival times of the pulse wave at predetermined locations along the arterial pathway using the same single ultrasonic sensing means.

10. the cardiac ejection event is a point in the electrical activation of the heart corresponding to the beginning of the pre-ejection period of the heart; or the cardiac ejection event corresponds to the end of the cardiac pre-ejection period; A controller according to any one of claims 1 to 9.

11. The controller of claim 1 , wherein the transfer function comprises a machine learning algorithm.

12. 1. An apparatus for deriving an estimate of at least one hemodynamic parameter, the apparatus comprising: a first sensor means for detecting a cardiac ejection event; second sensor means coupled to a location along the subject's arterial pathway for detecting the arrival time of a blood pulse wave from the heart at said location; third sensor means for detecting blood flow through said arterial pathway; and A controller according to any one of claims 1 to 11, operatively coupled to the first, second and third sensor means. An apparatus having:

13. 1. A computer-implemented method for determining an estimate of at least one hemodynamic parameter, the computer-implemented method comprising: receiving a data input indicating an arterial blood flow measurement in at least one arterial line of the subject, the arterial line being a peripheral arterial line or a central arterial line; obtaining, for each of the central and peripheral arterial pathways, a time difference measurement ΔT between a cardiac ejection event and the arrival of a corresponding pulse wave at a predetermined location along each arterial pathway as a result of blood flow from the heart to that location; providing the blood flow measurements for the at least one arterial pathway and the time difference measurements ΔT for both the central arterial pathway and the peripheral arterial pathway, or parameters derived from the arterial blood flow measurements and the time difference measurements ΔT, as inputs to a predetermined transfer function, the transfer function generating an estimate of the at least one hemodynamic parameter based on the inputs and a predetermined functional relationship between the inputs and the at least one hemodynamic parameter. the providing step; and generating a data output indicative of the estimated value of the at least one hemodynamic parameter.

10. A computer-implemented method comprising:

14. 14. The computer-implemented method of claim 13, wherein obtaining the time difference measurement ΔT for each arterial line comprises obtaining a pulse arrival time (PAT) measurement for each arterial line and / or a pulse transit time (PTT) measurement for each arterial line.

15. 15. A computer readable medium having computer readable code embodied therein, the computer readable code, when executed by a suitable computer or processor, causing the computer or processor to perform the computer implemented method of claim 13 or 14.

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