WO2017137983A1 - Système et procédé permettant de surveiller les paramètres cardiaques de manière non invasive - Google Patents

Système et procédé permettant de surveiller les paramètres cardiaques de manière non invasive Download PDF

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WO2017137983A1
WO2017137983A1 PCT/IL2017/050151 IL2017050151W WO2017137983A1 WO 2017137983 A1 WO2017137983 A1 WO 2017137983A1 IL 2017050151 W IL2017050151 W IL 2017050151W WO 2017137983 A1 WO2017137983 A1 WO 2017137983A1
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lvedp
bio
parameter
impedance waveform
waveform
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Shay FAITELZON
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CardioLogic Innovations Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6801—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be attached to or worn on the body surface
    • A61B5/6813—Specially adapted to be attached to a specific body part
    • A61B5/6823—Trunk, e.g., chest, back, abdomen, hip
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/02—Detecting, measuring or recording for evaluating the cardiovascular system, e.g. pulse, heart rate, blood pressure or blood flow
    • A61B5/021—Measuring pressure in heart or blood vessels
    • A61B5/02108—Measuring pressure in heart or blood vessels from analysis of pulse wave characteristics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/02—Detecting, measuring or recording for evaluating the cardiovascular system, e.g. pulse, heart rate, blood pressure or blood flow
    • A61B5/026—Measuring blood flow
    • A61B5/0295—Measuring blood flow using plethysmography, i.e. measuring the variations in the volume of a body part as modified by the circulation of blood therethrough, e.g. impedance plethysmography
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/103—Measuring devices for testing the shape, pattern, colour, size or movement of the body or parts thereof, for diagnostic purposes
    • A61B5/11—Measuring movement of the entire body or parts thereof, e.g. head or hand tremor or mobility of a limb
    • A61B5/1107—Measuring contraction of parts of the body, e.g. organ or muscle
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
    • A61B5/316—Modalities, i.e. specific diagnostic methods
    • A61B5/318—Heart-related electrical modalities, e.g. electrocardiography [ECG]
    • A61B5/346—Analysis of electrocardiograms
    • A61B5/349—Detecting specific parameters of the electrocardiograph cycle
    • A61B5/352—Detecting R peaks, e.g. for synchronising diagnostic apparatus; Estimating R-R interval
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6801—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be attached to or worn on the body surface
    • A61B5/6813—Specially adapted to be attached to a specific body part
    • A61B5/6822—Neck
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2505/00—Evaluating, monitoring or diagnosing in the context of a particular type of medical care
    • A61B2505/07—Home care
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/0002—Remote monitoring of patients using telemetry, e.g. transmission of vital signals via a communication network
    • A61B5/0015—Remote monitoring of patients using telemetry, e.g. transmission of vital signals via a communication network characterised by features of the telemetry system
    • A61B5/002—Monitoring the patient using a local or closed circuit, e.g. in a room or building
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/02—Detecting, measuring or recording for evaluating the cardiovascular system, e.g. pulse, heart rate, blood pressure or blood flow
    • A61B5/02028—Determining haemodynamic parameters not otherwise provided for, e.g. cardiac contractility or left ventricular ejection fraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/72—Signal processing specially adapted for physiological signals or for diagnostic purposes
    • A61B5/7271—Specific aspects of physiological measurement analysis
    • A61B5/7275—Determining trends in physiological measurement data; Predicting development of a medical condition based on physiological measurements, e.g. determining a risk factor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/72—Signal processing specially adapted for physiological signals or for diagnostic purposes
    • A61B5/7271—Specific aspects of physiological measurement analysis
    • A61B5/7282—Event detection, e.g. detecting unique waveforms indicative of a medical condition

Definitions

  • the present invention generally pertains to systems and methods for non-invasively monitoring hemodynamic status of a patient's heart.
  • Heart failure is a growing epidemic and a leading cause of morbidity and mortality across the globe.
  • HF Heart failure
  • the prevalence, mortality, hospitalizations and cost associated with this condition continue to grow in Europe, the United States, and in developed countries (McMurray JJ et al. Eur. Heart J. 1998 (19) (suppl. P), 9-16).
  • Heart failure's incidence has increased by more than 100% over the last 20 years, affecting 5.8 million Americans, 15 million Europeans and 23 million people worldwide. Each year 670,000 Americans and 3.6 million Europeans are diagnosed. 280,000 deaths are attributed to the disease in the US only - nearly half of all heart disease related deaths.
  • Heart failure is also an extremely high-cost illness. In US alone, it accounts for over $39.2 billion per year. Of which, there is approximately 1 million hospital stays costing $20.9 billion. Particularly, high cost and mortality are associated with recurrent hospitalizations: 8-15% die and 30-38% are readmitted to the hospital within 90 days of hospitalization.
  • US patent application 2002/0035331 disclosed a device that measures pressures in animals and humans and includes a pressure transmission catheter (PTC) filled with a pressure transmitting medium and implantable in an area in having a physiological pressure.
  • PTC pressure transmission catheter
  • US patent No. 7,054,679 disclosed a method of and a device for non-invasively measuring the hemodynamic state of a subject or a human patient involve steps and units of non-invasively measuring cardiac cycle period, electrical-mechanical interval, mean arterial pressure, and ejection interval and converting the measured electrical-mechanical interval, mean arterial pressure and ejection interval into the cardiac parameters such as Preload, Afterload and Contractility, which are the common cardiac parameters used by an anesthesiologist.
  • said at least one impedance waveform parameter P is correlated with left ventricular end-diastolic pressure (LVEDP) such that an estimated value of said LVEDP is determined from said impedance waveform parameter P.
  • LVEDP left ventricular end-diastolic pressure
  • LVEDP left ventricular end-diastolic pressure
  • LVEDP left ventricular end-diastolic pressure
  • LVEDP left ventricular end-diastolic pressure
  • average waveform is median of a plurality of said bio-impedance waveforms acquired in a predetermined time period and superimposed thereof.
  • It is another object of the present invention to provide the method as defined above, wherein said at least one parameter P ranges from -1 to 1, where fully negative area is -1, negative area equals to positive area P 0 and fully positive area is 1.
  • bio-impedance waveform is recorded in AC, DC or both. It is another object of the present invention to provide the method as defined above, wherein said bio-impedance waveform is whole thoracic impedance waveform, trans-thoracic impedance waveform or any combination thereof.
  • a processor in communication with said means, configured to (a) analyze said bio-impedance waveform and extract at least one parameter P from said at least one bio-impedance waveform; (b) calculate either (i) estimated value of said LVEDP; (ii) change in left ventricular end-diastolic pressure (LVEDP); (iii) any combination thereof; wherein said at least one impedance waveform parameter P is correlated with left ventricular end-diastolic pressure (LVEDP) such that an estimated value of said LVEDP is determined from said impedance waveform parameter .P.
  • LVEDP left ventricular end-diastolic pressure
  • alerting means are configured to alert if said change in left ventricular end-diastolic pressure (LVEDP) is above ⁇ 2 mmHg. wherein said alerting means are configured to alert if said change in left ventricular end-diastolic pressure (LVEDP) is above ⁇ 10%.
  • average waveform is median of a plurality of said bio-impedance waveforms acquired in a predetermined time period and superimposed thereof.
  • It is another object for the present invention to provide the system as defined above, wherein said at least one parameter P ranges from -1 to 1, where fully negative area is -1, negative area equals to positive area P 0 and fully positive area is 1.
  • bio-impedance waveform is recorded at 20 KHz and 90 KHz.
  • bio-impedance waveform is recorded in AC, DC or both.
  • bio-impedance waveform is whole thoracic impedance waveform, trans-thoracic impedance waveform or any combination thereof.
  • bio-impedance waveform is recorded as CSV files.
  • a processor in communication with said means, configured to analyze said bio-impedance waveform and extract at least one parameter P from said at least one bio-impedance waveform; wherein said at least one impedance waveform parameter P is correlated with left ventricular end-diastolic pressure (LVEDP) such that an estimated value of said LVEDP is determined from said impedance waveform parameter P
  • LVEDP left ventricular end-diastolic pressure
  • alerting means adapted to alter the user if said LVEDP is above a predetermined threshold.
  • average waveform is median of a plurality of said bio-impedance waveforms acquired in a predetermined time period and superimposed thereof.
  • It is another object of the present invention to provide the system as defined above, wherein said at least one parameter P ranges from -1 to 1, where fully negative area is -1, negative area equals to positive area P 0 and fully positive area is 1.
  • bio-impedance waveform is recorded in AC, DC or both.
  • bio-impedance waveform is whole thoracic impedance waveform, trans-thoracic impedance waveform or any combination thereof.
  • a processor in communication with said means, configured to analyze said bio-impedance waveform and extract at least one parameter P from said at least one bio-impedance l O waveform; wherein said at least one impedance waveform parameter P is correlated with either (i) estimated value of said LVEDP; (ii) change in left ventricular end-diastolic pressure (LVEDP); (iii) any combination thereof; such that an estimated value of either (i) estimated value of said LVEDP; (ii) change in left ventricular end-diastolic pressure (LVEDP); (iii) any combination thereof; is determined from said impedance waveform parameter P;
  • alerting means adapted to alter the user if either (i) estimated value of said LVEDP; (ii) change in left ventricular end-diastolic pressure (LVEDP); (iii) any combination thereof; is above a predetermined threshold.
  • average waveform is median of a plurality of said bio-impedance waveforms acquired in a predetermined time period and superimposed thereof.
  • It is another object of the present invention to provide the system as defined above, wherein said at least one parameter P ranges from -1 to 1, where fully negative area is -1, negative area equals to positive area P 0 and fully positive area is 1.
  • bio-impedance waveform is recorded in AC, DC or both.
  • bio-impedance waveform is whole thoracic impedance waveform, trans-thoracic impedance waveform or any combination thereof.
  • step of monitoring is provided by correlating said at least one impedance waveform parameter P with either (i) estimated value of said LVEDP; (ii) change in left ventricular end-diastolic pressure (LVEDP); (iii) any combination thereof; and calculating an estimated value of either (i) estimated value of said LVEDP; (ii) change in left ventricular end-diastolic pressure (LVEDP); (iii) any combination thereof; from said impedance waveform parameter .P. It is another object of the present invention to provide the method as defined above, additionally comprising step of alerting if said change in left ventricular end-diastolic pressure (LVEDP) is above ⁇ 2 mmHg.
  • LVEDP left ventricular end-diastolic pressure
  • average waveform is median of a plurality of said bio-impedance waveforms acquired in a predetermined time period and superimposed thereof.
  • It is another object of the present invention to provide the method as defined above, wherein said at least one parameter P ranges from -1 to 1, where fully negative area is -1, negative area equals to positive area P 0 and fully positive area is 1.
  • bio-impedance waveform is whole thoracic impedance waveform, trans-thoracic impedance waveform or any combination thereof.
  • Figure 1 schematically illustrates Wiggers diagram of the cardiac physiology with the bio-impedance waveform integrated into the theoretical diagram
  • Figure 2 schematically illustrates the system (100) according to a preferred embodiment of the present invention
  • Figure 3 schematically illustrates the system (200) according to a preferred embodiment of the present invention
  • Figure 4 schematically illustrates the high-level overview of the method (400) according to a preferred embodiment of the present invention
  • Figure 5 illustrates waveform analysis tool panel showing individual cycles and mean waveform
  • FIG 6 illustrates relationship of extravascular Lung Water (EVLW) and resistivity (the present invention) during controlled volume infusion in the sheep model;
  • EDLW extravascular Lung Water
  • resistivity the present invention
  • Figure 7 shows Spearman's correlation coefficient between Resistivity and EVLW
  • Figure 8A shows changes in resistivity occurs concomitantly with changes in LVEDP
  • Figure 8B shows changes in resistivity lags behind changes in ITBV but precedes changes in pulmonary congestion defined by EVLW;
  • FIG 10 shows typical waveforms during baseline, congestion and decongestion.
  • Baseline and decongestion LVEDP and waveform parameter P values were identical, despite significant change in heart rate;
  • Figure 11 shows measured vs. estimated LVEDP in a sheep
  • Figure 12 shows estimated vs. measured LVEDP during early Congestion in a sheep
  • Figure 13 shows combined data for estimated vs measured LVEDP using waveform parameter P
  • Figure 14 shows combined data for estimated vs measured LVEDP using transthoracic resistance
  • Figure 15A illustrates high quality 11 mmHg LVEDP recordings in a human subject
  • Figure 15B illustrates low quality 11 mmHg LVEDP recordings in a human subject
  • Figure 16 shows the LVEDP measurements and their quality in the 7 evaluable subjects
  • Figure 17 shows waveform analysis panel showing individual cycles (upper panel) and mean waveforms (lower panel) captured during one recording cycle in a human subject;
  • Figure 18A shows superimposed individual wave measurements in a human subject
  • Figure 18B shows composite median measurements in a human subject
  • Figure 19 shows normalized median waveforms in each human subject showing the change between 'high' and 'low';
  • Figure 20 shows differences between the mean waveforms.
  • the red curve is the difference curve between the blue ('low' LVEDP) and green ('high' LVEDP) curves;
  • Figure 21 shows LVEDP and corresponding waveform parameter which is expressed as a numerical parameter
  • Figure 22 shows Bio-impedance waveform parameter - ALVEDP relationships in 7 human subjects. DETAILED DESCRIPTION OF THE PREFERRED EMB ODIEMNTS
  • the term 'subject' hereinafter refers to any human or animal that has heart conditions.
  • bio-impedance hereinafter refers to the response of a living organism (or a portion thereof, such as a body part, organ, tissue, or the like) to an externally applied electric current. It is a measure of the opposition to the flow of that electric current through the tissues.
  • the measurement of the bio-impedance has proved useful as a non-invasive method for measuring various parameters of the body such as blood flow (often referred to as bioimpedance plethymography) and body composition (known as bioelectrical impedance analysis or simply BIA).
  • the measurement of bio-impedance in the presentation is via adhesive electrodes applied to the skin of a subject, and a tiny alternating current at a frequency of 10-100 kHz is applied (typically a few milli-Amperes, and up to 9mA).
  • the Ohmic power dissipated is sufficiently small and diffused over the body to be easily handled by the body's thermoregulatory system - certainly below the threshold at which they would cause stimulation of nerves.
  • the frequency of the alternating current is sufficiently high not to give rise to electrolytic effects in the body (lower frequency current may increase electrode impedances, cause other noise factors, and risk the patient with an electric shock), but low enough for neglecting of displacement currents in the calculations.
  • 'thoracic region hereinafter refers to the region between the abdomen and neck wherein the ribs are located.
  • 'waveform' hereinafter refers to a curve showing the shape of a wave at a given time.
  • bio-impedance waveform' hereinafter refers to change of bio-impedance according to time during at least one cardiac cycle.
  • pre-load hereinafter refers to the amount of myocardial fiber stretch at the end of diastole, it also refers to the amount of volume in the ventricle at the end of this phase. It is clinically acceptable to measure the pressure required to fill the ventricles as an indirect assessment of ventricular preload. Left atrial filling pressure or pulmonary artery wedge pressure is used to assess left ventricular preload. End diastolic left ventricular pressure and volume are also common surrogates for preload. Preload increases with greater circulating volume, venoconstriction, exercise, arterioventricular fistulae, increased ventricular compliance, increased ventricular filling time, left ventricular systolic failure.
  • Preload decreases with volume depletion, decreased venous return, impaired atrial contraction, tricuspid or mitral stenosis, less compliant ventricles.
  • Cardiac preload is a semi-quantitative composite assessment that is variously described in different cardiovascular physiology texts and articles as end-diastolic myocardial fiber tension, end-diastolic myocardial fiber length, ventricular end-diastolic volume, and ventricular end-diastolic filling pressure.
  • preload is not synonymous with any one of these measurable parameters, but is rather a physiological concept that encompasses all of the factors that contribute to passive ventricular wall stress at the end of diastole.
  • ITBV intrathoracic blood volume
  • ITBV intrathoracic blood volume
  • GEDV intrathoracic blood volume
  • GEDV global end diastolic volume
  • ITBV comprises the volume of all four cardiac chambers and the pulmonary circulation whereas GEDV only comprises the cardiac volumes in end-diastole.
  • ITBV is a surrogate parameter for the central blood volume which serves as the fluid reservoir for the left ventricle. So, at least in theory a severe hypovolemia should be reflected by a decrease in ITBV and GEDV.
  • volume indices such as intrathoracic blood volume (ITBV) and global end-diastolic volume (GEDV) may form a physiological point of view, better estimate left ventricular preload.
  • the term 'conductivity' hereinafter refers to the ability of a certain tissue to conduct electricity, the conductance of a unit cube of tissue.
  • Conductivity ⁇ (Greek: sigma) is expressed in Siemens per meter (S/m) and it is defined as the inverse of resistivity, where resistivity is expressed in Ohm*meter ( ⁇ -m).
  • this ability is measured in the form of impedivity, the impedance of a unit cube of tissue.
  • the impedivity is the sum of resistivity and reactivity and is expressed in Ohm*meter ( ⁇ -m) or Ohm*cm ( ⁇ -cm).
  • Both conduction and displacement currents are generated in tissues when applying an electromagnetic field. In most biological tissues the conduction currents dominate in lower frequencies ( ⁇ 100 kHz). At high frequencies (>50 kHz) the displacement currents are dominant.
  • the term 'impedance cardio raphy' hereinafter refers to an application of the plethysmography technique used to detect the properties of the blood flow in the thorax.
  • the placement of four dual disposable sensors on the neck and chest are used to transmit and detect electrical and impedance changes in the thorax, which are used to measure and calculate hemodynamic parameters.
  • Bioimpedance has being widely used to detect cardiac output (CO) and its derivatives.
  • CO cardiac output
  • Another parameters typically measured by ICG systems is the Thoracic Fluid Content (TFC) or Trans-Thoracic Impedance, defined as the electrical conductivity of the chest cavity.
  • TFC Thoracic Fluid Content
  • Trans-Thoracic Impedance defined as the electrical conductivity of the chest cavity.
  • TFC is primarily determined by the intravascular, interstitial and intraalveolar fluids in the thorax and therefore responds to changes in lung fluids. The TFC decreases as the amount of fluid in the lungs increases.
  • the term 'Systolic dysfunction' refers to impaired ventricular contraction. In chronic heart failure, this is most likely due to changes in the signal transduction mechanisms regulating cardiac excitation-contraction coupling.
  • the loss of cardiac inotropy i.e., decreased contractility
  • These results in a decrease in stroke volume and a compensatory rise in preload (often measured as ventricular end-diastolic pressure or pulmonary capillary wedge pressure).
  • the rise in preload is considered compensatory because it activates the Frank- Starling mechanism to help maintain stroke volume despite the loss of inotropy. If preload did not rise, the decline in stroke volume would be even greater for a given loss of inotropy.
  • diastolic dysfunction refers to changes in ventricular diastolic properties that have an adverse effect on stroke volume. About 50% of heart failure patients have diastolic dysfunction, with or without normal systolic function as determined by normal ejection fractions. Ventricular function is highly dependent upon preload as demonstrated by the Frank-Starling relationship. Therefore, if ventricular filling (preload) is impaired, this will lead to a decrease in stroke volume.
  • Invasive left heart catheterization for the measurement of (LVEDP) is performed either by Pigtail catheter (Fluid-Filled Catheters) or by a Millar Mikro-CathTM pressure catheter (electronic pressure sensor). While adequate to monitor a patient's state, pressure waveforms from fluid-filled catheters can be unreliable for diagnostic purposes.
  • the disposable Mikro-CathTM (Millar Inc., Germany) pressure catheter produces a more complete and accurate representation of cardiovascular waveforms, making it the gold standard for clinical applications.
  • Pulmonary capillary wedge pressure (PCWP) is measured during right diagnostic cardiac catheterization using a Swan-Ganz catheter.
  • Intermittent pulmonary artery pressure is measured using a sphygmomanometer. Another method of measurement is of pulmonary artery pressure monitoring is done by permanent implant called CardioMEMSTM HF System (St. Jude Medical, USA).
  • the CardioMEMSTM HF System provides ambulatory pulmonary artery (PA) pressure monitoring using a small pressure sensor, permanently implanted in the distal pulmonary artery via a safe right heart catheterization procedure. Patient-initiated sensor readings are wirelessly transmitted to an external electronics unit and stored in a secure website for clinicians to access and review. Directly monitoring PA pressure not only enables early detection of worsening heart failure, but also allows the titration of medications for proactive and personalized patient management.
  • the CardioMEMSTM HF System is the first and only FDA-approved heart failure (HF) monitor proven to significantly reduce HF hospital admissions and improve quality of life in NYHA class III patients. When used by clinicians to manage HF, the CardioMEMS HF System is safe and reliable, clinically proven, proactive and personalized.
  • HF heart failure
  • the present invention provides an early detection device, using bio-impedance waveform algorithm analysis that identifies an increase in estimated left ventricular end diastolic pressure (LVEDP) and enables preventive therapeutic interventions aimed to reduce hospitalization rates and healthcare system costs of chronic heart failure management.
  • the present invention provides a waveform technique, in which a whole cardiac cycle is measured, is inferred from surface electrical (bio-impedance) measurements.
  • the waveform technology expands the usefulness of simple bio-impedance measurement by enabling the tracking of changes in LVEDP.
  • the physiological foundation for this measurement is based on the concept of preload which is a composite assessment of cardiac filling that represents the primary determinant of cardiac output. Both end diastolic left ventricular pressure (LVEDP) and volume are common surrogates for preload.
  • the present invention provides the system and method for evaluating the dynamic changes in the cardiac cycle on a beat-to-beat basis. It provides the aimed information by focusing on the heart and major vessels in the chest, rather than on the lungs. It is designed to detect and track small changes in preload (compared with changes in LVEDP).
  • the technology is less sensitive to changes in electrodes position and their contact with the chest wall than transthoracic bio-impedance since the bioimpedance waveform morphology is less sensitive to changes than the amplitude measured by other methods.
  • the raw signals are expressed as changes of the waveform over time as compared to baseline measurements. These changes (including systolic and diastolic components, as defined by simultaneous ECG recording - see Figure 1) are fed into the proprietary algorithm and translated to numeric parameters which provide the estimate of the changes in LVEDP.
  • the system comprises a means (110) to acquire bio-impedance waveform of the subject (102).
  • the measurement means comprises a plurality of electrodes 110a, 110b, 110c and llOd.
  • the electrodes are placed on a desecrate slim wearable patch, wire free and water resistant.
  • the electrodes are placed far away from the heart and the great vessels. It can be worn on the thorax for 30 days, acquiring the impedance waveform.
  • the electrodes which is integrated into one wearable patch, are placed near the heart in order to facilitate the shortest (electrical) path to the heart and the great vessels. Due to the fact that impedance waveform is measured, the position of electrodes is not so critical to the accuracy of the results.
  • the system (100) further comprise a transmitter (120) in communication with the electrodes configured to transmit acquired bio-impedance waveform to an external electronics (e.g. a mobile phone, a cloud, a monitoring center) and acquired bio-impedance waveform can be analyzed via a processor ( 130) using dedicated algorithm assessing the changes in LVEDP and presenting them via a display (140) to a trained physician/nurse assisting them to guide the patient about required changes in his or her therapy.
  • an external electronics e.g. a mobile phone, a cloud, a monitoring center
  • acquired bio-impedance waveform can be analyzed via a processor ( 130) using dedicated algorithm assessing the changes in LVEDP and presenting them via a display (140) to a trained physician/nurse assisting them to guide the patient about required changes in his or her therapy.
  • FIG. 3 illustrates the system (200) for non-invasively monitoring change in hemodynamic status of a subject with chronic heart failure according to a preferred embodiment of the present invention.
  • the system (200) applies a tiny currents using 4 skin surface electrodes (210) placed around the subject's chest and measures the resulting potential (voltage) on the body surface, thus, determining the body's bio-impedance. It then measures the bio-impedance resistance of the lungs, and the bio-impedance waveform from the heart and large vessels.
  • the system (200) further comprises ECG monitor applied with 3 ECG electrodes for Lead II tracing.
  • the ECG signal is required as an input for the definition of the cardiac cycle systolic and diastolic components and for application of algorithm calculation of changes in LVEDP.
  • the system (200) further comprises a display configured to show resistance values in Ohm (Qand the bio , (-impedance waveform graphs represented and expressed as the waveform parameter (P).
  • This information is displayed in real-time and the recorded numeric values and graphical trends will allow physicians to continuously monitor the status of chronic heart failure patients.
  • the system (200) is not a life-supporting device. It does not have any real-time alarms.
  • the displayed information is intended only to serve as a supplementary source of data. This additional information does not titute in any way diagnosis or treatment subs approaches based upon standard medical practice.
  • the user affixes on the subject's chest four standard pre-wired ECG electrodes which are provided with the system.
  • the four electrodes set (210) is designated for bio-impedance measurement.
  • the connector at the end of the electrodes wires is connected with the patient cable (220), which in turn connected to the monitor unit (240).
  • the user also affixes three standard ECG monitoring electrodes (RA, LA, N) and connect them with the snap on connector to the ECG cable (250).
  • the user connects the Monitor Unit USB cable (230) to a processor (e.g. a computer) configured to recognize the system with the S/N.
  • the processor fully controls the measurement, its settings and recordings.
  • the user can download a CVS file contains the all measurement, to a storage device, such as standard USB portable memory stick.
  • the monitoring unit (240) comprises a bio-impedance card and ECG card in a single enclosure, integrated USB cable and connector (230) for power supply and communication transfer, connector for patient cables (260) and connector for ECG cables (270).
  • the monitoring unit (240) is designed to be placed on a table or stroller.
  • the processing unit e.g. a Laptop
  • the processing unit is installed with "Cardio Sampler” software, and is used for viewing, recording and re-running recorded measurements.
  • the processing unit further comprises a micro Simulator configured to check the bio-impedance signal of the monitor unit.
  • the patient cable (220) is multiple use and non-sterile, it serves as extension from the monitor unit (240) to the bio-impedance electrodes (210).
  • the patient cable (220) is IP-D317 adapter cable used for IP-D316 electrodes (CE Mark, FDA cleared).
  • it is a generic ECG monitoring electrodes adapter cable.
  • the ECG Cable (250) is multiple use and non-sterile, it serves as extension from the monitor unit (240) to the ECG electrodes (not shown). It is a generic ECG monitoring electrodes adapter cable with snap-on connector.
  • the bio-impedance electrodes (210) are CE Marked and FDA cleared. They are non-sterile and for single use. Usually the bio-impedance electrodes (210) comprise 4 electrodes. They are either integral process pre-wired electrodes or generic ECG Electrodes.
  • the ECG electrodes are CE Marked and FDA cleared. They are non-sterile and for single use. Usually the ECG electrodes comprise 3 electrodes. They are generic ECG Electrodes.
  • the system is packaged with reusable use packaging and/or durable case.
  • transportation of the system (200) is in a single package at the first shipping to the site following electrodes and placement accessories can be shipped upon request.
  • the Monitor Unit (240) and the processing unit shall be connected by the USB cable. Monitoring control is done through the processing unit. The monitoring result is saved in a designated storage unit. At the end of the session the file can be downloaded to a standard USB portable memory stick.
  • the method (400) start with acquiring at least one bio-impedance waveform of the subject (410), via bio-impedance electrodes as described above.
  • the acquired bio-impedance waveform is then received by a processor (420).
  • the processor analyze the bio-impedance waveform (430) and extract at least one waveform parameter P (440).
  • the change in the impedance waveform parameter P is then correlated with change in left ventricular end-diastolic pressure (LVEDP) (450) such that an estimated value of change in LVEDP is provided (460).
  • LVEDP left ventricular end-diastolic pressure
  • Example 1 WAVEFORM ANALYSIS TOOL. PARAMETER DEFINITION AND THE PREDICTIVE ALGORITHM
  • the analysis tool is a MATLAB program that loads CSV measurement files containing bio-impedance waveform.
  • the program looks for repetitive data in order to determine the heart rate in each measurement, and 'break' the input data into heart rate cycles.
  • real-time ECG input is used to synchronize the beginning of each cycle to the peak of the ECG R wave.
  • Figure 5 shows the individual cycles, which include small red circles (502) at the time of the peak of the R wave that separate each cycle from the next one.
  • the lower graph shows in grey all the superimposed cycles and in red their average value.
  • the spread of the grey lines (504) around the red average (506) is a measure of the variation of waveform shape during the measurement. The main contributor to the variation in waveform shape was the respiratory cycle.
  • the animal studies is revised to overcome the well-known phenomena of poor signal/noise ratio when the subjects are human.
  • the revised method would be more stable and could serve as surrogate for changes in LVEDP during early congestion and also decongestion in heart failure.
  • the objective is to evaluate the accuracy of the present invention in estimating LVEDP in an animal model of gradual pulmonary congestion and decongestion.
  • Figure 10 presents typical waveforms during baseline, congestion and decongestion.
  • the waveforms morphology and P (-0.900 and -0.903) were very similar during baseline and decongestion, with identical LVEDP (9mmHg), despite the fact that heart rate during baseline was 103/min and after decongestion 165/min.
  • the P and LVEDP during congestion cycle were -0.334 and 29 mmHg, respectively (taken from recordings of sheep no 2).
  • the standard deviations of difference between the estimated and actual LVEDP for the early congestion period in the two sheep are 2.2 mmHg and 1.1 mmHg.
  • the standard deviations of the difference between the estimated and actual LVEDP in five sheep are: 2.7 mmHg, 3.5 mmHg, 2.8 mmHg, 3.0 mmHg and 2.3 mmHg.
  • Measuring the bio-impedance waveform and tracking the change in waveform morphology provides a sensitive measure of LVEDP changes in the five sheep included in the study. Although in the example, only a single waveform parameter is presented to show the correlation with LVEDP changes, but additional waveform morphology measures can also correlates to LVEDP - such as timing of critical points, slopes, relative areas, etc.
  • the waveform parameter serves as a surrogate measure of LVEDP with good correlation - R 2 > 0.8.
  • the clinical feasibility studies were preformed to explore the feasibility of bio-impedance methodology to detect changes in LVEDP in patients undergoing diagnostic left heart cardiac catheterization.
  • the pilot phase of the study was planned in advance to be based on analysis of the data in the first 5-10 subjects.
  • Study Design This was an observational, single-center, prospective, opened label, non-randomized, and comparative clinical investigation. The study was conducted in the catheterization laboratory of Hadassah Hebrew University Hospital, Jerusalem, Israel, during routine elective diagnostic left heart catheterization procedures.
  • the investigational non-invasive measurements were recorded simultaneously with the invasive LVEDP measurements.
  • the LVEDP measurements served as the gold standard to the investigational bio-impedance measurements.
  • LVEDP was measured with high fidelity Mikro-Cath tm (Millar Inc., USA).
  • the Mikro-CathTM disposable pressure catheters use pressure sensor technology to record precise measurements of LVEDP, which is not affected by motion artifacts or body position.
  • the primary and only predefined end point was the correlation between the bio-impedance waveform measured by the investigational device and changes in LVEDP measured by the Millar catheter.
  • Subject recruitment and Screening Subjects were recruited from patients scheduled for diagnostic left heart catheterization in the catheterization laboratory. Subjects were screened for eligibility.
  • Group 1 n 10 subjects with LVEDP > 15 mmHg and predominantly systolic dysfunction (LVEF ⁇ 45%) undergoing diagnostic left and possibly right heart catheterization
  • Group 2 n 10 subjects with LVEDP > 15 mmHg and with a normal/preserved systolic function (LVEF>45%) undergoing diagnostic left and possibly right heart catheterization
  • Group 3 n 10 subjects with normal LVEDP ⁇ 2 mmHg undergoing diagnostic left and possibly right heart catheterization
  • a second simultaneous measurement was done following raising the legs of the participant on a 25° triangular mattress (repeated 3 times). Alternatively, a second simultaneous measurement was done following a hand grip of both hands (repeated 3 times). A third simultaneous measurement was done during Valsalva maneuver performed by the participant (repeated 3 times).
  • the LVEDP tracing were recorded on paper kept as a source document. The bio-impedance recordings were saved as a CSV files in the computer and analyzed with MATLAB software. Interpretable recordings (LVEDP and waveforms) were required to show at least 10-20 consecutive stable morphology and values. The quality of both LVEDP and waveforms was classified as high, medium and low.
  • Bio-impedance measures voltage between electrodes. Since the applied current is kept constant, the measured voltage is a measure of body impedance, or resistance. The measured waveform is the temporal change of this resistance during a cardiac cycle. Hence the individual waveforms have 'resistance' as the vertical axis. Calculated waveform parameter is the integral of resistance overtime divided by another integral of resistance over time.
  • the LVEDP recordings were interpreted for numerical value and quality of the recording, by three independent reviewers.
  • the quality of the LVEDP recordings was classified as high (H), medium (M) and low (L) based on the stability, the length and the uniformity in morphology of the pressure waves.
  • the quality of the pressure recordings was influenced by the intra-cardiac position of the catheter, presence or absence of VPBs and the compliance of the subject with holding his/her breathing for 10 to 20 seconds, as well as with the right performance of the physiological maneuver (hand grip and Valsalva) during the procedure. We found that there was a good correlation between the quality of the bio-impedance waveforms and the quality of the LVEDP recordings.
  • Figure 16 summarizes the LVEDP values and their quality in the 7 subjects.
  • each state baseline, legs up, Valsalva
  • the PI decided to perform 4 measurements. Only high quality LVEDP measurements were included in the analysis.
  • the bio-impedance waveform recordings were recorded and saved as CSV files as described in Example 1.
  • the waveform data collection and analysis tool used was a MATLAB program that loads CSV measurement files.
  • the bio-impedance waveform and the ECG were recorded simultaneously.
  • the program identified the peaks of the R waves timing from the ECG and separated the bio-impedance waveform into individual cardiac cycles.
  • Figure 17 shows the individual cycles recorded, which is similar as shown in the example 1.
  • the small red circles mark the peak of the R wave that separates each cycle from the next one.
  • the lower graph shows in grey all the superimposed cycles acquired during one episode of data recording and in red their average value.
  • the spread of the grey lines around the red average is a measure of the variation of waveform shape during the measurement period.
  • the main contributors to the variation in waveform shape were the respiratory cycle and arrhythmias (i.e. VPBs). These were also the major reasons for exclusion of certain waveform recordings from analysis.
  • the mild variation due to changes in chest volume was considered to be acceptable of amplitude and the waveform recording was included in analysis.
  • the following graphs show the SUPERIMPOSED INDIVIDUAL RECORDINGS for each of the 7 evaluated subjects.
  • each individual measurement cycle for example, 3 baseline measurements
  • approximately 10 to 20 waveforms are continuously recorded.
  • Each measurement cycle is graphically presented by 2 consecutive waveforms which represent the overlay of all beats recorded during that specific measurement cycle.
  • Each measurement cycle provided one median LVEDP measurement which appears in the upper part of the waveform graph.
  • the measurement cycles are organized in three horizontal rows.
  • the first row shows the 3 baseline, the second the 3 legs up and the third shows the 3 Valsalva maneuver recordings.
  • Empty graphs indicate the exclusion of that measurement from analysis due to inadequate quality of LVEDP, waveform or both measurements.
  • the second series of graphs represent the overlay of the COMPOSITE MEDIAN OF THE RECORDINGS of the same cycles of measurements (i.e. in Subject 5: 3 baselines, 3 legs up, and 3 Valsalva procedures).
  • the corresponding LVEDP values measured during each recording appears in the box situated on the right upper area of the graphs.
  • each point on the graph represents one evaluable subject.
  • X axis represents the change in the LVEDP ( ⁇ ) (the lower LVEDP measurement value was subtracted from the higher LVEDP measurement value).
  • Y axis The bio-impedance waveform parameter. This analysis reveals that LVEDP change as low as 2 mmHg was detected by our system and methodology.
  • the initial clinical feasibility pilot studies includes 7 patients who underwent routine cardiac catheterization.
  • the investigational device detected even small changes in LVEDP, in the range of 2-7mmHg. These results provide a proof of concept of the utility of the bio-impedance waveform in detecting changes in LVEDP. More subtle changes in LVEDP is the focus as found during the legs up maneuver. This was achieved by elevating the legs on a triangular mattress at 25°. No subject's cooperation was required during this maneuver. Assuming that there was no or there was very little influence on the chest anatomy of the subject, therefore this maneuver is reliable and independent of the collaboration of the evaluated subjects.
  • waveform measurements were repeatable in the same measurement cycle, in recurrent measurements cycles, at different time intervals, in the same subject, during the same maneuver;

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Abstract

La présente invention concerne un procédé de surveillance non invasive de l'état hémodynamique du cœur d'un sujet, comprenant les étapes suivantes : a. acquisition d'au moins une forme d'onde de bio-impédance dudit sujet, ladite forme d'onde de bio-impédance étant la variation de bio-impédance pendant au moins un cycle cardiaque dudit sujet ; b. analyse de ladite au moins une forme d'onde de bio-impédance et extraction d'au moins un paramètre de forme d'onde P ; c. surveillance dudit état hémodynamique ; où ladite étape de surveillance est mise en œuvre en corrélant ledit au moins un paramètre de forme d'onde d'impédance P avec une pression ventriculaire gauche en fin de diastole (PVGFD), et calcul d'une valeur estimée de ladite PVGFD dudit paramètre de forme d'onde d'impédance P.
PCT/IL2017/050151 2016-02-08 2017-02-08 Système et procédé permettant de surveiller les paramètres cardiaques de manière non invasive Ceased WO2017137983A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
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CN109846464A (zh) * 2018-12-29 2019-06-07 曹乃钊 血液流动力学参数的无创测量系统和数据处理系统
CN114173645A (zh) * 2019-06-18 2022-03-11 生命解析公司 使用生物物理信号的动态分析来评估疾病的方法和系统

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US20030083582A1 (en) * 2001-10-31 2003-05-01 Robert Hirsh Non-invasive method and device to monitor cardiac parameters
US20090124867A1 (en) * 2007-11-13 2009-05-14 Hirsh Robert A Method and device to administer anesthetic and or vosactive agents according to non-invasively monitored cardiac and or neurological parameters
US8512252B2 (en) * 2002-10-07 2013-08-20 Integrated Sensing Systems Inc. Delivery method and system for monitoring cardiovascular pressures

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US4889133A (en) * 1988-05-25 1989-12-26 Protocol Systems, Inc. Method for noninvasive blood-pressure measurement by evaluation of waveform-specific area data
US20030083582A1 (en) * 2001-10-31 2003-05-01 Robert Hirsh Non-invasive method and device to monitor cardiac parameters
US8512252B2 (en) * 2002-10-07 2013-08-20 Integrated Sensing Systems Inc. Delivery method and system for monitoring cardiovascular pressures
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CN109846464A (zh) * 2018-12-29 2019-06-07 曹乃钊 血液流动力学参数的无创测量系统和数据处理系统
CN114173645A (zh) * 2019-06-18 2022-03-11 生命解析公司 使用生物物理信号的动态分析来评估疾病的方法和系统

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