WO2004002305A2 - Systemes et procedes d'evaluation non invasive d'un tissu cardiaque, et parametres s'y rapportant - Google Patents

Systemes et procedes d'evaluation non invasive d'un tissu cardiaque, et parametres s'y rapportant Download PDF

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Publication number
WO2004002305A2
WO2004002305A2 PCT/US2003/020764 US0320764W WO2004002305A2 WO 2004002305 A2 WO2004002305 A2 WO 2004002305A2 US 0320764 W US0320764 W US 0320764W WO 2004002305 A2 WO2004002305 A2 WO 2004002305A2
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tissue
acoustic
target
ultrasound
mode
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PCT/US2003/020764
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English (en)
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WO2004002305A3 (fr
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Pierre Mourad
Michel Kliot
Rex Patterson
Alec Rooke
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Allez Physionix
University Of Washington
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Priority to AU2003280416A priority Critical patent/AU2003280416A1/en
Priority to JP2004518187A priority patent/JP2005532097A/ja
Priority to CA002490999A priority patent/CA2490999A1/fr
Priority to EP03742372A priority patent/EP1531725A4/fr
Publication of WO2004002305A2 publication Critical patent/WO2004002305A2/fr
Publication of WO2004002305A3 publication Critical patent/WO2004002305A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/48—Diagnostic techniques
    • A61B8/485—Diagnostic techniques involving measuring strain or elastic properties
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/06—Measuring blood flow
    • A61B8/065—Measuring blood flow to determine blood output from the heart
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/08—Detecting organic movements or changes, e.g. tumours, cysts, swellings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/08—Detecting organic movements or changes, e.g. tumours, cysts, swellings
    • A61B8/0883—Detecting organic movements or changes, e.g. tumours, cysts, swellings for diagnosis of the heart
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/45—For evaluating or diagnosing the musculoskeletal system or teeth
    • A61B5/4519—Muscles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/50—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment specially adapted for specific body parts; specially adapted for specific clinical applications
    • A61B6/503—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment specially adapted for specific body parts; specially adapted for specific clinical applications for diagnosis of the heart
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/50—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment specially adapted for specific body parts; specially adapted for specific clinical applications
    • A61B6/504—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment specially adapted for specific body parts; specially adapted for specific clinical applications for diagnosis of blood vessels, e.g. by angiography
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/04—Measuring blood pressure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/08—Detecting organic movements or changes, e.g. tumours, cysts, swellings
    • A61B8/0808—Detecting organic movements or changes, e.g. tumours, cysts, swellings for diagnosis of the brain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/08—Detecting organic movements or changes, e.g. tumours, cysts, swellings
    • A61B8/0891—Detecting organic movements or changes, e.g. tumours, cysts, swellings for diagnosis of blood vessels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/42—Details of probe positioning or probe attachment to the patient
    • A61B8/4209—Details of probe positioning or probe attachment to the patient by using holders, e.g. positioning frames
    • A61B8/4236—Details of probe positioning or probe attachment to the patient by using holders, e.g. positioning frames characterised by adhesive patches

Definitions

  • This invention relates to systems and methods for assessing cardiac tissue and cardiac parameters noninvasively using ultrasound techniques.
  • Ultrasound imaging is a non-invasive, diagnostic modality that is capable of providing information relating to tissue properties.
  • ultrasound may be used in various modes to produce images of objects or structures within a patient.
  • a transmission mode an ultrasound transmitter is placed on one side of an object and the sound is transmitted through the object to an ultrasound receiver.
  • An image may be produced in which the brightness of each image pixel is a function of the amplitude of the ultrasound that reaches the receiver (attenuation mode), or the brightness of each pixel may be a function of the time required for the sound to reach the receiver (time-of-flight mode).
  • an image may be produced in which the pixel brightness is a function of the amplitude of reflected ultrasound (reflection or backscatter or echo mode).
  • the tissue (or object) is imaged by measuring the phase shift of the ultrasound reflected from the tissue (or object) back to the receiver.
  • Ultrasonic transducers for medical applications are constructed from one or more piezoelectric elements activated by electrodes.
  • Such piezoelectric elements may be constructed, for example, from lead zirconate titanate (PZT), polyvinylidene diflouride (PVDF), PZT ceramic/polymer composites, and the like.
  • the electrodes are connected to a voltage source, a voltage waveform is applied, and the piezoelectric elements change in size at a frequency corresponding to that of the applied voltage.
  • the piezoelectric elements emit an ultrasonic wave into the media to which it is coupled at the frequencies contained in the excitation waveform.
  • the piezoelectric element Conversely, when an ultrasonic wave strikes the piezoelectric element, the element produces a corresponding voltage across its electrodes.
  • Numerous ultrasonic transducer constructions are known in the art.
  • ultrasonic transducers When used for imaging, ultrasonic transducers are provided with several piezoelectric elements arranged in an array and driven by different voltages. By controlling the phase and amplitude of the applied voltages, ultrasonic waves combine to produce a net ultrasonic wave that travels along a desired beam direction and is focused at a selected point along the beam. By controlling the phase and the amplitude of the applied voltages, the focal point of the beam can be moved in a plane to scan the subject. Many such ultrasonic imaging systems are well known in the art.
  • acoustic radiation force is exerted by an acoustic wave on an object in its path.
  • the use of acoustic radiation forces produced by an ultrasound transducer has been proposed in connection with tissue hardness measurements. See Sugimoto et al., "Tissue Hardness Measure Using the Radiation Force of Focused Ultrasound", IEEE Ultrasonics Symposium, pp. 1377-80, 1990.
  • This publication describes an experiment in which a pulse of focused ultrasonic radiation is applied to deform the object at the focal point of the transducer. The deformation is measured using a separate pulse-echo ultrasonic system. Measurements of tissue hardness are made based on the amount or rate of object deformation as the acoustic force is continuously applied, or by the rate of relaxation of the deformation after the force is removed.
  • the object is probed by arranging the intersection of two focused, continuous-wave ultrasound beams of different frequencies at a selected point on the object. Interference in the intersection region of the two beams produces modulation of the ultrasound energy density, which creates a vibration in the object at the selected region. The vibration produces an acoustic field that can be measured.
  • ultrasound-stimulated vibro-acoustic spectrography has potential applications in the nondestructive evaluation of materials, and for medical imaging and noninvasive detection of hard tissue inclusions, such as the imaging of arteries with calcification, detection of breast microcalcifications, visualization of hard tumors, and detection of foreign objects.
  • U.S. Patents 5,903,516 and 5,921,928 disclose a method and system for producing an acoustic radiation force at a target location by directing multiple high frequency sound beams to intersect at the desired location.
  • a variable amplitude radiation force may be produced using variable, high frequency sound beams, or by amplitude modulating a high frequency sound beam at a lower, baseband frequency.
  • the mechanical properties of an object, or the presence of an object may be detected by analyzing the acoustic wave that is generated from the object by the applied acoustic radiation force.
  • An image of the object may be produced by scanning the object with high frequency sound beams and analyzing the acoustic waves generated at each scanned location.
  • the mechanical characteristics of an object may also be assessed by detecting the motion produced at the intersections of high frequency sound beams and analyzing the motion using Doppler ultrasound and nuclear magnetic resonance imaging techniques. Variations in the characteristics of fluids (e.g. blood), such as fluid temperature, density and chemical composition can also be detected by assessing changes in the amplitude of the beat frequency signal.
  • fluids e.g. blood
  • Various applications are cited, including detection of atherosclerosis, detection of gas bubbles in fluids, measurement of contrast agent concentration in the blood stream, object position measurement, object motion and velocity measurement, and the like.
  • An imaging system is also disclosed.
  • U.S. Patent 6,039,691 discloses methods and apparatus for soft tissue examination employing an ultrasonic transducer for generating an ultrasound pulse that induces physical displacement of viscous or gelatinous biological fluids and analysis techniques that determine the magnitude of the displacement.
  • the transducer receives ultrasonic echo pulses and generates data signals indicative of the tissue displacement.
  • This apparatus and method is particularly useful for examining the properties of a subject's vitreous body, in connection with the evaluation and/or diagnosis of ocular disorders, such as vitreous traction.
  • U.S. Patent 5,086,775 (Parker et al.) describes a system in which a low frequency vibration source is used to generate oscillations in an object, and a coherent or pulsed ultrasound imaging system is used to detect the spatial distribution of the vibration amplitude or speed of the object in real-time.
  • the reflected Doppler shifted waveform generated is used to compute the vibration amplitude and frequency of the object on a frequency domain estimator basis, or on a time domain estimator basis.
  • Applications of this system include examination of passive structures such as aircraft, ships, bridge trusses, as well as soft tissue imaging, such as breast imaging.
  • U.S. Patents to Sarvazyan relate to methods and devices for ultrasonic elasticity imaging for noninvasively identifying tissue elasticity. Tissue having different elasticity properties may be identified, for example, by simultaneously measuring strain and stress patterns in the tissue using an ultrasonic imaging system in combination with a pressure sensing array. The ultrasonic scanner probe with an attached pressure sensing array may exert pressure to deform the tissue and create stress and strain in the tissue. This system may be used, for example, to measure mechanical parameters of the prostate.
  • U.S. Patents to Sarvazyan also describe shear wave elasticity imaging using a focused ultrasound transducer that remotely induces a propagating shear wave in tissue. Shear modulus and dynamic shear viscosity at a given site may be determined from the measured values of velocity and attenuation of propagating shear waves at that site.
  • Cardiac output is important to the body for two reasons.
  • the major limitation in the delivery of nutrients to the tissues of the body is the delivery of oxygen.
  • Delivery of metabolic substrates ("food") and elimination of waste products require less blood flow than is necessary for adequate delivery of oxygen for the tissues' metabolic needs.
  • An inadequate cardiac output translates into some tissues of the body receiving too little oxygen and leads to dysfunction of the affected organ or even tissue damage or cell death of the deprived tissue.
  • the "gold standard" for measurement of cardiac output is the pulmonary artery catheter. It measures cardiac output via the thermodilution technique. It is effective, and not difficult to use, but it requires placing the catheter into a vein and threading the catheter through the heart and into the lungs. The risks to the patient from using the pulmonary artery catheter preclude routine use. Echocardiography can be used, either transthoracically or using esophageal echo. This technique is safer to the patient, but it is technically more difficult, less accurate, and impractical to use for longer than a few minutes at a time. Other techniques exist, but none have gained universal acceptance. A low risk method for measuring either cardiac output, or providing a good estimation of the components of cardiac output, would prove invaluable in critical care settings. Such a technique would likely be used in far more patients than is the number of patients who currently receive a pulmonary artery catheter.
  • Stroke volume is a function of two basic properties of the heart: volume status and contractility. Each of these parameters is as important to blood pressure as vascular resistance and heart rate.
  • volume status of a patient is manipulated by increasing or decreasing the blood volume of the body, what is really important is the volume status of the right and left ventricles.
  • the ventricles need to be "filled up" prior to contraction for two reasons. First, the ventricles cannot pump to the lungs or body (right and left ventricles, respectively) what the ventricles don't have in them at the start of contraction. The more blood in the chamber of the ventricle, the more blood could be potentially pumped out. Second, as more blood is put in the ventricle, the muscle cells of the heart become more stretched.
  • stroke volume is equal to the product of end-diastolic volume (EDV, the amount of blood in the chamber of the ventricle just before contraction begins) and the ejection fraction (EF, the percent of the EDV that is pushed out of the ventricle during heart contraction).
  • EDV end-diastolic volume
  • EF ejection fraction
  • the EF will not decrease even if blood pressure increases as a result of the improved stroke volume.
  • a heart with poorly functioning muscle will have a low EF at baseline and will not demonstrate much of an improvement in its contraction when EDV is increased (See Figure 1).
  • more volume may worsen the status of the patient if the heart does not improve its performance in response to the volume. If performance does not improve, the heart may become distended, which results in impaired function.
  • the increase in volume increases the filling pressures, that in rum must be matched by increased pressures in the atrium and veins.
  • the catheter can measure the pressure in the atria and thus provide an estimate of the pressure in the ventricular chamber during diastole when the heart muscle is relaxed. If these pressures are already high, then more fluid must be administered with great care, if at all.
  • inte ⁇ retation of pressures provided by the pulmonary artery catheter can be difficult, making optimal fluid management problematic.
  • the difficulty in part, is that the relationship between the filling pressure (end- diastolic pressure) and volume (end-diastolic volume) is not linear.
  • Figure 2 illustrates this relationship between end-diastolic pressure and volume for heart tissue that is stiff and compliant.
  • a change in pressure of a few mmHg could represent a big or a small change in ventricular volume, depending on the character of the heart tissue.
  • the curve can shift around making it harder to inte ⁇ ret the pressure measurements as a measure of end-diastolic volume.
  • ventricular wall stiffness if it could be provided, would be helpful because wall stiffness is directly affected by ventricular pressure.
  • knowledge of a wall stiffness parameter may be more useful than knowledge of a pressure parameter because stiffness is also affected by ventricular size.
  • Measurement of a ventricular wall stiffness parameter is likely to be more effective than measurement of a pressure parameter in determining when fluid volume administration will be ineffective or even harmful to a patient.
  • Ultrasound techniques such as Doppler tissue imaging modes, have recently been proposed for use in the diagnosis of cardiac tissue and function.
  • these techniques involve tracking of tissue movement, or velocity. Tissue velocities are used to derive an estimate of strain rate, and from strain rate, an estimation of tissue strain may be derived.
  • These techniques are dependent on accurate tissue motion estimates, when tissues are moving in different directions within a small spatial region.
  • U.S. Patent 6,527,717 discloses systems and methods for analyzing tissue motion in which motion estimates are corrected for transducer motion. Tissue motion may be used to determine a strain rate or strain, and motion estimates may be generated using data acquired by an intracardiac transducer array.
  • U.S. Patent 6,099,471 discloses ultrasound techniques for determining strain velocity from tissue velocity. Tissue velocity is determined based on measurements of the pulse-to- pulse Doppler shift at positions along an ultrasound beam.
  • U.S. Patent 6,517,485 discloses ultrasound systems and methods for calculating and displaying tissue deformation parameters, such as tissue Doppler and strain rate imaging.
  • U.S. Patent 6,537,221 relates to strain rate analysis for ultrasound images in which the spatial gradient of velocity is calculated in the direction of tissue motion.
  • U.S. Patents 6,579,240 discloses ultrasound display of a moving structure, such as a cardiac wall tissue within a region of interest, as a color representation.
  • Arterial Blood Pressure is a fundamental objective measure of the state of an individual's health. Indeed, it is considered a "vital sign" and is of critical importance in all areas of medicine and healthcare. The accurate measure of ABP assists in determination of the state of cardiovascular and hemodynamic health in stable, urgent, emergent, and operative conditions, indicating appropriate interventions to maximize the health of the patient.
  • ABP is most commonly measured noninvasively using a pneumatic cuff, often described as pneumatic plethysmography or Korotkoff s method. While this mode of measurement is simple and inexpensive to perform, it does not provide the most accurate measure of ABP, and it is susceptible to artifacts resulting from the condition of arterial wall, the size of the patient, the hemodynamic status of the patient, and autonomic tone of the vascular smooth muscle. Additionally, repeated cuff measurements of ABP result in falsely elevated readings of ABP, due to vasoconstriction of the arterial wall. To overcome these problems, and to provide a continuous measure of ABP, invasive arterial catheters are used.
  • U.S. Patent 4,869,261 to Penaz discloses a method for automatic, non-invasive determination of continuous arterial blood pressure in arteries compressible from the surface by first determining a set point with a pressure cuff equipped with a plethysmographic gauge of vascular volume and then maintaining the volume of the measured artery constant to infer arterial blood pressure.
  • a generator producing pressure vibrations superimposed on the basic blood pressure wave, and the changes in the oscillations of the blood pressure wave are monitored by an active servo-system that constantly adjusts the cuff pressure to maintain constant arterial volume; thus, the frequency of vibration of the blood pressure wave that is higher than the highest harmonic component of the blood pressure wave is used to determine arterial blood pressure.
  • U.S. Patent 4,510,940 to Wesseling discloses a method for correcting the cuff pressure in the indirect, non-invasive and continuous measurement of the blood pressure in a part of the body by first determining a set-point using a plethysmograph in a fluid-filled pressure cuff wrapped around an extremity and then adjusting a servo-reference level as a function of the shape of the plethysmographic signal, influenced by the magnitude of the deviation of the cuff pressure adjusted in both open and closed systems.
  • U.S. Patent 5,241,964 to McQuilkin discloses a method for a non-invasive, non- occlusive method and apparatus for continuous determination of arterial blood pressure using one or more Doppler sensors positioned over a major artery to determine the time-varying arterial resonant frequency and hence blood pressure.
  • Alternative methods including the concurrent use of proximal and distal sensors, impedance plethysmography techniques, infrared percussion sensors, continuous oscillations in a partially or fully inflated cuff, pressure transducers or strain gauge devices applied to the arterial wall, ultrasonic imaging techniques which provide the time-varying arterial diameter or other arterial geometry which changes proportionately with intra-mural pressure, radio frequency sensors, or magnetic field sensors are also described.
  • U.S. Patent 5,830,131 to Caro et al. discloses a method for determining physical conditions of the human arterial system by inducing a well-defined perturbation (exciter waveform) of the blood vessel in question and measuring a hemo-parameter containing a component of the exciter waveform at a separate site.
  • the exciter consists of an inflatable bag that can exert pressure on the blood vessel of interest, and is controlled by a processor. Physical properties such as cardiovascular disease, arterial elasticity, arterial thickness, arterial wall compliance, and physiological parameters such as blood pressure, vascular wall compliance, ventricular contractions, vascular resistance, fluid volume, cardiac output, myocardial contractility, etc. are described.
  • U.S. Patent 4,646,754 to Seale discloses a method for non-invasively inducing vibrations in a selected element of the human body, including blood vessels, pulmonary vessels, and eye globe, and detecting the nature of the responses for determining mechanical characteristics of the element.
  • Methods for inducing vibrations include mechanical drivers, while methods for measuring responses include ultrasound, optical means, and visual changes.
  • Mechanical characteristics include arterial blood pressure, organ impedance, intraocular pressure, and pulmonary blood pressure.
  • U.S. Patent 5,485,848 to Jackson et al. discloses a method and apparatus for noninvasive, continuous arterial blood pressure determination using a separable, diagnostically accurate blood pressure measuring device, such as a conventional pressure cuff, to initially calibrate the system and then measuring arterial wall movement caused by blood flow through the artery to determine arterial blood pressure.
  • a separable, diagnostically accurate blood pressure measuring device such as a conventional pressure cuff
  • Piezoelectric devices are used in wristband device to convert wall motion signals to an electric form that can be analyzed to yield blood pressure.
  • U.S. Patent 5,749,364 to Sliwa, Jr. et al. discloses a method and apparatus for the determination of pressure and tissue properties by utilizing changes in acoustic behavior of micro-bubbles in a body fluid, such as blood, to present pressure information.
  • This invention is directed at the method of mapping and presenting body fluid pressure information in at least two dimensions and to an enhanced method of detecting tumors.
  • PCT International Patent Publication WO 00/72750 to Yang et al. discloses a method and apparatus for the non-invasive, continuous monitoring of arterial blood pressure using a finger plethysmograph and an electrical impedance photoplethysmograph to monitor dynamic behavior of arterial blood flow. Measured signals from these sensors on an arterial segment are integrated to estimate the blood pressure in this segment based on a hemodynamic model that takes into account simplified upstream and downstream arterial flows within this vessel.
  • a noninvasive, continuous ABP monitor would provide medical personnel with valuable information on the hemodynamic and cardiovascular status of the patient in any setting, including the battlefield, emergency transport, clinic office, and triage clinics. Additionally, it would provide clinicians the ability to continuously monitor the ABP of a patient in situations where the risks of an invasive catheter are unwarranted or unacceptable (e.g., outpatient procedures, ambulance transports, etc.). Thus, the present invention is directed to methods and systems for the continuous assessment of ABP using non-invasive ultrasound techniques.
  • the present invention provides methods and systems using the application of ultrasound for noninvasively assessing, localizing and monitoring cardiac properties and parameters, and for diagnosing, localizing and monitoring various conditions, responses and disease states.
  • Acoustic properties of tissues, including cardiac tissues, and tissue displacement may be evaluated using the methods and systems described herein, as well as the techniques described in PCT International Publication WO 02/43564, which is inco ⁇ orated herein by reference in its entirety.
  • Acoustic properties of cardiac tissue may be determined, for example, by collecting acoustic scatter data using an ultrasound transducer, or transducer array, aimed at, or having a focus on or in cardiac tissue.
  • measurements of the "intrinsic" properties of cardiac tissue, in situ, such as tissue stiffness or tension or strain, etc. are taken using ultrasound techniques.
  • focused ultrasound beam(s) are applied to cardiac tissue to deform localized cardiac tissue, and one or more aspect(s) of the deformation, or a biological response produced by the deformation(s), is assessed and related to cardiac tissue properties and parameters.
  • the (intrinsic or induced) acoustic properties of cardiac tissue are related to physical and/or structural tissue properties, such as tissue stiffness, distension, tension, strain, strain rate, elasticity, compliance and the like, which are related to clinically important cardiac parameters and properties, such as cardiac output.
  • an oscillatory radiation force is applied to localized cardiac tissue to induce localized tissue oscillations.
  • Acoustic emissions produced by the oscillating cardiac tissue, and/or other properties of the oscillating tissue are related to the properties of the cardiac tissue and may be related, according to the present invention, to specified cardiac parameters and properties.
  • focused ultrasound beam(s) are used to make local sonoelasticity measurements to assess the properties of cardiac tissue. For some applications, observations of changes and trends in the properties of targeted cardiac tissue over time are desired, rather than absolute measurements of targeted cardiac tissue properties at a given time.
  • the methods and systems of the present provide important information about the health and condition of cardiac tissue, such as ventricular wall stiffness.
  • wall stiffness is a function of ventricular chamber volume, ventricular wall thickness and the pressure in the ventricular chamber. If the heart muscle is contracting, then wall stiffness increases, if for no other reason than the ventricular chamber pressure increases. From these first principles a wide variety of useful information can be extracted from the measurement of myocardial tissue properties, such as wall stiffness, at various times throughout the cardiac cycle.
  • the cardiac cycle is divided into systole and diastole.
  • systole the heart muscle contracts and blood is ejected.
  • diastole the muscle relaxes and the ventricular chamber fills with blood from the atrium.
  • Figure 3 illustrates the pressure and volume relationships of blood in the left and right ventricles during cardiac cycling.
  • the volume of blood in the ventricle just before ejection begins is called the end-diastolic volume (Point A, Figure 3) and is associated with the end-diastolic pressure (Point B, Figure 3).
  • Ventricular end-diastolic volume affects both wall thickness (the wall thins as the heart fills) and end- diastolic pressure (pressure goes up as volume increases, but in a non-linear fashion).
  • end-diastole the ventricular muscle should be maximally relaxed, and wall stiffness is therefore determined by the intrinsic stiffness of the muscle, ventricular chamber volume, wall thickness and end-diastolic pressure. Consequently, ventricular wall stiffness at the end of diastole is heavily influenced by end-diastolic volume. Ventricular wall stiffness is thus a good parameter, measurable using methods and systems of the present invention, for determining end-diastolic volume and pressure.
  • Determinations of cardiac wall stiffness parameters provide useful information throughout the cardiac cycle, and not just at end-diastole. Examination of the pressure and volume relationships during the cardiac cycle, as shown in Figure 3, reveals that ventricular chamber pressure changes continually (in this example, the left ventricle). Of particular interest are the periods when the ventricle begins to fill (Point C, when the atrial pressure exceeds the ventricular pressure); when the ventricle is rapidly relaxing (Period D); and when the ventricle is rapidly developing pressure (Period E). The changes in wall stiffness during Period D, along with the wall stiffness at Point B, are useful in the assessment of ventricular relaxation and in the diagnosis of diastolic dysfunction. The changes in wall stiffness during Period E are useful in the assessment of ventricular contraction (contractility) and the diagnosis of systolic dysfunction.
  • FIG. 4A illustrates the flow of blood into a normal ventricle.
  • the E wave is the initial rapid filling as the ventricle draws in blood.
  • FIG. 4B shows the pattern of filling in an abnormal circumstance.
  • the ventricular muscle does not relax rapidly (diastolic dysfunction)
  • the residual muscle activity present at the beginning of filling does not permit the ventricle to spring open and limits the amount of blood entering the ventricle in early diastole.
  • the rest of the diastolic period must now make up for that limited filling in early diastole - in this circumstance, the A wave is larger than the E wave.
  • the atrium must increase in pressure, and this pressure increase is transmitted to both the ventricle and the organs upstream of the atrium (such as the lungs). If the pressure gets too high, then heart failure symptoms appear, such as pulmonary congestion. At one time, heart failure was thought to be due exclusively to poor contractility. Now it is understood that diastolic dysfunction alone can cause heart failure. The problem is that diastolic dysfunction cannot be diagnosed as easily as just described. For example, old age causes the abnormal filling pattern shown in Figure 4B to develop. Furthermore, as atrial pressure increases, the E wave becomes bigger, thereby preventing the appearance of a diminished E wave to diagnose diastolic dysfunction.
  • cardiac tissue stiffness and contractility makes the diagnosis of diastolic dysfunction trivially easy (and non-invasive) because wall stiffness in late diastole reflects left atrial pressure.
  • the methods and systems of the present invention provide high time resolution information on myocardial tension (strain) throughout the cardiac cycle. Strain measurements can be further manipulated to yield strain rate, the rate of change in strain over time. This approach is fundamentally different from the technologies that use measurement of myocardial tissue velocities to predict strain rate and strain.
  • the present invention provides a direct determination of tissue strain, so that strain no longer has to be referenced to an arbitrary zero as a consequence of the use of integration to determine strain from strain rate.
  • methods and systems of the present invention provide determinations of myocardial contractility, myocardial strain and strain rate; detection of myocardial ischemia and infarction; determination of ventricular filling; and detection of diastolic dysfunction.
  • myocardial contractility has been defined as either dP/dt, the rate of change of mtraventricular pressure, or as peak elastance as determined by the highest value of the mtraventricular pressure - ventricular volume ratio during systole.
  • dP/dt peaks during isovolumic contraction and therefore is relatively, but not completely, uninfluenced by loading conditions.
  • the major drawback is that measurement of intraventricular pressure requires the invasive placement of a catheter into the ventricular chamber. Peak elastance not only requires ventricular pressure measurements, but ventricular volume measurements as well. Less accurate, but clinically useful estimates of peak elastance have been achieved with non-invasive brachial blood pressure measurements and echocardiographic estimates of ventricular volume or area.
  • FIG. 5 shows a sample intraventricular pressure tracing (bottom panel) and the rate of change in pressure tracing (dP/dT, top panel).
  • the slope of the intraventricular trace equals the rate of change in pressure at any given instant.
  • contractility is considered proportional to the maximum rate of change in pressure observed during the contraction (peak value of the dP/dT trace). Ventricles with high contractility contract more rapidly and exhibit a higher value for dP/dT. The peak rate of pressure development occurs before the ventricle begins to eject blood.
  • Peak systolic strain rate correlates with peak dP/dt and with peak elastance.
  • Pislaru C Abraham TP, Belohlavek M: Strain and strain rate echocardiography. Cu ⁇ Opin Cardiol 2002; 17:443-454; and Weidemann F, Jamal F, Sutherland GR et al.: Myocardial function defined by strain rate and strain during alterations in inotropic states and heart rate, Am J Physiol Heart Circ Physiol 2002;283:H792-H799.
  • the maximum rate of tissue acceleration (rate of velocity increase) also co ⁇ elates with dP/dt and elastance when the heart is subjected to positive or negative inotropic agents. See, e.g., Vogel M, Cheung MMH, Li J et al.: Noninvasive assessment of left ventricular force-frequency relationships using tissue doppler-derived isovolumic acceleration, Circulation 2003; 107:1647-1652.
  • Peak strain rate may thus provide the best clinical estimation of myocardial contractility, particularly if strain rates can be measured in a completely non-invasive fashion.
  • measurement of strain and strain rates require a high quality echocardiogram machine, or rely on predictions made from tissue velocity measurements. Predictions of strain based on tissue velocity measurements, though they can be made using non-invasive ultrasound techniques, are not consistently accurate.
  • Myocardial velocity measurements furthermore, conventionally relate to net, or bulk, tissue movement. Continuous measurement of contractility over a prolonged period of time using echocardiogram techniques is not practical or cost effective, especially in an intensive care unit or operating room, where it may be desirable to monitor many patients simultaneously.
  • Methods and systems of the present invention provide determinations of strain rate as the rate of change of strain, measured directly using non-invasive ultrasound techniques over time. Strain rate is measured, not as bulk movement of myocardial tissue but, rather, as relative movements of selected target sites within myocardial tissue. And, because the time of peak strain rate is evanescent, improvements in accuracy of peak strain measurements provided using methods and systems of the present invention, reduce the amount of necessary time averaging of the signal, and improve the cycling rate of the measurement. Both passive and active modes of the present invention may be implemented to determine strain in myocardial tissue. Moreover, the improved accuracy, non-invasiveness and cost-effective attributes of methods and systems of the present invention permit use of strain and strain rate measurements for monitoring myocardial contractility and tissue properties, as well as diagnosis of myocardial dysfunction.
  • Myocardial Ischemia and Infarction Tissue Doppler ultrasound techniques have been used to detect myocardial ischemia, primarily in experimental situations that involve severe ischemia and consequent impairment of systolic dysfunction. Strain rate patterns change dramatically with the onset of ischemia, characterized by a delayed onset of (contraction) strain rate, decreased peak systolic strain rate and strain, post-systolic shortening, and decreased peak strain rate during early ventricular filling.
  • Methods and systems of the present invention that provide direct measurement of tissue properties, such as stiffness, tension, strain, etc., using non-invasive ultrasound techniques, are well suited for early detection of myocardial ischemia and infarction.
  • Myocardial tissue properties determined using acoustic techniques may be used, for example, to monitor diastolic relaxation, which is often the first clinical indication of cardiac ischemia.
  • the degree of ventricular filling has important ramifications for management of the heart and heart function in virtually all critical care situations, including the intensive care unit and the operating room.
  • the relationship is curvilinear and may shift (for the same ventricular blood volume) to higher or lower filling pressures, depending on the stiffness of the myocardium that is, in turn, influenced by many factors including tissue injury and diastolic function.
  • the blood volume of the ventricle is important, because the heart cannot pump what it does not have. Without blood entering the ventricle, there is no cardiac output and no blood pressure. Furthermore, the strength of the ventricular contraction is in part dependent on the stretch of the myocytes at the initiation of contraction. Greater stretch, produced by greater blood volume, generally increases the strength of the contraction. Volume can be estimated non-invasively by 2-D echocardiography, but the cost of the equipment makes it difficult to obtain multiple measurements over the course of a day, let alone to monitor blood volume continuously. Currently, central venous or pulmonary wedge pressure is often used to estimate ventricular end-diastolic pressure, but the inte ⁇ retation of the value is problematic due to the curvilinear relationship between pressure and volume. This problem is particular true in the early part of the curve, where large changes in ventricular volume may have only small effects on end-diastolic ventricular and atrial pressure.
  • the ventricle fills radius increases and wall thickness decreases. Therefore, even if end-diastolic pressure changes minimally, increased volume results in increased tension.
  • the myocardial tension changes more than pressure as the ventricle expands thereby making tension a better measure of volume status than pressure alone.
  • Techniques that predict tissue strain rate and/or strain based on tissue velocity determinations are generally not suitable for making ventricular filling and/or volume predictions, because they don't directly determine a zero tension point at the beginning of diastole.
  • the ability to measure absolute myocardial strain permits the utilization of myocardial strain as an index of ventricular volume.
  • Atrial pressure is still an important clinical parameter. Whatever the atrial pressure, it must be exceeded by the veins taking blood to the atrium. If the back-pressure gets too high, then fluid leaks out of the upstream veins and capillaries and can lead to clinical problems such as anasarca, liver dysfunction and pulmonary congestion or edema, all of which can be life-threatening. Thus, when a clinician attempts to optimize ventricular filling, the clinician must also be cognizant of the impact higher atrial pressures might have on the body. As direct measurement of central venous or pulmonary artery wedge pressures requires an invasive catheter, attempts have been made to estimate wedge pressure with non-invasive echocardiographic techniques.
  • E/Ea ratio the peak blood inflow rate across the mitral valve in early diastole and Ea is the peak tissue velocity in early diastole as measured at the mitral annulus (Sengupta et al, 2002). It is believed that wall tension measurements and their rate of change may prove as useful as Ea or even the E/Ea ratio.
  • Diastolic dysfunction involves slowed and even incomplete relaxation of the ventricle during diastole.
  • the functional implication is that if the ventricle remains stiff, particularly in early diastole when it is supposed to be receiving rapid inflow of blood from the atrium, then either too little blood will enter the ventricle, or the pressure in the atrium will have to increase to force the blood into the ventricle. If the atrial pressures increase to unacceptably high values, then signs and symptoms of fluid overload develop.
  • alterations are observed in diastolic tissue velocities.
  • Myocardial velocity in early diastolic filling correlates with tau and, like tau, appears to be little affected by loading conditions (atrial pressure, aortic pressure) (Waggoner, 2001). Therefore strain rate in early diastolic filling may not be affected by loading conditions, and so prove to be a useful measure of diastolic relaxation, too. Furthermore, the time trace of absolute tension near the tension nadir may reflect how quickly the myocardium relaxes.
  • diastolic function may be accomplished using either the passive or active ultrasound modes of the present invention, or both modes simultaneously or alternately.
  • NIRS near-infrared spectroscopy
  • OCT optical coherence tomography
  • PET magnetic resonance techniques
  • a portable, relatively low-cost magnetic resonance scanner is described, for example, in the California Institute of Technology Engineering and Science publication, Vol. LXIV, No. 2, 2001. The use of these techniques to measure various spatial and temporal aspects of tissue deformation and associated biological responses is generally known.
  • Ultrasound sources and detectors may be employed in a transmission mode, or in a variety of reflection, palpation or scatter modes, including modes that examine the transference of pressure waves into shear waves, and vice versa. Ultrasound detection techniques may also be used to monitor the acoustic emission(s) from insonified tissue. Detection techniques involving measurement of changes in acoustic scatter, particularly backscatter, or changes in acoustic emission, are particularly preferred for use in methods and systems of the present invention operating in either the passive or active modes, or in both modes simultaneously or alternately.
  • Exemplary acoustic scatter or emission data that are related to tissue properties include: changes in scatter or acoustic emission, including changes in the amplitude of acoustic signals, changes in phase of acoustic signals, changes in frequency of acoustic signals, changes in length of scattered or emitted signals relative to the interrogation signal, changes in the primary and/or other maxima and/or minima amplitudes of an acoustic signal within a cardiac and/or respiratory cycle; the ratio of the maximum and/or minimum amplitude to that of the mean or variance or distribution of subsequent oscillations within a cardiac cycle, changes in temporal or spatial variance of scattered or emitted signals at different times in the same location and/or at the same time in different locations, all possible rates of change of endogenous tissue displacement or relaxation, such as the velocity or acceleration of displacement, and the like.
  • Multiple acoustic interrogation signals may be employed, at the same or different frequencies, pulse lengths, pulse repetition frequencies, intensities, and the multiple interrogation signals may be sent from the same location or multiple locations simultaneously and/or sequentially. Scatter or emission from single or multiple interrogation signals may be detected at single or at multiple frequencies, at single or multiple times, and at single or multiple locations.
  • Acoustic properties of scatter and/or emission data from selected target tissue site(s), or derivative determinations such as tissue displacement, tissue stiffness, and the like, are related, using empirical formulations and/or mathematical models, to tissue properties and/or clinical parameters.
  • the relation of acoustic properties may be used in combination with other parameters, such as blood pressure, to assess tissue properties and/or clinical parameters.
  • declining blood pressure during surgical procedures may indicate either diminished or elevated fluid volumes.
  • Blood pressure may be monitored concomitantly with the acoustic properties of targeted cardiac tissue to determine whether declining blood pressure is a result of diminished or elevated fluid volumes.
  • increases in cardiac wall stiffness provide evidence of elevated fluid volumes, while reductions in cardiac tissue stiffness provide evidence of reduced fluid volumes.
  • Single or multiple interrogation signals administered from different places and/or at different times may insonify single or multiple target tissue sites.
  • Intrinsic and/or induced acoustic properties of the insonated target tissue may be assessed, by acquiring scatter or emission data, simultaneously and/or sequentially.
  • target tissue sites may be volumetrically small, and spatially resolved, to provide data from localized tissue sites with a high degree of spatial resolution. In this way, localized differences in tissue properties may be identified and associated with a spatial location within the inte ⁇ ogated tissue.
  • tissue sites of varying size and/or location are assessed simultaneously or sequentially.
  • the use of acoustic source(s) and/or transducer(s) capable of interrogating and detecting target tissue sites having a volume of from 1 mm to 100 cm 3 are suitable.
  • the target tissue site is preferably at a selected site within or on a surface of cardiac tissue.
  • the ventricle or atrium walls are targeted; for some applications, for example, the right ventricular wall is targeted.
  • Assessment of cardiac tissue properties based on their intrinsic and/or induced acoustic properties may be supplemented with data relating to mean and/or continuous arterial blood pressure, cardiac cycle information, heart rate, and the like.
  • Determinations of mean and/or continuous arterial blood pressure may be made, using ultrasound according to methods and systems of the present invention, in parallel with determinations of cardiac tissue properties and parameters. Blood pressure determinations may be made, for example, by selecting a target tissue site within or on or in proximity to a blood vessel and, preferably, in proximity to cardiac tissue. In this way, a single, integrated acoustic system may be used for making determinations of mean and/or continuous arterial blood pressure in parallel with determinations of cardiac tissue properties and parameters.
  • noninvasive systems and methods of the present invention provide a measure of arterial or venous blood pressure using acoustic techniques to measure alternating compression and dilation of the cross-section or other geometric or material properties of an artery or vein, using empirically established relationships and/or mathematical models.
  • blood pressure is determined using acoustic techniques to measure alternating compression and dilation of tissue surrounding blood vessels that is displaced as the vessels are compressed and dilated with the cardiac cycle.
  • Geometrical properties that may be determined using acoustic detection techniques include changes in diameter, cross-sectional area, aspect ratio, rates of changes in diameter, velocity, and the like.
  • Material properties that may be determined using acoustic detection techniques include the stiffness of vessel walls or tissue in proximity to vessel walls.
  • Blood pressure may be assessed, for example, by acquiring acoustic data, in an active and/or passive mode, from target tissue sites at or in proximity to one or more blood vessels.
  • the acoustic data can be related to the stiffness of vessel walls or supporting tissue, which can be related to blood pressure.
  • Suitable target tissue sites for determination of arterial or venous blood pressure may comprise any blood vessel or surrounding tissue.
  • Detection of ultrasound scatter data may be related, for example, with synchronous Doppler flow measurements within the same vessel.
  • a calibration step using a measure of blood pressure taken with a conventional blood pressure device may be inco ⁇ orated in the blood pressure determination.
  • Acoustic proxies for the pulsatility of the blood vessel - such as oscillation rate of the blood vessel wall - may be substituted for direct measures of those quantities.
  • the spontaneous changes in the diameter (or other geometric property) of the vessel being monitored are assessed using ultrasound, and this information is related (e.g., using correlation techniques) to synchronous Doppler flow measurements within the same vessel.
  • blood pressure can be calculated from flow velocity measured by Doppler. By simultaneously measuring the pulsatility of the blood vessel of interest and the Doppler flow velocity proximal and distal to this site, continuous blood pressure can be determined.
  • an acoustic detector such as an ultrasound transducer detects ultrasound signals that are indicative of tissue displacements, or associated biological responses, in one or more of the following operating modes: transmission, reflection, scatter, emission, backscatter, echo, Doppler, color Doppler, harmonic, subharmonic or superharmonic imaging, a-mode, m-mode, or b-mode.
  • Ultrasonic interrogation pulses having a known frequency, intensity and pulse repetition rate are administered to a desired target tissue site.
  • the intensity, frequency and pulse repetition rates of the ultrasonic interrogation pulses are selected such that the interrogation pulses do not produce undesired side effects, and do not substantially interfere with intrinsic tissue displacements resulting, for example, from blood flow and respiration.
  • Transmitted signals, signal reflections, acoustic emissions, scatter such as backscatter, and/or echoes of the interrogation pulses are detected and used to assess intrinsic tissue displacements and/or tissue properties at the target tissue site.
  • an acoustic detector is implemented to detect the backscatter of administered inte ⁇ ogation signals.
  • An acoustic detector may additionally or alternatively be operated in a Doppler mode to measure the phase shift of ultrasound reflected back to the detector.
  • a variety of techniques may be used to analyze the acquired acoustic data relating to intrinsic and/or induced cardiac tissue displacement or associated biological responses.
  • analytical techniques developed and employed in connection with ultrasound imaging such as cross-co ⁇ elation, auto-co ⁇ elation, wavelet analysis, Fourier analysis, CW Doppler, sum absolute difference, and the like, may be employed to determine various properties of tissue deformation, and to relate tissue deformation to tissue properties.
  • ANNs artificial neural networks
  • linear filters including those with both infinite impulse response IIR and finite impulse response FIR properties
  • HMMs Hidden Markov Models
  • heuristics and fuzzy logic systems may be used to relate one or more variables, such as tissue deformation, displacement, ABP, etc., to desired cardiac tissue properties and cardiac parameters.
  • False peak correction techniques may be used to improve the accuracy of the assessment.
  • properties of the major and minor endogenous oscillations of cardiac tissue within a cardiac cycle, or relationships between major and minor endogenous oscillations within a cardiac cycle, or across several respiratory cycles may be empirically related to cardiac tissue properties and conditions.
  • ABP blood pressure
  • respiration and/or exogenous tissue displacements may be made with, or without, additional information relating to ABP and/or respiration and/or exogenous tissue displacements.
  • parameters such as ABP are measured using other techniques, and one or more externally measured parameters are used for calibrating determinations made by systems of the present invention.
  • Methods and systems of the present invention are preferably integrated with control and data storage and manipulation features similar to the control and data storage and manipulation features provided on other types of diagnostic and monitoring systems.
  • Various types of control features, data storage features, data processing features, data output features, and the like, are well known in the art and may be adapted for use with the present invention.
  • methods and systems of the present invention stimulate or probe target cardiac tissue, or induce a response at a target cardiac tissue site, by application of focused ultrasound.
  • the response of the targeted tissue to the application of focused ultrasound may be deformation or displacement (a change in relative position), a change in temperature, a change in blood flow, or another detectable response.
  • application of an acoustic radiation force to "palpate" a target cardiac tissue site may be accomplished by administering one or more acoustic signals.
  • Non-invasive techniques such as ultrasound, optical techniques such as near infrared spectroscopy and optical coherence tomography, and other techniques, including magnetic resonance techniques, external electrophysiological stimulation, patient response, and the like are used to assess at least one response to the application of focused ultrasound.
  • a visualization or imaging technique such as ultrasound imaging or magnetic resonance imaging, may also be employed to assist in targeting the focused ultrasound pulse(s) and to assist in differentially localizing responsive tissues.
  • Acoustic techniques such as ultrasound, may be used to induce biological responses in tissue and to deflect or deform biological materials.
  • Biological materials absorb some of the ultrasound as it propagates into and through the material. See, e.g., Rudenko et al. (1996), "Acoustic radiation force and streaming induced by focused nonlinear ultrasound in a dissipative medium," J. Acoust. Soc. Am 99(5) 2791-2798.
  • an 'impedance mismatch' that is, differences between the product of density and speed of sound from one tissue to another
  • there is an 'impedance mismatch' that is, differences between the product of density and speed of sound from one tissue to another
  • one or more acoustic transducer(s) is placed in contact with or in proximity to a subject's chest.
  • An initial environmental assessment described below and preferably employing ultrasound techniques, may be made, if desired, to assess the characteristics of the environment between the acoustic source and the target tissue site, so that the magnitude of the acoustic force applied to the target tissue may be determined.
  • Environmental factors such as the distance between the acoustic transducer and various structural landmarks, may be determined.
  • An initial environmental assessment may be determinative of various method and system parameters.
  • Environmental assessments may additionally be updated at intervals throughout a diagnostic or monitoring procedure.
  • an acoustic force is applied by an acoustic transducer, at a predetermined frequency, to displace targeted cardiac tissue at a targeted location.
  • the deformation may be produced at any desired location within cardiac tissue, depending on the focus (foci) of the ultrasonic transducer(s) producing the acoustic radiation force.
  • variable foci ultrasonic transducers are provided, and a diagnostic procedure is carried out using a plurality of target tissue sites.
  • the focus (foci) of the ultrasonic transducer(s) is preferably provided in proximity to the surface or a small distance below the surface of a ventricle wall, to maximize the tissue displacement induced by the radiation pressure that arises from the impedance mismatch between cardiac tissue and fluid.
  • the applied acoustic radiation force is sufficient to induce a detectable displacement in the cardiac tissue, or the applied ultrasound beam is sufficient to produce a detectable biological response, without producing any medically undesirable changes in the examined tissue.
  • the acoustic radiation force applied must not produce shear in tissues in proximity to the target tissue of a magnitude sufficient to tear or damage tissue.
  • the applied ultrasound moreover, must not appreciably increase the temperature of examined tissue to the point of causing unacceptable damage, and it must not induce extensive or damaging cavitation or other produce other deleterious mechanical effects in the examined tissue.
  • Suitable ultrasound dosages may be determined using well known techniques. For example, Fry et al. studied the threshold ultrasonic dosages causing structural changes in mammalian brain tissue and illustrate, in their Fig.
  • the acoustic frequency must be low enough to penetrate the tissues between the skin surface and the cardiac tissue, and high enough to produce measurable deformation in the target tissue at the location of interest. Within the parameters outlined above, higher frequency acoustic waves are more easily focused and, therefore, are preferred.
  • the intensity must be high enough to deform the tissue, but not be so great as to induce undesirable changes in the examined tissue.
  • the pulse length is preferably relatively short, but long enough to create a measurable deformation or oscillation of the target tissue, as desired, while the pulse repetition frequency must be large enough to resolve medically interesting temporal features in the tissue, without inducing medically unacceptable changes in the tissue.
  • At least one acoustic property related to tissue displacement, or an associated biological response is determined and related to a tissue property and, ultimately, to a clinically important parameter.
  • the magnitude, or amplitude, of the displacement induced by the known acoustic force is directly related to the elasticity (or stiffness or compliance, e.g., Young's modulus) of the cardiac tissue, and can therefore be empirically related to clinically relevant cardiac parameters, such as cardiac output.
  • Additional properties of the target tissue displacement that may be determined and related to tissue properties include: various components of amplitude, such as maximum amplitude in the direction of the acoustic force or maximum amplitude pe ⁇ endicular to the direction of acoustic force; all possible rates of change of the displacement or subsequent relaxation of the tissue, such as the velocity or acceleration of displacement or relaxation; the amplitude or rates of change of various components of the shape of the displacement; changes in Fourier or wavelett representations of the acoustic scatter signal associated with the displacement; properties of shear waves generated by the acoustic radiation force; properties of induced second harmonic deformation(s), and the like. Time displacements of pulse echoes returning from the target tissue are also indicative of the displacement amplitude and may be determined. These properties are all referred to as measures of "displacement.”
  • a second "active" mode of operation application of focused ultrasound produces oscillation of targeted tissue, and data relating to the acoustic signals emitted from the targeted tissue are collected. These signals are refe ⁇ ed to herein as acoustic emissions.
  • methods and systems of the present invention that relate to application of focused ultrasound may be used to produce oscillation of targeted tissue, and emitted acoustic signals are related to tissue properties and physiological conditions.
  • methods and systems of the present invention employ a confocal acoustic system comprising at least two acoustic transducers, driven at different frequencies, or a focal acoustic system comprising a single acoustic transducer driven at a given pulse repetition frequency (PRF), to induce an oscillatory radiation force in the target tissue, such as cardiac tissue.
  • the resulting oscillation is at a frequency that is the difference of the applied frequencies, at the target location that is marked by the overlap of the two confocal acoustic beams or, for the single transducer case, at the PRF.
  • the targeted tissue emits acoustic signals related to its intrinsic properties.
  • the second, active mode of operation may therefore be used to characterize tissue. Diagnostic ultrasound techniques may be used to measure the frequency or other properties of the emitted acoustic signal, which are empirically related to tissue properties.
  • acoustic techniques such as ultrasound
  • ultrasound backscatter and/or emission data are related to intrinsic tissue displacements, which can be related to various tissue properties.
  • Supplemental data such as measures of mean and/or continuous arterial blood pressure, blood flow, and the like, may additionally be used in these determinations.
  • the magnitude or amplitude or phase of acoustic scatter from target cardiac tissue sites undergoing intrinsic displacements during the course of the cardiac cycle is directly related to the stiffness, e.g. Young's modulus, of the cardiac tissue.
  • stiffness e.g. Young's modulus
  • relationships between the major and minor intrinsic oscillations of cardiac tissue within a cardiac cycle, or within a cardiac cycle as modulated by one or more respiratory cycles are empirically related to tissue properties.
  • Properties of the intrinsic tissue displacement that may be assessed and related to tissue properties include: various components of amplitude, such as maximum amplitude within a cardiac cycle, the ratio of the maximum amplitude to that of the mean or variance of subsequent oscillations within a cardiac cycle, all possible rates of change of intrinsic cardiac tissue displacement or relaxation, such as the velocity or acceleration of displacement, and the like. Additional data, such as ABP measurements and/or respiration data, may be collected and used, with the acoustic data, to make various assessments and clinical determinations.
  • Relative trend determinations of the target cardiac tissue properties such as stiffness, contractility, tension, strain and the like, at or near the relevant portions of the heart (e.g. ventricle walls and/or atrium walls) are made during certain portions of the cardiac cycle, and may be synchronized with EKG measurements.
  • the right ventricle is relatively easy to image with ultrasound.
  • data may be collected over many cardiac cycles, in some embodiments starting when the patient's ventricle wall tension is known to be normal, such as before or early in the time course of surgery, and continued until the patient is stabilized.
  • a system of the present invention comprises an inexpensive transducer with its own power supply, controller and display unit, designed to fit onto standard cardiac diagnostic ultrasound scan heads and interface electronically with standard diagnostic ultrasound machines.
  • one or more transducer array(s) are used for interrogation of and acquisition of acoustic data.
  • Fig. 1 shows the relationship between stroke volume and end-diastolic volume for normal cardiac tissue, as well as cardiac tissue that has high and poor contractility.
  • Fig. 2 shows the relationship between end-diastolic pressure and end-diastolic volume for stiff and compliant cardiac tissue.
  • Fig. 3 shows the pressure and volume relationships during the cardiac cycle.
  • Fig. 4A shows a normal ventricular filling profile, expressed in terms of volume over time, during a cardiac cycle.
  • Fig. 4B illustrates abnormal ventricular filling profile, expressed in terms of volume over time, during a cardiac cycle.
  • Fig. 5 shows a sample intraventricular pressure tracing (bottom panel) and the rate of change in pressure tracing (top panel).
  • Fig. 6 is a schematic diagram illustrating a system of the present invention for inducing and detecting tissue deformation for assessing cardiac tissue properties.
  • Fig. 7 is a schematic diagram illustrating another system of the present invention for inducing and detecting tissue deformation for assessing cardiac tissue properties.
  • Fig. 8 is a schematic cross-sectional diagram illustrating the use of confocal acoustic sources to produce tissue displacement and a diagnostic ultrasound probe to measure the amplitude of the displacement.
  • Fig. 9 shows a schematic illustration of a single cMUT array transducer cell structure.
  • Fig. 10A shows a plot demonstrating measured displacement of in vitro beef brain as a function of increasing simulated ICP and as a consequence to increasing brain CSF volume.
  • Fig. 10B shows a backscatter trace of human brain, in vivo, while the subject was holding his breath.
  • Fig. 10C shows the displacement of human brain, in vivo, while the subject was holding his breath.
  • Fig. 10D shows the displacement of human brain, in vivo, while the subject first held his breath and then inhaled.
  • Fig. 11 illustrates experimental results showing that the measured displacement of brain tissue, in vivo, is proportional to the acoustic radiation force applied, as indicated by the acoustic driving voltage.
  • exemplary systems of the present invention for acquiring data indicative of intrinsic and/or induced tissue displacements are described below. Although such systems may utilize commercially available components, the processing of the acquired data and the correlation of the acquired data to medically relevant physiological properties provides new modalities for noninvasively assessing numerous physiological parameters. Exemplary data processing techniques for detecting intrinsic and/or induced tissue displacements using acquired acoustic scatter data and correlating the acoustic scatter data or the displacement derivation with clinically important parameters, such as cardiac output, are also disclosed below. These techniques are exemplary and methods and systems of the present invention are not intended to be limited to the use of these exemplary techniques.
  • a single acoustic transducer may provide the interrogation signal(s) required for tissue assessment in passive modes, the acoustic force required for tissue displacement in active modes, and additionally may provide for detection of scattered interrogation signal(s) that are indicative of intrinsic (passive mode) or induced (active mode) tissue displacement.
  • a single transducer may be used to emit interrogation signal(s) for measuring intrinsic tissue displacements when operating at a first frequency, a first pulse repetition rate and a first intensity; to induce (exogenous) displacement or oscillation of tissue when operating at a second frequency, a second pulse repetition rate and a second intensity, and to detect signals reflected or backscattered or echoed or emitted from the tissue, e.g. when operated at a third frequency, or at additional frequencies, to assess the intrinsic or induced tissue displacement or emission, or to assess a biological response to the intrinsic or induced tissue displacement.
  • Multiple acoustic transducers may also be used.
  • one or more diagnostic ultrasound probes and one or more displacement ultrasound probes may be embodied in a single acoustic element.
  • acoustic interrogation pulses have larger peak positive pressure, have a higher frequency, and are shorter than acoustic palpation pulses.
  • Acoustic interrogation pulses may have a typical frequency between 0.5 and 15 MHz, use from 1-50 cycles per pulse, consist of 3-10,000 pulses per second, and have a time-averaged intensity of less than 0.5 W/cm 2 .
  • Acoustic palpation signals may, for example, have a frequency of from 0.5 to 10 MHz, consist of long tone bursts of from 0.1 - 100ms, consist of 1-100 pulses per second, and have a time averaged intensity of less than 100-lOOOW/cm , where longer pulses have lower intensities, for example.
  • Acoustic emissions from palpated or oscillated tissue are expected to be in the frequency range of 500Hz to lOKHz.
  • Fig. 6 is a schematic diagram illustrating a system of the present invention for inducing and/or detecting at least one aspect of intrinsic or induced tissue displacement for applications such as assessment of cardiac tissue properties.
  • systems of the present invention comprise an acoustic source and receiver combination 10 for noninvasively assessing tissue displacement or emission at a distance from the source/receiver combination.
  • acoustic source and receiver combination 10 comprises one or more acoustic source(s) 12 for producing an inte ⁇ ogation signal.
  • acoustic source and receiver combination 10 comprises one or more acoustic source(s) 22 for generating an acoustic radiation force, or for generating an oscillatory radiation force, or inducing an acoustic emission.
  • Acoustic source(s) 12 are driven by and operably connected to an amplifier or power source 14, which is operably connected to one or more function generator(s) 16, which is operably connected to a controller 20.
  • Controller 20 preferably has the capability of data acquisition, storage and analysis.
  • Controller 20, function generator 16 and amplifier 14 drive acoustic source(s) 12 in an interrogation (passive) or an acoustic radiation force (active) mode.
  • controller 30, function generator 28 and amplifier 26 drive acoustic source(s) 22 through the diplexer 24 at a desired frequency, intensity and pulse repetition rate to produce an interrogation signal for tissue target 32, such as cardiac tissue, without producing undesired side effects, and without producing a significant (exogenous) displacement.
  • tissue target 32 such as cardiac tissue
  • the resulting scattered signal is received at controller 30 via diplexer 24.
  • controller 20, function generator 16 and amplifier 14 drive acoustic source(s) 12 at a desired frequency, intensity and pulse repetition rate to produce a displacement in tissue target 32, such as cardiac tissue, without producing undesired side effects.
  • the controllers 20 and 30 communicate with one another to interleave their signals in time, for example.
  • the system based on transducer 22 can monitor the displacements and/or emissions induced by transducer 12.
  • the operating acoustic parameters are related to one another and suitable operating parameters may be determined with routine experimentation.
  • the focal point of the acoustic source(s), or transducer(s) may be fixed and non-adjustable as a consequence of the mechanical configuration of the transducer. Alternatively, multiple transducers may be provided and arranged to permit variation and adjustment of the focal point.
  • Acoustic sources, or transducers are preferably annular in configuration and, in preferred embodiment, acoustic source 12 comprises multiple annular transducers arranged in a concentric configuration. Acoustic sources and tranducers may be arranged axially or off-axis with respect to one another.
  • a second acoustic source 13 driven by and operably connected to a diplexer 15, which is operably connected to an amplifier or power source 17, which is operably connected to a function generator 19, which, in turn, communicates with controller 20 and/or controller 30 may also be provided, as shown in Fig. 6.
  • Acoustic source 13 may be used for assessing the characteristics of the environment between the acoustic source(s) and the target tissue, and may operate independently of transducer 12 and the related driver and controller components used for the assessment of the target tissue, or in coordination with transducer 12.
  • Fig. 7 illustrates one embodiment of an acoustic source and probe combination 40 that is especially suitable for use with the active mode of tissue assessment of the present invention.
  • Source and probe combination 40 comprises confocal, annular acoustic sources 42 and 44 and a diagnostic ultrasound probe 46. Phasing acoustic sources 42 and 44 at slightly different frequencies produces a significant radiation force only at their mutual focus, indicated in the cardiac tissue, such as near the ventricular wall surface, schematically illustrated at location 48, and deforms the tissue.
  • acoustic emissions may be generated from the transiently deformed tissue, with the emissions monitored by transducer 46 and related to tissue properties or physiological conditions.
  • the acoustic source and probe combination 40 illustrated in Fig. 7 may also be used, in combination with an imaging system, to acoustically palpate tissue at target sites to localize tissue responses to the focused ultrasound.
  • the imaging system may employ ultrasound or another tissue imaging modality, such as magnetic resonance imaging, computed tomagraphy, fluoroscopy, or the like.
  • Using an acoustic source and probe combination having ultrasound imaging capability provides visualization of the target site and aids targeting of the acoustic radiation force and localization of responses.
  • Fig. 8 illustrates another acoustic source and probe combination 50 comprising a plurality of ultrasonic transducers 51, 52, 53 and 54, arranged as concentric annular elements.
  • Each annular acoustic source represents a single frequency source of ultrasound that cooperates, with the other acoustic sources, to interrogate and/or displace tissue at a selected location.
  • the foci of the annular transducers is the focus of the interrogation signal, or the radiation force, and the location of assessment of intrinsic tissue displacement and/or induced tissue displacement and/or emissions. More or fewer ultrasonic transducers may be used.
  • a larger number of annular transducers generally provide a greater degree of control and precision of where the interrogation signals, or the radiation force, is focused.
  • This arrangement of annular transducers may also be used, in a variable frequency mode, to generate an oscillatory radiation force in target tissue.
  • each source is operated by a controller, amplifier and function generator, but operation of the separate acoustic sources is controllable using a centralized control system.
  • This acoustic system may be further generalized or modified for specific applications by using a non-annular or non-axial distribution of transducers to allow for additional ultrasound beam forming or electronic steering.
  • Detection element 56 is provided in acoustic combination 50 to detect at least one aspect of intrinsic and/or induced tissue displacement.
  • element 56 comprises a diagnostic ultrasonic probe that emits an ultrasonic pulse toward the site of tissue displacement and detects its echo to track the magnitude, or other aspects, of tissue displacement.
  • element 56 comprises an ultrasound probe, such as a transcranial Doppler, that detects the Doppler shift produced by the tissue displacement.
  • detection element 56 comprises a hydrophone that detects the sound waves emitted by tissue in which an acoustic radiation force is generated.
  • Commercially available components may be used in systems of the present invention. The following description of specific components is exemplary, and the systems of the present invention are in no way limited to these components.
  • Multi-element transducers have been used by researchers and are described in the literature. A multiple focused probe approach for high intensity focused ultrasound-based surgery is described, for example, in Chauhan S, et al., Ultrasonics 2001 Jan, 39(l):33-44. Multi-element transducers having a plurality of annular elements arranged, for example, co-axially, are suitable. Such systems may be constructed by commercial providers, such as Sonic Concepts, Woodinville, WA, using technology that is commercially available. Amplifiers, such as the ENI Model A- 150, are suitable and are commercially available. Diplexers, such as the Model REX-6 from Ritec, are suitable and are commercially available.
  • Function generators such as the Model 33120A from HP, are suitable and are commercially available. Many types of controllers are suitable and are commercially available.
  • a Dell Dimension XPS PC inco ⁇ orates a Gage model CS8500 A/D converter for data acquisition, and utilizes Lab View software from National Standards for data acquisition and equipment control.
  • an ATL transcranial Doppler probe, Model D2TC is used for detection.
  • an acoustic source/detector combination such as a TCD transducer/detector
  • a acoustic source/detector combination is stably mounted, or held, in proximity to a surface in proximity to an acoustic window, such that the focus of the acoustic source(s) is adjustable to provide an acoustic focal point within, or on, or in proximity to, myocardial tissue.
  • the acoustic source/detector combination is preferably provided as a unitary component, but separate components may also be used.
  • the acoustic source/detector combination may be mounted on a stabilizer, or in a structure, on the chest.
  • An applicator containing an acoustically transmissive material, such as a gel, may be placed between the surface of the acoustic source/detector combination and the chest.
  • An acoustic source/probe combination may be provided in a holder that is steerable to facilitate probing of various targeted tissue sites within a general situs. Steering of the acoustic device may be accomplished manually or using automated mechanisms, such as electronic steering mechanisms. Such mechanisms are well known in the art.
  • one or more transducer array(s) are used for acquisition of acoustic data, and data is processed using accompanying processing, storage and control functions.
  • such transducer arrays may be referred to as "phased arrays," since the individual acoustic elements within the array are coordinated with one another.
  • Transducer arrays may be used in either or both passive and active modes of operation, and may be used in imaging modes to display data relating to cardiac tissue properties and cardiac parameters. Many imaging and display techniques are known in the art and may be used to highlight various types and aspects of acquired data.
  • one or more transducer arrays may be operated simultaneously, or alternately, in active and passive modes of operation.
  • a programmable acoustic transducer array for example, multiple tissue sites may be acoustically interrogated in an active or passive mode simultaneously, or intermittently at pre-selected time intervals.
  • acoustic scatter data may be collected from multiple target cardiac tissue sites simultaneously, or intermittently.
  • tissue properties of target myocardial tissue may be determined based on acquired acoustic data while mean and/or continuous ABP is determined simultaneously based on acoustic data acquired from or in proximity to blood vessel(s).
  • acoustic arrays of the present invention comprise capacitive micromachined ultrasound transducers (cMUT).
  • cMUT transducer arrays may be used in both active and passive modes of operation according to the present invention.
  • cMUT ultrasonic transducers are manufactured using semiconductor processing techniques and have sufficient power and sensitivity to transmit and receive at diagnostic ultrasound energy levels, which is necessary and sufficient for our pu ⁇ oses.
  • the transducers are made by fabricating very small capacitive diaphragm structures in a silicon substrate.
  • Fig. 9 shows a single cMUT a ⁇ ay transducer cell structure. These diaphragm-structures convert acoustic vibrations into a modulated capacitance signal or vice versa.
  • a DC bias voltage is applied and an AC signal is either imposed on the DC signal in transmission or measured in reception.
  • a cMUT a ⁇ ay is composed of multiple individual cell structures a ⁇ ayed in rows and/or columns.
  • two cMUT acoustic a ⁇ ays are aligned in a sparse two- dimensional (2D) a ⁇ ay known as a "Mills Cross" configuration, which allows one a ⁇ ay to sweep vertically in send and receive modes and the other to sweep horizontally in receive and send modes.
  • 2D two-dimensional cMUT a ⁇ ays
  • two crossed linear cMUT a ⁇ ays alternatively transmit and receive ultrasound while electronically steering the sending and listening beams, to identify and focus on the acoustic signal that has the largest Doppler shift using, for example, range-dependent Doppler methodologies described below.
  • the send and receive modes of the acoustic a ⁇ ays may be reversed, or a single a ⁇ ay may be used to both send and receive acoustic signals.
  • Full 2D transducer a ⁇ ays having acoustic elements a ⁇ anged in any two-dimensional configuration may also be used.
  • Three dimensional transducer a ⁇ ays may also be used with appropriate control and processing systems.
  • a cMUT a ⁇ ay may be used in combination with a PZT transducer, with the PZT transducer serving as the acoustic source and transmitting around the cMUT a ⁇ ay, and the cMUT a ⁇ ay serving as the acoustic detector.
  • cMUT transducer a ⁇ ays have the potential of being produced very inexpensively, and may also have the support electronics integrated onto the same chip.
  • acoustic a ⁇ ays of the present invention are provided as a disposable component of an ICP monitoring device comprising one or more transducer a ⁇ ays in operative communication with a data processing, storage and display device.
  • the one or more transducer a ⁇ ays may communicate with a data processing, storage and display device by means of one or more cables, or using a radio frequency or other wireless technology.
  • the transducer a ⁇ ay(s) may be steerable and may be programmed to scan, identify one or more desired target site(s), and maintain focus on that target site in an automated fashion.
  • Transducer a ⁇ ays of the present invention may also be programmed to collect acoustic data from multiple target sites simultaneously, or at different times.
  • a transducer a ⁇ ay, or a plurality of a ⁇ ays may be programmed to operate alternatively as acoustic sources and detectors.
  • multiple transducer a ⁇ ays used for monitoring multiple patients provide data to and communicate with a single data processing, storage and display device.
  • an acoustic a ⁇ ay comprising PVDF (polyvinylidene fluoride) film transducers is used as an acoustic detector a ⁇ ay, in combination with a cMUT a ⁇ ay or a single element PZT transducer employed as the source.
  • the source transducer or a ⁇ ay transmits sound through the PVDF a ⁇ ay, sweeping the sound in a single dimension generally pe ⁇ endicular to the a ⁇ angement of the PVDF a ⁇ ay.
  • the PVDF a ⁇ ay serves as the acoustic detector, receiving and processing acoustic signals.
  • An acoustic a ⁇ ay of the present invention may comprise a combination of PVDF and cMUT a ⁇ ays.
  • the combined depth of the a ⁇ ays may be on the order of 1 cm.
  • the cMUT a ⁇ ay is a ⁇ anged below the PVDF a ⁇ ay and transmits sound through the PVDF a ⁇ ay.
  • the PVDF a ⁇ ay may be made in two dimensions, so that it can detect acoustic signals in two directions, rather than the single direction illustrated.
  • an acoustic a ⁇ ay of the present invention may comprise a combination of a PVDF a ⁇ ay and one or more PZT transducer(s).
  • the PVT transducer may be mounted below the PVDF a ⁇ ay and transmit through the PVDF a ⁇ ay in a single, broad beam.
  • the PVDF a ⁇ ay may be constructed as a single dimension a ⁇ ay, or as a two dimensional a ⁇ ay.
  • An acoustic a ⁇ ay having a two dimensional PVDF a ⁇ ay has the capability of receiving acoustic signals in two dimensions and an underlying PZT transducer.
  • This system may alternatively employ a cMUT a ⁇ ay in the place of the PZT transducer.
  • Systems of the present invention may comprise both non-disposable and disposable or reusable components. Costly elements of the acoustic system are provided as non-disposable components, while less costly components, which require close interaction with a patient and, perhaps, sterilization, are provided as disposable components.
  • an acoustic a ⁇ ay is provided as part of a disposable system element, in combination with a patient interface component.
  • the acoustic a ⁇ ay is preferably in contact with acoustically transmissive material, such as an acoustic gel, that provides high fidelity acoustic transmission into and from the target area.
  • acoustically transmissive material is preferably interfaced with a contact material, such as an adhesive material, that facilitates temporary positioning and affixation of the disposable system element to a patient's skin.
  • the patient contact material may be protected by a removable cover, which is removable at the time of use.
  • the disposable system element, including the acoustic a ⁇ ay may be provided as a unitary element that may be sterilized and packaged for one-time use.
  • acoustically transmissive material layers may be provided as a separately sterilized, packaged component that is designed to interface with a non-disposable component including the acoustic a ⁇ ay(s). Such layers may be provided with an adhesive layer on one side for contact with the patient's skin. Or, a recess may be provided for manual application of acoustically transmissive material. It will be evident that many different embodiments and a ⁇ angements of disposable and non-disposable elements may be employed.
  • This compact, disposable a ⁇ ay element may be placed in contact with the skin of a patient at an acoustic window and, when activated, electronically focuses the acoustic source(s) and detector(s) on the target site of interest, such as a target myocardial tissue site.
  • the acoustic a ⁇ ay monitors and stays focused on the target area of interest during operation.
  • the exposed surface of the acoustic gel is preferably interfaced with one or more adhesive elements that facilitate temporary placement on and consistent contact with a desired patient surface.
  • a removable cover may be provided over the acoustic gel to preserve the acoustic a ⁇ ay and other components.
  • These elements may be provided as a disposable unit that is mountable on non-disposable elements of the system.
  • Non-disposable elements of the system may include mounting hardware, one or more cables or wireless transmission interfaces, and a data processing, storage and display device.
  • Placement of the acoustic source(s) and detector(s) on a subject for assessment of acoustic properties of myocardial tissue (including blood and blood vessels) may be at known "acoustic windows.”
  • the placement of the source(s) with respect to the detector(s) will depend on the acoustic data desired - e.g., for collection of back scatter acoustic data, the source(s) and detector(s) are in proximity to one another, while the source(s) and detector(s) are positioned generally opposite one another for collection of forward scatter acoustic data.
  • Acoustic scatter or reflection data may be collected at various angles by placing the source(s) and detector(s) at various locations on the patient.
  • target tissue location must be volumetrically large enough to provide a representative sample.
  • the volumetric sampling requirements will vary, of course, according to tissue type and location. In general, target sites having tissue volumes of from 1 mm 3 to about 100cm 3 are suitable, and target tissue sites having tissue volumes of less than about 5 cm are prefe ⁇ ed.
  • Acoustic data acquisition techniques of the present invention may be used in combination with known ultrasound imaging techniques to provide visualization of the target tissue sites.
  • Data such as acoustic scatter data, relating to intrinsic and/or induced tissue displacements is processed according to methods and systems of the present invention and related to medically relevant physiological properties, such as cardiac output and other cardiac parameters.
  • exemplary data processing techniques for making various co ⁇ elations based on various types of acquired data are well known. Although these data processing techniques are based on the acquisition of acoustic scatter data, they may be applied, as well, with modifications that would be well known in the art, in other modalities, such as near infrared spectroscopic (NIRS) modalities and magnetic resonance modalities.
  • NIRS near infrared spectroscopic
  • a small specialized ultrasonic palpation device is placed on the subject's chest and aimed, through the ribs, to a target cardiac tissue site at or near the right ventricular wall. This may be achieved using a diagnostic ultrasound scan head placed confocally with the palpation device, so that the focus of the palpation device is registered on the screen and visible to the person implementing this procedure.
  • a simple A-mode transducer/hydrophone is used to aim, palpate and display data, and provides a stand-alone device.
  • the right ventricle is exemplary, but, in practice, this technique may be used to with focus ultrasound beams to targeted site at or near cardiac tissue.
  • This combined palpation and aiming scan head is preferably secured to the outside of the chest for the duration of the medical procedure, with the assessment being initiated when the patient's blood volume and cardiac volume are normal.
  • This may be done by the application of focused ultrasound with a dual-annular a ⁇ ay, with each annulus operating at slightly different frequencies from one another.
  • the frequency of the oscillatory radiation force will be that of the difference frequency of the two annuli.
  • there will be a difference frequency, hence oscillation rate, in the radiation force that maximizes the acoustic emissions from the point of application of the radiation force.
  • This frequency may be refe ⁇ ed to as the resonant frequency of the ventricle wall.
  • this resonant frequency will change: the greater the tension the higher the resonant frequency, while the lower the tension the lower the resonant frequency.
  • hydrophones may easily be integrated into the ultrasonic palpation device for tracking the acoustic signals emitted from the target cardiac tissue.
  • this resonant frequency starting with a baseline determined while the patient is awake,, preoperatively or newly anesthetized but before a change in blood volume, one can, with concomitant blood pressure measurements, assay where the patient is on the Starling curve. For example, if the resonant frequency dips significantly lower than the patient- specific average normal value, this would be consistent with the ventricle walls becoming more flaccid. If this were to occur while blood pressure drops, then these observations would be strong evidence of hypovolemia.
  • CW continuous wave
  • we apply a constant-amplitude oscillatory radiation force using one of the several methods described above. Rather than search for a resonant frequency, however, we work with a given frequency that from experience is known to be above or below the resonant frequency of the heart's right ventricle wall. We then track the amplitude of the palpation-induced acoustic emission from the heart, both within a cardiac cycle and over many cardiac cycles, starting while the patient's cardiac volume is normal, and then proceeding throughout the medical procedure of interest until the patient is safely stabilized. For example, consider the case where one was driving the local heart tissue into an oscillation whose frequency was always below the resonant frequency of the local heart tissue.
  • any one of several aspects of safe, ultrasound-induced deformation of the right ventricular wall of the heart is assayed, using, for example, an A- mode transducer placed confocally with the ultrasound palpation device.
  • the palpation device may have one of several manifestations. Also, one would likely not need the absolute value of the deformations, just the trend in those deformations over time, as well as concomitant measurements of blood pressure, starting when the patient's cardiac volume is normal, and ending when the patient is safely stabilized.
  • cardiac tissue is not "palpated" at all.
  • the local strain within a small portion of the cardiac ventricle wall tissue is tracked using, for example, an A-mode ultrasound system, optionally in conjunction with standard diagnostic ultrasound image.
  • the local strain is assayed using sonoelasticity analysis on the resulting acoustic backscatter signal, a well-known technique developed over the last 15 years and often applied for assaying the presence of breast cancer.
  • Sonoelasticity analysis would give a measure of the scale of the intrinsic deformations of tissue, essentially the average change in spacing of two close points within the tissue (distances of millimeters or less) divided by their average spacing at systole or diastole, for example.
  • the stiffness of the ventricle walls is monitored, which relates to cardiac output, as discussed above. For example, for a fall in blood pressure and cardiac output, as the stiffness of the heart tissue decreased, the intrinsic displacements of portions of the ventricle wall would increase, thereby suggesting hypovolemia. As the ventricle walls increased in stiffness, the intrinsic displacements of portions of the ventricle wall would decrease, thereby suggesting hypervolemia.
  • tissue displacement may be induced in a blood vessel or in tissue su ⁇ ounding a blood vessel by application of an acoustic radiation force, as described above.
  • tissue displacements at or near a blood vessel may be detected using a variety of techniques, with the use of ultrasound techniques being prefe ⁇ ed.
  • an initial assessment is performed, using Doppler flow measurements or ultrasound detection techniques, to locate a desired blood vessel and thereby provide a focus for identifying intrinsic and/or induced displacements at or near the vessel.
  • blood pressure can be calculated from flow velocity measured by Doppler.
  • Geometric properties of vessels that may be evaluated using methods and systems of the present invention include changes in diameter, cross-sectional area, aspect ratio, rate of change of diameter, velocity, and related parameters.
  • Blood pressure may also be assessed, in an active or passive mode, by examining acoustic properties of target tissue sites at or in proximity to blood vessels.
  • the acoustic properties of target tissue at or in proximity to blood vessels can be related to tissue stiffness or compliance, which can be related to blood pressure.
  • Blood pressure measurements made using the passive or active acoustic modes described herein may also be used for calibration of existing invasive or non-invasive blood pressure monitoring devices.
  • the methodology described below, particularly with reference to blood pressure determinations using the active acoustic mode may used in combination with existing blood pressure monitoring devices, which are available, for example, from Medwave Co ⁇ oration, St. Paul, Minnesota.
  • This method uses a derived relationship between spontaneous vessel wall displacement (due to blood pressure and smooth muscle tonal responses to the hemodynamic state), synchronous velocity of blood flow within the vessel of interest, and invasively monitored ABP to estimate ABP from non-invasively measured vessel wall displacement and Doppler flow velocity.
  • spontaneous vessel wall displacement due to blood pressure and smooth muscle tonal responses to the hemodynamic state
  • synchronous velocity of blood flow within the vessel of interest synchronous velocity of blood flow within the vessel of interest
  • ABP invasively monitored ABP to estimate ABP from non-invasively measured vessel wall displacement and Doppler flow velocity.
  • d t*1500 m/sec
  • d tissue displacement
  • t the time or phase shift of the reflected signal
  • 1500 m/sec the estimated speed of sound through tissue.
  • ABP F(d, i)
  • F can be any function, such as an exponential, vector, matrix, integral, etc., or a simply an empirical relationship.
  • a calibration step using, for example, a cuff plethysmograph to measure ABF, may be implemented before continuous, noninvasive ABP measurements are made. Correlation of ABP with amplitude of vessel wall signal and Doppler flow velocity
  • This method uses a derived relationship between the amplitude of the reflected vessel wall signal, Doppler flow velocity, and invasively monitored ABP to estimate ABP from non-invasively measured vessel wall signal and Doppler flow velocity (i).
  • a particular vessel of interest is insonated with a waveform of specific frequency and amplitude, and the amplitude of the backscatter is used to create a waveform of vessel wall reflection absorption.
  • This new waveform, ⁇ is generated by integrating the amplitude of the backscatter over a finite epoch (such as the cardiac cycle, measured with ECG tracing) and normalizing this by the time period of the epoch.
  • a calibration step using a cuff plethysmograph to measure ABP may be implemented before continuous, noninvasive ABP measurements are made.
  • the peak amplitude of the backscatter signal over a given epoch (e.g., cardiac cycle) is normalized by the baseline value of the backscatter signal over the same epoch, and this, along with Doppler flow velocity, is related to the simultaneous invasive measurements of ABP.
  • a calibration step using a cuff plethysmo raph to measure ABP may be implemented before continuous, noninvasive ABP measurements can be made.
  • Methods and systems of the present invention may be used in a variety of settings, including emergency medicine settings such as ambulances, emergency rooms, intensive care units, and the like, surgical settings, in-patient and out-patient care settings, residences, ai ⁇ lanes, trains, ships, public places, and the like.
  • the techniques used are non-invasive and do not i ⁇ eversibly damage the target tissue. They may thus be used as frequently as required without producing undesired side effects.
  • the methods and systems of the present invention do not require patient participation, and patients that are incapacitated may also take advantage of these systems.
  • the methods and systems of the present invention for assessing cardiac tissue may be used on a continuous or intermittent basis.
  • Brain tissue was used as a model experimental system.
  • Figure 10A in vitro
  • Figure 10B-D in vivo
  • TCD transcranial Doppler
  • Myocardial tissue displacement may be measured in the same fashion and related to tissue strain, tension, and the like, as described above, to make noninvasive assessment of cardiac tissue and parameters.
  • the displacement (compression and distension) waveforms shown in Figs. 10B-D were produced using ultrasound techniques to measure acoustic scatter signals associated with intrinsic displacements of human brain tissue in situ.
  • An acoustic transducer (ATL/Philips Medical System, Bothell,WA) was used to insonate target CNS tissue with acoustic inte ⁇ ogation signals having 10-10 3 acoustic pulses per second at 2.25 MHz containing 3-15 cycles of ultrasound with peak negative pressures less than 2MPa or 20 bar.
  • LeCroy Waverunner oscilliscope we collected acoustic waveforms backscattered from the brain generated by the inte ⁇ ogator and calculated the tissue displacement.
  • This calculation was made using a normalized co ⁇ elation of paired received signals. Given an estimate of the speed of sound in brain and the calculated temporal displacement, the spatial displacement of the tissue at a given moment may be calculated. Tracking the spatial displacement over time provides a direct measure of the displacement of the brain tissue that is being noninvasively inte ⁇ ogated by the diagnostic ultrasound. This calculation can also be made by co ⁇ elating the backscattered signal with a reference inte ⁇ ogation signal, noting when the inte ⁇ ogation signal is sent and when the backscattered signal is received. Changes in the amplitude of the backscatter from the region of interest may also be monitored to determine the ICP waveform.
  • the signal derived from following displacements or from following the normalized integral of the backscatter looks identical to the time course of the mean velocity of blood in the middle cerebral artery of the test subject.
  • Figs. 10B-D show changes in properties of a human brain over time, measured in situ, using ultrasound techniques according to the present invention, as described above. Certain physiological behaviors, such as holding breath, sneezing, etc., are known to transiently increase or decrease ICP.
  • Fig. 10B shows changes in the normalized amplitude of the acoustic backscatter as the human subject held his breath.
  • Fig. IOC shows the displacement of human brain as the human, based on co ⁇ elation techniques, while the subject was holding his breath, using pulses with 15 cycles of ultrasound.
  • Fig. 10C shows the net increased displacement of brain towards the transducer as the pressure on the brain increased due to an accumulation of blood volume in the brain, along with the cardiac-induced brain displacement signals.
  • Fig. 10B shows the same kind of received signal characteristics as Fig. 10C, where we used pulses with 5 cycles, but analyzed the data by integrating over the acoustic backscatter signal as described above.
  • both waveforms changed over the 10 seconds while the subject held his breath, consistent with known transient changes in ICP when subjects hold their breath.
  • the vascular pulse and autoregulation waveforms are present, in modified form, in Fig. IOC.
  • the time series of Figs. 10B and 10C look similar to the velocity pattern found in the patient's middle cerebral artery (data not shown). This measurement is therefore an accurate representation of the compression and distension of brain parenchyma in response to the major cerebral arteries, supplemented by contributions from the rest of the cerebral vasculature.
  • Fig. 10D shows an example of changes in near-surface brain displacement as the subject first held his breath for 2-3 seconds, then inhaled. Changes in respiration and the respiratory cycle are known to transiently change ICP. At first, the brain surface's net displacement toward the transducer increased. Upon inhalation, the brain tissue moved, over several cardiac cycles, away from the transducer. The observed displacement is consistent with the transient changes in ICP expected when a subject holds his breath (transient blood volume and ICP increase) and then inhales (transient blood volume and ICP decrease).
  • Fresh bovine brain was immersed in fluid in a water-tight, visually and acoustically transparent bottle attached to a hand-pump for changing the pressure on the brain.
  • ATL acoustic transducers (ATL-Philips Medical Systems, Bothell, WA), and the bottle, were placed in water so that the focus of the acoustic palpation and inte ⁇ ogation transducers were near the edge of the brain, but within the brain.
  • LeCroy Waverunner oscilloscope we collected acoustic inte ⁇ ogation wavefo ⁇ ns backscattered from brain.
  • the inte ⁇ ogation pulses were administered as described with respect to Fig. 10A, while the palpation pulses had a pulse repetition frequency of 1Hz, contained 30,000-50,000 cycles, and had a time-averaged intensity of less than 500W/cm .
  • Noninvasive, ultrasound-based measurements of ultrasonic palpation of brain tissue can be safely used to directly measure ICP in humans, without the need for blood pressure measurements, because by this method the brain will be subjected to a known (ultrasonic) force.
  • probing or palpation of brain tissue with a known force will also yield data ancillary to the passive method of ICP determination, by calibrating the amount of deformation brain tissue undergoes when subjected to a known compressive force.

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Abstract

L'invention concerne des systèmes et des procédés d'évaluation non invasive des propriétés d'un tissu cardiaque et de paramètres cardiaques par des techniques faisant appel aux ultrasons. Des déterminations concernant la rigidité, la tension, la dilatation, la vitesse de dilatation et analogue du tissu myocardique peuvent être utilisées pour évaluer la contractilité myocardique, l'ischémie myocardique et l'infarctus du myocarde, la pression de remplissage des ventricules et de l'oreillette, et les fonctions diastoliques. L'invention concerne également des systèmes non invasifs dans lesquels des techniques acoustiques, telles que des techniques mises en oeuvre par ultrasons, sont utilisées pour acquérir des données relatives à des déplacements de tissu intrinsèque. L'invention concerne en outre des systèmes non invasifs dans lesquels des techniques faisant appel aux ultrasons sont utilisées pour stimuler ou palper acoustiquement un tissu cardiaque cible, ou pour induire, au niveau d'un site cardiaque, une réponse se rapportant à des propriétés du tissu cardiaque et/ou des paramètres cardiaques.
PCT/US2003/020764 2002-07-01 2003-07-01 Systemes et procedes d'evaluation non invasive d'un tissu cardiaque, et parametres s'y rapportant WO2004002305A2 (fr)

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EP1633234A2 (fr) * 2003-06-03 2006-03-15 Allez Physionix Limited Systemes et procedes permettant de determiner la pression intracranienne de fa on non invasive et ensembles de transducteurs acoustiques destines a etre utilises dans ces systemes
WO2006046982A1 (fr) * 2004-10-21 2006-05-04 Siemens Medical Solutions Usa, Inc. Analyse automatique de la fonction diastolique par ultrasons
EP1768567A2 (fr) * 2004-05-07 2007-04-04 The John Hopkins University Therapies d'imagerie de tissus par ultrasons sous contrainte
JP2008514252A (ja) * 2004-09-28 2008-05-08 エコサンス 器官弾性を測定するための、センタリング手段を有するタイプの器具
WO2010125485A1 (fr) * 2009-05-01 2010-11-04 Koninklijke Philips Electronics, N.V. Système d'imagerie médicale acoustique et procédé de fonctionnement associé
US7999945B2 (en) 2007-07-18 2011-08-16 The George Washington University Optical coherence tomography / acoustic radiation force imaging probe
US8184351B2 (en) 2004-07-27 2012-05-22 The George Washington University Amplified bimorph scanning mirror, optical system and method of scanning
CN103385703A (zh) * 2012-05-08 2013-11-13 精工爱普生株式会社 心输出量监视装置和心输出量测定方法
WO2016009057A1 (fr) * 2014-07-17 2016-01-21 Institut National De La Sante Et De La Recherche Medicale (Inserm) Procédé pour obtenir un paramètre fonctionnel d'un muscle
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CN113382685A (zh) * 2019-01-24 2021-09-10 皇家飞利浦有限公司 用于研究血管特性的方法和系统
CN113974690A (zh) * 2015-11-12 2022-01-28 雷斯皮诺尔公共有限责任公司 用于呼吸监视的超声方法和装置

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WO2016009057A1 (fr) * 2014-07-17 2016-01-21 Institut National De La Sante Et De La Recherche Medicale (Inserm) Procédé pour obtenir un paramètre fonctionnel d'un muscle
CN106794003A (zh) * 2014-07-17 2017-05-31 国家健康与医学研究院 获得肌肉的功能参数的方法
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CN113974690A (zh) * 2015-11-12 2022-01-28 雷斯皮诺尔公共有限责任公司 用于呼吸监视的超声方法和装置
CN113974690B (zh) * 2015-11-12 2024-05-28 雷斯皮诺尔公共有限责任公司 用于呼吸监视的超声方法和装置
CN111885961A (zh) * 2018-03-21 2020-11-03 三星麦迪森株式会社 超声诊断设备及其控制方法
WO2020127615A1 (fr) * 2018-12-20 2020-06-25 Koninklijke Philips N.V. Méthodes et systèmes de surveillance d'une fonction cardiaque
CN113382685A (zh) * 2019-01-24 2021-09-10 皇家飞利浦有限公司 用于研究血管特性的方法和系统

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EP1531725A4 (fr) 2009-02-04
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AU2003280416A8 (en) 2004-01-19
EP1531725A2 (fr) 2005-05-25
WO2004002305A3 (fr) 2004-03-04

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