WO2003073046A1 - Flow-rate conservative doppler estimate - Google Patents

Flow-rate conservative doppler estimate Download PDF

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Publication number
WO2003073046A1
WO2003073046A1 PCT/IT2002/000115 IT0200115W WO03073046A1 WO 2003073046 A1 WO2003073046 A1 WO 2003073046A1 IT 0200115 W IT0200115 W IT 0200115W WO 03073046 A1 WO03073046 A1 WO 03073046A1
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Prior art keywords
flow
doppler
estimate
doppler data
constriction
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PCT/IT2002/000115
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French (fr)
Inventor
Gianni Pedrizzetti
Emidio Marchese
Giovanni Tonti
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Amid Srl
Esaote S.P.A.
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Priority to PCT/IT2002/000115 priority Critical patent/WO2003073046A1/en
Publication of WO2003073046A1 publication Critical patent/WO2003073046A1/en

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    • GPHYSICS
    • G01MEASURING; TESTING
    • G01FMEASURING VOLUME, VOLUME FLOW, MASS FLOW OR LIQUID LEVEL; METERING BY VOLUME
    • G01F1/00Measuring the volume flow or mass flow of fluid or fluent solid material wherein the fluid passes through the meter in a continuous flow
    • G01F1/72Devices for measuring pulsing fluid flows
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01FMEASURING VOLUME, VOLUME FLOW, MASS FLOW OR LIQUID LEVEL; METERING BY VOLUME
    • G01F1/00Measuring the volume flow or mass flow of fluid or fluent solid material wherein the fluid passes through the meter in a continuous flow
    • G01F1/66Measuring the volume flow or mass flow of fluid or fluent solid material wherein the fluid passes through the meter in a continuous flow by measuring frequency, phaseshift, or propagation time of electromagnetic or other waves, e.g. ultrasonic flowmeters
    • G01F1/663Measuring the volume flow or mass flow of fluid or fluent solid material wherein the fluid passes through the meter in a continuous flow by measuring frequency, phaseshift, or propagation time of electromagnetic or other waves, e.g. ultrasonic flowmeters by measuring Doppler frequency shift
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01FMEASURING VOLUME, VOLUME FLOW, MASS FLOW OR LIQUID LEVEL; METERING BY VOLUME
    • G01F17/00Methods or apparatus for determining the capacity of containers or cavities, or the volume of solid bodies
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01SRADIO DIRECTION-FINDING; RADIO NAVIGATION; DETERMINING DISTANCE OR VELOCITY BY USE OF RADIO WAVES; LOCATING OR PRESENCE-DETECTING BY USE OF THE REFLECTION OR RERADIATION OF RADIO WAVES; ANALOGOUS ARRANGEMENTS USING OTHER WAVES
    • G01S15/00Systems using the reflection or reradiation of acoustic waves, e.g. sonar systems
    • G01S15/88Sonar systems specially adapted for specific applications
    • G01S15/89Sonar systems specially adapted for specific applications for mapping or imaging
    • G01S15/8906Short-range imaging systems; Acoustic microscope systems using pulse-echo techniques
    • G01S15/8979Combined Doppler and pulse-echo imaging systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/06Measuring blood flow
    • A61B8/065Measuring blood flow to determine blood output from the heart

Abstract

A new method is introduced to evaluate the flow through a constriction based on Doppler data and the principle of mass conservation. This principle, properly inserted within a combination of data rearrangements allows the extraction of the complete velocity field and the optimal evaluation of the flow through the constriction. The digital implementation of the method into electronic equipments, like an echographic machine, gives an additional capability of quantifying specific valvular flows and improves diagnostic potential.

Description

FLOW-RATE CONSERVATIVE D OPPLER ESTIMATE
Technical field
Automatic processing of two- and three-dimensional echoDoppler digital data, primarily pertinent to medical imaging that improve the ability to evaluate the flow rate through a constriction on the basis of proximal Doppler imaging.
Background Art
Quantitative hemodynamic assessment of the flow through cardiovascular valves is a matter of fundamental importance in many clinical practical aspects for diagnosis and choice of optimal therapeutic options (W). A relevant example is represented by the flow that regurgitates through the mitral valve when this does not close correctly; the correct evaluation of such a regurgitant flow gives a functional measure of the actual valvular disease.
Information about the point-wise velocity in the blood are obtained by echographs that support measurements of the Doppler type, however the Doppler data acquired by echographic machines do not give explicitly, in general, values about the flow that passes through a valve and these data require a further analysis to produce an estimate of this important quantity. Several investigators have tried to quantify the regurgitant volume and the effective regurgitant orifice using the proximal iso-velocity surface area (PISA) concept by color flow mapping and the principle of flow continuity 5"7 . The PISA method is based on the assumption that the iso- velocity contours are hemispherical proximal to the regurgitant orifice. However, this assumption is severely hampered by the complex flow fields that are present in the heart (8). In addition, the two-dimensional color Doppler, while able to provide detailed information regarding the instantaneous velocity of flow parallel to the Doppler scan direction, is unable to represent the orthogonal components of flow velocities. Obviously, such an approach is inherently inaccurate for the estimation of the regurgitant volume.
We propose he a new method that, on the basis of the color Doppler data produced by echographic machines, is able to accurately quantify the valvular flow. The objective is to take 02 00115
2 an instantaneous two-dimensional color flow image of a valvular flow (mitral regurgitation) and evaluate the corresponding instantaneous discharge that passes through the valve.
Disclosure of the invention
We first read the two-dimensional velocity data obtained by a Doppler measure, these data are the axial (vertical) component of velocity. Let us identify a system of coordinates {x,z} where z represents the longitudinal and x the horizontal direction parallel to the valvular plane assumed to be at 2=0. Thus, the Doppler image is the map of the vertical component of velocity vz(x,z). The valve is centered at a position x=x0, and the velocity field has approximately similar parts on either side of valve centerline; the two-dimensional- velocity map is assumed to be representative of the valvular flow, i.e. it is assumed that it represents a cut centered on the valve and that no exceptional phenomena occur outside such plane (mathematically this means that a spectral decomposition in the properly defined azimuthal direction -as shown below- presents negligible intensity of even harmonics larger than zero). A typical example of velocity map (from mitral regurgitation) is show in figure 1.
The definition of a symmetry axis has relevance for the subsequent analysis. In fact, only the symmetric part of the velocity contributes to the evaluation of the flow rate, while the odd- components of the velocity give null contribution when integrated and therefore can be neglected as indicated in figure 2.
The optimal symmetric axis can be extracted manually, or on the basis of additional data, or estimated automatically from a maximum similarity concept between left and right velocity half- fields. The definition of a symmetry axis allows considering only the axisymmetric velocity field obtained by symmetrization of the original Doppler sampling. We can thus consider a cylindrical system of coordinates {r,z} where r=0 represents the symmetry axis of the extracted axisymmetric velocity field vz(r,z).
The continuity equation in its differential form gives a relation between the axial variation of the axial component of velocity, vz(r,z), and the radial variation of the radial component, vr(r,z). In three-dimensional cylindrical coordinates the continuity equation reads (9' 10) dv_ drvr n r +ι -0- <>
Integration of this equation along r, starting from the axis r=0 where the radial velocity is zero for symmetry reasons, allows the explicit evaluation of the radial velocity.
Figure imgf000003_0001
P T/IT02/00115
3
One example of the flow corresponding to the map in figure 1 is show in figure 3.
Once the complete velocity vector field is obtained, the flow rate passing through any axisymmetric surface can be immediately evaluated. Being blood incompressible, the flow through the valve is equal to the total flow crossing any axisymmetric surface surrounding the valve. Indicating with i the imprint-curve of the surface on a meridian plane, the flow rate Q is:
Figure imgf000004_0001
where v„ is the projection of the velocity vector in the direction normal to the curve (figure 4). By summating all the elementary contribution at the boundary of the control volume, we evaluate the total instantaneous flow rate Q from equation 3.
The result that is obtained from the velocity map of figure 1 is shown in figure 5 using two different surfaces surrounding the valve. The new method is essentially independent from the geometry and from the dimension of the control surface adopted, until this is large enough to intercept all the flow then entering the valve, and until it is small enough that the velocity values are larger than zero within the digital machine representation.
The accuracy of this method is inherently related to the "quality" and "consistency" of the image itself. The quality indicates the level of noise contained in the image. Although most mathematical passages are of integration-type that smooth out the noise, when horizontal bands noise is present this disturbance is amplified by the axial derivative appearing in equation (2), this problem can be partially circumvented by a careful evaluation of the derivatives.
This new methodology resulting from the serial combination of the passages outlined above is a method that allows to evaluate the valvular flow, on the basis of the normal Doppler data measured from echographs atad commonly represented in an image form.
Implementation of this technique is based on numerical analysis, therefore it is transformed into a software application for its exploitation. Its translation in algorithm form is rather immediate:
1. Read the echoDoppler digital data (from image or from raw data) and obtain the Doppler velocity array vD(i,j) where i and j are the pixel indexes that span all the image in the vertical and horizontal direction.
2. Define a region of interest (ROI) for the flow proximal to the valve bounded by the valvular plane itself; obtain a reduced field vD(i,j) where the indexes i and j are now restricted to the dimension of the ROI: i=l...N, j=l...M. 3. Determine the optimal symmetry axis (manually of by a best likelihood techniques), thus one index t*=tø,and symmetrize the Doppler velocity field by vz(ij)= VD(io+i-l,j)/2+ VD(io-i+l,j)/2 where the horizontal index i now covers the symmetric span: i=l...Ns.
4. Evaluate the radial component of velocity vr(i,j) by performing the integration in equation (2) with boundary condition vr(l,j)=0.
5. Define one surface (or a series of them) as a sequence of L points (possibly as close as the pixel size) defined by their coordinates ( kZt), k=l...L.
6. Evaluate the flowrate (for any surface specified) is performed by the integral (3), this can be achieved by several different nimierical techniques^ At the first order of accuracy this can be done by summation of the flow through any consecutive pair of points ( kz and (fk+ι,Zk+ι), k-l... -l. Assume any pair as connected by a rectilinear segment, thus the normal versor is defined, the normal component of velocity can be evaluated, and the unitary contribution to (3) is evaluated.
The eventual software applications is based on the core steps outlined above, the details of the eventual product depends on the hosting equipment, the required human interface, the programmer choices, and the features of the programming language chosen for the implementation. Two different software applications have been prepared, in two different languages, in order to start the testing of the method and its comparison with the former PISA technique. This new approach has been tested in a carefully controlled numerically generated Doppler map, with an in vitro standard equipment, and with clinical cases to verify its applicability. The results confirm the physical consistency and accuracy of the method.
Best mode for carrying out the invention
Implementation of this technique must be based on a numerical analysis (software application), therefore it should be supported in digital processing by an electronic instrument that can be the same echographic machine, or an external computer where the data are previously transferred. The procedure outlined above should be implemented through its software application into an echographic machine in order to allow the immediate evaluation of specific pathologies, like of valvular regurgitation for example. The inclusion of this additional measurement (more properly a quantification) in the echograph improves the quality of the information that can be obtained from the machine, thus giving an additional potential feature that is useful for diagnostic needs. In the case of more extensive analyses, the method has potential application into an external electronic equipment, a computer, that is equipped to read the echographic data. In this sense the computer becomes an offline system with the capability to quantify the valvular flow and eventually evaluate the severity of specific valvular diseases. This is suggested when several images or time-sequences of images must be analyzed with an effort that may not be allowed on an echograph.
REFERENCES
1. Enriquez-Sarano M, Bailey KR, Seward JB, et al. Quantitative Doppler assessment of valvular regurgitation. Circulation 1993;87:841-8.
2. Blumlein S, Bouchard A, Schiller NB, et al. Quantitation of mitral regurgitation by Doppler echocardiography. Circula-tion 1986;74:306-14.
3. Enriquez-Sarano M, Seward JB, Bailey KR, et al. Effective regurgitant orifice area: a noninvasive Doppler development of an old hemodynamic concept. J Am Coll Cardiol 1994;23:443-51.
4. Vandervoort PM, Rivera JM, Mele D, et al. Application of color Doppler flow mapping to calculate effective regurgitant orifice area: an in vitro study and initial clinical observations. Circulation 1993;88:1150-6.
5. Recusani F, Bargiggia GS, Yoganathan AP, et al. A new method for quantification of regurgitant flow rate using color Doppler flow imaging of the flow convergence region proxi-mal to a discrete orifice: an in vitro study. Circulation 1991;83:594-604.
6. Bargiggia GS, Tronconi L, Sahn DJ, et al. A new method for quantitation of mitral regurgitation based on color flow Doppler imaging of flow convergence proximal to regurgitant orifice. Circulation 1991;84:1481-9.
7. Utsunomiya T, Patel D, Doshi R, et al. Can signal intensity of the continuous wave Doppler regurgitant jet estimate severity of mitral regurgitation? Am Heart J 1992;123:166-71.
8. Walker P.G., Oyre S., Pedersen, et al. A new control volume method for calculating valvular regurgitation. Circulation 1995;92:579-586.
9. Batchelor G.K. An introduction to fluid dynamics. 1967, Cambridge University Press.
10. Pedrizzetti G. Unsteady tube flow over an expansion. J Fluid Mech 1996; 310 89- 111.

Claims

1) This novel technique of echographic Doppler data processing permits to evaluate the amount of fluid (blood) passing through a constriction with an automatic method. The direct use of Doppler data does not allow to directly evaluate such a quantity; this technique reconstruct the additional information that are required for such an estimate without additional assumption. It application to the Doppler data (e.g. images) of the proximal region of any heart valve permits to evaluate the valvular regurgitation flow and the regurgitant volume that give an information useful for the assessment of valvular diseases.
2) The same technique applied to Doppler data of the proximal region of other human valves gives a scientifically rigorous estimate of the flow passing through such valve and furnishes an information that can be used for diagnosis to be made by the physician.
3) The same technique applied to Doppler data of the proximal region of a vascular stenosis or constriction gives a scientifically based estimate of the unsteady flow-rate in correspondence of the stenosis that can be used for diagnostic purposes.
4) The same technique can be applied to other two-dimensional or three-dimensional Doppler measurements in the proximal region of a constriction to give a scientifically rigorous estimate of the instantaneous discharge passing through the orifice.
PCT/IT2002/000115 2002-02-27 2002-02-27 Flow-rate conservative doppler estimate WO2003073046A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010046330A1 (en) * 2008-10-24 2010-04-29 Tomtec Imaging Systems Gmbh Three-dimensional derivation of a proximal isokinetic shell of a proximal flow convergence zone and three-dimensional pisa flow measurement

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9028413B2 (en) * 2010-03-08 2015-05-12 Siemens Medical Solutions Usa, Inc. Prediction-based flow estimation for ultrasound diagnostic imaging
EP2514368B1 (en) 2011-04-18 2017-09-20 TomTec Imaging Systems GmbH Method for transforming a Doppler velocity dataset into a velocity vector field
JP5497821B2 (en) * 2012-03-16 2014-05-21 国立大学法人 東京大学 Fluid flow velocity detection device and program
US9462954B2 (en) * 2013-09-04 2016-10-11 Siemens Aktiengesellschaft Method and system for blood flow velocity reconstruction from medical images
JP5750181B1 (en) * 2014-03-31 2015-07-15 日立アロカメディカル株式会社 Ultrasonic diagnostic equipment

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5062427A (en) * 1988-05-06 1991-11-05 Kabushiki Kaisha Toshiba Ultrasonic doppler apparatus
WO2000051495A1 (en) 1999-03-05 2000-09-08 The General Hospital Corporation Measuring volume flow and area for a dynamic orifice

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4913159A (en) * 1989-03-17 1990-04-03 Hitachi Medial Corp. Method for determining blood flow through a narrowed orifice using color doppler echocardiography
US6149595A (en) * 1998-07-02 2000-11-21 Seitz; Walter S. Noninvasive apparatus and method for the determination of cardiac valve function
US6868739B1 (en) * 1999-10-19 2005-03-22 Transonic Systems, Inc. Method and apparatus to measure blood flow by an introduced volume change
US6719697B2 (en) * 2001-02-27 2004-04-13 Koninklijke Philips Electronics N.V. Ultrasonic quantification of valvular regurgitant blood flow

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5062427A (en) * 1988-05-06 1991-11-05 Kabushiki Kaisha Toshiba Ultrasonic doppler apparatus
WO2000051495A1 (en) 1999-03-05 2000-09-08 The General Hospital Corporation Measuring volume flow and area for a dynamic orifice

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
BARGIGGIA GS; TRONCONI L; SAHN DJ ET AL.: "A new method for quantitation of mitral regurgitation based on color flow Doppler imaging of flow convergence proximal to regurgitant orifice", CIRCULATION, vol. 84, 1991, pages 1481 - 9
BATCHELOR G.K.: "An introduction to fluid dynamics", 1967, CAMBRIDGE UNIVERSITY PRESS
BLUMLEIN S; BOUCHARD A; SCHILLER NB ET AL.: "Quantitation of mitral regurgitation by Doppler schocardiography", CIRCULA-TION, vol. 74, 1986, pages 306 - 14
ENRIQUEZ-SARANO M; SEWARD JB; BAILEY KR ET AL.: "Effective regurgitant orifice area: a nosinvasive Doppler development of an old hemodynamic concept", J AM COLL CARDIOL, vol. 23, 1994, pages 443 - 51
FNRIQUEZ-SARANO M; BAILEY KR; SEWARD JB ET AL.: "Quantitative Doppler assessment of valvular regurgitation", CIRCULATION, vol. 87, 1993, pages 841 - 8
PEDRIZZETTI G: "Unsteady tube flow over an expansion", J FLUID MECH, vol. 310, 1996, pages 89 - 111
RECUSANI F; BARGIGGIA GS; YOGANATHAN AP ET AL.: "A new method for quantification of regurgitant flow rate using color Doppler flow imaging of the flow convergence region proxi-mal to a discrete orifice: an in vitro study", CIRCULATION, vol. 83, 1991, pages 594 - 604
UTSUNOMIYA T; PATEL D; DOSHI R ET AL.: "Can signal intensity of the continuous wave Doppler regurgitant jet estimate severity of mitral regurgitation?", AM HEART J, vol. 123, 1992, pages 166 - 71
VANDERVOORT PM; RIVERA JM; MELE D ET AL.: "Application of color Doppler flow mapping to calculate effective regurgitant orifice area: an in vitro study and initial clinical observations", CIRCULATION, vol. 88, 1993, pages 1150 - 6
WALKER P.G.; OYRE S., PEDERSEN ET AL.: "A new control volume method for calculating valvular regurgitation", CIRCULATION, vol. 92, 1995, pages 579 - 586

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010046330A1 (en) * 2008-10-24 2010-04-29 Tomtec Imaging Systems Gmbh Three-dimensional derivation of a proximal isokinetic shell of a proximal flow convergence zone and three-dimensional pisa flow measurement
US8911375B2 (en) 2008-10-24 2014-12-16 Tomtec Imaging Systems Gmbh Three-dimensional derivation of a proximal isokinetic shell of a proximal flow convergence zone and three-dimensional PISA flow measurement

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EP1511974B1 (en) 2016-08-10
US7270635B2 (en) 2007-09-18
US20050107705A1 (en) 2005-05-19

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