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WO2000062659A1 - Methodes non invasives pour depister des anomalies chez un sujet, telles qu"une maladie ou un dysfonctionnement - Google Patents

Methodes non invasives pour depister des anomalies chez un sujet, telles qu"une maladie ou un dysfonctionnement Download PDF

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Publication number
WO2000062659A1
WO2000062659A1 PCT/US2000/010224 US0010224W WO0062659A1 WO 2000062659 A1 WO2000062659 A1 WO 2000062659A1 US 0010224 W US0010224 W US 0010224W WO 0062659 A1 WO0062659 A1 WO 0062659A1
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WIPO (PCT)
Prior art keywords
subject
fluid
tissue
temperature
detecting
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PCT/US2000/010224
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English (en)
Inventor
Brent W. Snow
Patrick C. Cartwright
John T. Mansfield
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University of Utah Research Foundation Inc
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University of Utah Research Foundation Inc
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Priority to US09/959,030 priority Critical patent/US7217245B1/en
Priority to AU43534/00A priority patent/AU4353400A/en
Publication of WO2000062659A1 publication Critical patent/WO2000062659A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/01—Measuring temperature of body parts ; Diagnostic temperature sensing, e.g. for malignant or inflamed tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/41—Detecting, measuring or recording for evaluating the immune or lymphatic systems
    • A61B5/414—Evaluating particular organs or parts of the immune or lymphatic systems
    • A61B5/416—Evaluating particular organs or parts of the immune or lymphatic systems the spleen

Definitions

  • the present invention relates to a noninvasive method for measuring temperature changes in tissues in a subject during and after heating to detect disease or dysfunction of the tissues, to monitor the progress and/or treatment of such disease or dysfunction and to detect the flow of body fluids.
  • such measurements may be used to prepare images of the tissues, fluid pathways and related matter.
  • Body tissues including solid tissues such as organs, for example the kidney, liver and spleen, are vulnerable to a number of diseases, such as cancer, inflammation, scarring and deleterious changes in functioning that cause a change in physical characteristics of the tissue.
  • diseases such as cancer, inflammation, scarring and deleterious changes in functioning that cause a change in physical characteristics of the tissue.
  • inflammation causes swelling, scarring results in increased density, and alterations in function can create changes in metabolic energy.
  • Such physical changes may also result in changes in the manner in which tissue warms and dissipates applied heat.
  • tissues infiltrated by cancer have been observed to exhibit differential heating characteristics when heat is applied to the tumors (Song,
  • Radio frequency and electromagnetic radiation have been used to treat tumors.
  • US Patent No. 3,991,770 and U.S. Patent No. 4,140,130 Microwave radiometry has been used to measure body temperatures (U.S. Patent No. 4,583,869) for diagnosis, for example for tumor detection (see Foster and Cheever, Bioelectromagnetics 13:567-579 (1992)).
  • vesicoureteral reflux involves movement of urine from the bladder through the ureters to the kidneys contributing to kidney infection, particularly in children.
  • gastroesophageal reflux is common in young children and requires nasogastric tubes to be placed to instill x-ray contrast to image whether reflux occurs.
  • Other conditions involve disruptions in blood flow or myocardial function resulting from narrowing of the aorta, blood clots, or malfunction of the enterohepatic circulation or a portion of this system, e.g. the intestine, liver or gall bladder, or disruptions in flow of cerebrospinal fluid.
  • diagnosis of such conditions has required invasive procedures such as use of catheters or tubes.
  • Reflux is c ⁇ tical to diagnose because in its presence the majority of kidney damage during childhood occurs.
  • NCUG voiding cystourethrogram
  • a nuclear cystogram a nuclear cystogram.
  • a NCUG is performed in humans of all ages by first placing a sterile catheter in the patient's urethra and through the catheter instilling radiopaque contrast, such as Hypaque tm , into the bladder under 60 centimeters of gravity pressure. The kidneys and bladder are observed during a bladder filling and emptying cycle using x-rays. The patient has as initial x-ray film taken, then an anterior-posterior film and then films in each lateral oblique. When voiding is initiated, fluoroscopy is utilized, and spot films are taken to document changes during voiding. This process is necessary to evaluate bladder anatomy, function, elimination and vesicoureteral reflux.
  • Nuclear cystogram An alternative diagnostic study called a nuclear cystogram still requires the ordeal of catheter passage into the urethra and then radioactive particles are instilled into the bladder. Nuclear cystogram is performed after a sterile catheter is placed in the patient's urethra. Radionuclide is instilled into the bladder and the patient is imaged with a gamma camera to evaluate bladder function, elimination and vesicoureteral reflux . The radiation dose is reduced but not eliminated. Moreover, visual images obtained from this study are typically of poor quality. Although it is the bladder that is invaded by a catheter in these diagnostic procedures, the critical information obtained involves the kidneys and leads to protection from kidney damage. If reflux of urine to the kidney is detected, the diagnostic tests need to be repeated in the same child at regular intervals until the reflux is resolved. Repeat tests heighten the anxiety of the child and the parents.
  • embodiments of the present invention provide a noninvasive method for determining the flow of bodily fluids in a subject by administering external energy, such as microwave or ultrasound energy, to warm a fluid in the organ or tissue, and then detecting the path of the warmed fluid.
  • the body fluid can be urine, blood, cerebrospinal fluid, bile, lymph, or gastric fluid.
  • a temperature change i.e. temperature increase, in a location distant from the site of warming of the fluid, indicates that the warmed fluid has passed into the distant location.
  • urine in the bladder is warmed and the presence of warmed urine in the kidney is detected to determine whether a reflux condition is present.
  • bladder functioning i.e. bladder emptying, is determined using the methods of the invention.
  • the warmed body fluid is gastrointestinal fluid, and flow into the stomach of the subject from other locations is detected.
  • the warmed body fluid is blood, and flow from or to the heart is detected.
  • the body fluid is cerebrospinal fluid, and flow of the fluid to or from the brain, or through the spine, is detected.
  • a warmed fluid is introduced into the subject and the flow of the fluid throughout the body of the subject is detected.
  • heat dissipation after heating may be measured and compared to measurements on a normal or control tissue. Differences in the temperature changes during heating and heat dissipation of the tissue may indicate the presence of disease or dysfunction, and can be used to monitor the progress and/or treatment of the condition. Rates of temperature increase or decrease of heated tissue are also compared with rates of temperature increase or decrease for corresponding normal tissues to detect the presence of disease or dysfunction.
  • Embodiments of the present invention provide noninvasive methods for detecting and monitoring the condition of a subject by administering external energy such as microwave or ultrasound to heat selected tissue or fluids and measuring temperature changes of the tissue or fluids during heating and heat dissipation and comparing such changes to measurements for normal tissue or fluids during heating and heat dissipation. These methods are useful, for example, to detect disease or dysfunction or to monitor the progress of a condition in a subject.
  • external energy such as microwave or ultrasound
  • Some methods of the present invention rely on the non-invasive heating of selected regions of tissue in a subject using an externally applied energy source, and the non-invasive measurement of the temperature changes throughout the tissue using a temperature sensing device. Any diseases or dysfunctional portions of the tissue will absorb the heat from the external source differently, i.e. exhibit different rates of temperature change, than temperature changes measured in normal tissue during heating. Similarly, diseased tissue will dissipate heat differently than normal tissue.
  • the measurements of temperature changes of the selected regions of tissue in the subject are then compared to measurements obtained for corresponding normal tissue (i.e. non- diseased tissue) from subjects to determine the presence and extent, if any, of diseased or dysfunctional tissue. Measurements are also taken of the rate of temperature change upon heating or heat dissipation in selected tissue and compared to rates measured in corresponding normal tissue to diagnose the presence and extent of disease or dysfunction.
  • the temperature measurements of heat absorption or dissipation of the selected tissue or the rate of temperature change may be used to construct an image, such as a color image, of the tissue to provide a rapid diagnostic test for determining deleterious changes in anatomy and/or function of the selected tissue.
  • the image is produced, for example, and not by way of limitation, by integrating the temperature data with the temperature sensor location (direction) and the depth of the temperature signal. For this application, multiple sensors are preferred to provide the image.
  • the data are assigned colors which are then displayed as an image on a device for viewing.
  • the image may be generated and displayed essentially simultaneously during temperature measurements of the selected tissue.
  • the external applied energy for heating selected tissues or fluids in the methods of the present invention may be any form of energy capable of safely heating human tissue, including microwave energy or ultrasound.
  • Devices for applying microwave energy to heat using 600 to 1500 MHz electromagnetic power are known (e.g. Chou, Bioelectromagnetics 13:582-597 (1992); BSD Systems, Salt Lake City, Utah) and may be modified as needed to apply energy of the desired frequency and penetration.
  • Ultrasound heating systems for use in the invention can be readily assembled using ultrasound crystals of a range of emitting frequencies from 500 Kilohertz to 12 MHz (Channel Industries, Santa Barbara, CA) and a suitable amplifier providing from 0 to 100 watts to heat tissues within the subject at different depths. The crystals are positioned manually or by computer to focus the applied heat as desired.
  • the device To apply the external energy to warm the fluid, the device is positioned on the skin of the subject above the tissue to be warmed or above the organ or tissue containing the fluid to be warmed, and is activated for the selected time sufficient to warm the fluid or tissue, but not to the point that the warmed fluid or tissue would cause pain or damage, typically less than 45 ° C. Ultrasound detection may be used to assist in positioning of the heating device over the space containing the fluid to be warmed. External energy is typically applied for less than 20 minutes to uniformly heat the fluid, for example to heat a bladder to warm the urine contained within.
  • the energy sensor for measuring temperatures of the tissue may be a radiometer (RES Ltd., Moscow, Russia).
  • microwave radiometers can measure subsurface temperatures at depths of millimeters to centimeters. Temperature changes of at least 0.3 °C can be detected.
  • Further embodiments of the present invention provide noninvasive methods for detecting the flow of fluids in organs and tissues in a subject by administering external energy such as microwave or ultrasound. The method is useful, for example, to detect vesicoureteral reflux in subjects, and to quantify the amount of reflux to the kidney, and to study characteristics of emptying the bladder to detect disease or dysfunction.
  • the method relies on the non-invasive warming of a bodily fluid in a selected space, for example urine in a bladder or cerebrospinal fluid in the brain and/or spinal column, using an externally applied energy source, and the non-invasive measurement of a temperature change in the space into a distal space through which the warmed fluid passes or into which the warmed fluid passes and collects (e.g. kidney) resulting from the inflow of the warmed fluid.
  • a bodily fluid in a selected space for example urine in a bladder or cerebrospinal fluid in the brain and/or spinal column
  • the methods of the invention may be used to detect and characterize the flow of various fluids in the body including, but not limited to, urine, blood, cerebrospinal fluid, bile and gastric fluid.
  • the temperature change in tissues or organs distal to the point of application of energy resulting from the presence of the warmed fluid is detected and measured by a non-invasive device such as a radiometer.
  • Microwave radiometers e.g. from RES Ltd., Moscow Russia operating in the 1 100 to 1200 MHz range
  • the detecting device is positioned on the skin over the kidney to detect the presence of any warmed fluid indicating reflux.
  • a temperature change of at least 0.3 °C stable for at least 1 minute detected in the kidney indicates that the warmed fluid has traveled into the kidney suggesting a reflux condition exists.
  • the amount of urine present in the kidney is used to establish the severity of reflux, typically stated as a value from 1 to 5 (see Walker, Vesicoureteral Reflux and Urinary Tract Infection in Children in Adult and Pediatric Urology. 3 rd Ed., Mosby, St. Louis, MO 1996).
  • the amount of liquid refluxing to the distal location can be determined from the amount of temperature change detected in the distal location.
  • a measured temperature change in a given area e.g. kidney
  • bladder functioning in terms of characteristics of bladder emptying can be determined using the methods of the invention.
  • the rate (volume change/time) of bladder emptying can be determined from the rate of temperature decrease in the bladder as the warmed fluid exits during voiding, and is then compared to "normal" flow rates of emptying that have been established for specific age groups by the medical profession.
  • gastrointestinal fluids in the stomach are warmed to less than 45 °C and the flow of the warmed fluids is followed to detect possible reflux of such fluids into the esophagus and duodenum to detect antegrade and retrograde flow (gastroesophageal reflux) by detecting temperature changes in the esophagus and/or duodenum.
  • bile acid is warmed in the gall bladder to detect bile acid reflux from the duodenum to the stomach to diagnose duodenal gastric reflux, and to detect malfunction of the enterohepatic circulation or a portion of the circulation, e.g. the intestine, liver or gall bladder.
  • blood is warmed in the heart, and the flow of the warmed blood flow is followed through the vascular tree to evaluate adequacy of blood flow through the body and to detect any obstructions of blood vessels by detecting temperature changes at various positions in the circulatory system.
  • cerebrospinal fluid is warmed in the spinal column and/or cranial vault and the flow of fluid is followed throughout to detect any problems in the cerebrospinal anatomy and extent of any disease processes by detecting temperature changes in the spinal column and cranium.
  • warm liquid is introduced into the subject and the path of the liquid is followed, for example by detecting temperature changes in the stomach and esophagus.
  • the methods of the invention eliminate the need for invasive procedures to detect diseased or dysfunctional tissue while also reducing risk to patients.
  • the methods of the invention do not require a catheter, nasogastric tube or other similar device or invasive procedure which cause discomfort to the subject and can contribute to tissue injury or infection.
  • the methods eliminate the need for examination using ionizing x-ray radiation, reducing risk to patients.
  • a subject is screened to detect disease or dysfunction of kidney tissues using the methods of the invention as follows.
  • a temperature sensing radiometer is used to determine the "before" temperature throughout the kidney.
  • a portable microwave or ultrasound capable of penetrating to at least 10 cm is placed on the skin over the kidney of a subject and the device is activated to direct 100 to 200 watts (W) (variable power) at 27 to 1500 MHz to uniformly heat the kidney in order to elevate the temperature of the kidney from its existing temperature to between 37 °C and 45 °C.
  • W watts
  • the temperature increases throughout the kidney are sensed using a radiometer for 1 to 20 minutes during heating, by placing the radiometer on the skin of the subject over the kidney.
  • Multiple heat sensing devices e.g. radiometers, may be used for the measurements throughout the kidney.
  • the measurements obtained during heating are compared to temperature changes measured in tissue in kidneys in normal subjects that have undergone the same non- invasive heating and temperature measuring procedures. This comparison establishes differences in "test" kidney tissue to determine the presence of disease or dysfunction that alters the tissue's ability to absorb heat.
  • the temperature changes throughout the kidney during heat dissipation are measured by the radiometer, or using multiple radiometers. Again, these measurements are compared to temperature changes measured after heating of tissue in "normal" kidneys to detect disease or dysfunction that has altered the kidney tissue's ability to dissipate heat. Rates of heating or dissipation may also be determined and compared to rates of heating or dissipation of normal kidney tissue.
  • the temperature data can be converted to images by assigning color values to increases or decreases and the images obtained compared to images for temperature changes in tissue of normal kidneys.
  • differences in heat absorption and heat dissipation between the subject's kidney and values pre-determined for normal kidneys provide information to the medical practitioner regarding the presence and extent of disease, as well as disease progression and the success of medical intervention.
  • EXAMPLE 2 Detection of Urine Flow in a Subject by Measuring Temperature Chan es To Detect Vesicoureteral Reflux From The Bladder
  • a subject is administered fluids and tested using the following procedures to determine whether the subject suffers from vesicoureteral reflux.
  • a radiometer is used to determine the "before" temperature of the kidney.
  • a portable microwave or ultrasound capable of penetrating to at least 10 cm is placed on the skin over the bladder of a subject and the device is activated to direct 100 to 200 watts (W) (variable power) at 27 to 1500 MHz to heat the urine in the bladder to 42 °C stable for 1 minute.
  • W watts
  • the subject then voids urine from the bladder, and after 1 minute a radiometer is placed on the skin of the subject over the kidney and the temperature of the kidney is measured to determine whether any increase is detected (the "after" temperature) indicating reflux of urine from the bladder to the kidney.
  • the temperature changes registered in the kidney are a direct result of the amount of thermal energy the warmed urine brings to the kidney as a result of reflux.
  • the temperature deflection of at least 0.3 °C in the kidney due to the presence of warmed fluid indicates the presence of refluxed urine. 10 to 20 minutes after the subject voids, if no temperature change is detected in the kidney, a diagnosis of no reflux can be made.

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Abstract

Les systèmes, méthodes et dispositifs de la présente invention font appel à des méthodes non invasives pour mesurer les variations de température et les taux de variation de température dans des tissus et des liquides organiques sélectionnés, résultant de l"absorption et/ou de la dissipation de chaleur appliquée de façon externe. Ces systèmes, méthodes et dispositifs servent au dépistage et à la surveillance de maladies ou de dysfonctionnement, ainsi qu"à la préparation d"images de diagnostic des tissus et des zones associées, à partir desdites mesures. Dans certains modes de réalisation de l"invention, la température des tissus chauffés est surveillée directement tandis que dans d"autres modes de réalisation de l"invention, la températures est mesurée sur des tissus qui sont chauffés par un flux de fluide chauffé, circulant à travers lesdits tissus.
PCT/US2000/010224 1999-04-15 2000-04-14 Methodes non invasives pour depister des anomalies chez un sujet, telles qu"une maladie ou un dysfonctionnement Ceased WO2000062659A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US09/959,030 US7217245B1 (en) 1999-04-15 2000-04-14 Noninvasive methods for detecting abnormalities in a subject such as disease or dysfunction
AU43534/00A AU4353400A (en) 1999-04-15 2000-04-14 Noninvasive methods for detecting abnormalities in a subject such as disease or dysfunction

Applications Claiming Priority (4)

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US12945799P 1999-04-15 1999-04-15
US12946199P 1999-04-15 1999-04-15
US60/129,457 1999-04-15
US60/129,461 1999-04-15

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004000112A3 (fr) * 2002-06-25 2004-03-11 Glucon Inc Procede et dispositif servant a determiner la viabilite d'un tissu

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4140130A (en) * 1977-05-31 1979-02-20 Storm Iii Frederick K Electrode structure for radio frequency localized heating of tumor bearing tissue
US5496271A (en) * 1990-09-14 1996-03-05 American Medical Systems, Inc. Combined hyperthermia and dilation catheter

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4140130A (en) * 1977-05-31 1979-02-20 Storm Iii Frederick K Electrode structure for radio frequency localized heating of tumor bearing tissue
US5496271A (en) * 1990-09-14 1996-03-05 American Medical Systems, Inc. Combined hyperthermia and dilation catheter

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004000112A3 (fr) * 2002-06-25 2004-03-11 Glucon Inc Procede et dispositif servant a determiner la viabilite d'un tissu

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