U.S. patent application number 10/682808 was filed with the patent office on 2004-07-01 for measurement of capillary related interstitial fluid using ultrasound methods and devices.
Invention is credited to Lang, Philipp, Mendlein, John D..
Application Number | 20040127790 10/682808 |
Document ID | / |
Family ID | 25434479 |
Filed Date | 2004-07-01 |
United States Patent
Application |
20040127790 |
Kind Code |
A1 |
Lang, Philipp ; et
al. |
July 1, 2004 |
Measurement of capillary related interstitial fluid using
ultrasound methods and devices
Abstract
The present invention provides for methods and devices for
monitoring capillary related interstitial thickness. The invention
also includes methods of measuring capillary related interstitial
fluid, as well as cardiac, vascular, renal and hepatic function.
Specific devices, particularly probes, are provided for such
methods.
Inventors: |
Lang, Philipp; (Lexington,
MA) ; Mendlein, John D.; (Leucadia, CA) |
Correspondence
Address: |
HALE AND DORR, LLP
60 STATE STREET
BOSTON
MA
02109
|
Family ID: |
25434479 |
Appl. No.: |
10/682808 |
Filed: |
October 9, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10682808 |
Oct 9, 2003 |
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09650431 |
Aug 28, 2000 |
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6659949 |
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09650431 |
Aug 28, 2000 |
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08914527 |
Aug 19, 1997 |
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Current U.S.
Class: |
600/438 |
Current CPC
Class: |
A61B 8/4236 20130101;
A61B 8/0858 20130101; A61B 8/4422 20130101; A61B 8/4472
20130101 |
Class at
Publication: |
600/438 |
International
Class: |
A61B 008/00 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 19, 1998 |
WO |
PCT/US98/17238 |
Claims
We claim:
1. A method of detecting capillary related edema in a subject,
comprising: a) positioning an ultrasound probe on an epidermal
surface of an appendage region of a subject in need of capillary
related edema detection and said subject is suspected of comprised
or challenged cardiac, arterial, venous, renal, hepatic function,
b) applying at least one ultrasound pulse to a subcutaneous layer
of said appendage region, c) recording a least one ultrasound
signal with said ultrasound probe from said appendage region, and
d) detecting the presence or absence of a capillary related edema
layer in said subcutaneous layer of said appendage region from said
at least one ultrasound signal.
2. The method of claim 1, wherein said subject is a human.
3. The method of claim 2, wherein said appendage region is a tibia
region.
4. The method of claim 3, wherein said detecting of said capillary
related edema layer extends from an inner surface of skin to either
a bone or fat surface in said tibia region.
5. The method of claim 4, wherein said recording does not determine
the degree of skin echogenicity.
6. The method of claim 5, further comprising calculating a distance
from said inner surface to said bone or fat surface of said tibia
region.
7. The method of claim 6, wherein said distance is calculated by
determining the shortest reflective distance.
8. The method of claim 6, wherein said human has diabetes,
compromised renal function or compromised cardiac function.
9. The method of claim 8, further comprising: a) administering a
diuretic agent, a cardiac agent or a diabetic agent, b) positioning
an ultrasound probe on an appendage region of a subject in need of
capillary related edema detection after said administration, and c)
recording ultrasound signals with said ultrasound probe from said
appendage region; d) wherein said ultrasound signals can be used to
measure a capillary related edema layer in said appendage region
after said administration.
10. The method of claim 5, wherein said ultrasound probe is an
autonomous, hand-held ultrasound system capable of self
measurement.
11. The method of claim 10, wherein said ultrasound system has a
grip that readily permits said human to position said ultrasound
probe on said tibia region of said human and said ultrasound system
permits said human to monitor said capillary related edema
layer.
12. The method of claim 8, further comprising measuring said
capillary related edema layer between the inner surface of the skin
and the anterior aspect of the tibia based on said at least one
ultrasound signal.
13. The method of claim 12, wherein said measuring further
comprises measuring skin thickness with said at least one
ultrasound signal.
14. The method of claim 12, further comprising comparing said
capillary related edema layer to a standard subcutaneous layer
thickness for said tibia region, wherein said tibia region is about
halfway between the ankle joint and the knee joint.
15. The method of claim 14, wherein said comparing comprises
subtracting said standard subcutaneous layer thickness from said
capillary related edema layer thickness or dividing said capillary
related edema layer by said standard subcutaneous layer thickness
to assess the amount of capillary related edema in the lower
extremity.
16. The method of claim 1, wherein said capillary related edema is
not in a non-muscle organ.
17. The method of claim 1, wherein further comprising: a)
positioning an ultrasound probe on an appendage region of said
subject in need of capillary related edema detection 24 or more
hours after detecting said capillary related edema layer, and b)
recording ultrasound signals with said ultrasound probe from said
appendage region; c) wherein said ultrasound signals can be used to
measure a change of said capillary related edema layer in said
appendage region after detecting said capillary related edema
layer.
18. A dedicated ultrasound system for measuring capillary related
edema, comprising an appendage ultrasound probe having a probe head
and grip adapted for positioning said appendage probe on an
appendage, and a computational unit.
19. The dedicated ultrasound system of claim 18, wherein said
system is dedicated for self measurement and said grip is adapted
for self measurement.
20. The dedicated ultrasound system of claim 19, wherein said
appendage ultrasound probe has a self operator display.
21. The dedicated ultrasound system of claim 20, wherein said grip
is no less than about 9 to 12 cm and no more than about 18 to 30
cm.
22. The dedicated ultrasound system of claim 19, wherein said grip
projects from a surface of said appendage at about a 30 to 60
degree angle when said probe head is flush with said surface.
23. The dedicated ultrasound system of claim 19, wherein said
system is an autonomous, hand-held ultrasound system.
24. The dedicated ultrasound system of claim 19, wherein said
computational unit comprises a computer program to calculate
capillary related edema layer thickness.
25. The dedicated ultrasound system of claim 19, wherein said
computer program comprises a standard thickness for skin layer
thickness.
26. A health care kit comprising: a) a dedicated ultrasound system
for measuring capillary related edema, comprising an appendage
ultrasound probe having a probe head and grip adapted for
positioning said appendage probe, and b) a computational unit; and
c) a health care product in at least one dosage; wherein said
system can monitor for a therapeutic effect of said dosage.
27. The therapeutic kit of claim 26, wherein said health care
product enhances water loss.
28. The therapeutic kit of claim 27, wherein said health care
product is a drug selected from the group consisting of
antiarrhythmics, anticholinergics, antihypertensives, alpha- and
beta-adrenergic blockers, calcium channel blockers, cardiac
glycosides, hydantoin derivatives, and nitrates.
29. The therapeutic kit of claim 26, wherein said health care
product enhances cardiovascular function.
30. The therapeutic kit of claim 27, wherein said health care
product is a drug selected from the group consisting of diuretics
such as aldosteron antagonists, carbonic anhydrase inhibitors, loop
diuretics and thiazides or thiazide-like agents
31. The therapeutic kit of claim 26, wherein said health care
product enhances renal function.
32. The therapeutic kit of claim 27, wherein said health care
product a drug selected from the group consisting of anticoagulants
and vasoactive substances.
33. A method of measuring capillary related interstitial fluid,
comprising: a) transmitting at least one ultrasound pulse to a
tissue in a subject in need of capillary related interstitial fluid
assessment, b) recording at least one ultrasound signal from said
tissue, and c) determining a capillary related interstitial layer
thickness from a first reflective surface to an internal reflective
surface, wherein said capillary related interstitial layer
thickness is an assessment of capillary related interstitial
fluid.
34. The method of claim 33, wherein said first reflective surface
is a probe skin interface and said internal reflective surface is
from a bone.
35. The method of claim 34, wherein said tissue is located in an
appendage and said subject is a human.
36. The method of claim 35, wherein said steps (a), (b), and (c)
are performed prior to a medical treatment and a first capillary
related interstitial layer thickness is determined and further
comprising repeating said steps (a), (b), and (c) after, or
simultaneous to, said medical treatment and during a clinically
relevant time period, and further comprising comparing a second
capillary related interstitial layer thickness to said first
interstitial layer thickness, wherein if said second capillary
related interstitial layer thickness is larger than said first
capillary related interstitial layer thickness then said medical
treatment failed or induces an increase in capillary related
interstitial fluid or if said second capillary related interstitial
layer thickness is smaller than said first capillary related
interstitial layer thickness then said medical treatment induces a
decrease in capillary related interstitial fluid or if said second
capillary related interstitial layer thickness is approximately
equal to said first capillary related interstitial layer thickness
then said medical treatment produces no change in capillary related
interstitial fluid.
37. The method of claim 36, wherein said medical treatment
comprises administration of a drug to said subject.
38. The method of claim 37, wherein said steps (a), (b), and (c)
are repeated at predetermined intervals as an assessment of
capillary related interstitial fluid balance of said subject over a
clinically relevant time period.
39. The method of claim 38, wherein said drug is a cardiovascular
agent.
40. The method of claim 38, wherein said drug is a renal agent.
41. The method of claim 36, wherein said medical treatment
comprises surgery.
42. The method of claim 41, wherein said steps (a), (b), and (c)
are repeated at predetermined intervals as an assessment of
capillary related interstitial fluid balance of said subject over a
clinically relevant time period.
43. The method of claim 42, wherein said medical treatment further
comprises administration of a general anesthetic.
44. The method of claim 36, wherein said medical treatment
comprises intubation.
45. The method of claim 44, wherein said steps (a), (b), and (c)
are repeated at predetermined intervals as an assessment of
capillary related interstitial fluid balance of said subject over a
clinically relevant time period.
46. The method of claim 34, wherein said steps (a), (b), and (c)
are initiated within 36 hours of a trauma to said subject and an
initial capillary related interstitial layer thickness is
determined and said steps (a), (b), and (c) are repeated during a
clinical relevant time period after said trauma and sequential
capillary related interstitial layer thicknesses are determined,
wherein a progressive increase in capillary related interstitial
layer thickness indicates an increase in capillary related
interstitial fluid and a progressive decrease in capillary related
interstitial layer thickness indicates a decrease in capillary
related interstitial fluid.
47. The method of claim 33, wherein said at least one ultrasound
signal is from an ultrasound probe positioned on an epidermal
surface of a tissue, wherein positioning permits measurement of an
interstitial layer between bone and skin and said subject has been
diagnosed as requiring a capillary related interstitial fluid
assessment and said ultrasound probe is specifically adapted for
capillary related interstitial fluid assessment.
48. The method of claim 47, wherein said probe is positioned,
either continuously or intermittently, at approximately the same
anatomical site on an epidermal surface of said tissue, and said
transmitting and recording occur at clinically relevant time
intervals over at least about a 4 hour time period.
49. The method of claim 47, wherein said ultrasound probe is
secured to said subject with an adhesive, wherein said adhesive can
acoustically couple said ultrasound probe to the skin of said
subject.
50. The method of claim 49, wherein said ultrasound probe has a
surface area no more than about 2 cm.sup.2.
51. The method of claim 42, wherein said determining further
comprises comparing capillary related interstitial layer thickness
with a standard value for capillary related interstitial layer
thickness for a particular anatomical region.
52. A method of assessing vascular performance, comprising: a)
reducing or increasing blood flow to a tissue in a subject, b)
monitoring a capillary related interstitial layer thickness of said
tissue with an ultrasound probe after or concurrent with said step
(a), c) increasing said blood flow to said tissue after said
reducing in step (a) and said monitoring in step (b) or decreasing
said blood flow to said tissue after said increasing in step (a)
and said monitoring in step (b), and d) monitoring said capillary
related interstitial layer thickness of said tissue with an
ultrasound probe, after or concurrent with said step (c), wherein
said reduction in blood flow controllably reduces blood flow to
said tissue for a clinically relevant period of time in step (a)
and said increase in blood flow controllably increases blood flow
to said tissue for a clinically relevant period of time in step
(c), or wherein said increase in blood flow controllably increases
blood flow to said tissue for a clinically relevant period of time
in step (a) and said reduction in blood flow controllably reduces
blood flow to said tissue for a clinically relevant period of time
in step (c).
53. The method of claim 52, wherein said tissue is in an appendage
and step (a) further comprises applying a tourniquet to said
appendage to reduce blood flow to said appendage.
54. The method of claim 53, wherein said ultrasound probe is a part
of a B scan ultrasound system.
55. The method of claim 54, wherein said monitoring in either said
steps (b) or (d) occurs at, at least one predetermined time.
56. The method of claim 55, wherein said monitoring can detect a
15% change in interstitial layer thickness.
57. The method of claim 56, wherein said appendage is a leg.
58. The method of claim 57, wherein said tissue is located in the
pretibial region of said leg.
59. The method of claim 58, wherein said steps (a) through (d) are
performed before a medical treatment and either after or concurrent
with said medical treatment.
60. The method of claim 59, wherein said medical treatment is the
administration of a cardiovascular agent.
61. The method of claim 52, further comprising monitoring a
capillary related interstitial layer thickness of said tissue with
an ultrasound probe, before said step (a).
62. The method of claim 54, wherein said clinically relevant period
is between about five and 90 minutes.
63. The method of claim 55, wherein said monitoring in either said
steps (b) or (d) occurs continuously.
64. The method of claim 52, wherein said ultrasound probe is
adapted to measure interstitial layer thickness.
65. The method of claim 64, wherein said monitoring in either said
steps (b) or (d) occurs during at least one predetermined time.
66. The method of claim 65, wherein said monitoring can detect
about a 1% or more change in leg diameter arising from changes in
interstitial layer thickness.
67. The method of claim 66, wherein said appendage is a leg and
said tissue is located in a tibial region of said leg.
68. The method of claim 67, wherein said increase in blood flow in
step (c) occurs with either 1) the tibial region elevated at a
level approximately above the heart of said subject, 2) the tibial
region at approximately the same level as the heart of said subject
or 3) the tibial region located at a level approximately below the
heart of said subject.
69. The method of claim 68, wherein the tibial region is located at
a level approximately below the heart of said subject and said
monitoring detects an increase in capillary related interstitial
layer thickness during said reduction in blood flow and said
monitoring detects a decrease in capillary related interstitial
layer thickness during said increase in blood flow, wherein a less
than 50% decrease in capillary related interstitial layer thickness
after 60 minutes of said increase in blood flow indicates venous
insufficiency.
70. The method of claim 64, wherein said steps (a) through (d) are
performed before a medical treatment and either after or concurrent
with said medical treatment.
71. The method of claim 70, wherein said medical treatment is the
administration of a cardiovascular agent.
72. A method for non-invasively estimating dynamic cardiac
performance in a human, comprising: a) monitoring interstitial
fluid content with an ultrasound probe positioned on the skin of a
human in need of cardiac performance evaluation and in an
anatomical region suitable for monitoring changes in interstitial
fluid content during a clinically relevant time period, and b)
comparing said capillary related interstitial fluid content
monitored in step (a) with a standard value for capillary related
interstitial fluid content or with a measurement of capillary
related interstitial fluid content in said human.
73. The method of claim 72, wherein said comparing qualitatively
compares interstitial fluid content to a predetermined standard
value for interstitial fluid content, wherein said comparison
provides a diagnostic measure of cardiac performance.
74. The method of claim 72, wherein said human is suspected of
having a medical condition that increases interstitial fluid
content.
75. The method of claim 74, wherein monitoring occurs before and
after elevating legs of said human.
76. The method of claim 74, wherein said monitoring occurs before
and during exercise challenge.
77. The method of claim 74, wherein said monitoring occurs before
and after application of a tissue compression appendage
stocking.
78. The method of claim 74, wherein said medical condition is
abnormally elevated afterload.
79. The method of claim 74, wherein said monitoring occurs before
and during administration of a sufficient amount of isotonic saline
to cause a temporary interstitial fluid challenge.
80. A method of detecting rapid changes in capillary related
interstitial fluid volume in a human, comprising: a) positioning a
first ultrasound probe on a skin surface of a first anatomical
region of said human in need of capillary related interstitial
fluid volume detection during a clinically relevant time period, b)
interrogating said first anatomical region with ultrasound pulses
from said first ultrasound probe, and c) detecting a first
capillary related interstitial fluid volume between an inner
surface of skin and either a bone or fat surface in said first
anatomical region with ultrasound signals from said ultrasound
pulses, wherein said first capillary related interstitial fluid
volume is an indicator of capillary related interstitial fluid
volume of said first anatomical region or optionally is an
indicator of systemic capillary related interstitial fluid
volume.
81. The method of claim 80, further comprising the step of
comparing said first capillary related interstitial fluid volume to
a predetermined value for capillary related interstitial fluid
layer volume.
82. The method of claim 81, wherein said anatomical region is
selected from the group consisting of a tibial region, a humerus
region, a chest region, an abdominal region, and a cranial
region.
83. The method of claim 82, wherein said measuring is a
quantitative measurement of capillary related interstitial fluid
volume comprising determining a capillary related interstitial
layer thickness or a capillary related interstitial layer
volume.
84. The method of claim 83, wherein said quantitative measurement
can detect about a 1 millimeter or greater change in interstitial
layer thickness.
85. The method of claim 84, wherein said measuring occurs during at
least two predetermined monitoring times or measuring occurs
continuously during said clinically relevant time period.
86. The method of claim 85, wherein said measuring occurs over more
than a 20 minute time frame.
87. The method of claim 86, wherein said probe remains in
approximately the same position during said measuring and said
measurements occur no less than 1 per minute at regularly spaced
intervals.
88. The method of claim 87, further comprising placing a plurality
of probes at different anatomical regions and performing steps (a)
through (c) for each anatomical region.
89. The method of claim 88, wherein said plurality of probes
comprises a left tibial region probe, and a right tibial region
probe, wherein said steps (a) through (c) are performed
concurrently with said plurality of probes.
90. The method of claim 89, wherein said plurality of probes
further comprises a humerus probe, cranial probe, chest probe, and
an abdominal probe.
91. A compact ultrasound probe for in situ ultrasound measurements,
comprising: a) at least one ultrasound crystal in acoustic
communication with an acoustic coupling material, b) an ultrasound
crystal holder adapted for securing said acoustic coupling material
to a surface of an object or subject for in situ ultrasound
measurements, and c) an electrical coupling for electrically
connecting said at least one ultrasound crystal to an ultrasound
output or recording system, wherein said electrical coupling is
compatible with securing said ultrasound probe for in situ
ultrasound measurements.
92. The compact ultrasound probe of claim 91, wherein said at least
one ultrasound crystal is a plurality of crystals.
93. The compact ultrasound probe of claim 92, wherein said acoustic
coupling material and said ultrasound crystal holder are
flexible.
94. The compact ultrasound probe of claim 91, wherein said acoustic
coupling material has an adhesive coating or adhesive
properties.
95. The compact ultrasound probe of claim 91, wherein said subject
is a human and said ultrasound crystal holder is adapted to attach
to a securing member that secures an appendage of said human and
secures said ultrasound crystal holder, wherein said acoustical
coupling material is secured in acoustical contact with said
surface and optionally containing an acoustic coupling gel between
said surface and said coupling material.
96. The compact ultrasound probe of claim 91, wherein said
electrical coupling comprises a light weight wire for transmitting
electrical signals to an ultrasound computational unit.
97. The compact ultrasound probe of claim 91, wherein said
electrical coupling comprises an infrared coupler to an ultrasound
computational unit.
98. The compact ultrasound probe of claim 91, wherein said
electrical coupling comprises a radio frequency coupler that
transmits signals to an ultrasound computational unit.
99. The compact ultrasound probe of claim 98, wherein said radio
frequency coupler receives signals from said ultrasound
computational unit.
100. The compact ultrasound probe of claim 96, wherein said
coupling material has a surface area of about 2 cm.sup.2.
101. The compact ultrasound probe of claim 96, wherein said probe
is not adapted for Doppler measurements.
102. The compact ultrasound probe of claim 96, wherein said probe
is not adapted for positioning on the surface of a body cavity.
103. A screen display comprising a predetermined set of anatomical
features that appears on the screen, and at least one processed
signal that appears on the screen and corresponds to at least one
anatomical feature of said predetermined set of anatomical
features.
104. The screen display of claim 103, wherein said predetermined
set of anatomical features appears as a simulated image of an
anatomical region, said image reflects distances between anatomical
features, and at least one distance corresponds to at least one
processed signal.
105. The screen display of claim 104, wherein said image comprises
an anatomical feature selected from the group of bone, skin,
interstitial layer and muscle.
106. The screen display of claim 105, wherein said at least one
processed signal is an ultrasound signal.
107. The screen display of claim 106, further comprising at least
one image reflecting at least one processed signal previously
stored in a storage device.
108. An in situ probe holder comprising a holder member to hold and
secure a probe to a surface, wherein said probe is an ultrasound
probe, or MRI probe.
109. The in situ probe holder of claim 108, further comprising a
plurality of extending members disposed on said holder member to
secure said holder member to said surface and said surface is skin
and said probe is an ultrasound probe.
110. The in situ probe holder of claim 109, wherein said extending
members comprise an adhesive surface.
111. The in situ probe holder of claim 110, wherein said holder
member is permanently attached to said extending members, said
holder member and said extending members are made of a flexible
plastic.
112. The in situ probe holder of claim 109, wherein said holder
member and said extending members form a unit that weighs about 30
to 50 grams or less and said unit is sterile and further comprises
a covering to protect said unit from contamination.
113. The in situ probe holder of claim 109, wherein disposed on
said holder is an adhesive surface to secure said holder to said
surface, said surface is a skin, said probe is an ultrasound
probe.
114. The in situ probe holder of claim 109, wherein said holder
comprises a film to permit acoustic coupling of said ultrasound
probe to said skin.
115. The in situ probe holder of claim 109, wherein said holder
further comprises an ultrasound micro-transducer.
116. The in situ probe holder of claim 115, wherein said holder is
about 3 cm.sup.2 or less.
117. A micro-transducer comprising an acoustic surface acoustically
coupled to an ultrasound source, said acoustic surface and said
ultrasound source are disposed in a frame adapted for directly or
indirectly securing said micro-transducer to a skin.
118. The micro-transducer of claim 117, wherein said
micro-transducer is adapted for monitoring interstitial
thickness.
119. The micro-transducer of claim 118, wherein said
micro-transducer has surface area of about 3 cm.sup.2 or less.
120. The micro-transducer of claim 119, wherein said
micro-transducer is 1 cm or less in thickness.
121. The micro-transducer of claim 108, wherein said
micro-transducer transmits signals to an ultrasound system using
infrared or radio frequency signals.
122. The micro-transducer of claim 121, wherein said
micro-transducer is sterile and further comprises a covering to
protect said unit from contamination.
123. A multi-probe set comprising a first ultrasound probe
comprising a first output port, said first ultrasound probe adapted
for continuous or in situ monitoring at a first anatomical region
and a second ultrasound probe comprising a second output port, said
second ultrasound probe adapted for continuous or in situ
monitoring at a second anatomical region.
124. The multi-probe set of claim 123, further comprising an
ultrasound system to concurrently process first signals from said
first ultrasound probe and second signals from said second
ultrasound probe.
125. The multi-probe set of claim 123, wherein an anatomical region
is selected from the group consisting of the forehead region,
anterior tibia region, foot region, distal radius region, elbow
region, prestemal region and temporal bone region.
126. The multi-probe set of claim 125, wherein said ultrasound
probe is a micro-transducer adapted for monitoring interstitial
layer thickness.
127. The multi-probe set of claim 126, further comprising a third
ultrasound probe comprising a third output port, said third
ultrasound probe adapted for continuous or in situ monitoring at a
third anatomical region.
128. A method of multisite monitoring, comprising: a) transmitting
an ultrasound pulse from a first ultrasound probe to a first
anatomical region, b) transmitting an ultrasound pulse from a
second ultrasound probe to a second anatomical region, c) recording
ultrasound signals from a first ultrasound probe to a first
anatomical region, d) recording ultrasound signals from a second
ultrasound probe to a second anatomical region, and e) monitoring
interstitial layer thickness of said first and second anatomical
regions.
129. The method of claim 128, wherein said monitoring from said
first anatomical region is concurrent with said monitoring from
said second anatomical region.
130. The method of claim 128, wherein said step (a) is within about
10 seconds of step (b) and is automatically controlled by a
computational unit.
131. The method of claim 130, wherein said steps (a) through (e)
are repeated about every 30 to 600 seconds.
132. The method of claim 131, wherein said first and second
ultrasound probes are micro-transducers.
133. The method of claim 132, further comprising a third
micro-transducer.
134. The method of claim 131, further comprising a step of
comparing interstitial layer thickness from said first and second
anatomical regions.
135. The method of claim 131, further comprising a step determining
the rate of change over time of an interstitial layer thickness
from said first and second anatomical regions.
136. The method of claim 134, wherein said micro-transducers are
secured to the skin for continuous monitoring during at least about
a 1 to 24 hour period.
137. The method of claim 136, wherein an anatomical region is
selected from the group consisting the forehead region, anterior
tibia region, distal radius region, presternal region and temporal
bone region.
138. The method of claim 134, wherein said micro-transducers are
secured to the skin for continuous monitoring during a clinically
relevant time period.
Description
TECHNICAL FIELD
[0001] The invention relates to the measurement of capillary
related interstitial fluid using ultrasound methods, compositions
and devices, particularly methods, compositions and devices that
provide for the measurement and monitoring of edema in tissues,
especially a capillary related edema layer in a human.
BACKGROUND
[0002] Edema underlies a myriad of human medical conditions. Yet,
despite the relatively common occurrence of edema, and its
potentially life threatening nature, accurate and reliable
assessments of edema are not available to the clinician or patient
alike. Traditionally, methods have consisted of visual inspection
of the extremities, tissue palpation by a clinician, and
measurement of the circumference of the extremity. Although these
methods are familiar assessments to clinicians, none of these
methods is quantitative and all suffer from tremendous variability
due to inter- and intra-clinician variability of the
measurements.
[0003] Visual inspection of the affected body region yields
information on changes in the color and texture of the skin. Skin
changes in patients with edema include discoloration and
ulceration. Unfortunately, such skin changes occur typically only
in patients with long-standing, chronic edema and are not useful
for diagnosing early or discrete edema. Furthermore, skin changes
are difficult to assess on a quantitative scale and are not useful
for monitoring a response to treatment of edema or the underlying
cause of the edema.
[0004] Visual inspection can also yield information on arteries and
veins, e.g. varicose veins may be visible and may be identified as
a potential cause for capillary related edema. Such identification
of vascular pathology, unfortunately, is only qualitative, is
limited to assessment of the vascular system, and cannot provide
information on the patient's fluid status or on cardiac, renal or
hepatic performance.
[0005] Manual palpation can be used to evaluate edema. For manual
palpation, a finger is pressed gently but firmly into the patient's
skin and subjacent tissue. The depth of the resultant indentation
and persistence of the indentation after the finger has been
released yield information on the severity of the edema. A
semiquantitative scale can be used to assess the severity of the
edema, typically consisting of five different grades: I.) absent,
II.) slight, III.) mild, IV.) moderate, and V.) severe (see Bates
et al., J. B. Lippincott, 1995). Results obtained with manual
palpation are, however, subjective and difficult to reproduce.
[0006] Circumference measurements of appendage regions and limbs
have also been employed for assessing edema. These measurements of
changes in circumference of a limb or an appendage region are
limited to detecting large increases in interstitial fluid. Subtle
increases or also decreases in interstitial fluid in early or mild
forms of capillary related edema will be masked since the change in
circumference induced by the interstitial fluid shift (usually on
the order of few millimeters or less) will be small compared to the
overall circumference of the appendage region or limb (usually on
the order of several centimeters or decimeters).
[0007] Consequently, the present inventors have recognized the
need, among other things, to provide reliable, quantitative and
accurate ultrasound devices and methods for such applications,
particularly hand held devices capable of being operated by
untrained operators. The methods and devices provided herein permit
continuous, cost effective monitoring and accurate measurement of
capillary related interstitial fluid of patients in a variety of
diverse clinical settings.
TABLE OF CONTENTS
[0008] TECHNICAL FIELD . . .
[0009] BACKGROUND . . .
[0010] SUMMARY . . .
[0011] BRIEF DESCRIPTION OF FIGURES . . .
[0012] DETAILED DESCRIPTION OF THE INVENTION . . .
[0013] 1.0 ABBREVIATIONS AND DEFINITIONS . . .
[0014] 2.0 INTRODUCTION . . .
[0015] 3.0 METHODS AND DEVICES FOR MEASURING CAPILLARY RELATED
INTERSTITIAL FLUID . . .
[0016] Application Sites . . .
[0017] Application to Medical Treatments . . .
[0018] Different Types of Monitoring . . .
[0019] Calculations and Standards . . .
[0020] Empirical Methods for Determining Standards . . .
[0021] 4.0 METHODS AND DEVICES FOR MEASURING CAPILLARY RELATED
EDEMA . . .
[0022] Anatomical Regions . . .
[0023] Use in Medical Conditions and Treatments . . .
[0024] Devices for Testing for Capillary Related Edema . . .
[0025] Calculations and Standards . . .
[0026] 5.0 METHODS AND DEVICES FOR MEASURING VASCULAR PERFORMANCE .
. .
[0027] 6.0 METHODS AND DEVICES FOR EVALUATING CARDIAC PERFORMANCE .
. .
[0028] 7.0 METHODS AND DEVICES FOR MEASURING RENAL DISORDERS AND
FUNCTION . . .
[0029] 8.0 METHODS AND DEVICES FOR MEASURING HEPATIC DISORDERS AND
FUNCTION . . .
[0030] 9.0 METHODS AND DEVICES FOR MULTISITE MONITORING . . .
[0031] 10.0 ULTRASOUND PROBES FOR IN SITU MEASUREMENTS . . .
[0032] EXAMPLES . . .
[0033] GENERAL MATERIALS AND METHODS . . .
[0034] EXAMPLE 1: ULTRASONOGRAPHIC MEASUREMENT OF . . . TISSUE
THICKNESS IN AN IN VITRO MODEL OF CAPILLARY RELATED EDEMA
[0035] EXAMPLE 2: ULTRASONOGRAPHIC MEASUREMENT OF . . . THICKNESS
OF CAPILLARY RELATED EDEMA IN A MODEL OF VENOUS INSUFFICIENCY AND
RIGHT VENTRICULAR CARDIAC FAILURE
[0036] EXAMPLE 3: ULTRASONOGRAPHIC MEASUREMENT OF . . . THICKNESS
OF PRETIBIAL EDEMA IN A MODEL OF CAPILLARY RELATED EDEMA SECONDARY
TO ABNORMAL COLLOID OSMOTIC PRESSURE AND/OR RENAL FAILURE
[0037] PUBLICATIONS . . .
[0038] U.S. PATENT DOCUMENTS . . .
[0039] FOREIGN PATENT DOCUMENTS . . .
[0040] OTHER PUBLICATIONS . . .
[0041] CLAIMS . . .
[0042] ABSTRACT . . .
SUMMARY
[0043] The present invention recognizes for the first time that
ultrasound can be applied to the measurement of capillary related
interstitial fluid. The invention finds particular application for
convenient and cost effective measurements in a variety of clinical
settings. Previously, it was not recognized that diagnostic
ultrasound measurements of capillary related interstitial fluid
were possible, or precise. Nor was it recognized that clinically
rapid shifts in capillary related interstitial fluid distribution
in tissues could be monitored using ultrasound methods or devices.
The invention includes monitoring of capillary related interstitial
fluid in a subject using ultrasound wave devices and methods as
described herein. Aspects of the invention are directed to
continuous or intermittent monitoring, such as capillary related
edema monitoring in a human.
[0044] In one embodiment, the invention includes a method of
measuring capillary related interstitial fluid comprising:
transmitting at least one ultrasound signal to a tissue in a
subject in need of capillary related interstitial fluid assessment,
recording at least one ultrasound signal from the tissue, and
determining a capillary related interstitial layer thickness from a
first reflective surface to a second, usually an internal,
reflective surface, wherein the capillary related interstitial
layer thickness is an assessment of capillary related interstitial
fluid. Typically, such a subject will be a human desiring a
capillary related interstitial fluid assessment because a clinician
wishes to use the invention as a part of a diagnosis or the subject
wishes to perform a self assessment of the subject's capillary
related interstitial fluid.
[0045] The inventors were also the first to recognize that
ultrasound methods and devices could be applied to the assessment
of different aspects of integrated cardiac, vascular, renal or
hepatic function. Numerous aspects of the present invention
circumvent many of the disadvantages of the current techniques for
evaluating dynamic performance of the heart or vascular system.
[0046] For example, the present invention provides for a
noninvasive assessment of vascular performance that is relatively
inexpensive, easily performed by a clinician (not necessarily a
physician trained in ultrasound techniques) and can integrate
tissue effects into the assessment, especially capillary related
tissue effects. Typically, a test of vascular performance, includes
two basic steps: reducing or increasing blood flow (or pressure) to
a tissue in a subject in need of vascular performance assessment
(step (a)), and monitoring an interstitial layer thickness (ILT) of
the tissue (step (b)). Monitoring ILT with an ultrasound probe can
be before, after or concurrent with reducing or increasing blood
flow in step (a).
[0047] Other techniques and devices are described herein for
assessments of cardiac, renal, capillary and hepatic function. Such
aspects of the invention can also be used to assess the effect of
medical treatments on such physiological functions.
[0048] The invention also provides for the first time methods and
devices for multisite monitoring of different anatomical regions
either concurrently or at predetermined time intervals. Monitoring
anatomical changes during clinically relevant time periods or
continuous monitoring provide an important diagnostic tool for
detecting short or rapid changes in tissue structure, particularly
interstitial layer thickness. In contrast to previous work, the
invention is able to measure rapid changes in ILT and monitor ILT
from different anatomical regions simultaneously or within short
time frames to compare ILTs from different regions.
[0049] In one aspect, the invention provides for a method of
multisite monitoring of ILT. The method comprises transmitting an
ultrasound pulse from a first ultrasound probe to a first
anatomical region and transmitting an ultrasound pulse from a
second ultrasound probe to a second anatomical region. The method
includes recording ultrasound signals from a first ultrasound probe
to a first anatomical region and recording ultrasound signals from
a second ultrasound probe to a second anatomical region. The method
also includes monitoring interstitial layer thickness from the
first and second, or more, anatomical regions. Typically, the
method is practiced by monitoring from the first anatomical region
concurrently with monitoring from the second anatomical region.
[0050] Another related aspect of the invention includes a
multi-probe set that may be used for multi-site monitoring. The
multi-probe set comprises a first ultrasound probe comprising a
first output port, the first ultrasound probe adapted for
continuous or in situ monitoring at a first anatomical region and a
second ultrasound probe comprising a second output port, the second
ultrasound probe adapted for continuous or in situ monitoring at a
second anatomical region. The set can include an ultrasound system
to concurrently process first signals from the first ultrasound
probe and second signals from the second ultrasound probe. Systems
or sets with more than two probes can also be used. Each probe in
the set can be adapted for a particular anatomical region or
indication. For example, the anatomical region can be selected from
the group consisting of the forehead region, anterior tibia region,
foot region, distal radius region, elbow region, presternal region
and temporal bone region. Preferably, the ultrasound probe is a
micro-transducer adapted for monitoring interstitial layer
thickness.
[0051] The invention provides for the first time micro-transducers
applied to the skin of a subject for ultrasound measurements of
tissue structure. Typically, the micro-transducers are adapted for
either monitoring ILT or capillary related edema, usually on the
skin in a predetermined anatomical region. As described herein, the
micro-transducers are typically small about 10 to 20 mm.sup.2 or
less in surface area, not hand-held but rather attachable to the
skin surface, and light weight. Preferably, micro-transducers are
isolated and not connected to an ultrasound system or display by a
conductive wire, as described herein. In use, the micro-transducers
are usually secured to the skin of a subject for continuous
monitoring of the interrogated region.
BRIEF DESCRIPTION OF THE FIGURES
[0052] FIG. 1A-C show an example of capillary related interstitial
fluid accumulation. FIG. 1A shows normal leg tissue prior to an
increase in capillary related interstitial layer thickness. Skin is
"S". Tibia is "T". Fibula is "F". Muscle is "M" and interstitial
layer is "IL". The probe interrogation site 100 is a preferred site
for monitoring capillary related changes in ILT. The tissue plane
110 is approximately illustrated by the arrows. FIG. 1B and C
illustrate a small but progressive increase in ILT around 100 over
time.
[0053] FIG. 2A-C shows a magnified view of probe interrogation site
100 from FIG. 1. IL is located between skin 200 (dotted layer) and
muscle or bone 210 (cross-hatched layer). FIG. 2B and C illustrate
that IL (wave-line layer) increases dramatically due to an increase
in capillary related interstitial fluid.
[0054] FIG. 3 shows selected, exemplary anatomical regions that can
be used for ultrasound monitoring of capillary related interstitial
fluid and capillary related edema in a human in need of such
monitoring. Exemplary ultrasound interrogation sites include but
are not limited to the forehead region 300, the temporal region
310, the forearm region 320, the humeral region 330, the prestemal
region 340, the lateral chest wall region 350, the lateral
abdominal region 360, the tibial region 370, and the foot region
380. The exemplary regions illustrated in FIG. 3 can be used alone
or in combination, as described herein.
[0055] FIG. 4 is a magnified view of the tibial region 370
demonstrating the proximal third of the tibia region 400, the
mid-tibia region 410, the distal third of the tibia region 420, and
the medial malleolus region 430.
[0056] FIG. 5A and B show embodiments of the invention comprising
an ultrasound transducer secured to a subject or a tissue surface
with an adhesive probe holder, which is preferably used for
intermittent or continuous recording. The ultrasound transducer can
be electrically coupled to an ultrasound computational unit (not
shown) using a light weight wire 500. An electrical connector 510
connects the computational unit and the ultrasound transducer 520
using an electrical connecting socket or connector means 530. The
ultrasound transducer 520 is optionally seated inside a positioning
frame 540. The undersurface of the positioning frame consists of an
acoustic coupler 550. The positioning frame is attached to the
subject or tissue surface using an adhesive 560. The adhesive 560
can acoustically couple the ultrasound probe to the skin of the
subject or the interrogated tissue surface 570. The adhesive 560
can also be interspersed with an acoustic coupling material, such
as a gel (not shown). Tibia is "T". Fibula is "F". Muscle is "M"
and interstitial layer is "IL". FIG. 5B shows that the ultrasound
transducer 520 can also be coupled to an ultrasound computational
unit (not shown) using an infrared coupler or a radio frequency
coupler 580 or other connector means that transmits signals 590 to
an ultrasound computational unit.
[0057] FIG. 6 shows one embodiment of the invention comprising an
ultrasound transducer 600 attached to a separate positioning frame
620 with an attachment member 610. The extending members 630 of the
positioning frame are attached to securing members 640 to secure
the frame to the skin away from the interrogation site. The
securing members are secured to the skin using an adhesive or other
anatomical region attachment means (not shown). The ultrasound
transducer is electrically coupled to an ultrasound computational
unit (not shown) using a light weight wire 650. Alternatively, the
ultrasound transducer can be coupled to an ultrasound computational
unit using an infrared or radio frequency coupler (not shown).
[0058] FIG. 7 shows one embodiment of the invention comprising a
predetermined display arrangement 700 that includes symbols or
illustrative graphics of preselected anatomical features of the
interrogated tissue. Such graphics or symbols can be used to
display calculated distances or estimated features, such as
measured interstitial layer thickness "ILT". In this exemplary
illustration, a graphic presentation of bone, e.g. the tibia 710 is
displayed stationary, while a graphic presentation of the subject's
skin 720 and of the ultrasound transducer 730 can move to the left
or the right side. The displayed distance between the bone 710 and
the skin 720 corresponds to measured ILT. The position of skin 720
and ultrasound transducer 730 can also provide a diagnostic scale
740 indicating whether the patient's fluid status is normal
"normal", elevated "elevated", or critical "critical" for the
patient's underlying condition. Such a diagnostic scale 740 can be
useful in multiple medical conditions, e.g. impaired vascular,
cardiac, renal, or hepatic function. The display unit can have a
light 750 indicating, if the device is turned on, and contrast and
brightness adjustments 760.
[0059] FIG. 8 shows one embodiment of the invention in which first
reflective distance "FRD", usually the distance from the ultrasound
probe to the inner surface of the skin, and second reflective
distance "SRD", typically the distance from the ultrasound probe to
the bone or to the inner border of the subcutaneous fat, can be
displayed on an analog scale in millimeters "mm" and the operator
can manually calculate interstitial layer thickness. The analog
display can include a diagnostic scale "DS" which indicates if the
patient's fluid status is normal "normal", elevated "elevated", or
critical "critical" for the patient's underlying condition.
DETAILED DESCRIPTION OF THE INVENTION
1.0 ABBREVIATIONS AND DEFINITIONS
[0060] ABBREVIATIONS include first reflective distance (FRD),
interstitial fluid (IF), interstitial fluid content (IFC)
interstitial fluid layer (IFL), interstitial fluid monitoring
(IFM), interstitial layer thickness (ILT), interstitial fluid
volume (IFV) and second reflective distance (SRD).
[0061] Acoustic communication refers to the passage of ultrasound
waves between two points in a predetermined manner. Usually, this
is accomplished by selecting a desired pathway between the two
points that permits the passage of ultrasound waves either directly
or indirectly. Direct passage of ultrasound waves would occur, for
instance, when an ultrasound crystal is directly disposed to
(usually touching) an acoustic coupling material, such as a
composite. Indirect passage of ultrasound waves would occur, for
instance, when an ultrasound crystal is located at a predetermined
distance from an acoustic coupling material or when a number of
acoustic coupling materials, often heterogenous materials, form two
or more layers.
[0062] Acoustic coupler refers to a connection or plurality of
connections between an ultrasound crystal and a substance that
reflects or passes ultrasound pulses and is not part of the device.
The acoustic coupler will permit passage of ultrasound waves. It is
desirable for such couplers to minimize attenuation of ultrasound
pulses or signals and to minimize changes in the physical
properties of an ultrasound wave, such as wave amplitude,
frequency, shape and wavelength. Typically, an ultrasound coupler
will either comprise a gel or other substantially soft material,
such as a pliable polymer matrix, that can transmit ultrasound
pulses. Alternatively, an ultrasound sound coupler can be a
substantially solid material, such as a polymer matrix, that can
transmit ultrasound pulses. An ultrasound coupler is usually
selected based on its acoustic impedance match between the object
being interrogated and the ultrasound crystal(s). If a reflective
surface is desired, for instance as a spatial marker, a larger
impedance difference is selected compared to situations where it is
advantageous to minimize a reflective surface to avoid a sharp
reflective surface.
[0063] Acoustic coupling material is a material that passes
ultrasound waves, usually from a probe to a subject or tissue to be
interrogated. It is usually not a living material and is most often
a polymer or gel.
[0064] Anatomical region refers to a site on the surface of the
skin, tumor, organ or other definable biomass that can be
identified by an anatomical features or location. Usually, such a
region will be definable according to standard medical reference
methodology, such as that found in Williams et al., Gray's Anatomy,
1980.
[0065] Appendage region refers to a site on the surface of a limb
of a subject. Examples of appendage regions include a variety of
sites on a leg or an arm, such as a humeral or tibia region.
[0066] A--scan refers to an ultrasound technique where an
ultrasound source transmits an ultrasound wave into an object, such
as patient's body, and the amplitude of the returning echoes
(signals) are recorded as a function of time. Only structures that
lie along the direction of propagation are interrogated. As echoes
return from interfaces within the object or tissue, the transducer
crystal produces a voltage that is proportional to the echo
intensity. The sequence of signal acquisition and processing of the
A-scan data in a modern ultrasound instrument usually occurs in six
major steps:
[0067] Detection of the echo (signal) occurs via mechanical
deformation of the piezoelectric crystal and is converted to an
electric signal having a small voltage.
[0068] Preamplification of the electronic signal from the crystal,
into a more useful range of voltages is usually necessary to ensure
appropriate signal processing.
[0069] Time Gain Compensation compensates for the attenuation of
the ultrasound signal with time, which arises from travel distance.
Time gain compensation may be user-adjustable and may be changed to
meet the needs of the specific application. Usually, the ideal time
gain compensation curve corrects the signal for the depth of the
reflective boundary. Time gain compensation works by increasing the
amplification factor of the signal as a function of time after the
ultrasound pulse has been emitted. Thus, reflective boundaries
having equal abilities to reflect ultrasound waves will have equal
ultrasound signals, regardless of the depth of the boundary.
[0070] Compression of the time compensated signal can be
accomplished using logarithmic amplification to reduce the large
dynamic range (range of smallest to largest signals) of the echo
amplitudes. Small signals are made larger and large signals are
made smaller. This step provides a convenient scale for display of
the amplitude variations on the limited gray scale range of a
monitor.
[0071] Rectification, demodulation and envelope detection of the
high frequency electronic signal permits the sampling and
digitization of the echo amplitude free of variations induced by
the sinusoidal nature of the waveform.
[0072] Rejection level adjustment sets the threshold of signal
amplitudes that are permitted to enter a data storage, processing
or display system. Rejection of lower signal amplitudes reduces
noise levels from scattered ultrasound signals. Blood refers to
whole blood. Blood does not refer to red blood cell
concentrates.
[0073] Blood flow refers to blood movement in a blood vessel (e.g.,
coronary, vein, artery, venole, arteriole, shunt, or capillary).
Blood flow is usually associated with blood entering or leaving a
tissue or definable anatomical region, such as an appendage or a
specific vessel (e.g., artery, vein, naturally occurring and
non-naturally occurring shunt, or coronary).
[0074] B-scan refers to an ultrasound technique where the amplitude
of the detected returning echo is recorded as a function of the
transmission time, the relative location of the detector in the
probe and the signal amplitude. This is often represented by the
brightness of a visual element, such as a pixel, in a
two-dimensional image. The position of the pixel along the y-axis
represents the depth, i.e. half the time for the echo to return to
the transducer (for one half of the distance traveled). The
position along the x-axis represents the location of the returning
echoes relative to the long axis of the transducer, i.e. the
location of the pixel either in a superoinferior or mediolateral
direction or a combination of both. The display of multiple
adjacent scan lines creates a composite two-dimensional image that
portrays the general contour of internal organs.
[0075] Cardiac performance refers to at least one physical
functioning property of the heart at rest, such as an EKG, ST
segment, QRS wave, estimated cardiac output, estimated
contractility, afterload or preload. Dynamic cardiac performance
refers to at least one physical functioning property of the heart
during a physiological challenge, such as physical exercise (e.g.
predetermined physical exercise or uncontrolled exercise), mental
stress, medical treatment or diagnostic maneuvers (e.g. breath
holding).
[0076] Chip refers to any current and future electronic hardware
device within a computational unit that can be used as an aid in
controlling the components of an ultrasound unit including: 1)
timing and synchronizing trigger pulses and subsequent transmission
of ultrasound waves, 2) measuring and analyzing incoming ultrasound
signals, 3) determining the shortest reflective distance generated
from ultrasound signals reflected from multiple different
ultrasound waves emitted at different transmission angles, 4)
estimating body fat and edema using various equations, 5) measuring
various anatomic landmarks, 6) comparing data to predetermined
standards and data cut-offs (e.g. electronic filtering), and 7)
performing multiple other simple and complex calculations.
[0077] Clinically relevant time period refers to a period of time
when changes in physiology are expected or detected. Such periods
can be on the order of seconds (e.g., 5 to 300 seconds or less) for
rapid physiological changes, such as changing position from sitting
to standing; minutes (e.g. about 2 to 40 minutes or less) for
relatively rapid physiological changes, such as shock or
inflammation; and hours to days (e.g. about 0.5 to 4 hours or about
0.5 days to 1 week or more) for slow physiological changes, such as
altitude acclimation, long term medical treatment that might
require weeks or months to detect a change, and diet
acclimation.
[0078] Computational unit refers to any current or future software,
chip or other device used for calculations, such as reflective
distance calculations, now developed or developed in the future.
The computational unit is capable of determining the shortest
reflective distance when two or more ultrasound sources are
employed at different transmission angles. The computational unit
may also be used for controlling the ultrasound generator or
source, for defining or varying the firing rate and pulse
repetition rate (as well as other parameters related to the
ultrasound generator or source), for measuring the reflected
signal, for image reconstruction in B-scan mode and for filtering
and thresholding of the ultrasound signal. Other applications of
the computational unit to the methods and devices described herein
will be recognized by those skilled in the art. The computational
unit may be used for any other application related to this
technology that may be facilitated with use of computer software or
hardware.
[0079] Crystal refers to the material used in the ultrasound
transducer to transmit ultrasound waves and includes any current
and future material used for this purpose. Crystals typically
consist of lead zirconate titanate, barium lead titanate, lead
metaniobate, lithium sulfate and polyvinylidene fluoride or a
combination thereof. A crystal is typically a piezoelectric
material, but any material that will contract and expand when an
external voltage is applied can be used, if such a material can
generate ultrasound waves described herein and known in the art.
Crystals emit ultrasound waves because the rapid mechanical
contraction and expansion of the material moves the medium to
generate ultrasound waves. Conversely, when incoming ultrasound
waves deform the crystal, a current is induced in the material. The
materials them emits an electrical discharge that can be measured
and, ultimately, with B-scan technology be used to reconstruct an
image. Crystals or combinations of crystals with dipoles that
approximate the acoustic impedance of human tissue are preferred,
so as to reduce the impedance mismatch at the tissue/probe
interface.
[0080] C-scan refers to an ultrasound technique where additional
gating electronics are incorporated into a B-scan to eliminate
interference from underlying or overlying structures by scanning at
a constant-depth. An interface reflects part of the ultrasound beam
energy. All interfaces along the scan line may contribute to the
measurement. The gating electronics of the C-mode rejects all
returning echoes except those received during a specified time
interval. Thus, only scan data obtained from a specific depth range
are recorded. Induced signals outside the allowed period are not
amplified and, thus, are not processed and displayed. C-mode-like
methods are also described herein for A-scan techniques and devices
in order to reduce the probe/skin interface reflection.
[0081] Detector refers to any structure capable of measuring an
ultrasound wave or pulse, currently known or developed in the
future. Crystals containing dipoles are typically used to measure
ultrasound waves. Crystals, such as piezoelectric crystals, shift
in dipole orientation in response to an applied electric current.
If the applied electric current fluctuates, the crystals vibrate to
cause an ultrasound wave in a medium. Conversely, crystals vibrate
in response to an ultrasound wave that mechanically deforms the
crystals, which changes dipole alignment within the crystal. This,
in turn, changes the charge distribution to generate an electric
current across a crystal's surface. Electrodes connected to
electronic circuitry sense a potential difference across the
crystal in relation to the incident mechanical pressure.
[0082] Echogenicity refers to the brightness of a tissue in an
ultrasound image relative to the adjacent tissues, typically on a
B-scan image. Echogenicity is dependent on the amount of ultrasound
waves reflected by the tissue. Certain tissues are more echogenic
than other tissues. Fatty tissue, for example, is more echogenic
than muscle tissue. For identical imaging parameters, fatty tissue
will thus appear brighter than muscle tissue. Consequently, image
brightness can be used to identify different tissues.
[0083] Grip refers to a portion of a probe that is grasped by an
operator. As described herein, most grip designs permit a human to
self measure anatomical regions that are normally difficult to
accurately interrogate using a handheld probe designed to be
operated by a person that is not the subject.
[0084] Heart failure refers to the pathophysiologic state in which
an abnormality of cardiac function is responsible for the failure
of the heart to pump blood at a rate commensurate with the
requirements of the metabolizing tissues and/or in which the heart
can do so only from an abnormally high filling pressure.
Compensated heart failure refers to a condition in which the heart
functions at an altered, but stable physiologic state, e.g. at a
different but stable point on the Frank-Starling-curve through an
increase in preload or after development of myocardial hypertrophy.
Decompensated heart failure refers to a condition in which the
heart functions at an altered and unstable physiologic state in
which cardiac function and related or dependent physiologic
functions deteriorate progressively, slowly or rapidly. Compensated
or decompensated heart failure can result in multiple
complications, such as progressive increase in capillary related
edema, progressive renal failure, or progressive ischemic tissue
damage.
[0085] Linear array refers to a transducer design where the
crystals are arranged in a linear fashion along one or more axes.
Crystals can be fired in sequential, as well as non-sequential and
simultaneous firing patterns or a combination thereof. With
sequential firing, each crystal can produce an ultrasound beam and
receive a returning echo for data collection. The number of
crystals in one array usually determines the number of lines of
sight for each recording. With segmental firing, a group or segment
of crystals can be activated simultaneously resulting in a deeper
near field and a less divergent far field compared with sequential
activation. A segmental linear array produces, however, a smaller
number of lines of sight when compared to a sequential linear array
with the same number of crystals.
[0086] Lymphedema refers to a condition that can be congenital or
acquired and is characterized by abnormal lymphatic drainage from
damage to, or obstruction of, the lymph vessels. Causes of
secondary lymphedema, include bacterial lymphangitis, surgery,
radiation, and trauma. Unlike capillary related edema, which can
develop within minutes or few hours, lymphedema develops slowly
over days and months. In chronic stages of lymphedema, the affected
body part has a woody texture and the tissues become fibrotic and
indurated.
[0087] Mechanically connected refers to a connection between two or
more mechanical components, such as an ultrasound source having at
least two transmission positions. A mechanical connection between
two transmission positions may be accomplished using a mechanical
motor to rotate or move an ultrasound source. Optionally, the
ultrasound source can be rotated or moved on a track.
[0088] Mechanical motor refers to any device that can move the
ultrasound source from a first to a second position and, if
desired, to additional positions. A mechanical motor may employ a
spring-like mechanism to move the ultrasound source from said first
to said second position. A mechanical motor may also employ a
hydraulic, a magnetic, an electromagnetic mechanism or any other
current and future mechanism that is capable of moving the
ultrasound source from a first to a second position.
[0089] Medical condition refers to a physiological state of a
subject, usually a human, that is not normal and would usually
benefit from, or require, medical treatment. Such states may arise
from a variety of conditions, including diseases, physiological
challenges, trauma, infection, stress, drug abuse, and accelerated
aging.
[0090] Medical treatment refers to an action intended to confer a
medical or physiological benefit on a subject, including surgery,
catheterization, drug administration (e.g. either by the subject or
by a health care worker), exercise, diet and non-invasive medical
techniques (e.g. ultrasound and intravenous administration of
electrolytes or osmotically active substances).
[0091] Myxedema refers to an infiltrative lesion of the skin of the
pretibial area. Myxedema can occur in patients with autoimmune
thyroid disease, such as Graves' disease. Unlike capillary related
edema, pretibial myxedema results from deposition of mucin in the
dermis. Myxedema develops slowly over months and years. The
affected area is demarcated from normal skin by the fact that it is
raised, thickened, and may be pruritic and hyperpigmented. The
lesions are usually discrete assuming a plaque-like or nodular
configuration.
[0092] Non-orthogonal probe alignment refers to alignment of the
probe at an angle other than 90 degrees relative to the object or
tissue plane to be measured, such as the probe/skin interface or
the subcutaneous fat/muscle interface.
[0093] Parallax adjustment refers to a correction of distance
measurements for probe mis-alignment. Parallax will result when the
ultrasound transducer is placed on the skin in a non-orthogonal
orientation thereby creating a transmission angle smaller or
greater than 90 degrees. As the difference between the ideal
transmission angle of 90 degrees, i.e. perpendicular probe
alignment, and the actual transmission angle increases, the
ultrasound beam has to travel along an increasingly longer path
through the object thereby artifactually overestimating the actual
object or tissue layer thickness. A parallax adjustment, i.e. a
correction of artifactually elongated distance measurements can,
however, be obtained by transmitting multiple ultrasound waves at
different transmission angles. The ultrasound wave that has the
transmission angle that is closest to 90 degrees will yield the
smallest parallax error and therefore provide the best parallax
adjustment.
[0094] Plane refers to the surface of a cross-sectional area of
tissue interrogated by an ultrasound probe. In ultrasound, the
portion of the tissue included in the measurement or image is more
accurately referred to as a volume. The x-dimension of this volume
reflects the length of the tissue plane, i.e. the length of imaged
tissue. The x-dimension typically varies between 1 and 10 cm or
more. The y-dimension reflects tissue depth from the plane, e.g.
the distance from the skin surface to a reflection point in the
tissue. The y-dimension (or depth of the interrogation) depends,
among other things, on the type of transducer, the type of tissue,
and the frequency with which the ultrasound beam is transmitted.
With higher frequencies, tissue penetration decreases and the
maximum depth from the tissue plane will decrease. The y-dimension
typically varies between 1 and 30 cm. The z-dimension corresponds
to the width of the plane that is interrogated. It typically varies
between 1 and 15-20 mm.
[0095] Potential fluid space refers to a compartment of the body
that may fill with fluid, including blood, under certain
conditions. Such conditions include medical conditions, such as
trauma, blood vessel breakdown (e.g., partial or complete),
breakdown (e.g., partial or complete) of epithelium and infection.
Potential fluid spaces include the subarachnoid, subdural,
epidural, mediastinal, perinephric, peritoneal or pleural
spaces.
[0096] Self measurement refers to the ability of a subject to
monitor or measure a portion of a subject's body, preferably in
real time.
[0097] Shortest reflective distance refers to the shortest distance
between the surface of an ultrasound transducer and a particular
layer interface in a object, such as a transducer and a subjacent
tissue interface that can be measured with ultrasound. The shortest
reflective distance represents the best approximation of the
distance measured by ultrasound of the true anatomic distance
between the surface of a transducer and a subjacent tissue
interface, such as the fat/muscle interface. Skin thickness can
also be measured or estimated and subtracted from the shortest
reflective distance to calculate the fat layer thickness, as
described herein. The shortest reflective distance can be measured
when an ultrasound transducer is oriented to the tissue interface
in an orthogonal fashion. The reflective distance can be calculated
as:
RD=SOS.times.t/2, [Eq. 1]
[0098] where RD is the reflective distance, SOS is the speed of
sound in a given medium and t is the time interval between
transmission of the ultrasound wave and return of the signal to the
transducer. The shortest reflective distance can be determined by
selecting the appropriate RD as described herein.
[0099] The shortest reflective distance can be determined by using
at least two or preferably multiple ultrasound pulses, where an
ultrasound source provides a pulse at a predefined transmission
angle. Transmission angles from an ultrasound source typically
differ by at least 1 degree. Reflective distances between an
ultrasound source and the tissue interface in question will be
measured using the formulae described herein or developed in the
art. The ultrasound source that has the transmission angle that is
closest to 90 degrees will usually yield the smallest value for
reflective distance. This value is least affected by parallax
between the probe and the tissue interface and is referred to as
shortest reflective distance. Calculation of shortest reflective
distance refers to electronic or mathematical determination of the
shortest reflective distance using the methods described herein.
Reflective distance will be calculated for ultrasound waves
obtained at various transmission angles. A computational unit can
then determine which wave yielded the smallest RD value in order to
select the shortest reflective distance.
[0100] Skin refers to the external tissue layer in humans and
animals consisting of epidermis and dermis.
[0101] Skin Related Definitions:
[0102] Epidermis refers to the outer, protective, nonvascular layer
of the skin of vertebrates, covering the dermis. The epidermis
consists historically of five layers, i.e. the stratum corneum, the
stratum lucidum, the stratum granulosum, the stratum spinosum, and
the stratum basale.
[0103] Dermis refers to the sensitive connective tissue layer of
the skin located below the epidermis, containing nerve endings,
sweat and sebaceous glands, and blood and lymph vessels.
Historically, the dermis consists of a papillary layer and a
reticular layer. The papillary layer contains the vessels and nerve
endings supplying the epidermis. The reticular consists
predominantly of elastic fibers and collagen.
[0104] Subcutaneous tissue layer refers to a tissue layer located
below the skin. This tissue layer is typically characterized by a
loose meshwork of connective tissue such as collagen and elastic
fibers. It is rich in small vessels, e.g., arterioles and venoles,
and capillaries. In edematous states, the subcutaneous tissue layer
can expand extensively. Edema will expand the space between the
cells and may also result in diffuse swelling of the cells. Owing
to its loose cellular network and abundant amount of capillaries,
the subcutaneous tissue layer is often the first or one of the
first locations affected by early, developing edema. The relative
amount of the different tissues will vary depending on the anatomic
location. In the anterior tibial region, for example, connective
tissue predominates, while in the abdominal or buttocks region
adipose tissue will predominate. If it is desired to quantitatively
measure interstitial layer thickness, it is preferable to select
sites that contain predominantly connective tissue and vessels,
since these sites can potentially change more rapidly or and expand
to a greater extent than sites predominantly containing adipose
tissue.
[0105] Tibia Related Definitions:
[0106] Anterior aspect of the tibia refers to the surface of the
tibia facing in anterior direction. The cross-section of the tibia
is triangular with an anteriorly, a laterally, and a posteriorly
facing surface. The laterally and posteriorly facing surfaces are
covered by several centimeters of muscle tissue. The anterior
surface of the tibia, however, is only covered by skin and, in
healthy, non-edematous subjects, a thin subcutaneous tissue layer.
This subcutaneous tissue layer can enlarge extensively in subjects
with capillary related edema. Since there is no interposed muscle
layer, the thickness of the subcutaneous tissue/edema layer can be
assessed clinically in this location by compressing the tissue
against the underlying bone. Cortical bone at the anterior aspect
of the tibia is also a strong ultrasound reflector demonstrating a
sharply defined reflective interface in the ultrasound image
thereby facilitating measurements of the thickness of the
subcutaneous tissue/edema layer.
[0107] Proximal third of the tibia refers to a measurement site at
the anterior aspect of the upper tibia. The medial knee joint space
and the medial malleolus are localized by manual palpation. The
distance between the medial knee joint space and the medial
malleolus is measured with a tape measure and subdivided into three
equidistant portions, upper, middle, and lower. Alternatively, the
distance between the lateral knee joint space and the lateral
malleolus can be measured and subdivided into three equidistant
portions. The border between the midportion and the upper portion
defines the proximal third of the tibia site.
[0108] Mid-tibia refers to a measurement site at the anterior
aspect of the tibia halfway between the medial knee joint space and
the medial malleolus or, alternatively, the lateral knee joint
space and the lateral malleolus.
[0109] Distal third of the tibia refers to a measurement site at
the anterior aspect of the lower tibia. The border between the
midportion, as measured above (see "proximal third of the tibia"),
and the lower portion defines the distal third of the tibia
site.
[0110] Lateral malleolus refers to a bony protuberance at the
lateral aspect of the ankle joint. The lateral malleolus is formed
by the fibula and represents the lateral portion of the ankle
mortise.
[0111] Medial malleolus refers to a bony protuberance at the medial
aspect of the ankle joint. The medial malleolus is formed by the
tibia and represents the medial portion of the ankle mortise.
[0112] Therapeutic agent refers to an active substance or
collection of active substances that produce a beneficial effect in
a subject when administered in a therapeutically effective amount
using a therapeutically effective modality. Such agents include
active substances directed to specific physiological processes or
systems, such as, but not limited to, diuretic, hepatic, pulmonary,
vascular, muscular, cardiac or diabetic agents. Usually, such
agents will modify the physiological performance of a target tissue
or cell in order to shift the physiological performance of the
target tissue or cell towards a more homeostatic physiological
state.
[0113] Therapeutic kit refers to a collection of components that
can be used in a medical treatment.
[0114] Therapeutic dosage refers to a dosage considered to be
sufficient to produce an intended effect.
[0115] Therapeutically effective modality refers to a manner in
which a medical treatment is performed and is considered to be
sufficient to produce an intended effect.
[0116] Tissue Related Definitions:
[0117] Fat/fascia interface refers to the border between the
proximal surface of the subcutaneous fat tissue layer and a
potential distal surface of the fascial tissue layer.
[0118] Fat/muscle interface refers to the border between the
proximal surface of the subcutaneous fat tissue layer and the
distal surface of the muscle tissue layer.
[0119] Inner border of subcutaneous fat tissue refers to the
interface between the subcutaneous fat and the subjacent muscle, if
present, or the interface between the subcutaneous fat and the
subjacent fascia, if present.
[0120] Muscle/bone interface refers to the border between the
proximal surface of the muscle tissue layer and the distal surface
of the subjacent layer of bone, e.g. the femur in the thigh, the
tibia or fibula in the calf, the humerus in the upper arm, or the
radius or ulna in the forearm.
[0121] Muscle/internal organ interface refers to the border between
the proximal surface of the muscle tissue layer and the adjacent
distal surface of the internal organs.
[0122] Outer border of subcutaneous fat tissue refers to the
interface between the patient's skin and the subcutaneous fat.
[0123] Skin/fat interface refers to the border between the proximal
surface of the skin layer and the distal surface of the
subcutaneous fat tissue layer.
[0124] Tissue refers to an organized biomaterial usually composed
of cells. For dietary purposes, a distinction is made between fatty
tissue and lean tissue. Fatty tissue is composed of adipose cells,
while lean tissue includes all other tissues except for bone.
[0125] Tissue volume may contain several different layers of
tissue, such as skin, subcutaneous fat, fascia, muscle, bone,
internal organs and other tissues. Ideally, an ultrasound generator
is oriented in an orthogonal fashion relative to the interrogated
tissue. However, when an ultrasound generator is oriented to the
skin in a non-orthogonal fashion, i.e. when the transmission angle
is less than 90 degrees, a parallax can result that will
artifactually increase the apparent thickness of the interrogated
tissue layers.
[0126] Tissue Swelling Related Definitions:
[0127] Edema refers to a pathologic accumulation of fluid within or
between body tissues. Edema fluid can accumulate in potential fluid
spaces, e.g. the pleural space, the pericardial space, and the
intraperitoneal space. Edema fluid can accumulate in the
interstitial space (e.g., in extracellular location) between tissue
cells thereby expanding the interstitial space. Edema fluid can
also accumulate within the cells, i.e. in an intracellular location
(e.g., in toxic, metabolic, infectious, inflammatory, and
autoimmune disorders). Causes of edema include but are not limited
to impairment of vascular, cardiac, renal, and hepatic function,
neurologic disorders, metabolic disorders, trauma, burns, tissue
damage, changes in intravascular and intracellular colloid osmotic
pressure, overhydration, e.g. in transfusion therapy or parenteral
nutrition, exposure to toxic substance, e.g. inhalational or by
ingestion, and drugs (see also Tables 3 and 4).
[0128] Capillary related edema refers to an abnormal fluid
imbalance arising from capillaries and leading to abnormal local
fluid retention. Capillary related edema results from an abnormal
physiological function or physiological challenge to the venous
system, arterial system, cardiovascular system, renal system,
hepatic system, pulmonary system or other non-circulatory, internal
organ systems normally involved in homeostasis of normal fluid
retention. The present invention is particularly applicable to the
systemic aspects of capillary related edema. For clarity, capillary
related edema does not refer to pretibial myxedema, which is a
lesion in the dermis that leads to tissue swelling. Pretibial
myxedema is associated with abnormal mucin production in the dermis
that disrupts the surrounding tissue. Any water associated with
mucin that might be considered related to pretibial myxedema is not
considered capillary related edema, as mucin is an extracellular
protein, which in pretibial myxedema, is not considered to be
associated with an internal organ system normally involved in
homostasis of normal fluid retention. For further clarity,
capillary related edema does not refer to tissue swelling
associated with the lymph system. Venous or arterial systems do not
refer to the lymphatic system. Potential capillary related edema
layer refers to an anatomical region where capillary related edema
might occur.
[0129] Edema detection refers to the determination of abnormal
fluid retention in a subject or a subject's tissue. In many
instances edema detection can occur without detecting or knowing
the underlying cases of the edema. Often edema detection will lead
to additional tests to determine the cause or cause of the edema.
For clarity, edema detection does not refer to detection of tissue
swelling primarily associated with pretibial myxedema or a
malfunctioning of the lymphatic system.
[0130] Capillary related interstitial fluid refers to fluid between
internal tissues of the body that is on the outside of cells and
arising from capillaries. Usually, this fluid is subcutaneous,
which makes it easier to examine. Capillary related interstitial
fluid, however, may also be found in any tissue or layer, unless
otherwise indicated herein. Capillary related interstitial fluid is
usually comprised of water, body salts and extracellular
biomolecules, such as proteins or sugars. Intracellular
biomolecules may be found in capillary related interstitial fluid,
especially adjacent to traumatized or compromised tissue. For
clarity, capillary related interstitial fluid does not refer to 1)
blood in either blood vessels or blood released in a potential
fluid space of the body (e.g., the subarachnoid, subdural,
epidural, or pleural space) by a traumatic, abrupt or accidental
lesion (including an aneurysm) of a blood vessel, 2) ascites in the
intraperitoneal cavity, 3) fluid in the pleural space (e.g.,
pleural effusion), 4) fluid in the fetus, 5) fluid in the dermis,
6) fluid in the mouth and 7) fluid, usually blood or pericardial
effusion, in the pericardium.
[0131] Interstitial fluid content (IFC) refers to an amount of
interstitial fluid in a given anatomical region. IFC can be
expressed as mm.sup.2 when derived as the measured thickness of the
interstitial fluid layer and multiplied by length of the area
interrogated. IFC can be used to estimate total size of an
interstitial fluid layer or interstitial fluid volume.
[0132] Interstitial fluid layer (IFL) refers to layer of
interstitial fluid that forms a stratum either within or around an
internal tissue. Often such layers substantially circumscribe a
tissue, especially a tissue of an appendage or an organ. Such
layers can also be localized and appear as pockets or lakes of
fluid apposite or interpersed in a tissue. For clarity, IFL does
not refer to a stratum formed by pretibial myxedema, which is a
lesion in the dermis that leads to tissue swelling. Pretibial
myxedema is associated with abnormal mucin production in the dermis
that disrupts the surrounding tissue.
[0133] Interstitial fluid volume (IFV) refers to a volume of
interstitial fluid in a subject or a tissue. Usually this term is
used in reference to the IFV of an entire human, which may change
in response to various physiological challenges, such as medical
conditions or treatments. The methods and devices described herein
can assess IFV qualitatively both on the level of the entire
subject or a portion thereof, such as a tissue. The methods and
devices described herein can also measure IFV quantitatively both
on the level of the entire subject (indirect measurement by
estimate as described herein) or a portion thereof, such as a
tissue (indirect or direct measurement depending on the
tissue).
[0134] Transmission angle refers to the angle of an ultrasound beam
that intersects the object or tissue plane. The transmission angle
is normally measured with respect to the object or tissue plane.
The object or tissue plane has a reference angle of zero
degrees.
[0135] For example, as the transmission angle increases toward 90
degrees relative to the tissue plane, the ultrasound beam
approaches an orthogonal position relative to the tissue plane.
Preferably, ultrasound measurements of the fat/muscle or fat/bone
interface are performed when the ultrasound beam is orthogonal to
the plane of the tissue. Operator error, however, often leads to a
parallax between the object or tissue plane and the probe.
Tissue/probe parallax most often occurs when an operator fails to
place the outer probe surface parallel to the tissue plane. Thus,
the operator inadvertently creates a transmission angle less than
ninety degrees with respect to the tissue plane, i.e. not
orthogonal to the tissue plane, that skews the ultrasound beam and
the return signal. The resultant skewing creates a parallax when
using an ultrasound beam to measure tissue thickness, such as
subcutaneous fat thickness or any other thickness measurement of a
layer in an object.
[0136] Non-orthogonal ultrasound beam transmission creates an
apparent displacement of the ultrasound beam compared to an
ultrasound beam transmitted at 90 degrees with respect to the
tissue plane. The return signal, which is a fraction of an
ultrasound beam that is reflected at a tissue interface, travels
through the tissue along a longer distance when returning back to
the ultrasound detector compared to a return signal that originated
from a beam transmitted orthogonal to the tissue plane. To increase
the accuracy of the measurement of tissue thickness, preferably the
transmission angle is between 90 to 60 degrees, more preferably 90
to 80 degrees. Lower transmission angles can be used, as low as 1
degree, but are not preferred due to the large error associated
with the distance measurements of the fat/muscle or fat/bone
interface. Such errors can be compensated for by techniques
previously described, U.S. patent application Ser. No. 08/731,821,
filed Oct. 21, 1996 (Lang et al).
[0137] Transmission frequency refers to the frequency of the
ultrasound wave that is being transmitted from the ultrasound
source. Transmission frequency typically ranges between 0.2 MHz and
25 MHz. Higher frequencies usually provide higher spatial
resolution. Tissue penetration decreases with higher frequencies,
especially in dense fat tissue. Lower transmission frequencies are
generally characterized by lower spatial resolution with improved
tissue penetration. Methods and devices for optimizing and matching
transmission frequencies to the measured object's acoustic
properties are described herein.
[0138] Vascular performance refers to the ability of a blood vessel
to conduct blood away from or towards the heart.
[0139] Venous performance refers to the ability of a venous vessel
(e.g., a vein) to return blood towards the heart.
[0140] Ultrasound pulse refers to any ultrasound wave transmitted
by an ultrasound source. Typically, the pulse will have a
predetermined amplitude, frequency, and wave shape. Ultrasound
pulses may range in frequency between 20 kHz and 20 Mhz or higher.
Preferably, for ILT measurements pulses range from 2.5 Mhz to 25
Mhz and more preferably from 3.5 to 10 Mhz. Ultrasound pulses may
consist of sine waves with single frequency or varying frequencies,
as well as single amplitudes and varying amplitudes. In addition to
sine waves, square waves or any other wave pattern may be employed.
Square waves may be obtained by adding single-frequency sine waves
to other sine waves. The summation of waves can then result in a
square wave pattern.
[0141] Ultrasound signal refers to any ultrasound wave measured by
an ultrasound detector after it has been reflected from the
interface of an object or tissue. Ultrasound signals may range in
frequency between 20 kHz and 20 Mhz or higher. Preferably, for ILT
measurements signals range from 2.5 Mhz to 25 Mhz.
[0142] Ultrasound source refers to any structure capable of
generating an ultrasound wave or pulse, currently known or
developed in the future. Crystals containing dipoles are typically
used to generate an ultrasound wave above 20 khz. Crystals, such as
piezoelectric crystals, that vibrate in response to an electric
current applied to the crystal can be used as an ultrasound source.
As referred to herein, an ultrasound source usually has a
particular transmission angle associated with it. Consequently, a
single ultrasound generator, as defined herein, can be used at
different transmission angles to form more than one ultrasound
pulse at different transmission angles. An ultrasound generator can
include single or multiple ultrasound sources that can be arranged
at different angles to produce ultrasound beams (or pulses) with
variable transmission angles. In some ultrasound generators,
multiple ultrasound sources may be arranged in a linear fashion.
This arrangement of ultrasound sources is also referred to as a
linear array. With linear arrays, ultrasound sources are typically
fired sequentially, although simultaneous firing of groups of
adjacent ultrasound sources or other firing patterns of individual
or groups of ultrasound sources with various time delays can be
achieved as described herein or developed in the art. The time
delay between individual or group firings can be used to vary the
depth of the beam in an object.
[0143] Ultrasound transmission parallax refers to an error in the
measurement of distances between two distinct layers in an object,
such as tissue, resulting from non-orthogonal probe placement.
Ideally, the probe is oriented orthogonal to the object or tissue
to be measured. In this fashion, the distance between two tissue
layers measured on the ultrasound will more accurately reflect the
true anatomic distance. However, if the probe is applied to the
skin at an angle smaller or greater than 90 degrees, artifactual
elongation of all measured distances will result. The difference
between the distance measured with ultrasound and the true anatomic
distance at the point where the probe is placed will increase the
more the probe-to-skin angle differs from 90 degrees.
[0144] Generally, tissue thickness, especially capillary related
interstitial fluid layer, can be measured using more than one
ultrasound source (e.g. at least a first and second ultrasound
source) to permit multiple transmission angles or one ultrasound
source positioned at different transmission angles. The use of
multiple transmission angles facilitates the determination of the
shortest reflective distance. If only one transmission angle is
used to calculate the shortest reflective distance, the shortest
reflective distance could have a considerable ultrasound
transmission parallax error associated with it.
[0145] Ultrasound wave refers to either an ultrasound signal or
pulse.
2.0 Introduction
[0146] The present invention recognizes for the first time that
ultrasound can be applied to the convenient and cost effective
measurement of capillary related interstitial fluid. The invention
includes continuous or intermittent monitoring of capillary related
interstitial fluid in a subject, such as capillary related edema
assessment in a human, using ultrasound wave devices and methods as
described herein for the embodiments of the invention. Previously,
it was not recognized that diagnostic ultrasound measurements of
capillary related interstitial fluid were possible or precise. Nor
was it recognized that clinically rapid shifts in capillary related
interstitial fluid distribution in tissues could be monitored using
ultrasound methods or devices. Previous work also failed to
recognize that capillary related interstitial fluid layers in a
tissue could be monitored over time and, if desired, accurately
quantitated, as described herein. The inventors were also the first
to recognize that ultrasound methods and devices could be applied
to the assessment of different aspects of integrated cardiovascular
function, including venous performance and dynamic cardiac
performance. Nor was it previously recognized that ultrasound
devices dedicated to measurement of capillary related interstitial
fluid, particularly autonomous hand-held devices for
self-measurement of capillary related edema, could accurately
determine capillary related interstitial fluid status, as described
herein. It was also not previously recognized that ultrasound
devices dedicated to continuous monitoring of interstitial fluid,
particularly autonomous hand-held devices for self-measurement of
capillary related edema or small remote probes located on the
subject, could accurately determine interstitial fluid status, as
described herein.
[0147] By way of introduction, and not limitation of the various
embodiments of the invention, the invention includes at least eight
general aspects:
[0148] 1) an ultrasonic method of measuring capillary related
interstitial fluid, including capillary related interstitial fluid
layer thickness in a subject, particularly a capillary related
edema layer, by determining the distance between reflective
surfaces (e.g., bone or fat) and skin with ultrasound,
[0149] 2) an ultrasonic method of detecting capillary related edema
by determining the distance between the reflective surfaces of bone
and skin at predetermined anatomical sites with ultrasound,
[0150] 3) an ultrasonic method of assessing vascular performance by
clinically challenging or enhancing vascular performance and
measuring capillary related interstitial fluid in a tissue that is
clinically relevant to either the challenge or enhancement of
vascular performance with ultrasound,
[0151] 4) an ultrasonic method of assessing cardiac performance by
clinically challenging or enhancing cardiac performance and
measuring capillary related interstitial fluid in a tissue that is
clinically relevant to either the challenge or enhancement of
cardiac performance with ultrasound,
[0152] 5) an ultrasonic method of detecting capillary related
interstitial fluid volumes in humans by measuring capillary related
interstitial fluid in a tissue with ultrasound prior to, before or
concurrent with a medical condition or treatment,
[0153] 6) a hand-held ultrasound device for measuring capillary
related edema that is optionally capable of self-measurement,
[0154] 7) a dedicated ultrasound system for measuring interstitial
fluid, and
[0155] 8) an ultrasound probe for in situ ultrasound monitoring,
particularly of interstitial fluid layers.
[0156] These aspects of the invention, as well as others described
herein, can be achieved using the methods and devices described
herein. To gain a full appreciation of the scope of the invention,
it will be further recognized that various aspects of the invention
can be combined to make desirable embodiments of the invention. For
example, the invention includes an interstitial fluid monitor (IFM)
that can desirably include characteristics of aspects (1), (2), (3)
and (8) to create a system for periodic or continuous monitoring of
patient interstitial fluid. Such combinations result in
particularly useful and robust embodiments of the invention.
3.0 Methods and Devices for Measuring Capillary Related
Interstitial Fluid
[0157] Multicellular, living organisms with more than one body
compartment tightly regulate the interstitial fluid that baths
their cells. Such organisms manage their interstitial fluid using a
variety of physiological mechanisms that can include adjusting
excretory, secretory, and circulatory processes. These
physiological processes, as well as others, have evolved to
compensate for small and rapid changes in capillary related
interstitial fluid that can dramatically alter homeostasis due to
physiological challenges and responses.
[0158] The invention recognizes for the first time that capillary
related interstitial fluid can be assessed with ultrasound
techniques by interrogating a tissue of interest and measuring
distances between reflective interfaces within the tissue of
interest that anatomically correspond to capillary related
interstitial fluid or capillary related interstitial fluid layers.
Because interfaces between different biological layers arise due to
differences in the relative amounts of water and biomaterials in
such layers, the ultrasound methods and devices described herein
can advantageously utilize such differences to qualitatively or
quantitatively measure capillary related interstitial fluid in the
tissue of interest.
[0159] The invention's methods and devices are broadly applicable
to any tissue, including internal organs, having one or more
reflective interface(s) that can be interrogated using ultrasound.
Usually, such interfaces will arise from differences in water or
biomaterial content, such as interfaces between bone and muscle
layer, skin layer and fat layer, cell mass and interstitium, tumor
and interstitium, or bone and interstitial layer. Consequently, the
present invention finds broad application in a variety of settings
in health care and health management.
[0160] By way of example, and not limitation, FIG. 1A-C illustrates
capillary related interstitial fluid accumulation. FIG. 1A shows
normal leg tissue prior to an increase capillary related
interstitial layer thickness. Skin is "S." Tibia is "T." Fibula is
"F." Muscle is "M" and interstitial layer is "IL." The probe
interrogation site 100 is a preferred site for monitoring capillary
related changes in ILT. The tissue plane 110 is approximately
illustrated by arrows. FIG. 1B and C illustrate a small but
progressive increase in ILT around 100 over time. Such changes in
ILT can be measured using the devices and methods of the present
invention.
[0161] Increases in ILT are further illustrated in FIG. 2A and B,
which is a closer view of interrogation site 100. Skin 200 shows
little change in thickness over time due to an increase in
capillary related interstitial fluid. In contrast, the IL thickness
changes dramatically due to an increase in capillary related
interstitial fluid. Bone 210 and skin 200 (skin/bone interface)
typically provide reflective surfaces for detecting ILT.
[0162] In one embodiment, the invention includes a method of
measuring capillary related interstitial fluid comprising:
transmitting at least one ultrasound signal to a tissue in a
subject in need of capillary related interstitial fluid assessment,
recording at least one ultrasound signal from the tissue, and
determining a capillary related interstitial layer thickness from a
first reflective surface to a second, usually an internal,
reflective surface, wherein the capillary related interstitial
layer thickness is an assessment of capillary related interstitial
fluid. Typically, such a subject will be a human desiring a
capillary related interstitial fluid assessment because a clinician
wishes to use the invention as a part of a diagnosis or the subject
wishes to perform a self assessment of the subject's capillary
related interstitial fluid. Often such diagnosis will relate to a
clinician's desire to assess capillary related interstitial fluid
to determine the status of a subject's homeostasis to ensure that
the subject's physiological mechanisms are functioning
appropriately. In the case of self-measurement, such measurements
will often relate to the subject's desire to monitor changes in
homeostatic physiological mechanisms in their own body for health,
medical, athletic, or intellectual reasons.
[0163] The transmitting step requires transmitting at least one
ultrasound signal with sufficient power to permit the signal to
travel in the tissue of interest. Typically, the transmitted signal
will be reflected off an interface that separates two layers that
contain differing amounts of water and biomaterials. Any suitable
frequency, as described herein or in the future or known in the art
can be used. The frequencies used can be selected for maximum
transmission and reflective performance, and lowest noise by
recording signals from a tissue at different frequencies. Thus, for
a particular tissue, the frequency with the best properties can be
selected and a dedicated probe can be constructed using such a
frequency. Typically, the frequencies used will range from 0.2 to
20 MHz, preferably from 0.5 to 8 MHz and more preferably from 0.5
to 4 MHz.
[0164] The transmitting step is desirably practiced using multiple
signals. A plurality of signals can be transmitted and their return
signals ("echoes") from reflective interfaces recorded. Signal
averaging will improve the accuracy of the measurements and can be
conducted over a relatively short period of time. Generally,
multiple signals for signal averaging will be transmitted in less
than 1 to 2 seconds and more often in less than 100 to 300
milliseconds and preferably in less than 50 milliseconds.
[0165] The transmitting step can be optionally practiced using
multiple signals over longer lengths of time that would not
typically be used for signal averaging. Such lengths of time permit
monitoring of shifts or changes in capillary related interstitial
fluid. For example, water can shift from blood into capillary
related interstitial fluid (or vice versa) and change the amount of
capillary related interstitial fluid in a tissue. Such shifts can
result from changes in physiological processes or regulated
parameters, such as ion transport, oncotic pressure of the
capillary related interstitial fluid, oncotic pressure of blood,
the amount of osmotically active substances in the capillary
related interstitial fluid or blood, extracellular pH or
intracellular pH. By transmitting ultrasound signals over lengths
of time that correspond to such physiological events, changes in
capillary related interstitial fluid can be assessed and compared
to normal or standard values and over time. Most physiological
events will occur over a much longer time frame than required for
signal averaging. Typically, such monitoring will occur over
minutes, hours, days and even in some instances, as described
herein, it will be desirable to monitor subjects over months or
years.
[0166] The recording step requires recording at least one
ultrasound signal from the tissue. Usually, the signal will be a
reflected signal from a reflective interface. Desirably, a
plurality of reflected signals are averaged, as described for
transmitted signals or known in the art. The returning signals can
be optionally filtered or sampled to remove noise and scatter. For
example, if a layer(s) at a predictable (or estimated) distance
from the probe is present that produces scatter and is not relevant
for determining capillary related interstitial fluid volume, return
signals can be appropriately sampled to remove such scattering by
preferentially recording the signal at times not corresponding to
the return signal times from the interfering layer(s). Such methods
are also described in patent application Ser. No. 08/731,821 filed
Oct. 21, 1996 (Lang et al), which is herein incorporated by
reference.
[0167] A, B or C scan modes of ultrasound interrogation and
recording can be used with the methods and devices of the
invention. Preferably, A scan systems will be used to provide
relatively inexpensive diagnostic tools. Because most applications
only require detecting the distance between layers that contain
capillary related interstitial fluid or the thickness of a
capillary related interstitial fluid layer, information relating to
a third dimension is not necessary.
[0168] The determining step requires determining a capillary
related interstitial layer thickness from a first reflective layer
and a second reflective layer in the tissue or anatomical region.
Typically, signals from the first and second reflective layer will
be detected by an ultrasound detector at different times. The
difference in time of reception between the signal from the first
reflective layer and the signal from the second reflective layer
can be used to determine the time required for sound to travel from
the medium between first and second reflective layers. For example,
capillary related interstitial layer thickness can be a reflection
of transmission times as described by the following
calculation:
ILT.varies.(.tau.2-.tau.1).div.2 [Eq. 2]
[0169] wherein ILT is the interstitial layer thickness, .varies.
refers to a relationship of proportion (and can include the
relationship of equality if calculated using the appropriate
factor(s)), .tau.2 is the time of transmission of the ultrasound
signal from an ultrasound probe (the transmitting signal) to the
second reflective layer and back to an ultrasound probe (detecting
the return signal), and .tau.1 is the time of transmission of the
ultrasound signal from an ultrasound probe (transmitting the
signal) to the first reflective layer and back to a ultrasound
probe (detecting the return signal). ILT for this type of
calculation can be expressed in relation to transmission time.
[0170] ILT can also be calculated in terms of actual distance, such
as centimeters (cm). For example, the transmission time related to
the ILT in [Eq. 2], which is units of time, can be multiplied by
the speed of sound in the medium being measured. If more than one
medium is being interrogated and more than two reflective layers
are being interrogated, then the speed of sound for each medium can
be incorporated into the calculation. The speed of sound for
various tissues and substances typically varies from 331 to 5000
(meters/second), such as air (331), water (1430), saltwater (1510),
fat (1450), soft tissue (1540), blood (1585), muscle (1585), PZT-4
transducer (4000), skull bone (4080) and metal (5000) (all in
meters per second). Speed of sound in a medium can also be measured
empirically, by separating two ultrasound probes by a predetermined
distance with the medium of interest between the two probes and
transmitting and detecting ultrasound signals between the two
probes. Such measurements can be relatively easily accomplished,
especially with appendages, and can increase the information
content of the data.
[0171] It is not, however, necessary to record signals reflected
from the first reflective layer. In some is instances, the first
reflective layer will be a predictable transmission time and
distance form the ultrasound probe and such a predictable
transmission time or distance can be used in [Eq. 2] to estimate
the ILT. As described further in further detail herein standard
transmission times and ILTs can be estimated by sampling subjects
or by providing predetermined standards. Thus, capillary related
interstitial layer thickness can be qualitatively or quantitatively
determined. Nor is it necessary, even for quantitative
calculations, to calculate an exact value for the interstitial
layer because a delta (i.e. change) in ITL may be all that is
clinically relevant.
[0172] This embodiment of the invention can be applied to a variety
of application sites and medical treatments as described herein,
developed in the future or known in the art. This embodiment of the
invention also can be used with many different types of suitable
probes, systems, and methods relating to ultrasound measurements,
and calculations and biological standards, as described herein,
developed in the future or known in the art.
[0173] Application Sites
[0174] Capillary related interstitial fluid can be measured in any
tissue or continues anatomical region that contains within it at
least one reflective surface and a sufficient amount of water or
other acoustic medium to permit ultrasound signals to penetrate and
return through the tissue for detection. Often the first reflective
surface is the probe-skin interface and the internal reflective
surface is a bone-ILT interface . An internal reflective surface
refers to a reflective surface on the inside of the body that is
not accessible from the outside and is in contact with interstitial
fluid. Table 1 shows a number of potential reflective surface
combinations for potential application sites for ultrasound probes
and some potential diagnostic applications for assessing certain
physiological functions. Table 1 is by no means exhaustive, it is
only illustrative of the many potential sites and reflective
surfaces to monitor capillary related interstitial fluid. Table 1
also includes some embodiments of the invention not associated with
capillary related interstitial fluid monitoring, such as ascites
and cranial edema. Typically, the subjects will be humans, however,
the present invention may be used with other animals, especially
large mammals in veterinary settings.
1TABLE 1 First Second Reflective Reflective Surface Surface Probe
Site Diagnostic Application Skin Bone Leg (preferably mid, Heart,
renal, and anterior tibia) circulatory function Skin Bone Arm
(preferably Heart, renal, or distal radius or alna) circulatory
function Skin or Lung tissue Chest (preferably mid Pulmonary edema,
bone or or pleural axillary line, e.g. pleural effusion, heart
chest surface and circulatory wall between function muscles
10.sup.th/11.sup.th rib) Skin or Bone Presternal Heart, renal, and
muscle circulatory function Skin Traumatized Skin above internal
Trauma, progression tissue trauma site of trauma or healing Skin or
Liver tissue Skin above left or Ascites, heart failure, muscle or
or splenic right paracolic gutter renal failure, cirrhosis liver
tissue tissue or or splenic abdominal tissue fat Skin Bone Cranium
(preferably Head trauma, cerebral temporal bone, edema, heart
function forehead or nuchal region)
[0175] The sites listed in Table 1 can also be used in combination.
By using combinations of probe sites (i.e. multisite monitoring),
fluid movement throughout the body can be monitored. This permits
monitoring fluid shifts from fluid compartments of the body.
Multisite monitoring also permits exquisitely sensitive monitoring
of physiological processes related to edema, capillary related
interstitial fluid shifts and other fluid related changes in the
body, such as processes that either induce, prevent or reduce fluid
shifts, as well as therapeutic treatments thereof. Multisite
monitoring is further described in detail herein, particularly in
the section relating to monitoring physiological functions and in
situ probes.
[0176] By way of example, and not of limitation, FIG. 3 and 4
illustrates selected sites that can be used for ultrasound
monitoring of capillary related interstitial fluid and capillary
related edema as well as other methods described herein. FIG. 3
shows a human subject in need of monitoring of capillary related
interstitial fluid. Exemplary ultrasound interrogation sites
include, but are not limited to, the forehead region 300, the
temporal region 310, the forearm region 320, the humeral region
330, the prestemal region 340, the lateral chest wall region 350,
the lateral abdominal region 360, the tibial region 370, and the
foot region 380.
[0177] FIG. 4 is a magnified view of the tibial region
demonstrating the proximal third of the tibia site 400, the
mid-tibia site 410, the distal third of the tibia site 420, and the
medial malleolus site 430. FIG. 3 and 4 is by no means exhaustive,
it is only illustrative of the many potential regions and sites
that are available to monitor capillary related interstitial fluid.
The exemplary regions and sites illustrated in FIG. 3 and 4 can be
used alone or in combination.
[0178] Application to Medical Treatments
[0179] Medical treatments often affect interstitial fluid levels.
Many medical treatments are designed to modulate the function of an
organ or physiological process in order to improve fluid
homeostasis. There are numerous examples of drugs designed to
modulate heart, renal or pulmonary function and, as a consequence,
improve fluid homeostasis. Often when such medical treatments are
initiated, it is difficult to establish a baseline for fluid
homeostasis other than a general diagnosis of abnormal or
pathological fluid imbalance or fluid retention that may or may not
be associated with another diagnosed medical condition.
[0180] For example, a patient may have pronounced fluid retention
in the extremities resulting from right ventricular failure. A
clinician when posed with this medical situation might prescribe a
drug to improve cardiac performance. The effectiveness of the
medical treatment could be measured by examining the patient,
similar to the original examination. Often the original examination
will only involve a physical examination that may be difficult to
directly compare to the second examination, especially the amount
of fluid retention in the extremities. Although examination of
heart function may be easier to compare between first and second
examinations because heart function is often more quantifiable,
patients may show changes in systemic function that suggest
improvement without measurable improvement in cardiac
performance.
[0181] In this case, comparing the first and second examination
results has a number of drawbacks. The medical treatment for right
ventricular failure might not actually improve right ventricular
performance even though heart rate may be lowered or contractility
improved. Apparent cardiac improvements may also not actually
improve water retention in the extremities. Comparing systemic
effects in the first and second examination may also be complicated
by the fact that the clinician conducting the first examination may
not be the same clinician as the one conducting the second
examination. It is therefore desirable to compare measurements of
fluid retention in a manner that is more easily repeated upon a
second examination, less influenced by variability between
clinicians, more reproducible, and more quantifiable than physical
examination. The methods and device of the present invention permit
measurement of fluid retention in a manner that is more easily
repeated upon a second examination, less influenced by variability
between clinicians, more reproducible, and more quantifiable than
physical examination.
[0182] The steps of (a) transmitting, (b) recording, and (c)
determining related to the method monitoring capillary related
interstitial fluid can be performed as multiple patient
examinations over different time spans. This is an advantage over
the prior art, since this technique can generate values for the
interstitial layer that can be compared over time and is less
susceptible to inter-clinician and intra-clinician variation. For
example, steps of transmitting, recording and determining can be
conducted as a baseline for patient monitoring. Such an examination
could occur prior to a medical treatment. In the first examination,
a first capillary related interstitial layer thickness is
determined. In a subsequent examination, steps (a), (b), and (c)
are repeated. Examinations subsequent to the first examination
could occur after, or simultaneous to, the medical treatment. The
timing of subsequent examinations can be any desired by the
subject, operator, or clinician. Usually, examination will be
periodic or during a predetermined clinically relevant time
period.
[0183] Routine periodic examinations, such as part of an annual
examination, can monitor long term changes in the physiology due a
number of medical conditions, such as those described herein. Such
periodic examinations can be applied to other methods described
herein, such as methods related to monitoring vascular or cardiac
performance during a clinically induced stress.
[0184] Examinations during a clinically relevant time period can be
used to monitor the progress of expected changes in a subject's
physiology. Clinically relevant time periods usually relate to a
medical treatment regime or medical conditions. The method includes
comparing a second capillary related interstitial layer thickness
(measured in the subsequent examination) to the first capillary
related interstitial layer thickness (measured in a prior
examination). The change in capillary related interstitial layer
thickness can be indicative in a change in the physiological
condition of the subject. For instance, if the second capillary
related interstitial layer thickness is larger than the first
capillary related interstitial layer thickness, then the medical
treatment, or medical condition, has usually induced an increase
capillary related interstitial fluid. As a second alternative, if
the first capillary related interstitial layer thickness is larger
than the second capillary related interstitial layer thickness,
then the medical treatment, or medical condition, has usually
induced a decrease in capillary related interstitial fluid. As a
third alternative, if the first capillary related interstitial
layer thickness is equal to the second capillary related
interstitial layer thickness, then the medical treatment, or
medical condition, has usually induced no change in capillary
related interstitial fluid. This type of comparative monitoring,
subsequent to a first examination, can be applied to a monitor a
number of medical conditions or assess a number of medical
treatments.
[0185] A desirable aspect of periodic or clinically relevant
monitoring is to determine if a change in capillary related
interstitial layer thickness relates to more than one physiological
change. For example, a change in capillary related interstitial
layer thickness may be induced by both short term and long term
physiological changes. In such a subject the short term effect can
be assessed by inducing physiological changes in the subject that
would alter capillary related interstitial layer thickness at the
relevant anatomical region in a relatively short examination period
(e.g., within about 40 to 120 minutes). Depending on the outcome of
such assessment, the clinician can weigh the relative contribution
of long term and short term effects on interstitial layer
thickness. Preferably, the same type of monitoring was previously
performed on the subject so a comparison can be made. Generally,
the more rapid or greater the change in interstitial layer
thickness, compared to an expected or previous reading, the greater
the short term effect. The subsequent diagnosis can then be guided
by the relative contributions of short and long term effects.
[0186] For example, a typical short term effect on capillary
related interstitial layer thickness in the tibial region is
prolonged standing (e.g., 4 to 6 hours of continuous standing). A
subject monitored using the tibial monitor methods described
herein, for instance, may be responding to antidiuretic treatments
to reduce capillary related interstitial fluid volume while
contemporaneously responding to shorter term effects of standing
upright. In such a subject the effect of standing upright for a
prolonged period of time can be assessed by inducing physiological
changes in the subject that would alter tibial capillary related
interstitial layer thickness in a relatively short examination
period. For example, by monitoring tibial capillary related
interstitial layer thickness in the upright position and in the
prone, or leg raised positions, the short term effect of standing
upright can be assessed. Rapid changes in tibial capillary related
interstitial layer thickness can be generally influenced by short
term effects. Note, however, methods described herein, where rapid
changes in tibial interstitial thickness can be indicative of
increased capillary permeability, compromised venous valves, or
insufficient cardiac output. Preferably, a baseline is established
for capillary related interstitial layer thickness so comparisons
can be made in subsequent measurements.
[0187] One of the most common clinical settings for a method of
measuring capillary related interstitial layer thickness is the
assessment of the efficacy or side-effects of medical treatments.
Monitoring regimes can be conveniently and appropriately tailored
using the methods described herein to evaluate the progress of
treatment. Typically, a drug will be administered to a subject and
the steps (a) transmitting, (b) recording, and (c) determining
related to the method of monitoring capillary related interstitial
fluid are repeated at predetermined intervals as an assessment of
capillary related interstitial fluid balance of the subject over a
clinically relevant time period. Preferably, baseline monitoring
prior to drug administration is also conducted. Typical drugs
amenable to such treatment monitoring include cardiovascular agents
and renal agents. Other drugs include antihypertensives, diuretics,
anticoagulants, and vasoactive substances (see also Table 3).
Clinicians, however, can use the method with any drug, particularly
those drugs thought to change capillary related interstitial fluid
levels either as a treatment for altering capillary related
interstitial fluid levels or for monitoring side-effects of drugs
that may alter capillary related interstitial fluid levels in
undesired or unintended ways.
[0188] Another common clinical setting for a method of measuring
capillary related interstitial layer thickness is to assess the
efficacy or side-effects a medical treatment comprising surgical
procedures and treatments. Typically, a surgical treatment will be
provided to the subject and the steps of (a) transmitting, (b)
recording, and (c) determining related to the method of monitoring
capillary related interstitial fluid are repeated at predetermined
intervals as an assessment of capillary related interstitial fluid
balance of the subject over a clinically relevant time period.
Preferably, baseline monitoring prior to surgical treatment is also
conducted. The surgical treatment may be directed, in whole or in
part, to modulating capillary related interstitial fluid levels.
Examples of such surgical treatments include cardiac surgery (e.g.,
cardiac valve replacement and coronary bypass graft surgery), renal
surgery (e.g., surgical or interventional radiologic repair of
renal artery stenosis or urinary outflow stenosis), renal and
hepatic transplantation, pulmonary arterial embolectomy, peripheral
venous or arterial embolectomy, and peripheral vascular surgical
and interventional radiologic procedures (e.g., stripping of
varicose veins, sclerotherapy, bypass grafting, and thrombolytic
therapy), as well as others known in the art or developed in the
future. Usually, the clinical relevant time period for monitoring
of the efficacy of surgical treatments will be periodically over
about days to months.
[0189] In other indications related to surgical treatments,
monitoring of the side-effects of surgical treatments will be
desired. Side effects of surgical treatments include blood loss,
cardiac arrest, fat and air embolism, heart failure, hepatic
failure, hepatic or renal ischemia and infarction, hypoxic tissue
damage, intestinal ischemia and infarction, mechanical tissue
damage, myocardial ischemia or infarction, myolysis, pulmonary
edema, pulmonary embolism, renal failure, urinary obstruction,
respiratory arrest, sepsis, shock, spinal cord injury,
overhydration or dehydration, fluid retention in dependent
anatomical regions, lower or upper extremity venous thrombosis, and
arterial dissection and/or occlusion.
[0190] Usually, the clinically relevant time period for monitoring
of the side-effects of surgical treatments will be during the
surgical procedure or treatment and periodically over about 24 to
96 hours post procedure or treatment. The use of multi-site
monitoring and continuous monitoring, as described in further
detail herein, will be particularly applicable in this clinical
setting. Multi-site monitoring and continuous monitoring can be
used to prevent the progression of capillary related interstitial
fluid retention, especially in specific anatomical regions during
and post surgical treatment, such as the forehead, the temporal
region, the occiput, the nuchal region, the cervical region, the
thoracic region, the low back region, sacral region, and buttocks
region, the sternal region, the anterior or the lateral chest wall,
the anterior or the lateral abdominal wall, the humerus region, the
forearm region, the hand, the thigh, the tibial region, the calf,
the medial and lateral malleolus, the foot, and preferably any such
dependent anatomical region (see also FIG. 3 and 4).
[0191] Another common clinical setting for a method of measuring
capillary related interstitial layer thickness is to assess the
efficacy or side-effects a medical treatment comprising general
anesthetic procedures and treatments. Typically, a general
anesthetic procedure or treatment will be provided to the subject
and the steps (a) transmitting, (b) recording, and (c) determining
related to the method of monitoring capillary related interstitial
fluid are repeated at predetermined intervals as an assessment of
capillary related interstitial fluid balance of the subject over a
clinically relevant time period. Usually, the clinically relevant
time period will be during a general anesthetic procedure or
treatment and periodically over about 24 to 72 hours post procedure
or treatment. Preferably, baseline monitoring prior to general
anesthetic procedure or treatment is also conducted. Side-effects
of general anesthetic procedures or treatments include hypoxic or
embolic brain damage, cardiac arrest, drug-induced complications,
heart failure, hypoxic tissue damage, intestinal ischemia and
infarction, myocardial ischemia or infarction, myolysis, pulmonary
edema, pulmonary embolism, renal failure, respiratory arrest, line
sepsis, shock, overhydration or dehydration, and lower or upper
extremity arterial or venous thrombosis. The use of multi-site
monitoring and continuous monitoring, as described in further
detail herein, will be particularly applicable in this clinical
setting. Multi-site monitoring and continuous monitoring can be
used to prevent the progression of capillary related interstitial
fluid retention, especially in specific anatomical regions during
and post general anesthetic procedure or treatment, such as the
forehead, the temporal region, the occiput, the nuchal region, the
cervical region, the thoracic region, the sternal region, the
anterior or the lateral chest wall, the anterior or the lateral
abdominal wall, the humerus region, the elbow region, the forearm
region, the hand, the thigh, the tibial region, the calf, the
medial and lateral malleolus, the foot, and dependent anatomical
regions (see also FIG. 3 and 4).
[0192] Intubation of a subject is another common clinical setting
to apply a method of measuring capillary related interstitial layer
thickness to assess the efficacy or side-effects associated with
this medical treatment. Typically, an intubation procedure will be
provided to the subject and the steps of (a) transmitting, (b)
recording, and (c) determining related to the method of monitoring
capillary related interstitial fluid are repeated at predetermined
intervals as an assessment of capillary related interstitial fluid
balance of the subject over a clinically relevant time period.
Usually, the clinically relevant time period will be during an
intubation procedure and periodically over about 24 to 72 hours
post procedure to treatment. Preferably, baseline monitoring prior
to an intubation procedure is also conducted. Side effects of
intubation procedures include airway obstruction, airway damage,
barotrauma, gastric intubation, tracheal or bronchial perforation,
tracheopleural and bronchopleural fistula, tracheoesophageal
fistula, hepatic or renal ischemia and infarction, hypoxic brain
damage, hypoxic tissue damage, intestinal ischemia and infarction,
myocardial ischemia or infarction, pulmonary edema, respiratory
arrest, spinal cord and cervical spine injury, and tetraparesis or
paraparesis. The use of multi-site monitoring and continuous
monitoring, as described in further detail herein, will be
particularly applicable in this clinical setting. Multi-site
monitoring and continuous monitoring can be used to prevent the
progression of capillary related interstitial fluid retention,
especially in specific anatomical regions post intubation
procedure, such as the forehead, the temporal region, the cervical
region, the thoracic region, the low back region, the sternal
region, the anterior or the lateral chest wall, the anterior or the
lateral abdominal wall, the humerus region, the elbow region, the
forearm region, the hand, the thigh, the tibial region, the calf,
the medial and lateral malleolus, the foot, and dependent
anatomical regions (see also FIG. 3 and 4).
[0193] Another important application of the present invention is in
trauma, intensive or critical care units, or emergency room
settings. Such settings normally require critical care procedures
of a subject to assess medical conditions that have serious or life
threatening consequences. In critical care situations, the steps of
(a) transmitting, (b) recording, and (c) determining related to the
method of monitoring capillary related interstitial fluid are
typically initiated as quickly as possible. In many critical care
situations rapid fluid shifts occur and the present invention, in
part, because of its sensitivity to small fluid shifts, can warn a
clinician of a potentially harmful or life threatening fluid
shift.
[0194] The method can also be used to monitor the progression of
capillary related interstitial fluid that is common in critical
care settings. Fluid is often retained in the extremities, the head
and neck region, dependent body regions (i.e., regions subjected to
fluid accumulation due to gravity) and areas with subcutaneous
tissue rich in vascularized tissue and collagen and elastic fibers,
such as the scrotum. It will be desirable to repeat the steps of
(a) transmitting, (b) recording, and (c) determining related to the
method of monitoring capillary related interstitial fluid,
particularly at predetermined intervals, as an assessment of
capillary related interstitial fluid balance of the subject over a
clinically relevant time period. Steps (a), (b), and (c) are
typically initiated within 36 hours of a trauma or other critical
care setting, preferably within about 24 hours, more preferably
within about 6 hours and most preferably within about 15 minutes.
Typically, a progressive increase in capillary related interstitial
layer thickness indicates an increase in capillary related
interstitial fluid and a progressive decrease in capillary related
interstitial layer thickness indicates a decrease in capillary
related interstitial fluid. Monitoring of capillary related
interstitial fluid can occur in many critical care situations,
including patients with acquired immunodeficiency syndrome (AIDS),
autoimmune disorders, burns, bacteremia, cancer leading to local or
distant organ failure, cardiac arrest, coma, drowning or
near-drowning, drug-induced complications, drug overdose, heart
failure, hepatic failure, infections, inhalation of toxic
substances, intestinal ischemia and infarction, myocardial ischemia
or infarction, poisoning, pulmonary embolism, renal failure,
respiratory arrest, trauma, transplant complications, sepsis,
shock, and arterial or venous thrombosis. The use of multi-site
monitoring and continuous monitoring, as described in further
detail herein, will be particularly applicable in this clinical
setting. Multi-site monitoring and continuous monitoring can be
used to prevent the progression of capillary related interstitial
fluid retention, especially in specific anatomical regions post
trauma or other critical care event, such as the forehead, the
temporal region, the occiput, the nuchal region, the cervical
region, the thoracic region, the low back region, the sternal
region, the anterior or the lateral chest wall, the anterior or the
lateral abdominal wall, the humerus region, the elbow region
including the olecranon, the forearm region, the hand, the thigh,
the tibial region, the calf, the medial and lateral malleolus, the
foot, and preferably dependent anatomical regions (see also FIG. 3
and 4).
[0195] Different Types of Monitoring
[0196] Monitoring of capillary related interstitial fluid can
include any temporal method, including periodic, intermittent,
predetermined and continuous. In many instances, at least one
ultrasound signal is from an ultrasound probe positioned on the
surface of a tissue. The positioning guides the probe to a specific
and routinely recognizable anatomical region and permits
measurement of an interstitial layer, often between bone and skin.
The probe can be positioned to allow for periodic, continuous or
intermittent monitoring. The more reproducible the positioning the
better the monitoring over time. Thus, the probe is preferably
positioned at approximately the same anatomical site on the surface
of the tissue. The transmitting and recording can occur at
clinically relevant time intervals. In many settings where the
subject is relatively immobile, such as a hospital or convalescent
home, and continuous or intermittent monitoring is preferred, the
time intervals are over at least about a 4 hour time period. Other
acceptable time interval include monitoring over at least about a
6, 12, 24, 48, 72, or 96 hour time periods. Longer or shorter
monitoring periods can also be applied. Usually, the clinical
situation the subject has been diagnosed with requires chronic or
continual capillary related interstitial fluid assessment.
[0197] The ultrasound probe used for interstitial fluid monitoring
preferably is specifically adapted for interstitial fluid
assessment. Examples of such specifically adapted probes are
described herein for the first time. Preferably, for
self-measurement the probe is part of an ultrasound system
dedicated to monitoring interstitial fluid assessment. Such systems
can be primarily designed to measure interstitial fluid levels,
usually based on specific anatomical regions using an ultrasound
probe. Often such systems will include a chip for computing
interstitial layer thickness. Equivalently, the calculation of a
proxy that approximately simulates interstitial fluid volume or
capillary related interstitial fluid thickness based on ultrasound
signals may be substituted for computing the ILT thickness. Other
features that can be included in dedicated probes are more fully
described herein. Although, imaging systems can be used to practice
some embodiments of the invention, it will be preferred to use
non-imaging systems that can determine interstitial layer
thickness. Probes known in the art and developed in the future can
also be used for practicing methods of the invention.
[0198] In one embodiment, the ultrasound probe can be secured to
the subject with an adhesive as shown in FIG. 5A and B. This is
preferred for methods that use intermittent or continuous
recording. The ultrasound transducer can be electrically coupled to
an ultrasound computational unit (not shown) using a light weight
wire 500. An electrical connector 510 connects the computational
unit and the ultrasound transducer 520 using an electrical
connecting socket or connector means 530. The ultrasound transducer
520 is optionally seated inside a positioning frame 540. The
undersurface of the positioning frame consists of an acoustic
coupler 550. The positioning frame is attached to the subject or
tissue surface using an adhesive 560. Usually, for better
acoustical coupling the skin of the subject is hairless or the hair
is removed. Although, this is not necessary in most instances.
Preferably, the adhesive 560 can acoustically couple the ultrasound
probe to the skin of the subject or the interrogated tissue surface
570. Although, the adhesive can also be interspersed with an
acoustic coupling material, such as a gel. An adhesive may also be
applied to a securing band that is disposed on at least a portion
of the probe that does not contact the skin. The adhesive contacts
a region adjacent the probe to secure the probe's position.
Preferably the adhesive contacts the skin on either side of the
probe.
[0199] FIG. 6 shows one embodiment of the invention comprising an
ultrasound transducer 600 attached to a separate positioning frame
620 with an attachment member 610. The extending members 630 of the
positioning frame are attached to securing members 640 to secure
the frame to the skin away from the interrogation site. The
securing members are secured to the skin using an adhesive or other
anatomical region attachment means. The ultrasound transducer is
electrically coupled to an ultrasound computational unit using a
light weight wire 650. Alternatively, the ultrasound transducer can
be coupled to an ultrasound computational unit using an infrared or
radio frequency coupler.
[0200] Dedicated and secured probes can have many different cross
sectional areas. As the size of the cross sectional area increases,
a larger area is monitored, which in some applications is desirable
because a greater surface area can produce better signal averaging.
If the probe surface, however, is larger than the anatomical region
to be interrogated the signal quality will diminish. Consequently,
probe size can be tailored to fit a particular anatomical region.
In some applications it will also be desirable to have a probe that
specifically interrogates a smaller region in order to improve
sensitivity. In some anatomical regions, such as the tibial region,
a focused interrogation, in terms of surface area, can permit more
sensitive measurements. Typically, the ultrasound probe has a
surface area of no more than 7 cm.sup.2, preferably 5 cm.sup.2, and
more preferably 2 cm.sup.2.
[0201] Calculations and Standards
[0202] Calculations relating to capillary related interstitial
fluid and layers can be used with the devices and methods of the
present invention. Many of the calculations are related to signal
processing, including calculating the ILT, signal averaging,
calculating the shortest reflective distance, and threshhold
setting. Generally, ILT is calculated as follows:
FRD-SRD [Eq. 3],
[0203] wherein FRD (first reflective distance) is calculated as the
time of travel from a probe to a first reflective layer (usually
skin) and back to the probe multiplied by the speed of sound in a
given tissue(s) and divided by two, and SRD (second reflective
distance (such as an internal reflective distance, usually bone) is
calculated as the time of travel from a probe to a second
reflective layer (usually bone or fat) and back to the probe
multiplied by the speed of sound in a given tissue(s) and divided
by two.
[0204] A computational unit can be included in a system to
calculate ILT using Eq. 3 or any other calculation that can be used
in the methods described herein or known in the art or developed in
the future for ultrasound. For instance, it may not be necessary in
some applications to use Eq. 3 because the first reflective
distance is filtered out by the system and only the second
reflective distance is calculated. The second reflective distance
will still often be, even in the absence of a first reflective
distance correction, an indicator of ILT, in appendage regions.
Skin thickness usually does not change as much as interstitial
layer thickness, therefore ILT is often not greatly influenced by
such correction. Skin thickness usually does not provide a large
relative contribution to overall tissue thickness. Consequently,
ILT is often relatively insensitive to the inclusion of skin
thickness in ILT measurements.
[0205] Skin thickness can also be standardized and subtracted (see
methods described herein) from the second reflective distance to
determine ILT. This is preferred in applications where skin
thickness becomes a significant contributor to tissue thickness
(e.g., young individuals, tibial regions, and subject of normal or
below normal weight). Preferably, the invention does not include a
computational unit capable of processing signals for imaging. In
the preferred embodiments of the invention, the system simply
processes the signals without reconstructing an image from the
signal. By using an A scan type ultrasound system, a dedicated
system can be built relatively inexpensively. The invention also
includes a computer program product that includes a computer
readable storage media that includes a computer program to
calculate or estimate ILT using Eq. 3.
[0206] Determination of a reflective layer will typically
constitute either analysing signals for the most intense, narrow
signals or by threshold setting. Signals received from the tissue
by the detector are processed or stored by the system for
subsequent processing. Selection of reflective layers can include
determining which signal contains the highest amplitude or
averaging a number of signals and determining the highest amplitude
for the averaged signals. Once the highest amplitude has been
selected, the travel time associated with the highest amplitude is
used to determine the distance to the reflective layer. Either
travel times or distances can be used in an electronic or
computational filter to remove data with either travel times or
distances that are considered a priori as artifacts. For instance
data can be excluded with travel times considered to be too short
to be associated with a first reflective layer associated with
skin. Often inexperienced operators can inadvertently include an
air gap between the probe and skin or not properly apply a coupling
gel to the surface of the skin. Such operator errors can lead to
anomalous data that includes abnormal short travel times or
distances that can be excluded from the analysis by a computational
unit. Optionally, the computational unit can electronically apprise
the operator of the potential error by signaling the operator, such
as with a bell, flashing light or other error message. The system
can also include an override function to enable the operator to
dismiss the error. Upon repetition of the measurement the operator
may determine the signal is not in error and wish to override the
preprogrammed error function of the system.
[0207] Signals received by the detector can be subjected to
threshold processing. Typically, threshold processing excludes
signals of a predetermined value or range of values. The signal
processing can potentially exclude signal either above or below the
predetermined threshold value. The predetermined threshold value
for a signal can include: 1) predetermined values correlated with,
or selected from, anatomical sites and structures (e.g., estimates
of actual thicknesses), 2) predetermined values generated from
interrogating the tissue under examination (e.g., generating
average values for the tissue under examination), and 3)
predetermined values generated from interrogating tissues to
determine normative values for different tissues, subject
populations, medical conditions, etc. (e.g., generating average
values from particular anatomical sites or structures using
multiple qualified subjects).
[0208] A system or detector can exclude signals at different levels
of signal detection or processing. For instance, signals can be
excluded by time gating, electronic filtering, digital filtering,
analog filtering, and amplitude gating. Such filtering can be
applied to both B-scan and A-scan devices. Preferably, such
filtering is applied to A-scan devices in the form of a simple
electronic circuit.
[0209] Time gating can be used to exclude or filter out signals
received by the detector. For example, signals received by crystals
can be excluded by switching off the circuit receiving electrical
impulses from the crystals during a selected time window. Signals
received during this time window are not subjected to further
processing. The circuit receiving electrical impulses from the
crystals need not be switched completely off. Instead such circuit
can be instructed not to receive signals during the time window,
such as by electrical gating of an amplifier receiving signals from
the crystals. Alternatively, signals can be time gated by analysing
the signals received by the crystals. Through analysis of the
signals as a function of time, signals received during selected
time windows can be simply excluded.
[0210] Electronic circuits or devices can be used to exclude or
filter out signals received by the crystals to accomplish
electronic filtering. A circuit can be connected to the crystals to
exclude signals with unwanted transmission times or amplitudes.
Signals received either too quickly or too slowly can be excluded
using circuits with appropriate time responses, such as capacitive
devices with different time constants. Signals received with either
too small or too large of an amplitude can be excluded using
circuits with appropriate amplitude responses. For example,
avalanche type circuits can be used. When an electrical threshold
is surpassed (e.g., gating current), the current activates an
amplifier. The signal current rapidly increases from zero to a
value substantially above background. Reverse amplifier circuits
can be used to reduce or eliminate signals with amplitudes such as
capacitive devices with different time constants. Alternatively,
the signals can be digitized as known in the art and signals
excluded based on digital exclusion criteria (either amplitude,
timing, or frequency information) that can form part of either a
chip (e.g., a programmed chip) or program.
[0211] Signals, results of calculations, or signal processing can
be displayed on a digital or analog display for the operator or the
subject to observe. The display can also include a predetermined
display arrangement that includes symbols or illustrative graphics
of preselected anatomical features of the interrogated tissue.
Results of calculations can then used in the graphic to display the
calculated distances (or other suitable information) associated
with the predetermined anatomical features. For example, FIG. 7
shows bone 710, ILT "ILT", skin 720 and probe 730 that were
preselected and designed as a graphic for display on a screen.
After the computational unit processes the data, processed
information, such as calculated distances, can then be inserted
into the displayed graphic. It will also be desirable to provide
display features that show the change in absolute ILT (in mm or cm)
over time (or the derivative of absolute ILT as a function of time)
or the percent change in ILT over time. Such time based displays
will be particular useful in chronic, continuous, and short term
periodic monitoring. Such displays are another useful aspect of the
invention. The displays generally include a screen that is
electronically controlled by a computational unit and shows a
calculation or representation of an ILT. Such displays do not
include images generated by ultrasound recordings, such as a B-scan
image.
[0212] One aspect of the invention includes a screen display
comprising a predetermined set of anatomical features that appear
on the screen. Usually, the predetermined set of anatomical
features that appear on the screen reflect at least one processed
signal. The processed signal could, for instance, be a distance
measurement that is displayed on the screen and corresponds to at
least one anatomical feature of the predetermined set of anatomical
features. The predetermined set of anatomical features can include
any features known for an interrogated tissue. Such features can
appear as a simulated image on the screen of an anatomical region.
The image can reflect distances between anatomical features.
Usually, at least one distance corresponds to at least one
processed signal. The image typically comprises common anatomical
features, such as bone, skin, interstitial layer and muscle. This
aspect of the invention is particularly useful for displaying
signals from dedicated diagnostic device, such as ultrasound
devices (particularly A-scan devices), NMR devices, computed
tomography devices, nuclear medicine devices, bone densitometry
devices, radiographic devices, and other current and future
diagnostic devices. The screen can optionally include subject data,
such as historic records from previous examinations. For example,
the screen display can include at least one image that reflects at
least one processed signal previously stored in a storage
device.
[0213] Not all aspects of the invention require calculations for
determining ILT. Instead, either ILT can be read on an analog
display or a proxy for ILT can be substituted. For instance, the
first and second reflective distances can be calculated and
displayed on an analog display along with a distance scale and the
operator can manually calculate the ILT. For example, FIG. 8 shows
a screen with an analog display and a distance scale for FRD "FRD"
and SRD "SRD". The analog display may optionally include a
diagnostic scale "DS" for clinical use. The diagnostic scale may be
predetermined by the clinician, created by an expert system or by
the methods described herein. Alternatively, the analog display may
have only a diagnostic scale. The diagnostic scale could also be
based on predetermined values for the ratio of the SRD to FRD or
absolute values of the SRD or FRD. The diagnostic scale may also
reflect vascular, cardiac, hepatic, or renal function. The
diagnostic scale may be adjustable for the patient's underlying
condition, e.g. the scale may be switchable from a cardiac to a
renal mode. Physiological performance may be subdivided into
categories such as normal, abnormal, and critical or modifications
thereof.
[0214] The method or the system can further include comparing
capillary related interstitial layer thickness with a standard
value for capillary related interstitial layer thickness for a
particular tissue. A computational unit can compare measured ILTs
to ILT standards described herein. By comparing ILT values the
clinician or operator can be apprised of the clinical situation.
Warning or diagnostic signals can be programmed into the system to
alert the clinician or operator of the possible medical
implications of the ILT evaluation. Diagnostic thresholds can be
used to alert operators of sub- or supra-medical thresholds related
to medical conditions. Although, a particular subject may not
ultimately require medical treatments if the measured ILT falls
below or exceeds a sub- or supra-medical threshold, respectively,
such sub- or supra-medical thresholds can provide indications or
clinical warning signs that may provoke additional testing either
with ultrasound or with other diagnostic tools.
[0215] The methods and devices of the invention for detecting ILT
can be extremely sensitive. Typically, the present invention can
measure changes in ILT as small as about 0.4 to 1.0 mm. Smaller and
larger changes in ILT can also be measured. The ability to detect
small changes in ILT is primarily influenced by probe frequency,
tissue depth and the strength of the reflective layer interrogated,
as described further herein. The higher the probe frequency, in
general, will improve probe interrogation of shallow interrogation
depths (e.g., about 1 to 20 mm). Generally, probes above 18 MHz are
preferred (e.g., about 20 to 30 MHz) for shallow interrogation
depths. For deeper interrogation depths (e.g., greater than about
20 mm) shorter frequency probes are desirable (e.g., about 5 to 15
MHz). Even shorter frequency probes, are desirable for
interrogating particularly thick tissues (e.g., extremely thick
appendages or large subjects). As the tissue thickness increases, a
relatively small change in ILT (e.g., about 0.5 mm) will become a
smaller percentage of total ILT. This can lead in some instance to
decreases in the signal-to-noise ratio and make it more difficult
to determine ILTs at deep interrogation depths. Consequently, it
will be desirable to match probe frequency to the tissue depth or
anticipated depth of interrogation. Generally, percentage changes
in ILT can be measured at about 25 percent or higher, preferably
about 10 percent or higher, more preferably about 5 percent or
higher, and most preferably about 1 percent or higher.
Consequently, with shorter clinically relevant time periods, it is
desirable to provide high sensitivity aspects of the invention in
order to detect small changes in ILT over time.
[0216] For example, the present invention can detect small changes
in ILT as function of time. Generally, for physiological processes
or challenges that rapidly affect ILT, changes in ILT can be
detected in about 1 to 90 or less, preferably about 1 to 30 minutes
or less, and more preferably about 5 to 30 minutes or less. At
these time frames, the more sensitive aspects of the invention are
preferred. Generally, for physiological processes or challenges
that slowly affect ILT less sensitive aspects of the invention can
be used.
[0217] Empirical Methods for Determining Standards
[0218] In one embodiment of the invention, ILT measured in a
patient is compared to reference ILT's obtained from a control
population (e.g. age-, sex-, race-, or weight-matched normal
subjects). Reference ILT's can be generated by measuring
interstitial layer thickness in healthy subjects with normal
vascular, cardiac, hepatic, or renal function and no other
underlying medical condition. Reference ILT's can be expressed as
but are not limited to, mean and standard deviation or standard
error. Reference ILT's can be obtained independently for pediatric
patients and patients 15-20, 20-30, 30-40, 40-50, 50-60, 60-70,
70-80, and 80 and more years of age. Reference ILT's for these age
groups can be obtained separately for men and women and for race
(e.g. Asian, African, Caucasian, and Hispanic subjects).
Additionally, reference ILT's can be obtained for different subject
weights within each age, sex, and racial subgroup. For each
subgroup defined in this fashion by age, sex, race, and weight,
reference ILT's can be measured at various anatomic sites, such as
the forehead, the temporal region, the occiput, the nuchal region,
the cervical region, the thoracic region, the low back region, the
sacral region, the buttocks region, the sternal region, the
anterior or the lateral chest wall, the anterior or the lateral
abdominal wall, the humerus region, the elbow region including the
region of the olecranon, the forearm region, the hand, the thigh,
the tibial region, the calf, the medial and lateral malleolus, and
the foot (see also FIG. 3 and 4).
[0219] Similarly, reference values for skin thickness, e.g. first
reflective distance, can be obtained in healthy subjects with
normal vascular, cardiac, hepatic, or renal function and no other
underlying medical condition. Reference values for skin thickness
can be obtained independently for pediatric patients and patients
15-20, 20-30, 30-40, 40-50, 50-60, 60-70, 70-80, and 80 and more
years of age. Reference values for skin thickness for these age
groups can be obtained separately for men and women and for race
(e.g. Asian, African, Caucasian, and Hispanic subjects).
Additionally, reference values for skin thickness can be obtained
for different subject weights within each age, sex, and racial
subgroup. For each subgroup defined in this fashion by age, sex,
race, and weight, reference skin thickness can be measured at
various anatomic sites such as the forehead, the temporal region,
the occiput, the nuchal region, the cervical region, the thoracic
region, the low back region, the sacral region, the buttocks
region, the sternal region, the anterior or the lateral chest wall,
the anterior or the lateral abdominal wall, the humerus region, the
elbow region including the region of the olecranon, the forearm
region, the hand, the thigh, the tibial region, the calf, the
medial and lateral malleolus, and the foot (see also FIG. 3 and
4).
[0220] When reference values of skin thickness have been determined
for a given anatomic site, ILT may be calculated by subtracting the
reference value of skin thickness for the patient's age, sex, race
and weight group from the measured second reflective distance.
Alternatively, reference data for skin thickness published in the
literature may be subtracted from the second reflective distance.
For example, skin thickness at the dorsal side of the mid-forearm
has been reported to be approximately 0.95 mm at age 5 years of
age, increasing to 1.2 mm at 45 years of age, and decreasing to
approximately 0.7 mm at 80 years of age. Skin thickness at the
ventral side of the forearm has been reported to be 0.8 mm at 5
years of age without significant variation between the first and
the seventh decade of life (deRigal et al., J Invest. Dermatol.
1989). Other investigators reported a skin thickness of 1.3
mm.+-.0.2 at the palm and the dorsum of the hand, 1.4 mm.+-.0.3 at
the forearm, 1.6 mm.+-.0.3 at the calf, 1.9 mm.+-.0.4 at the
posterior sole, 2.0 mm.+-.0.3 at the forehead, 2.3 mm.+-.0.5 at the
lower back (Fomage et al., Radiology 1993).
[0221] If skin thickness does not provide a large relative
contribution to overall tissue thickness, no correction may be
necessary. Alternatively, the device may measure the first
reflective distance, e.g. skin thickness, in each individual
patient directly and ILT may then be obtained by subtracting
measured first reflective distance from measured second reflective
distance.
[0222] In another embodiment of the invention, measured ILT can be
compared to the control population (e.g. age, sex, race, or
weight-matched normal subjects) reference ILT for a given patient.
If the measured ILT falls outside a certain range defined based on
the reference ILT, an alarm such as a bell, a flashing light, or a
message will be generated by the device indicating that the patient
has an ILT and, ultimately, an amount of interstitial fluid lower
or higher than the healthy reference population. The device may be
set to generate the alarm when the measured ILT is one, two, or
three standard deviations above or below the reference ILT. In this
fashion, the device can be used to diagnose capillary related
edema. The magnitude of the discrepancy between measured ILT and
reference ILT can also give an indication of the severity of
interstitial fluid accumulation or depletion.
[0223] Normal ILT in healthy subjects will vary significantly
depending on the anatomic site. In the pretibial region, normal ILT
may range from 0.2 mm to 3 mm. At the dorsum of the foot, normal
ILT may range from 0.2 mm to 2 mm. In the thigh, normal ILT may
range from 1 mm to 2.5 cm. In the low back, sacral, and buttock
region, normal ILT may range from 0.5 mm to 4 cm. In the abdominal
region, normal ILT may range from 2 mm to 5 cm. In the sternal and
chest wall region, normal ILT may range from 2 mm to 3 cm. In the
humeral region, normal ILT may range from 0.5 mm to 1.5 cm. In the
forearm region, normal ILT may range from 0.2 to 3 mm. In the
forehead and temporal region, normal ILT may range from 0.2 mm to 2
mm. In the occipital region, normal ILT may range from 0.5 mm to 3
mm. In the nuchal region, normal ILT may range from 0.5 mm to 1.5
cm. Values in all of these regions may be significantly higher in
obese patients.
[0224] ILT will change significantly depending on the patient's
fluid status. In patients with a low interstitial fluid volume,
e.g. from dehydration, blood loss, or high intracapillary colloid
osmotic pressure, ILT's may be as low as about 25% of the control
population reference value. In patients with capillary related
edema, e.g. patients with heart failure, renal failure, hepatic
failure, or venous insufficiency, ILT may increase 20 fold or even
more. If the patient's clinical situation deteriorates, e.g. the
patient develops heart failure or his condition worsens, ILT can
increase by 35% or more within 15 minutes (see Example 2).
[0225] Changes in ILT may vary depending on the patient's age.
Younger patients are more likely to compensate for a sudden
physiological imbalance or challenge, e.g. intraoperative
overhydration by rapid saline infusion. Thus, increases in ILT may
be less significant in younger than in older subjects. However, the
elastic properties of the skin and ILT may decrease with age
thereby reducing rapid expansion of the ILT in older patients with
sudden fluid challenge.
[0226] Similarly, expansion or decreases of the ILT may be masked
in very obese patients since the change in ILT induced by the
interstitial fluid shift may be small compared to the patient's
already large ILT prior to the fluid shift.
[0227] Different medical conditions may demonstrate regional
variations in the amount of capillary related edema and ILT. These
regional variations may potentially be useful for differentiating
different etiologies of capillary related edema. Capillary related
edema secondary to varicosity of the deep calf veins and other
veins may be more prominently seen at distal sites such as the foot
and calf. Edema induced by abnormal colloid-osmotic pressure as is
seen in hepatic disease with associated hypalbuminemia may involve
both proximal and distal sites in a more uniform fashion.
[0228] Different medical conditions may also show regional
variations between dependent and non-dependent body regions.
Capillary related edema in venous disorders may preferentially
affect the dependent body portions, while capillary related edema
in patients with abnormal capillary permeability from allergic
reactions may affect both dependent as well as non-dependent body
regions.
4.0 Methods and Devices for Measuring Capillary Related Edema
[0229] Edema is a medical condition that primarily relates to
inappropriate or compromised regulation of fluid in cells or
interstitial compartments. As a secondary consequence of a
compromised or faltering physiological process, it is often
associated with death in many disease states. Comprised cardiac,
capillary, hepatic, or renal function can all lead to edematous
states, particularly in the appendages.
[0230] Capillary related edema refers to an abnormal fluid
imbalance arising from capillaries and leading to abnormal local
fluid retention. This type of edema is associated with vast
majority of edema related medical conditions. Capillary related
edema results from an abnormal physiological function or
physiological challenge to the venous system, arterial system,
cardiovascular system, renal system, hepatic system, pulmonary
system or other non-circulatory, internal organ systems normally
involved in homeostasis of normal fluid retention in the
capillaries. The present invention is particularly applicable to
the systemic aspects of capillary related edema. Unlike edema,
capillary related edema does not refer to lymphatic related edemas,
which have a completely different etiology. For example, pretibial
myxedema is a lesion in the dermis that leads to tissue swelling
and is associated with the disruption of the lymph system.
[0231] One of the clinically important aspects of the invention are
methods and devices for monitoring capillary related edema. One
embodiment of the invention includes a method of detecting
capillary related edema in a subject. An ultrasound probe is
positioned on an anatomical region, such as an appendage region of
a subject in need of capillary related edema detection. Positioning
is typically on the surface of the subject's skin. At least one
ultrasound pulse is applied to the region at a duration and
frequency to permit detection of bodily tissues. At least one
ultrasound signal is then recorded with an ultrasound probe from
the region. This permits the detection of the presence or absence
of a capillary related edema layer in the region from the
ultrasound signal(s).
[0232] Anatomical Regions
[0233] Capillary related interstitial fluid can be measured in any
tissue that contains at least one reflective surface and a
sufficient amount of water or other acoustic medium to permit
ultrasound signals to penetrate and return through the tissue(s)
for detection. Preferred anatomical regions are characterized by a
first reflective surface comprised of a skin-ILT interface and
second reflective surface comprised of a bone-ILT interface. Table
2 shows a number of preferred potential application sites for
ultrasound probes preferred for certain types of capillary related
edema. While these sites are preferred, non-preferred sites can be
readily used in most applications and empirical tests can be
quickly performed to determine other diagnostically useful sites.
Preferably, probes are adapted to permit self measurement in most
of these regions or adapted for dedicated measurement in these
regions. Probes dedicated to measurement of capillary edema in a
particular region may function in other regions, although they have
been configured to optimize signals from a particular region, as
described herein. Table 2 is by no means exhaustive, it is only
illustrative of the many potential preferred sites and reflective
surfaces to monitor capillary related edema. Particularly preferred
sites include the tibia region (even more preferably the proximal
tibia), sites where a potential capillary related edema layer
extends from the inner surface of the skin to either a fat or bone
surface (especially in the tibia or humeral region), the forehead,
the anterior or posterior forearm region, the dorsum of the hand,
and the medial or lateral malleolus. Typically, the subjects will
be humans, however, the present invention may be used with other
animals, especially large mammals in veterinary settings.
2TABLE 2 First Second Reflective Reflective Type of Capillary
Surface Surface Probe Site Related Edema Skin Bone Leg (preferably
mid, Cardiac, venous, anterior tibia) renal, and hepatic system;
hypertension; physiological challenge Skin Bone Arm (preferably
Cardiac, and arterial distal radius or alna) system: hypertension;
Skin or Bone Presternal Cardiac and arterial muscle system Skin
Traumatized Skin above internal Trauma tissue trauma site Skin Bone
Cranium (preferably Physiological temporal bone, challenge forehead
or nuchal region)
[0234] The sites listed in Table 2 can also be used in combination.
By using combinations of probe sites (i.e. multisite monitoring),
systemic or regional fluid shifts can be assessed. Multisite
monitoring also permits exquisitely sensitive monitoring of
physiological processes related to capillary related edema, such as
processes that either induce, prevent or reduce capillary related
edema, as well as therapeutic treatments thereof. Multisite
monitoring is further described in detail herein, particularly in
the section relating to monitoring physiological functions and in
situ probes. These aspects of the invention do not necessarily, and
preferably do not, include measuring the degree of skin
echogenicity. Methods described herein can be used to improve the
signal from tissues interrogated for a capillary related edema
layer. For instance, the thickness of a capillary edema layer can
be measured by determining the shortest reflective distance
described herein.
[0235] Use in Medical Conditions and Treatments
[0236] In many instances it will be useful to interrogate tissues
for a capillary related edema layer before, concurrent with, or
after the diagnosis of a medical condition. Often subjects with
diabetes, compromised renal function, compromised vascular
function, or compromised cardiac function have or will have
capillary related edema, especially in the appendages. Early
traditional clinical signs of capillary related edema may be
difficult to register. In contrast, the present invention provides
an unparalleled ability to register slight increases in capillary
related edema. Early diagnosis of the capillary related edema
permits the clinician to follow the progress of capillary related
edema and provide the appropriate clinical response, if warranted
(e.g., prescription of diuretics).
[0237] A number of medical conditions described herein can produce
capillary related edema. The present invention is particularly well
suited for testing capillary related edema in medical conditions
that increase capillary blood pressure, increase intracapillary
oncotic pressure, or increase capillary permeability. Such medical
conditions include but are not limited to compromised cardiac
function (particularly right ventricular failure and valvular
insufficiency), compromised renal function (particularly renal
failure with decreased urine production, compromised ability to
concentrate urine in the distal nephron or improper glomerular
filtration, hepatic failure water load (particularly the rapid
administration (e.g., IV) of isotonic or isosomotic fluids) and
hypertension. Table 3 shows a number of potential medical
conditions and medical treatments side effects that may cause, in
part or in whole, capillary related edema. Table 3 also indicates
the medical conditions in which the present invention is
particularly clinical relevant and extremely clinically relevant.
Table 3 is by no means exhaustive, as it is only illustrative of
the many clinically relevant medical settings in which the present
invention can be applied.
3TABLE 3 Selected Medical Conditions and Medical Treatment Side
Effects That may Cause Capillary Related Edema Diabetes (secondary
complications, see renal and vascular related disorders) +
Discontinuation of antihypertensive agents, cardiovascular drugs,
diuretics, or anticoagulants ++ Disorders resulting in increased
capillary permeability ++ (e.g. burn, electrical injuries,
poisoning, sepsis, and systemic toxins) Drug-induced + (e.g.
estrogens) Heart related causes ++ Heart failure secondary to
myocardial infarction, myocardial ischemia, arrhythmia, valvular
dysfunction, hypoxia, cardiotoxic substances, recent initiation of
a .beta.-blocking agent, myocardial infections, or pericardial
effusion Hypertensive related causes (with secondary heart failure)
++ Idiopathic Liver disease (e.g. liver cirrhosis, hepatic failure)
Physiologic challenges ++ (e.g. alcohol, altitude-induced,
orthostasis, pregnancy, psychological stress, salt load, trauma,
water load) Neurogenic edema + (e.g. after stroke, epidural,
subdural, and subarachnoid hemorrhage) Trauma ++ Oncotic pressure
disorders ++ (e.g. hypoproteinimic states, protein-losing
enteropathy, nutritional deficiency states, congenital
hypoalbuminemia, and chronic liver disease) Pulmonary related
causes (e.g. pneumonia, pulmonary embolism) Renal related disorders
++ (e.g. renal failure, nephrotic syndrome, chronic pyelonephritis,
glomerulonephritis, and discontinuation of diuretics) Vascular
related disorders ++ (e.g. varicose veins, and obstruction of
venous drainage) +: particularly clinically relevant; ++ extremely
clinical relevant (some of the listed disorders may be applicable
to two or more of the listed categories)
[0238] A number of drugs can also produce capillary related edema.
The present invention is particularly well suited for testing
capillary related edema before, concurrent with, or after drug
administration. Table 4 shows a number of drugs that may cause, in
part or in whole, capillary related edema as a side effect. Table 4
is by no means exhaustive, as it is only illustrative of the many
drugs that may cause capillary edema.
4TABLE 4 Selected Drugs That May Induce Capillary Related Edema
Antidiuretic hormone (ADH) Antimicrobial agents (see also under
"hepatotoxic drugs" and "nephrotoxic drugs") Chemotherapeutic drugs
(see also under "hepatotoxic drugs" and "nephrotoxic drugs")
Hepatotoxic drugs and drugs causing impairment of hepatic function
(e.g. aflatoxine, antiepileptic drugs [e.g. vaiproic acid],
antimicrobial drugs [e.g. rifampicin, fluconazole], antiviral drugs
[e.g. vidarabine]) Hormones (e.g. estrogen and estrogen
derivatives) Immunosuppressive drugs (see also under "hepatotoxic
drugs" and "nephrotoxic drugs") Myocardial depressant agents and
cardiotoxic drugs (e.g. verapamil, disopyramide, adriamycin, and
daunomycin) Nephrotoxic drugs and drugs causing impairment of renal
function (e.g. anticancer drugs [e.g. carboplatin, carmustine,
cisplatin, cyclophosphamide, ifosfamide, lomustine, semustine,
streptozocin, and thioguanine], antimicrobial agents [e.g.
aminoglycosides, amphothericin B, cephalosporines such as
cephalotin, cephalexin, cefamandole, pentamidine], antiviral agents
[e.g. amantidine, foscarnet], contrast agents for radiologic and
other imaging procedures, immunosuppressants [e.g. cyclosporine],
non-steroidal antiinflammatory drugs) Neuro- and
psychopharmacologic drugs Salt retaining agents
[0239] As a further example, the present invention may be used for
the early diagnosis of or for monitoring the progression of
capillary related edema in conjunction with a medical treatment.
For instance, after testing for capillary related edema it may be
advantageous to administer a diuretic agent, a cardiac function
agent or a diabetic agent to the subject. Testing for capillary
related edema can then be repeated by positioning an ultrasound
probe on an appendage region of a subject in need of capillary
related edema detection after the administration of an agent, and
recording ultrasound signals with the ultrasound probe from the
appendage region. The therapeutic value of the treatment with
respect to the capillary related edema can be then assessed. This
aspect of the invention can be used with a number of the medical
treatments described herein, particularly those treatments
affecting capillary related edema in the appendages. Table 5 shows
a number of potential medical treatments that may reduce, in part
or in whole, capillary related edema. Table 5 is by no means
exhaustive, as it is only illustrative of the many medical
treatments that can apply to capillary related edema. Selected
routes of administration for various agents include: intradermal
injection, subcutaneous injection, intramuscular injection,
intravenous injection, intraperitoneal injection, intracavitational
injection (e.g., injection into a pre-existing physiologic or
pathologic body cavity), oral, anal, inhalational, nasal spray, and
dermal patch. One skilled in the relevant art can easily select the
route most likely to be a therapeutically effective modality for a
particular agent.
5TABLE 5 Selected Medications That Can Be Used To Treat Capillary
Related Edema or Its Underlying Cause Anticoagulants (for treatment
of deep venous thrombosis or pulmonary embolism) (e.g. dicumarol,
cumarine derivatives, heparin calcium, heparin sodium, and warfarin
sodium) Antihypertensives Alpha-adrenergic blockers (e.g.
bunazosin, phenoxybenzamine hydrochloride, phentolamine mesylate,
prazosin hydrochloride, terazosin hydrochloride, tolazoline
hydrochloride, and urapidil) Angiotensin-converting enzyme
inhibitors (e.g. benazepril, captopril, enalaprilat, enalapril
maleat, fornopril, lisinopril, monopril, perindropril, quinapril,
and ramipril) Beta-adrenergic blockers (see under "cardiovascular
agents") Calcium channel blockers (see under "cardiovascular
agents") Centrally acting antihypertensives (e.g. alphamethyldopa,
clonidine, guanfacine, rilmenidine, and guanobenz) Monoamine
oxidase inhibitors (e.g. pargyline hydrochloride) Miscellaneous
(e.g. clonidine hydrochloride, diazoxide, guanabenz acetate,
guanadrel sulfate, guanethidine sulfate, guanfacine hydrochloride,
hydralazine hydrochloride, mecamylamine hydrochloride, methyldopa,
metyrosine, minoxidil, nitroprusside sodium, and trimethaphan
camsylate) Rauwolfia alkaloids (e.g. deserpidine, rauwolfia
serpentina, rescinnamine, and reserpine) Cardiovascular agents (see
also listing for antihypertensives) Antiarrhythmics and
miscellaneous (e.g. adenosine, amiodarone hydrochloride, bretylium
tosylate, disopyramide phosphate, encainide hydrochloride,
flecainide acetate, indecainide hydrochloride, lidocaine, lidocaine
hydrochloride, mexiletine hydrochloride, molsidomine, procainamide
hydrochloride, propafenone hydrochloride, propanolol, quinidine
gluconate, quinidine, polygalacturonate, quinidine sulfate,
sotalol, and tocainide) Anticholinergics (e.g. atropine sulfate)
Beta-adrenergic blockers (e.g. acebutolol, atenolol, betaxolol,
bisoprolol, labetalol, metoprolol tartrate, nadolol, oxprenolol,
pindolol, propanolol hydrochloride, sotalol, and timolol maleate)
Calcium channel blockers (e.g. amlodipine, diltiazem hydrochloride,
felodipine, isladipine, lacadipine, nicardipine, nifedipine,
nitrendipine, and verapamil hydrochloride) Cardiac glycosides (e.g.
deslanoside, digitalis glycoside, digitoxin, digoxin, and
strophantin) Hydantoin derivates (e.g. phenytoin sodium) Nitrates
(e.g. nitroglycerin, isosorbide, pentaerythritol tetranitrate, and
erythrityl tetranitrate) Phosphodiesterase inhibitors (e.g.
methylxanthines) Thrombolytics (e.g. streptokinase, urokinase,
tissue plasminogen activator (tPA), and anisoylated plasminogen
streptokinase activator complex (APSAC)) Vasodilators and
vasoconstrictors (see under "Antihypertensives" and "Vasoactive
Substances") Diuretics Aldosteron antagonists and potassium sparing
diuretics (e.g. amiloride, canrenone, spironolactone, and
triamterene) Carbonic anhydrase inhibitors (e.g. acetazolamide,
acetazolamide sodium, dichlorphenamide, and methazolamide) Loop
diuretics (e.g. bumetanide, ethacrynate sodium, ethacrynic acid,
furosemide, and torsemide) Miscellaneous (e.g. alcohol and
caffeine) Natural medicinal products (e.g. terminalia arjuna and
moringo oleifera) Osmotic agents (e.g. mannitol, glycerin and
hyperosmolar solution) Plasma expanders (e.g. dextran) Thiazides
(e.g. bendroflumethiazide, benzthiazide, chlorothiazide,
cyclothiazide, hydrochlorothiazide, hydroflumethiazide, indapamide,
methyclothiazide, polythiazide, and trichlormethiazide)
Thiazide-like agents (e.g. chlorthalidone, metolazone, and
quinethazone) Serum albumin Vasoactive substances (e.g. bamethan,
bencyclane, bethahistine, cyclandelate, cinnarizine, citicoline,
dihydroergocristine, dihydroergotoxine, dipyridamole, ebunamonine,
flunarizine, ginko-biloba extracts, horse-chestnut seed extract,
isoxsuprine, naftidrofuryl, nicergoline, nicotinic aid derivatives,
nylidrin, oxerutms, i.e. hydroxyethyl derivatives of rutin,
pentoxifylline, papaverine, piracetam, piribedil, raubasine,
suloctidil, and vincamine)
[0240] Monitoring of capillary related edema is also particularly
relevant in many critical care situations including patients with
acquired immunodeficiency syndrome (AIDS), autoimmune disorders,
bums, bacteremia, cancer leading to local or distant organ failure,
cardiac arrest, coma, drowning or near-drowning, drug-induced
complications, drug overdose, heart failure, hepatic failure,
infections, inhalation of toxic substances, intestinal ischemia and
infarction, myocardial ischemia or infarction, poisoning, prolonged
non-ambulatory convalescence, pulmonary embolism, renal failure,
respiratory arrest, trauma, transplant complications, sepsis,
shock, and arterial or venous thrombosis. The use of multi-site
monitoring and continuous monitoring, as described in further
detail herein, will be particularly applicable in this clinical
setting.
[0241] Devices for Testing for Capillary Related Edema
[0242] Many aspects of monitoring or testing for capillary related
edema can be performed with currently available ultrasound
equipment designed for imaging. Although this approach is certainly
feasible and offers the clinician the opportunity to perform such
diagnostic tests using a multi-use ultrasound system, such systems
are not preferred for use with the present invention. Multi-use
ultrasound systems, such as those used for pelvic, abdominal,
thoracic, cranial, scrotal, thyroid and other small parts, fetal
and vascular ultrasound, are expensive and not tailored either at
the level of the probe or signal transmission or processing to test
for capillary related edema.
[0243] Preferably a dedicated ultrasound system is used to test for
capillary related edema. In a dedicated system the probe can be
adapted for measuring capillary related edema. The probe frequency
can be selected to optimize interrogation of a selected region and
to increase the sensitivity of detection of a first and second
reflective layer, as described herein. Probe size can also be
optimized to sample a specific area, as described herein. Signal
processing can be also be optimized for this particular application
as described herein. A scan probe and signals can be used to reduce
cost and size of the units. Since many such dedicated systems will
be designed to primarily interrogate one particular type of
capillary related edema probe site, which has a well known anatomy,
imaging will not be necessary and signals can be displayed as
described herein.
[0244] It will be particularly desirable to provide the ability for
the subject to monitor their own capillary related edema status.
Many subjects may be inflicted with a chronic medical condition or
involved in a long medical treatment. In these types of settings,
as well as others, the invention offers systems with an ultrasound
probe that is hand-held ultrasound probe and capable of self
measurement of capillary related edema. Preferably, the probe is
autonomous and includes the components necessary to accomplish
signal processing and display. Preferably, the subject can read the
display while the subject is determining their capillary edema
status. Alternatively, the system can have display that is not part
of the probe so that the subject can read the display while the
subject is determining their capillary edema status.
[0245] In one embodiment, the ultrasound system has an extended
grip that permits the human to position the ultrasound probe on the
tibia region and the ultrasound system permits the human to monitor
the measurement of the capillary related edema layer. In this
embodiment the probe may or may not have a display. Preferably,
probe frequency, shape or size, or a combination thereof, is
adapted for testing capillary related edema layer between the inner
surface of the skin and anterior aspect of the tibia based on at
least one ultrasound signal. The system can optionally measure skin
thickness as well with plurality of ultrasound signals. Preferably,
the extended grip is sufficiently long that the subject can test
for a capillary related edema layer in the tibia region which is
about halfway between the ankle joint and the knee joint. The
system can optionally include a standard subcutaneous layer
thickness for the tibia region for comparison or as a diagnostic
gauge, as described herein.
[0246] Calculations and Standards Calculation and standards can be
performed as described herein for other embodiments of the
invention.
5.0 Methods and Devices for Measuring Vascular Performance
[0247] The vascular system performs essential physiological
processes, including maintaining tissue fluid balance, tissue
perfusion, tissue oxygenation and nutrient and metabolite
transport. Although many current techniques can be used to evaluate
vascular performance, such as pulse oxymetry, conventional
angiography after intravascular injection of iodinated contrast
agents, B-scan ultrasound imaging of vascular structures, Doppler
ultrasound, computed tomography after intravenous injection of
iodinated contrast agents, and magnetic resonance angiography,
these techniques, unfortunately, suffer from a number of
shortcomings. Many currently available techniques are either
invasive, require complicated or costly procedures, or fail to
account for tissue perfusion, especially capillary perfusion of a
particular tissue.
[0248] One aspect of the present invention circumvents many of the
disadvantages of the current techniques for evaluating vascular
performance. The present invention provides for a noninvasive
assessment of vascular performance that is relatively inexpensive,
easily performed by a clinician (not necessarily a physician
trained in ultrasound techniques), and can integrate tissue effects
into the assessment, especially capillary related tissue effects.
The present invention can be applied to monitoring the venous as
well as the arterial system for disorders or function. For example,
the invention may be applied (a) to diagnose presence or absence of
vascular disorders, (b) to detect a malfunction of aspects of
vascular system, (c) to differentiate disorders or malfunction of
the vascular system from other causes of capillary related edema,
and (d) to monitor various types of medical treatments of vascular
disorders or malfunction.
[0249] Typically, a test of vascular performance, includes two
basic steps: reducing or increasing blood flow (or pressure) to a
tissue in a subject in need of vascular performance assessment
(step (a)), and monitoring a capillary related interstitial layer
thickness of the tissue (step (b)). Monitoring ILT with an
ultrasound probe can be before, after or concurrent with reducing
or increasing blood flow in step (a). Without providing a limiting
mechanism by which the invention operates, increasing or decreasing
blood flow (or pressure) to the tissue will change the physical
forces on the capillaries supplying the tissue thereby affecting
fluid balance in the tissue, particularly the blood pressure and
amount of blood flow. By reducing or increasing the blood pressure
in the capillaries, the hydrostatic gradient across the capillary
cells will change and typically drive fluid from the tissue and
into the capillary or fluid out of the capillary and into the
tissue. By reducing or increasing the blood flow (or pressure) in
the capillaries, the amount of fluid and solute transport per unit
of time through the tissue will change and typically increase
accumulation of tissue metabolites or decrease accumulation of
tissue metabolites.
[0250] Usually a test of vascular performance will include
increasing the blood flow (or pressure) to the tissue after the
reducing the blood flow in step (a) and monitoring in step (b) or
decreasing the blood flow (or pressure) to the tissue after the
increasing the blood flow in step (a) and monitoring in step (b).
By monitoring before, after or concurrent with controlled,
predeteremined maneuvers that change blood flow (or pressure) to
the tissue, the change in ILT can provide a diagnostic evaluation
of the level of vascular performance Typically, a first
controllable maneuver reduces blood flow (or pressure) controllably
reduces blood flow (or pressure) to the tissue for a clinically
relevant period of time in step (a). A subsequent, second
controllable maneuver to increase blood flow (or pressure) and
permits an increase in blood flow (or pressure) to the tissue for a
clinically relevant period of time in step (a). Monitoring
typically occurs after each maneuver. Alternatively, the first
controllable maneuver increases blood flow (or pressure) and
permits a controllable increase in blood flow (or pressure) to the
tissue for a clinically relevant period of time in step (a). A
second controllable maneuver reduces blood flow (or pressure) to
reduce blood flow (or pressure) to the tissue for a clinically
relevant period of time in step. Again, monitoring occurs after
each maneuver.
[0251] For example, the first maneuver increases blood flow by the
administration (e.g., local) of a vasodilator (step (a)),
monitoring ILT (step (b)), then decreasing blood flow by the
administration (e.g., local) of a vasoconstrictor (step (c)), then
monitoring ILT (step (d)). Steps b and d may be concurrent with
steps (a) and (c).
[0252] A number of physiological challenges can be used to enhance
testing of vascular performance. Typically such challenges are
controllable, predetermined maneuvers that result in changes to
blood pressure, blood flow or blood velocity. For instance, ILT can
be measured in the pretibial region before and after the subject
has been standing for 15 min or longer. Prior or after such a
maneuver, the subject's leg can be raised above the level of the
subject's chest, for instance at an angle of about 30.degree. or
greater to reduce blood pressure in the leg. The leg can be
maintained in this position for 15 min, 30 min, or longer.
Monitoring can optionally occur continuously during this maneuver.
ILT is typically remeasured in the same location. If non-elevated,
baseline ILT is markedly greater than the ILT with leg elevation,
the result is suggestive of a venous disorder, such as incompetent
venous valves. If ILT is unchanged or has only slightly decreased
with leg elevation, especially at shorter time frame of elevation,
the result suggests that a disorder other than incompetence of
venous valves or venous insufficiency is responsible for the
patient's capillary related edema, such as hepatic failure.
[0253] Another potential maneuver to change blood flow or pressure
is application of a tourniquet to an extremity. ILT will be
measured prior to application of the tourniquet as well after, for
instance at about 15 minutes, 30 minutes, and 1 hour after
application of the tourniquet. Time intervals can be changed
depending on the clinical situation, such as the age of the subject
or suspected medical condition (e.g., to prevent deleterious side
effects). Tourniquet pressure may be adjusted so that the
superficial veins, such as the greater saphenous vein, are
occluded. Communicating veins and deep veins, however, typically
remain open. With occlusion of superficial veins, both healthy
subjects as well as subjects with malfunction of vascular
performance will develop capillary related edema of the extremity
measured as an increase in ILT. The amount of capillary related
edema and resultant measured ILT, however, will be larger in
subjects with incompetent valves of the communicating veins and the
deep veins, since venous drainage is even further impaired by the
presence of valvular incompetence.
[0254] Additional maneuvers with application of a tourniquet or
other devices can be performed at multiple different sites and with
the extremity positioned above the level of the right atrial heart
chamber, at the level of the right atrial heart chamber, and below
the level of the right atrial heart chamber. For instance, the
increase in blood flow (or blood pressure) in step (c) or (a)
occurs with either 1) the tibial region elevated at a level
approximately above the heart of the subject, 2) the tibial region
at approximately the same level as the heart of the subject or 3)
the tibial region located at a level approximately below the heart
of the subject. The elevation changes in an appendage region (e.g.,
tibial region) can be induced by tilting the examination table to
induce changes in appendage blood pressure. A tourniquet can be
applied optionally to reduce blood flow. Differential effects of
blood flow versus blood pressure can be evaluated using such
combination maneuvers and applied to determining the type of
impairment of vascular performance. Blood flow alterations are
generally related to capillary impairments and arteriole
impairments. Blood pressure alterations are generally related to
venous impairments, as well as arteriole impairments. Evaluations
of particular subjects can be cross verified to place greater
clinical certainty on the diagnosis.
[0255] Additionally, maneuvers can be performed or modified using
physiological challenges such as a fluid challenge with isotonic
saline or using drug-induced manipulations. Other maneuvers can
also be applied such as local administration of a vasodilator,
invasive tamponade, gravitational challenge, rapid changes in
distal limb blood pressure, and shunting (artificial and
natural).
[0256] Other maneuvers can be used to diagnose malfunction of
vascular performance of the arterial tree. ILT can be measured in
the pretibial region prior to administration (preferably local
administration) of vasoactive substances that preferentially affect
the arterial system, such as hydralazine or tolazoline. ILT can
then be remeasured at various time intervals after drug
administration, e.g. 30 minutes, 1 hour and 2 hours later. A
significant decreases in ILT after drug administration, i.e. a
decrease in capillary related edema owing to improved peripheral
perfusion, is indicative of a disorder of the arterial tree such as
atherosclerosis. Bilateral difference can also indicate whether
different branches of the tree are more or less impaired. If ILT
remains unchanged, other conditions such as venous insufficiency
are likely to account for the capillary related edema.
[0257] The presented maneuvers are only exemplary. One skilled in
the art can easily apply many other maneuvers that can be used to
diagnose the presence and severity of malfunction of vascular
performance. ILT measured in patients can be compared to normal
reference values for each provocative maneuver in the various
anatomic regions obtained in age, sex, race, and weight-matched
controls and can also be compared to the contralateral side.
[0258] In another embodiment of the invention, ultrasound
measurements of ILT and capillary related edema can be used to
predict the possibility of venous thrombosis. Traditionally, venous
thrombosis is diagnosed using conventional venography after
intravenous injection of iodinated contrast media, Doppler
ultrasound interrogation of the veins, or magnetic resonance
angiography. Conventional venography is invasive and as such is
hampered by multiple, even fatal, side effects such as contrast
reaction. Conventional venography, Doppler ultrasound, and MR
angiography require advanced technical skills for image acquisition
as well as subsequent interpretation. Typically, these techniques
can only be performed by trained physicians. Venous thrombosis, in
particular deep venous thrombosis, is associated with high
morbidity and mortality. Frequent complications include pulmonary
embolism and cardiorespiratory arrest. Venous thrombosis reduces or
interrupts local blood flow resulting in venous stasis with
increased hydrostatic gradient across capillary cells. It often
occurs in patients after surgery, stroke, catheter treatments or
trauma. The increased hydrostatic gradient across capillary cells
will drive fluid from the capillary into the tissue with resultant
capillary related edema.
[0259] Capillary related edema secondary to venous thrombosis can
be diagnosed using ultrasound measurements of ILT. The presence of
venous thrombosis can be suggested, if ILT is elevated and
particularly elevated beyond a certain threshold value. Threshold
values can be defined based on the contralateral, healthy
extremity. Threshold values can also be defined on the basis of
reference values for healthy age, sex, weight, and race matched
control subjects in a given anatomic location. The percent change
in ILT per unit time can also provide diagnostically useful
information about presence or absence of venous thrombosis as well
as chronicity of thrombosis which is a diagnostic dilemma for the
other techniques. Ultrasound measurements of ILT have several
unique advantages over Doppler ultrasound interrogation of the
venous structures and conventional venography and magnetic
resonance angiography. Specifically, unlike the other techniques,
ultrasound measurements of ILT do not require high technical skills
for diagnosing the presence of venous thrombosis. The technique is
simple and can be performed by an untrained physician, a nurse, or
the patient.
[0260] In one embodiment, patients at risk for venous thrombosis,
e.g. patients with previous venous thrombosis or patients with
coagulopathies, may perform the test by themselves using a
dedicated hand-held device. The device can store results of ILT
measurements and compare them to previous measurements. If the
measured ILT has increased significantly when compared to previous
measurements, an alarm such as a bell, a flashing light, or a
message will be generated by the device and the patient will be
asked to repeat the measurement. If the repeat measurement confirms
the increase in ILT, the device can generate a message informing
the patient to consult his physician who may then confirm the
result with another diagnostic test and/or initiate medical or
surgical treatment.
[0261] Ultrasound measurement of ILT may also be used to
differentiate disorders or malfunction of vascular performance from
other diseases such as cardiac, renal or hepatic disorders.
Capillary related edema induced by malfunction of the vascular
system may be more prominent at distal sites, such as the foot and
calf. While capillary related edema induced by compromised hepatic
function, for instance, may induce a more uniform increase at
proximal and distal sites. Similarly, capillary related edema
induced by malfunction of the vascular system may preferentially
affect dependent body regions (regions subjected to fluid
accumulation due to gravity), while capillary related edema induced
by compromised hepatic function may induce a more homogeneous
increase in ILT in dependent and non-dependent body portions
(regions not subjected to fluid accumulation due to gravity).
Furthermore, unlike capillary related edema induced by compromised
hepatic function, capillary related edema induced by malfunction of
the vascular system may be anatomically limited to the region with
impaired vascular performance. Often additional diagnostic tests of
vascular performance, as well as hepatic, cardiac and renal
function, can be used in parallel with the methods described herein
to cross correlate findings for improved differential diagnosis and
enhances diagnosis based on integrative assessments of patient
physiological function. Multi-site monitoring can also assist in
pinpointing the abnormality.
[0262] In another embodiment of the invention, longitudinal
ultrasound measurements of ILT, optionally in conjunction with
maneuvers to change blood flow or pressure, can be used to monitor
and quantify a response to a treatment of vascular performance. In
subjects with a malfunction of vascular performance, ILT may be
measured with ultrasound prior to initiation of a new treatment
regimen, e.g. topical application of venoactive substances. ILT
will then be remeasured at several intervals after initiation of
treatment, e.g. 2 weeks, 4 weeks and 2 months later. If ILT has
decreased significantly when compared to the baseline value, the
result indicates that treatment is effective and should be
continued. If ILT is not significantly changed, the result is
indicative of treatment failure and treatment should be changed. In
this fashion, longitudinal ultrasound measurement of ILT and
assessment of capillary related edema can be used (a) to improve
subject management and improve the patient's quality of life, and
(b) to decrease health care costs by identifying ineffective
treatment modalities and discontinuing them early. Medical
treatments will typically include cardiovascular agents. Such
measurements will be particularly important with subjects diagnosed
with hypertension or diabetes.
[0263] Another particularly interesting aspect of testing vascular
performance relates to the effect of weightlessness and gravity on
the physiology of mammals, particularly humans. Continuous
monitoring of air and space traveling subjects is a desirable
feature of the invention. For air travel, particularly fighter
pilots that are subjected to intense G-forces, continuous
monitoring of ILT can be applied. Optionally, fluid shifts can be
part of a feedback system that would increase externally applied
pressure to tissues using a flight suit with a mechanical pressure
means. For space travel ultrasound monitoring of ILT can indicate
critical times to take precautionary measures to minimize fluid
shifts or changes in vascular performance.
[0264] Depending on the clinically relevant time period for these
applications, ultrasound measurements of ILT may be performed at a
single time point, at time intervals of at least about 15 minutes,
at time intervals of several days, or at time intervals of several
weeks. Additionally, diagnostic information may be enhanced by
measuring ILT prior to and after maneuvers or physiological
challenges. Presence of a vascular disorder or malfunction of
vascular performance can be diagnosed using ultrasound measurement
of ILT at a single time point. If ILT in a given anatomic location,
such as the pretibial region, is elevated above the reference value
(e.g. that of age, sex, race, or weight-matched controls), presence
of a malfunction of vascular performance is suggested. This is a
particularly strong diagnosis if the subject has no clinical or
laboratory findings or diagnosis indicating an underlying cardiac,
renal, hepatic or other non-vascular disorder.
[0265] Tests of vascular performance can be conducted using either
A scan or B scan devices. For dedicated systems for tests of
vascular performance A scan is preferred. Typically, such devices
can detect a 15% or less change in interstitial layer thickness.
Preferred embodiments for detecting ILT for this application can be
ascertained by examining other embodiments of the invention
described herein. Preferably, the ultrasound probe is adapted to
measure interstitial layer thickness. Preferably, the monitoring
can detect about a 1% or more change in leg diameter arising from
changes in interstitial layer thickness.
[0266] Another aspect of the present invention is the assessment of
vascular performance in disorders with pathologically increased
capillary permeability. Pathologically increased capillary
permeability can be observed in a large number of disorders such as
bacteremia, bums, electric injury, exposure to systemic toxins,
poisoning, or sepsis. Increased capillary permeability is another
cause of capillary related edema. Ultrasound measurements of ILT
provide information on (a) the presence of capillary related edema
in patients with pathologically increased capillary permeability,
(b) the severity of capillary related edema, (c) response to
treatment of pathologically increased capillary permeability or
response to treatment of the underlying condition, and (d) changes
in capillary permeability due to physiologic or pharmacologic
interventions.
[0267] Presence of capillary related edema can be diagnosed in
patients with pathologically increased capillary permeability, if
ILT at a given anatomic site such as the pretibial region is
elevated above a reference value (e.g. that of age, sex, race, or
weight-matched controls). The severity of the pathologic increase
in capillary permeability can be assessed using ultrasound
measurements of ILT. Slightly elevated values of ILT when compared
to an age, sex, race, and weight-matched healthy reference
population indicate a mild increase in capillary permeability. High
ILT values at a given anatomic site are indicative of a severe
increase in capillary permeability. A severe increase in capillary
permeability can lead to intravascular volume depletion and
hypovolemia with resultant shock and possible cardiorespiratory
arrest. The risk of severe intravascular volume depletion and
hypovolemia in patients with pathologically increased capillary
permeability can be assessed by comparing ultasound measured ILT
with reference values of healthy control subjects and by analyzing
changes in ILT of the individual patient longitudinally over
time.
[0268] Patients who are being treated medically for disorders
resulting in pathologically increased capillary permeability can be
monitored using ultrasound measurements of ILT. ILT is measured
with ultrasound prior to initiation of therapy. ILT is then
remeasured at several intervals after initiation of treatment. A
decrease in ILT during medical treatment indicates a decrease in
abnormal capillary permeability either secondary to successful
treatment of the underlying condition or of abnormal capillary
permeability. If ILT does not change signficantly during treatment,
treatment of the underlying condition or of increased capillary
permeability is ineffective and another therapeutic approach should
be chosen.
[0269] Multiple new drugs, hormones, tissue and blood factors, and
other substances are currently being developed that can alter
capillary permeability. These include but are not limited to tumor
necrosis factor, vascular endothelial growth factor, and substance
P. Additionally, other treatments such as hyperthermia and
radiation therapy are available that can modulate capillary
permeability. Ultrasound measurements of ILT provide a diagnostic
gauge to evaluate changes in capillary permeability in subjects
treated in such fashion. If ILT increases, the increase is an
indication of increased capillary permeability. Conversely,
decreases in ILT indicate decreased capillary permeability,
possibly due to modulation of the capillary endothelial wall. The
amount of change in ILT provides a quantitative measure for the
amount of change in capillary permeability induced by the
treatment. Such information is clinically extremely useful in
evaluating new therapies that can decrease or, if clinically
desirable, increase capillary permeability.
[0270] In another embodiment of the invention, increased capillary
permeability can be measured directly by injecting intravenously
ultrasound contrast agents, e.g. particles carrying microbubbles,
of sizes large enough not to cross normal capillary endothelial
membranes but small enough to cross capillary endothelial membranes
with pathologically increased permeability. Once such an agent has
crossed the endothelial membrane, it will alter local tissue
echogenicity. These changes in echogenicity reflect the degree of
capillary permeability and can be used to evaluate or quantitate
the amount of capillary leakiness. Such measurements alone or in
combination with ultrasound measurements of ILT, possibly before
and after reducing or increasing blood flow or pressure, can
provide assist in diagnosing between capillary related edema due to
oncotic affects versus capillary permeability effects. Such
clinical insights into the pathophysiological mechanisms of various
diseases and disorders with pathologically increased capillary
permeability or capillary related edema can be used to guide
therapy.
6.0 Methods and Devices for Evaluating Cardiac Performance
[0271] Heart failure can often lead to decreased cardiac output or
increased systolic and/or diastolic pressures that induce systemic
effects. Among these systemic effects is edema, especially
capillary related edema. Capillary related edema due to heart
failure can lead to deleterious systemic effects, such as tissue
ischemia, capillary breakdown, and, in extreme instances, necrosis
of tissue subjected to prolonged or sudden ischemia.
[0272] Current methods of evaluating cardiac performance focus on
direct measurements of cardiac function. Methods include
auscultation, EKG, myocardial scintigraphy, exercise stress test
(e.g., EKG measurements in the absence or presence of exercise),
other forms of stress test (e.g. EKG or myocardial scintigraphy
after injection of dipyridamole, adenosine, or other cardiac drugs)
catheter related techniques (e.g. right heart catheterization such
as Swan-Gantz catheter methods, wedge pressures, and cardiac output
and flow studies, left heart catheterization, and measurements of
ejection fraction) and imaging techniques (e.g., MRI, CT, and
ultrasound). While such techniques enjoy a large measure of success
in many subjects, these techniques focus in on the heart, rather
than on the heart as an integrated component of the circulatory
system or as a key component in the physiological process of
regulating fluid balance. Currently, no techniques are available
for evaluating cardiac performance as a component of systemic fluid
balance.
[0273] The inventors, for the first time, present a method of
evaluating cardiac performance associated with, or as a function
of, capillary edema or interstitial fluid balance. Because heart
function is intimately associated with, and modified by, systemic
effects, it can be advantageous to test for, or monitor, capillary
related edema. The present invention offers a number of advantages
that can reduce health care costs, improve patient quality of life
and provide for more reproducible and facile tests of cardiac
function. Testing for capillary related edema or monitoring ILT can
provide early signs of cardiac failure. Testing for capillary
related edema or monitoring ILT can also be combined with current
techniques of cardiac function to provide a powerful diagnostic
tool that evaluates the heart both as an isolated component and as
an integrated component of maintaining fluid balance. Described
herein for the first time are a number of techniques that alter
cardiac function and monitor its affect on fluid balance, both
short and long-term effects of dynamic cardiac performance can be
evaluated.
[0274] Heart failure refers to the pathophysiologic state in which
an abnormality of cardiac function is responsible for the failure
of the heart to pump blood at a rate commensurate with the
requirements of the metabolizing tissues and/or in which the heart
can do so only from an abnormally high filling pressure. Without
providing a limiting mechanism by which the invention operates, the
inability to pump a sufficient amount of blood per unit time or a
compromised cardiac output can lead to capillary related edema.
Because tissues may receive insufficient blood flow in the early
stages of heart failure, capillary related edema can occur due to a
variety of effects including ischemic tissue damage, increased
afterload, capillary breakdown due to an increase in tissue
metabolites, or tissue acidosis. By testing for capillary related
edema or monitoring ILT, early signs of heart failure can be
detected prior to or during compensatory adjustment of heart
function, which can ultimately lead to irreversible and often
deleterious effects on heart muscle. Once the heart attempts to
compensate for insufficient blood flow to the systemic tissue by
pumping more blood less efficiently, the ventricular performance
begins to decline and capillary related edema can actually
intensify.
[0275] Multiple myocardial and non-myocardial disorders and
conditions can lead to heart failure. These include, but are not
limited to, myocardial infarction, myocardial ischemia, myocardial
infections, arrhythmias, valvular dysfunction, hypoxia, cardiotoxic
substances, pericardial effusion, hypertension, recent initiation
of a .beta.-blocking agent, and discontinuation of antihypertensive
agents, cardiovascular drugs, diuretics, or anticoagulants. Such
heart disorders can lead to abnormally high filling pressures that
can result in systemic increases in capillary pressure.
[0276] Right heart failure causes an increase in venous pressure
and venous distension in the superior and inferior vena cava and
the peripheral venous system with resultant venous stasis and
elevated intracapillary pressures. Elevated capillary pressure
increases the hydrostatic gradient for fluid movement out of the
capillaries and the elevated pressure increases the capillary
permeability to large molecular weight molecules. Either condition
or both can lead to capillary related edema.
[0277] Left heart failure can cause decreased renal perfusion
resulting in decreased glomerular filtration and urinary excretion,
as well as fluid retention. Patients in whom the left ventricle is
mechanically overloaded or weakened develop dyspnea and orthopnea
as a result of pulmonary vascular congestion and, ultimately,
pulmonary edema. When left heart failure is more chronic and has
existed for months and years, patients will often develop ankle
edema, congestive hepatomegaly, or systemic venous distension, i.e.
signs and symptoms of right heart failure, even though the abnormal
hemodynamic burden was initally placed on the left ventricle. This
is in part the result of secondary pulmonary hypertension and
resultant right-sided heart failure but also because of the
persistent retention of salt and water.
[0278] Ultrasound measurements of ILT can be used to (a) diagnose
presence of capillary related edema in patients with heart failure,
(b) assess the severity of capillary related edema in patients with
left and right ventricular failure, and (c) monitor response to
treatment of heart failure, e.g. with positive inotropic or
chronotropic drugs or diuretics.
[0279] The presence and severity of capillary related edema can be
assessed in patients and can lead to the early diagnosis of
progressive heart failure. For instance, if ILT at a given anatomic
site such as the anterior tibial region is elevated above the
reference value of a healthy reference population (e.g., an age,
sex, race, or weight-matched healthy reference population) heart
failure is implicated. Typically, the patient will then be
subjected to additional tests of cardiac function either separately
or in conjunction with ILT measurements. Slightly elevated values
of ILT can be compared to historic records of the same patient or
when compared to a healthy reference population (e.g., an age, sex,
race, and weight-matched healthy reference population) may indicate
mild heart failure. High values of ILT values at a given anatomic
site are indicative of more advanced and severe heart failure.
Changes in cardiac function can be assessed by longitudinal or
continuous monitoring of ILT at different anatomic sites. Often,
the patient will be suspected of having a medical condition that
compromises heart function or is need of heart function
testing.
[0280] In another embodiment of the invention, ultrasound
measurements of changes in ILT over time can be used to diagnose
progression of heart failure from a compensated to a decompensated
state. Such information is clinically useful in many situations,
e.g. hospitalized patients after myocardial infarction with heart
failure or patients with chronic heart failure. For example, if ILT
increases above a certain threshold value, this change can be
indicative of decompensation of cardiac function which can indicate
a serious threat to the patient's life. Threshold values can be
defined by comparing measured ILT at a given time point with the
patient's baseline ILT, e.g. ILT measured at the time of hospital
admission or at the time of a previous outpatient visit. Threshold
values can also be defined by comparing measured ILT at a given
time point with the patient's baseline ILT and/or normal reference
values of ILT (e.g. ILT values in an age, sex, race, or
weight-matched healthy reference population). ILT can be measured
continuously or in an intermittent fashion, e.g. every 30 minutes
or at intervals greater than 1, 2, 5, and 24 hours. Threshold
values in evaluating changes in ILT can also be based on the
calculation of the slope of the curve of ILT plotted against time
or of the slope of the curve of change in ILT plotted against time.
The slope of the ILT-time-curve or the .DELTA.ILT-time-curve can
yield useful diagnostic information on progression of heart failure
from a compensated to a decompensated state. One skilled in the art
will readily recognize substitute methods and equations for
assessing changes in ILT.
[0281] By monitoring such changes in ILT, systemic effects of
cardiac performance can be assessed continuosly or during
clinically relevant time periods. Unlike other cardiac monitoring
techniques, such as EKG methods, ILT changes provide an assessment
of the ability of cardiac performance to adequately maintain
systemic tissue perfusion. For instance, continues EKG monitoring
may provide information concerning damaged heart tissue, or
comprised electrical conduction, however, the clinician can only
infer the systemic effects of such compromised heart function. In
the present invention, the monitoring of compromised heart function
provides additional information on the heart's ability to supply
tissues with sufficient amounts of blood to prevent or minimize
tissue perfusion effects, such as metabolite build up, insufficient
oxygenation or insufficient nutrient delivery.
[0282] In addition, because ILT can be exquisitely sensitive in
monitoring rapid or small changes, changes in cardiac function may
be detected systemically by changes in ILT before changes in EKG or
other techniques demonstrate a clinically important change. For
example, a small change in EKG pattern might be readily detectable,
but go unnoticed. The effect of such a change on the patient's
homeostasis may often not be detected clinically. Such a change,
however, may lead to systemic effects that will complicate the
patient's homeostasis or be indicative of progressive effects
systemically. Such a small change in heart function may negatively
synergize with other bodily functions (e.g. respiratory, renal or
hepatic functions) that manifest in an increase in ILT but not a
direct measurement of cardiac function. ILT changes may occur prior
to a clinically definable intervention point based solely on a
measurement of cardiac function (e.g., EKG). Consequently, the
present invention can detect changes in cardiac function that are
useful in defining a clinical intervention point, particularly a
clinical intervention point defined in advance of changes in
cardiac function detected using measurements of cardiac function
alone.
[0283] The invention also provides for self-assessment of capillary
related edema in patients with chronic heart failure using
hand-held or automated monitoring ultrasound devices. If ILT
increases above a predefined threshold value or at an accelerated
rate exceeding a predefined range of clinically acceptable values
of change in ILT over time, the device may alert the patient and/or
the physician with an alarm such as a bell, a flashing light, or a
message indicating that the patient is at risk for decompensation
of heart failure.
[0284] In another embodiment, the invention provides for risk
assessment of pulmonary edema in patients with left heart failure.
As outlined above, patients with left heart failure will often
develop capillary related edema. The severity of capillary related
edema is directly related to the severity of heart failure. For
example, if ILT increases above a certain threshold value, this
change can indicate an increased risk for pulmonary edema or, if
high enough, can be indicative of the development of pulmonary
edema.
[0285] The slope of the curve of ILT plotted against time or change
in ILT plotted against time can also provide useful information for
assessing the risk of pulmonary edema. If the slope of the
ILT-time-curve or the AILT-time-curve exceeds a predefined value,
the patient is at increased risk for pulmonary edema. This
information is extremely useful in situations where it is difficult
to monitor the patient's cardiac function closely, e.g. during
surgery, or in situations where frequent or continuous monitoring
is required.
[0286] Another embodiment of the invention includes a method for
non-invasively estimating dynamic cardiac performance in a human,
comprising: (a) monitoring capillary related interstitial fluid
content with an ultrasound probe positioned on the skin of a human
in need of such monitoring and in a region suitable for monitoring
changes in capillary related interstitial fluid content during a
clinically relevant time period and (b) measuring capillary related
interstitial fluid content prior to and after pharmacologic
interventions, exercise, and other current and future types of
stress induction designed to evaluate cardiac performance. If ILT
is measured in conjunction with cardiac stress testing, changes in
ILT can be compared to reference values obtained from a healthy
reference population (e.g., an age, sex, race, and weight-matched
healthy reference population). Impairment of cardiac function is
diagnosed if changes in ILT exceed a predefined reference range.
Testing of dynamic cardiac performance using ultrasound
measurements of ILT prior to and after stress induction can also be
used to evaluate the patient's risk for progressing from a
compensated to a decompensated state of heart failure.
[0287] Calculations and Standards
[0288] Calculations and Standards can include those described
herein, known in the art or developed in the future. Standards can
be used to qualitatively or quantitatively compare capillary
related interstitial fluid content to a predetermined standard
value for capillary related interstitial fluid content, wherein the
comparison provides a useful diagnostic measure of cardiac
performance.
7.0 Methods and Devices for Measuring Renal Disorders and
Function
[0289] Compromised renal function can be observed with multiple
disorders, such as urinary obstruction, vasculitides, diabetes,
glomerulonephritis, interstitial nephritis, chronic pyelonephritis,
ischemic kidney damage, or, in transplant patients, transplant
malfunction, e.g. from transplant rejection. Compromised renal
function will lead to electrolyte disturbances and fluid retention
resulting in capillary related edema. The present invention can be
applied to monitoring the renal system for disorders or to
evaluating renal function. For example, the invention may be
applied (a) to diagnosing presence of capillary related edema in
patients with compromised renal function, (b) to assess the
severity of capillary related edema, and (c) to monitor a subject's
response to the treatment of compromised renal function or
capillary related edema, e.g. diuretic therapy.
[0290] Presence of capillary related edema can be diagnosed in
patients with compromised renal function, if ILT at a given
anatomic site such as the anterior tibial region is elevated above
the reference value (e.g. the values in age, sex, race, or
weight-matched controls). Ultrasound measurements of ILT provide
also information on the severity of the compromise of renal
function. Slightly elevated values of ILT when compared to a
healthy reference population indicate mild compromise of renal
function. High values of ILT values at a given anatomic site are
indicative of severe compromise of renal function. The risk of
acute renal failure and anuria can be assessed by comparing
ultrasound measured ILT with reference values of healthy control
subjects (or historic values from the same patient) and by
analyzing changes in ILT of the individual patient longitudinally
over time. To enhance distinguishing between renal failure and
compromised cardiac of vascular performance, ILT can be measured in
the face of different physiological challenges as described herein
for different organ systemsRenal function can be further assessed
by measuring ILT prior to and after physiologic challenges, such as
saline administration and/or administration of drugs such as
angiotensin converting enzyme inhibitors or antidiuretic hormone.
Reference values for changes in ILT following such physiologic
challenges and/or drug administration obtained in healthy control
subjects (e.g., age, sex, race, and weight-matched healthy control
subjects) can be compared to the change in values measured in a
patient. If the change in ILT measured in the patient differs
significantly from the change in the reference population, it is a
diagnostic indicator of compromised renal function. The difference
in change in the patient and change in the reference population is
a diagnostic gauge of the severity of impairment of renal function.
Furthermore, the rate of change of ILT post-administration of IV
saline or isoosmotic solution can give a further indication of
renal function. If ILT changes rapidly, especially in nondependent
sites, due to such maneuvers impaired renal function is
suggested.
[0291] Patients who undergo medical treatment of compromised renal
function can be monitored using aspects of the present invention.
ILT can be measured prior to initiation of therapy, e.g. diuretic
therapy. ILT can then be remeasured at several intervals after
initiation of treatment, e.g. 2 weeks, 4 weeks and 2 months later.
A decrease in ILT during medical treatment indicates improvement in
renal function and/or successful diuretic treatment. If ILT does
not change significantly during treatment, therapy is ineffective
and another therapeutic approach should be considered.
[0292] Noninvasive ultrasound measurements of ILT are particularly
advantageous when frequent monitoring of the status of kidney
function is necessary as is often the case in patients with
compromised renal function. In this setting, ultrasound
measurements of ILT may help avoid frequent blood draws for
laboratory analysis of renal function, since treatment can be
tightly monitored by following ILT. Furthermore, ultrasound
assessment of ILT in conjunction with laboratory tests and urine
output can provide a more complete and physiologic assessment of
renal function than was previously possible.
[0293] Continuous or intermittent ultrasound monitoring of ILT is
particularly useful in dialysis patients. Frequently, excess plasma
fluid is removed during dialysis, in particular hemodialysis.
However, if too much fluid is removed or fluid is removed too
rapidly, patients can develop hypovolemia with the potential for
shock and cardiorespiratory arrest. ILT can be monitored at
intervals of approximately 15 minutes for the duration of dialysis
and an observation period of 1-2 hours after dialysis. If ILT
decreases below a certain threshold value defined based on the
baseline value of the patient's ILT measured immediately prior to
dialysis or if ILT decreases at an accelerated rate greater than a
predefined maximum value of change in ILT per unit time, the device
may alert the patient and/or the physician with an alarm such as a
bell, a flashing light, or a message indicating that the patient is
at risk for hypovolemia.
[0294] Similarly, if infusion or transfusion therapy or other types
of treatment with intravenous fluid administration is performed in
renal patients as well as patients with other disorders, ultrasound
measurements of ILT can be obtained to monitor the patient's fluid
balance closely. In this setting, ILT will be measured prior to
initiation of intravenous treatment and at intervals of
approximately 15-30 minutes after initiation of therapy. If ILT
increases above a certain threshold value defined based on the
baseline value of the patient's ILT measured immediately prior to
treatment or if ILT increases at an accelerated rate exceeding a
predefined maximum range of change in ILT per unit time, fluid
administration has to be slowed down or discontinued or the patient
has to be treated with a diuretic drug in order to avoid
complications of overhydration such as pulmonary edema. Continuous
or intermittent measurements of ILT during intravenous fluid
administration can also be used to estimate the risk of pulmonary
edema.
[0295] In another embodiment of the invention, patients with
chronic compromise of renal function, e.g. patients with diabetes
mellitus or dialysis patients, can monitor ILT at home on a daily
basis using a dedicated hand-held ultrasound device. The device can
store results of ILT measurements and compare them over a period of
several months. If the measured ILT has increased significantly
when compared to previous measurements, an alarm such as a bell, a
flashing light, or a message will be generated by the device and
the patient will be asked to repeat the measurement. If the repeat
measurement confirms the increase in ILT, the device can generate a
message informing the patient to consult his physician who may then
intensify medical treatment.
[0296] Ultrasound monitoring of ILT can also be used to monitor
renal transplant function both in the early postoperative period as
well as days, weeks, months, and years after successful
transplantation. ILT measurements can be used to identify
transplant complications such as acute or chronic rejection and
other forms of transplant compromise.
8.0 Methods and Devices for Measuring Hepatic Disorders and
Function
[0297] Compromised hepatic function is a common cause of capillary
related edema. The liver is an important site of biomolecule
metabolism and synthesis, such as protein synthesis of albumin.
Plasma albumin is the most abundant circulating protein. Albumin
contributes significantly to the plasma colloid osmotic pressure.
One of the clinically most important derangements in protein
synthesis is the development of hypoalbuminemia and
hypoproteinemia. This results largely from reduced hepatic
synthetic activity due to decreased number of hepatocytes as well
as decreased function of hepatocytes. Although synthetic activity
may also be reduced as a result of a decrease in dietary supply of
amino acids, compromised hepatic function and hepatic failure is
the most important cause for hypoalbuminemia and
hypoproteinemia.
[0298] The present invention is ideally suited for measuring
capillary related edema resulting from compromised hepatic
function. As hepatic function deteriorates, hypoalbuminemia and
hypoproteinemia will increase resulting in a decrease in plasma
colloid osmotic pressure and an increase in capillary related edema
and ILT. Ultrasound measurements of ILT can be used (a) to diagnose
the presence of capillary related edema in patients with
compromised hepatic function, (b) to differentiate capillary
related edema resulting from compromised hepatic function from
other causes of edema, and (c) to monitor response to treatment of
capillary related edema in patients with compromised hepatic
failure.
[0299] Capillary related edema induced by compromised hepatic
function may induce a relatively uniform increase in ILT at
proximal and distal sites, while capillary related edema induced by
malfunction of vascular performance may preferentially affect
distal sites. Similarly, capillary related edema induced by
compromised hepatic function may induce a relatively uniform
increase in ILT in both dependent (regions subjected to fluid
accumulation due to gravity) and nondependent (regions not
subjected to fluid accumulation due to gravity) body regions, while
capillary related edema induced by malfunction of vascular
performance may preferentially affect dependent body regions or may
be limited to anatomic regions with impaired vascular performance.
Such information can be used to differentiate capillary induced
edema resulting from compromised hepatic function from that
resulting from impaired vascular performance.
[0300] Information on regional distribution of edema can be
particularly useful in patients who suffer from both impaired
vascular performance, e.g. venous insufficiency, and compromised
hepatic function. In these patients, ultrasound measurements of ILT
may be particularly advantageous since differences in regional
distribution of edema may help identify the cause of the edema and
treatment may be directed towards the primary cause of capillary
related edema. One skilled in the art can readily recognize other
methods and techniques how information on regional distribution and
accumulation of capillary related edema can be exploited to obtain
additional diagnostic information in patients with hepatic and
other disorders.
[0301] Patients who undergo medical treatment of compromised
hepatic function can be monitored using ultrasound measurements of
ILT. A decrease in ILT during medical treatment indicates
improvement in hepatic function and improved synthesis of hepatic
proteins with resultant increase in plasma colloid osmotic
pressure. In this setting, ultrasound measurements of ILT provide
an effective and cost-efficient means of assessing improvement in
hepatic function thereby obviating the need for expensive repeat
laboratory analysis of serum albumin.
[0302] Similarly, ultrasound measurements of ILT can be
advantageous in patients who have undergone liver transplantation.
During the early phase after transplantation, ILT should
continuously decrease as capillary related edema decreases and
resolves with reconstitution of normal or near normal hepatic
function. Transplant complications resulting in impaired hepatic
function, such as chronic transplant rejection, may in turn be
detected by an increase in ILT
9.0 Methods and Devices for Multisite Monitoring
[0303] The invention provides for the first time methods and
devices for multisite monitoring of different anatomical regions
either concurrently or at predetermined time intervals. Monitoring
anatomical changes during clinically relevant time periods or
continuous monitoring provide an important diagnostic tool for
detecting short or rapid changes in tissue structure, particularly
interstitial layer thickness. In contrast to previous work, the
invention is able to measure rapid changes in ILT and monitor ILT
from different anatomical regions simultaneously or within short
time frames to compare ILT from different regions.
[0304] In one aspect, the invention provides for a method of
multisite monitoring of ILT. The method comprises transmitting an
ultrasound pulse from a first ultrasound probe to a first
anatomical region and transmitting an ultrasound pulse from a
second ultrasound probe to a second anatomical region. The method
includes recording ultrasound signals from a first ultrasound probe
to a first anatomical region and recording ultrasound signals from
a second ultrasound probe to a second anatomical region. The method
also includes monitoring interstitial layer thickness from the
first and second anatomical regions. The order of the transmitting,
recording and monitoring from different regions can be sequential,
intermixed, continuous or a combination thereof or any other
sequence that permits monitoring. Typically, the method is
practiced by monitoring from the first anatomical region
concurrently with monitoring from the second anatomical region.
[0305] Transmitting steps can be sequentially performed. For
example transmitting from one probe is within about 10 seconds of
transmitting from another probe. Transmitting is usually
automatically controlled by a computational unit in a ultrasound
system or chip. The method steps often are repeated over time to
monitor changes in tissue structure. Typically, the steps of
transmitting and recording are repeated about every 30 to 600
seconds. Monitoring can be concurrent or at preselected time
periods.
[0306] The first and second ultrasound probes can be
micro-transducers, as described herein. Any other suitable probe
known in the art or developed in the future or described herein can
also be used. Often the method will include the use of three, four
or more probes. The use of multiple probes enables comparing
interstitial layer thickness from the first and second anatomical
regions or more regions. Concurrent comparisons provide valuable
information on fluid shifts in the body. By monitoring such shifts,
the clinician can address the situation with the appropriate
action. The method also includes determining the rate of change
over time of an interstitial layer thickness from two or more
anatomical regions. Such methods are particularly sensitive and
give diagnostic indications of rapid fluid shifts.
[0307] The multi-site monitoring can taken place over a variety of
time frames as described herein for various indications and other
methods. Typically, the time frame is hours to days. Often the
micro-transducers of the invention are secured to the skin for
continuous monitoring during at least about a 1 to 24 hour period.
Many anatomical regions can be used such the regions described
herein. Preferably, the anatomical region is selected from the
group consisting of the forehead region, anterior tibia region,
foot region, distal radius region, elbow region, prestemal region
and temporal bone region. Micro-transducers or other probes can be
secured to the skin over such regions for continuous monitoring
during a clinically relevant time period.
[0308] The sites listed in Table 1 and shown in FIG. 3 and 4 can
also be used in combination. By using combinations of probe sites
(i.e. multisite monitoring), fluid movement throughout the body can
be monitored. This permits monitoring fluid shifts from fluid
compartments of the body. Multisite monitoring also permits
exquisitely sensitive monitoring of physiological processes related
to capillary related edema, such as processes that either induce,
prevent or reduce capillary related edema, as well as therapeutic
treatments thereof. The invention includes multisite monitoring of
interstitial fluid during space flight. The invention includes
multisite interstitial fluid monitoring for 1) blood in either
blood vessels or blood released in a potential fluid space of the
body (e.g., the subarachnoid, subdural, epidural, or pleural space)
by a traumatic, abrupt or accidental lesion (including an aneurysm)
of a blood vessel, 2) ascites in the intraperitoneal cavity, 3)
fluid in the pleural space (e.g., pleural effusion), 4) fluid in
the fetus and 5) fluid in the pericardium, usually blood or
pericardial effusion. Different sites on the body can be used as a
clinical measure of changes in various physiological states. By
comparing values from different sites, assessment of fluid shifts
between different fluid compartments can be evaluated.
[0309] Another aspect of the invention includes a multi-probe set
that may be used for multi-site monitoring methods described
herein. The multi-probe set comprises a first ultrasound probe
comprising a first output port, the first ultrasound probe adapted
for continuous or in situ monitoring at a first anatomical region
and a second ultrasound probe comprising a second output port, the
second ultrasound probe adapted for continuous or in situ
monitoring at a second anatomical region. The set can include an
ultrasound system to concurrently process first signals from the
first ultrasound probe and second signals from the second
ultrasound probe. Systems with more probes can also be used. Each
probe in the set can be adapted for a particular anatomical region
or indication. For example, the anatomical region can be selected
from the group consisting of the forehead region, anterior tibia
region, foot region, distal radius region, elbow region, presternal
region and temporal bone region. Preferably, the ultrasound probe
is a micro-transducer adapted for monitoring interstitial layer
thickness. Additional probes can be added to the system or supplied
as a kit with multi-probes that includes directions for use and
appropriate packaging. The multi-probe set, for example, can
include a third ultrasound probe comprising a third output port,
said third ultrasound probe adapted for continuous or in situ
monitoring at a third anatomical region. The multi-site methods, as
well as multi-site probe sets, may be used with other methods known
in the ultrasound art, such as Doppler based measurements, speed of
sound measurements, imaging measurements (including ultrasound
imaging for surgical procedures (e.g., trocar assisted surgery)),
echogenicity measurements and ultrasound measurements using
contrast reagents.
10.0 Ultrasound Probes for in Situ Measurments
[0310] The invention provides for the first time micro-transducers
for ultrasound measurements and imaging. Typically, the
micro-transducers are adapted for either monitoring capillary
related ILT or capillary related edema, usually on the skin in a
predetermined anatomical region. As described herein, the
micro-transducers are typically small about 10 to 20 mm.sup.2 or
less in surface area, not hand-held but rather attachable to the
skin surface, and light weight. Preferably, micro-transducers are
isolated and not connected to an ultrasound system or display by a
conductive wire, as described herein. In use, the micro-transducers
are usually secured to the skin of a subject for continuous
monitoring of the interrogated region.
[0311] The size and shape of the micro-transducer can be sculpted
to maximize the ability of the micro-transducer to detect the
desired signals in a particular anatomical region. In the case of
monitoring capillary related ILT, the size of the micro-transducer
is generally considerably smaller than the anatomical region to be
interrogated. As the size of the cross sectional area of the
micro-transducer increases, a larger area is monitored, which in
some applications is desirable because a greater surface area can
produce better signal averaging. If the micro-transducer surface,
however, is larger than the anatomical region to be interrogated
the signal quality will diminish. A smaller cross sectional area
also increases the selectivity of interrogation to a specific area.
Consequently, micro-transducer size is generally tailored to fit a
particular anatomical region. In some applications it will also be
desirable to have a micro-transducer that specifically interrogates
a smaller region in order to improve sensitivity. In some
anatomical regions, such as the tibial region, a focused
interrogation, in terms of surface area, can permit more sensitive
measurements. Typically, the ultrasound micro-transducer has a
surface area of no more than about 3 cm.sup.2, preferably about 3
cm2, and more preferably about 2 cm.sup.2.
[0312] The micro-transducer may also be adapted to snugly fit a
particular anatomical region. While a flat, planar and relatively
stiff micro-transducer is desirable in many applications and easy
to manufacture, other shapes and flexibility properties find
application with the present invention. Micro-transducers may be
disposed with a curved surface to either aid in capturing a better
ultrasound recording or aid in securing the micro-transducer to the
skin or both. For instance, in the anterior tibial region, a
micro-transducer can be slightly curved to aid in fixing the
micro-transducer to the skin of the leg or to aid in providing a
better geometric arrangement for transmitting or receiving signals.
The crystals of the micro-transducer may only be disposed over a
portion of the micro-transducer surface. Micro-transducers may be
disposed with a flexible housing or surface to permit the
micro-transducers to be slightly "bent." The flexible nature of the
micro-transducers preferably allows the housing or surface to be
bent and the induced bend to be maintained, especially in
embodiments where the micro-transducers may be contoured to a
particular skin surface. In other embodiments, a flexible
micro-transducer housing that returns to its original shape are
preferred for applications where the surface needs not to be
contoured but the micro-transducer might be subjected to accidental
mechanical deformation by either the subject or the operator.
Plastics known in the plastic art can be used for either
application. Shortest reflective distance techniques can also be
applied to accommodate varying angles that may be induced by
non-planar micro-transducer surfaces.
[0313] The micro-transducer interrogation frequency can be selected
to match the interrogated tissue. As the interrogation frequency of
the micro-transducer decreases, generally, the ability to resolve
reflective surfaces at deeper depths improves. At fairly deep
interrogation depths (e.g., greater than about 20 to 30 mm) shorter
frequency micro-transducers are desirable (e.g., about 5 to 15
MHz). Even shorter frequency micro-transducer, are desirable for
interrogating particularly thick tissues (e.g., extremely thick
appendages or large subjects), such as 0.5 to 3 MHz
micro-transducers.
[0314] As the tissue thickness increases, a relatively small change
in ILT (e.g., about 0.5 mm) will become a smaller percentage of
total ILT. This can lead in some instance to decreases in the
signal-to-noise ratio and make it more difficult to determine ILTs
at deep interrogation depths. In such instances, as well as others,
it will be desirable to provide a tunable micro-transducer that can
transmit multiple micro-transducer frequencies. The
micro-transducer can then either be adjusted by the operator to use
the best frequency for the interrogation depth selected or the
micro-transducer or the ultrasound system to which it is
electrically coupled can automatically adjust the micro-transducer
to the best frequency. For instance the micro-transducer can be
designed with four ultrasound sources with different basic
frequencies and the micro-transducer or the ultrasound system to
which it is connected can provide a micro-circuit to switch to the
appropriate ultrasound source based on the type or quality of
signals being received. Preferred frequencies include about 1, 3
and 5 MHz.
[0315] A higher micro-transducer frequency, in general, will
improve micro-transducer interrogation of shallow interrogation
depths (e.g., about 1 to 30 mm). Generally, micro-transducers above
18 MHz are preferred (e.g., about 20 to 30 MHz) for shallow
interrogation depths. Most of the micro-transducers with these
frequencies are for monitoring capillary related ILT in anatomical
regions where bone is very close to the skin, such as in small, and
often thin, subjects (particularly younger subjects) and in the
head or the cranium. Even in the tibial regions, however, where
bone can be relatively close to the skin, especially in thin legged
subjects, other interrogation frequencies will be desirable.
Consequently, it will be desirable to match micro-transducer
frequency to the tissue depth or anticipated depth of interrogation
to improve the sensitivity of monitoring or testing.
[0316] Generally, micro-transducers can be constructed that are
extremely sensitive. Micro-transducers can typically detect
percentage changes in capillary related ILT on the order of about
10 percent or higher, preferably about 5 percent or higher, and
more preferably about 1 percent or higher. Consequently, with
shorter clinically relevant time periods it is desirable to provide
high sensitivity micro-transducers in order to detect small changes
in ILT over time. Such micro-transducers are particularly
applicable to multi-site monitoring, continuous monitoring, and
critical care monitoring.
[0317] Typically, a micro-transducer can measure changes in a
capillary related ILT as small as about 0.2 to 1.0 mm. Smaller and
larger changes in ILT can also be measured. Preferably, a universal
micro transducer can measure changes in capillary related ILT
across a broad range of thicknesses of about 0.5 to 50 mm, more
preferably about 0.2 to 80 mm and most preferably about 0.2 to 120
mm. Preferably, an anatomical region specific micro transducer can
measure changes in capillary related ILT across a selective range
of thicknesses at a specific interrogation depth range. Such
micro-transducers can measure changes in thickness of about 0.2 to
30 mm at an interrogation depth of about 1 to 50 mm, about 0.4 to
50 mm at an interrogation depth of about 2 to 75 mm and about 1 to
50 mm at an interrogation depth of about 2 to 100 mm.
[0318] One aspect of the invention includes a compact
micro-transducer for in situ ultrasound measurements, comprising:
at least one ultrasound crystal in acoustic communication with an
acoustic coupling material, an ultrasound crystal holder adapted
for securing the acoustic coupling material to a surface of an
object or subject for in situ ultrasound measurements, and an
electrical coupling electrically connecting the at least one
ultrasound crystal and to an ultrasound output or recording system.
The electrical coupling is disposed to allow the micro-transducer
to be secured for in situ ultrasound measurements. Typically, the
micro-transducer uses a plurality of crystals. A small number of
crystals is often desirable to reduce weight and mass if circuitary
is included in the micro-transducer. Preferably, a computer chip is
included in the micro-transducer to facilitate signal transmission,
reception or processing, or a combination thereof. The electrical
connections, housing and micro-transducer materials can also be
selected to reduce weight. Micro-transducer weights generally range
between 5 and 150 grams, although larger and smaller
micro-transducers can be used as well. Preferably, the
micro-transducer is light to reduce pressure on the skin for
continuos monitoring. Micro-transducer weights are preferably about
50 grams or less and more preferably about 25 grams or less. The
micro-transducer can also be adapted for continues monitoring
applications in the skin. The time of continuous monitoring will
vary depending on the clinically relevant time period. In some
embodiments the acoustic coupling material and the ultrasound
crystal holder are flexible.
[0319] Micro-transducers can be secured to skin using any means
compatible with ultrasound transmission and detection. Typically,
the micro-transducer can be lightly and securely taped to the skin
using standard adhesive tape or adhesives that can provide for both
secure attachment to the skin, as well as acoustic coupling as
shown in FIG. 5A and B. Although securely fastened to the skin, the
pressure of the micro-transducer should be minimized to avoid
artifacts. In the initial minutes of monitoring signals may vary
due to short term skin effects or pressure effects. Such effects
can be minimized or avoided by using biocompatible or
hypoallergenic materials and minimum skin pressure. In some
embodiments, the micro-transducer can include a separate
positioning frame, generally only abut 10 to 20 percent larger than
the micro-transducer, that holds the micro-transducer. As shown in
FIG. 6, the frame 620 can have extending members 640 that can be
secured to the skin and away from the interrogation site in order
to reduce artifacts associated with probe placement. The structure
of the frame can resemble a spider, where the body of the frame 620
secures the micro-transducer 600 and the legs of the positioning
frame 630 secure the frame to the skin application site. Such
spider embodiments of the positioning frame are particularly useful
for securing the micro-transducer to an appendage region either by
taping the legs or adjusting the legs to interlock. The positioning
may be disposable and optionally include a sterile film disposed in
the frame so as to provide a sterile micro-transducer surface.
Acoustic coupling materials can be applied to either side of the
film to enhance acoustic communication. The positioning frame can
also include other fastening systems known in the art, such as
velcro.
[0320] Alternatively the micro-transducer can be secured with
adhesive coating. The adhesive coating can be applied to the skin
of the subject or as part of the micro-transducer. Preferably, when
acoustic coupling materials are applied to the skin, such as a gel,
an adhesive can be included in the acoustic coupling materials to
secure the micro-transducer.
[0321] In another embodiment the ultrasound crystal holder is
adapted to attach to a securing member that secures an appendage of
the human and secures the ultrasound crystal holder. This
embodiment can immobilize the appendage and/or the
micro-transducer. The acoustical coupling material can be secured
in acoustical contact with the surface of the skin. An acoustic
coupling gel can be optionally applied between the surface of the
skin and the acoustical coupling material.
[0322] A micro-transducer can transmit signals that it receives to
an ultrasound system for display or processing. Typically, a
micro-transducer is electrically coupled to a system. Preferably, a
light weight wire for transmitting electrical signals to an
ultrasound computational unit is used. A micro-transducer can also
be coupled with an infrared coupler to an ultrasound computational
unit. More preferably, a micro-transducer is coupled using a radio
frequency coupler that transmits signals to an ultrasound
computational unit. Radio frequency and infrared coupling offers a
number of advantages including reducing the weight of the
micro-transducer by not requiring wires, permitting greater
movement capabilities for either the subject or operator, and
remote sensing.
[0323] Another aspect of the invention includes a micro-transducer
comprising an acoustic surface acoustically coupled to an
ultrasound source, wherein the acoustic surface and the ultrasound
source are disposed in a frame adapted for directly or indirectly
securing the micro-transducer to a skin. Typically, the
micro-transducer is adapted for monitoring interstitial thickness.
Preferably, the micro-transducer has surface area of about 3
cm.sup.2 or less. Preferably, the micro-transducer is about 1 cm or
less in thickness. To eliminate the inconvenience and weight of
wiring to the micro-transducer the micro-transducer can transmit
signals to an ultrasound system using infrared or radio frequency
signals. The micro-transducer can be disposable. The
micro-transducer can be sterile and further comprises a covering to
protect the unit from contamination. The micro-transducer can also
be connected to an ultrasound system with a coupling means for
transmitting signals as known in the art or developed in the
future.
[0324] Micro-transducers of the invention do not include ultrasound
probes adapted for Doppler measurements in vessels and other
ultrasound probes adapted for positioning on the surface of a body
cavity.
EXAMPLES
General Materials and Methods
[0325] The following materials and methods are exemplary of the
materials and methods that can be used to achieve the results
described herein. One skilled in the art will readily recognize
substitute materials and methods.
[0326] In vitro and in vivo ultrasound measurements were performed
using an Ultramark 9 HDI ultrasound system (Advanced Technologies
Laboratories ("ATL"), 22100 Bothell Everett Hwy, Bothell, Wash.
98041-3003). All examinations were performed using a 5 MHz linear
array transducer manufactured by ATL. An acoustic coupling gel was
applied to the transducer surface and the object to be examined in
order to reduce the impedance mismatch between the transducer
surface and the object surface, usually skin. Data were acquired in
B-scan mode. Two-dimensional gray-scale images of the various
tissue/edema layers were obtained. Images were displayed on a
computer monitor attached to the scanner hardware and capable of
displaying the full gray scale range. Distance measurements were
performed by saving a representative image displaying the various
tissue layers, e.g. skin, subcutaneous fat and bone, on the display
monitor. A trained physician identified the various tissue
interfaces visually and placed cursors manually at the probe/skin,
soft-tissue/bone, and other interfaces. Software provided with the
ultrasound scanner was then used to calculate the distance between
the calipers. All measurements were expressed in mm.
[0327] To maintain the anatomic location of the selected sites, a
dye was used to mark the sites on the skin of the human subjects.
Similarly, in the in vitro experiments, a dye was used to mark the
measurement site on the external tissue surface.
Example 1
Ultrasonographic Measurement of Tissue Thickness in an In Vitro
Model of Capillary Related Edema
[0328] In order to evaluate the accuracy of ultrasonographic
measurements for detecting edema and measuring interstitial fluid,
experiments were performed with a sample of porcine muscle tissue
creating a model of capillary related edema. Ultrasound
measurements were correlated to results of anatomic examination.
Ultrasonographic measurements were performed in a large piece of
muscle tissue obtained from the gluteal region of a pig. The tissue
was cut into thin sections using a rotating electric blade.
[0329] Two fluid-filled polymer film bags that were approximately 7
mm-thick when fully filled were prepared for insertion between the
cut, separated muscle tissue layers. The surfaces of the polymer
film bags and tissue were covered with a thin film of acoustic
coupling gel. One or two bags were then placed in a sandwich-like
fashion between the superior and the inferior muscle tissue layers
thereby simulating an interposed fluid layer(s). A region of
interest was defined at the external surface of the superior muscle
tissue layer centered over the area where the bags had been placed
and the region was marked with a dye. The ultrasound transducer was
placed flush with the tissue surface in this region. An
ultrasonographic image covering the total thickness of the tissue,
defined as the distance from the outer surface of the superior
muscle tissue layer to the outer surface of the inferior muscle
tissue layer, was obtained. Both total tissue thickness as well as
the thickness of the interposed fluid layer were measured on the
image. Additionally, total tissue thickness with an empty polymer
film bag inserted that was not filled with fluid and the thickness
of the empty bag were measured with ultrasound. Total thickness and
thickness of the interposed fluid layer were also determined
anatomically with use of a ruler. The results of these experiments
are set forth in Tables 6 and 7.
[0330] Table 6 compares the total tissue thickness measured by 1)
anatomic measurement and 2) ultrasound measurements.
6TABLE 6 Anatomic Ultrasound Measurement of Total Measurement of
Total Tissue Thickness Tissue Thickness Interposed Layers (in mm)
(in mm) Empty 17 16.7 1 layer 24 23.6 2 layers 32 31.2
[0331] Table 7 compares the thickness of the interposed fluid layer
measured by 1) anatomic measurement and, 2) ultrasound
measurements.
7TABLE 7 Anatomic Measurement of Ultrasound Measurement of
Interposed Interposed Fluid Layer Interposed Fluid Layer Layers (in
mm) (in mm) Empty 0.8 0.7 1 layer 7.0 7.0 2 layers 14.0 14.3
[0332] Ultrasound and anatomic measurements were compared and the
absolute and relative error of ultrasound measurements of total
tissue thickness and of the thickness of the interposed fluid layer
were calculated. The absolute error is defined as:
AE=US-AN, [Eq. 4],
[0333] where AE is the absolute error of the ultrasound measurement
in mm, US is the ultrasonographic measurement of tissue thickness
in mm, and AN is the tissue thickness determined by anatomic
measurement in mm.
[0334] The relative error is defined as:
RE={(US-AN)/AN}.times.100 [Eq. 5]
[0335] Table 8 shows the absolute values of the absolute and
relative errors of ultrasound measurements of total tissue
thickness for different interposed fluid layers when compared to
anatomic measurement.
8 TABLE 8 Absolute Error Relative Error Interposed Layers (in mm)
(in %) Empty 0.3 1.8 1 layer 0.4 1.7 2 layers 0.8 2.5
[0336] Table 9 shows the absolute values of the absolute and
relative errors of ultrasound measurements of the thickness of the
interposed fluid layers when compared to anatomic measurement.
9 TABLE 9 Absolute Error Relative Error Interposed Layers (in mm)
(in %) Empty 0.1 12.5 1 layer 0.0 0.0 2 layers 0.3 2.1
[0337] Table 10 shows the mean absolute and mean relative errors of
ultrasound measurements averaged over all measurements of 1) total
tissue thickness and 2) thickness of the interposed fluid
layer.
10TABLE 10 Mean Absolute Error Mean Relative Error Ultrasound
Measurements (in mm) (in %) Total Tissue Thickness 0.5 2.0
Thickness of Interposed 0.1 4.9 Fluid Layer
[0338] The data generated in this in vitro model of pretibial edema
demonstrate that ultrasound is a highly accurate technique for
measuring thickness of a tissue with interposed fluid layers and
for measuring the thickness and severity of the edema layer. Based
on the results presented in Tables 6-10, the mean absolute error
for measuring total tissue thickness and measuring the thickness of
the interposed fluid layers ranged between 0.2 and 0.5 mm. Relative
errors ranged between 2 and 4.9%. These results indicate that
ultrasound techniques can monitor edema accurately and
non-invasively in vitro, as well as in vivo.
Example 2
Ultrasonographic Measurement of Thickness of Capillary Related
Edema in a Model of Venous Insufficiency and Right Ventricular
Cardiac Failure
[0339] This example documents, among other things, that ultrasound
can be used in vivo to:
[0340] 1) document rapid interstitial fluid shifts,
[0341] 2) detect presence or progression of capillary related
edema, e.g., capillary related edema secondary to impairment of
cardiac or vascular function and
[0342] 3) monitor presence or modulation of capillary related edema
as a result of therapeutic intervention.
[0343] Two healthy male volunteers aged 36 and 34 years were
studied. Distances between the knee joint space and the medial
malleolus of the right calf were measured in each individual. The
following landmarks were defined and marked in the right calf along
the anterior aspect of the tibia:
[0344] 1.) anterior aspect of the proximal third of the tibia,
[0345] 2.) anterior aspect of the mid-tibia,
[0346] 3.) anterior aspect of the distal third of the tibia,
and
[0347] 4.) medial aspect of the medial malleolus.
[0348] Measurement sites were marked on the skin with a pen. The
circumference of the extremity was measured at these sites using a
tape measure in both volunteers. Ultrasound measurements were then
obtained at these sites. In the medial malleolus, the most
protuberant portion was selected for scanning. A baseline
measurement of tissue thickness was obtained at all four sites in
both individuals prior to intervention. Individuals were in an
upright and standing position before and during the experiments.
Tissue thickness was defined as the distance from the probe/skin
interface to the soft-tissue/bone interface. The soft-tissue/bone
interface was prominently displayed on the B-scan images as a
bright, echogenic reflector.
[0349] After a baseline was established, a tourniquet was applied
to the distal thigh as a controllable maneuver to reduce blood
flow. The tourniquet was sufficiently tight to retard venous
drainage. Arterial pulses in the region of the posterior tibial and
dorsalis pedis artery were, however, intact and preserved.
Ultrasound measurements of tissue thickness were repeated at each
site 15 min, 30 min, and 1 hour after application of the
tourniquet. The tourniquet was removed after 1 hour and
measurements were repeated at each site 30 min and 1 hour after
release of the tourniquet.
[0350] In addition to the ultrasound measurements of capillary
related edema, a trained physician examined both volunteers
clinically for visual or palpatory evidence of edema at each time
interval, i.e. prior to application of the tourniquet, 15 min, 30
min, and 1 hour after application of the tourniquet, as well as 30
min and 1 hour after removal of the tourniquet. Edema was
clinically evaluated at the mid-tibial site by visual inspection
and manual palpation. Using standard clinical techniques (see Bates
et al., J. B. Lippincott, 1995), edema was subdivided into 5
grades:
[0351] I.) absent,
[0352] II.) slight,
[0353] III.) mild,
[0354] IV.) moderate, and
[0355] V.) severe.
[0356] One skilled in the art can readily recognize that the
techniques described herein can be applied to measuring changes in
interstitial fluid in any other body region as well as in other
living organisms in vivo.
[0357] Table 11 shows the ultrasound measurement of the thickness
of the pretibial tissue/capillary related edema layer in the region
of the proximal third of the tibia for different time intervals
after application of the tourniquet.
11TABLE 11 Ultrasound Measurements of Thickness of Duration of
Pretibial Tissue/Capillary Related Edema Layer Impaired Venous in
the Proximal Third of the Tibia (in mm) Drainage (in hr) Subject 1
Subject 2 0* 3.0 3.4 0.25 3.1 4.8 0.5 4.4 5.1 1 5.5 5.5 *measured
immediately prior to application of tourniquet.
[0358] Table 12 shows the ultrasound measurement of the thickness
of the pretibial tissue/capillary related edema layer in the region
of the mid-tibia for different time intervals after application of
the tourniquet.
12TABLE 12 Ultrasound Measurements of Thickness of Duration of
Pretibial Tissue/Capillary Related Edema Layer Impaired Venous in
the Mid-Tibia (in mm) Drainage (in hr) Subject 1 Subject 2 0* 2.3
2.3 0.25 2.3 4.0 0.5 2.9 3.8 1 4.0 4.5 *measured immediately prior
to application of tourniquet.
[0359] Table 13 shows the ultrasound measurement of the thickness
of the pretibial tissue/capillary related edema layer in the region
of the distal third of the tibia for different time intervals after
application of the tourniquet.
13TABLE 13 Ultrasound Measurements of Thickness of Duration of
Pretibial Tissue/Capillary Related Edema Layer Impaired Venous in
the Distal Third of the Tibia (in mm) Drainage (in hr) Subject 1
Subject 2 0* 2.5 3.3 0.25 2.5 4.5 0.5 3.8 4.0 1 3.5 3.8 *measured
immediately prior to application of tourniquet.
[0360] Table 14 shows the ultrasound measurement of the thickness
of the pretibial tissue/capillary related edema layer in the region
of the medial malleolus of the tibia for different time intervals
after application of the tourniquet.
14TABLE 14 Ultrasound Measurements of Thickness of Duration of
Tissue/Capillary Related Edema Layer Impaired Venous in the Region
of the Medial Malleolus (in mm) Drainage (in hr) Subject 1 Subject
2 0* 1.6 2.3 0.25 1.8 2.7 0.5 1.7 2.7 1 2.7 3.5 *measured
immediately prior to application of tourniquet.
[0361] Table 15 shows the results obtained with clinical assessment
of pretibial edema in the region of the mid-tibia for different
time intervals after application of the tourniquet.
15TABLE 15 Duration of Clinical Assessment of Impaired Venous
Pretibial Edema Drainage (in hr) Subject 1 Subject 2 0* 0 0 0.25 0
0 0.5 0 0 1 1 1 *measured immediately prior to application of
tourniquet.
[0362] Tables 16-19 present the data obtained after release of the
tourniquet.
[0363] Table 16 shows the ultrasound measurement of the thickness
of the pretibial tissue/capillary related edema layer in the region
of the proximal third of the tibia for different time intervals
after removal of the tourniquet.
16TABLE 16 Ultrasound Measurements of Thickness of Duration of
Pretibial Tissue/Capillary Related Restoration of Edema Layer in
the Proximal Venous Drainage Third of the Tibia (in mm) (in hr)
Subject 1 Subject 2 0* 5.5 5.5 0.5 4.2 4.9 1 3.6 3.9 *measured
immediately prior to removal of tourniquet.
[0364] Table 17 shows the ultrasound measurement of the thickness
of the pretibial tissue/capillary related edema layer in the region
of the mid-tibia for different time intervals after removal of the
tourniquet.
17TABLE 17 Duration of Ultrasound Measurements of Thickness of
Restoration of Pretibial Tissue/Capillary Related Edema Layer
Venous Drainage in the Mid-Tibia (in mm) (in hr) Subject 1 Subject
2 0* 4.0 4.5 0.5 3.5 3.3 1 2.9 2.4 *measured immediately prior to
removal of tourniquet.
[0365] Table 18 shows the ultrasound measurement of the thickness
of the pretibial tissue/capillary related edema layer in the region
of the distal third of the tibia for different time intervals after
removal of the tourniquet.
18TABLE 18 Duration of Ultrasound Measurements of Thickness of
Restoration of Pretibial Tissue/Capillary Related Edema Layer
Venous Drainage in the Distal Third of the Tibia(in mm) (in hr)
Subject 1 Subject 2 0* 3.5 3.8 0.5 3.4 3.5 1 3.4 3.1 *measured
immediately prior to removal of tourniquet.
[0366] Table 19 shows the ultrasound measurement of the thickness
of the pretibial tissue/capillary related edema layer in the region
of the medial malleolus of the tibia for different time intervals
after removal of the tourniquet.
19TABLE 19 Duration of Ultrasound Measurements of Thickness of
Restoration of Tissue/Capillary Related Edema Layer Venous Drainage
in the Region of the Medial Malleolus (in mm) (in hr) Subject 1
Subject 2 0* 2.7 3.5 0.5 1.4 2.3 1 1.6 2.0 *measured immediately
prior to removal of tourniquet.
[0367] Table 20 shows the results obtained with clinical assessment
of pretibial edema in the region of the mid-tibia for different
time intervals after removal of the tourniquet.
20TABLE 20 Duration of Restoration of Clinical Assessment of Venous
Drainage Pretibial Edema (in hr) Subject 1 Subject 2 0* 1 1 0.5 1 1
1 1 1 *measured immediately prior to removal of tourniquet.
[0368] Based on the data presented in Tables 11-14 and 16-19
percent change in thickness of the pretibial tissue/capillary
related edema layer was calculated for the four different sites for
measurements obtained after application and after removal of the
tourniquet. Percent increase after application of the tourniquet
was calculated as:
%
increase={(US.sub.ts-US.sub.PreTourniquet)/US.sub.PreTourniquet}.times.1-
00 [Eq. 6].
[0369] Percent decrease after removal of the tourniquet was
calculated as:
%
decrease={(US.sub.ts-US.sub.Tourniquet)/US.sub.Tourniquet}.times.100
[Eq. 7],
[0370] where is US.sub.ts is the ultrasonographic measurement of
the thickness of the pretibial tissue/capillary related edema layer
for a given time point "t" and a given measurement site.
US.sub.PreTourniquet is the thickness of the pretibial tissue/edema
layer prior to application of the tourniquet for the experiments in
which the tourniquet had been applied. US.sub.Tourniquet is the
thickness of the pretibial tissue/capillary related edema layer
prior to removal of the tourniquet for the experiments in which the
tourniquet had been removed.
[0371] The percent change in thickness of the pretibial
tissue/capillary related edema layer after application of the
tourniquet, e.g. to simulate onset of diseased state, and after
removal of the tourniquet, e.g. to simulate medical intervention
and treatment of diseased state, is shown in Tables 21 and 22 and
is averaged for both volunteers.
[0372] Table 21 shows the mean percent increase in thickness of the
pretibial tissue/edema layer from baseline (US.sub.PreTourniquet)
compared to the different time intervals after application of the
tourniquet measured by ultrasound at all four sites.
21TABLE 21 Mean Percent Increase in Thickness of Pretibial
Tissue/Capillary Related Duration of Edema Layer after Application
of Tourniquet* Impaired Venous Proximal Third of Distal Third of
Medial Malleolus Drainage (in hr) Tibia (in %) Mid-Tibia (in %)
Tibia (in %) (in %) 0.25 22.3 37.0 18.2 14.9 0.5 48.3 45.7 36.6
11.8 1 72.5 84.8 27.6 60.5 *data averaged for both volunteers.
[0373] Table 22 shows the mean percent decrease in thickness of the
pretibial tissue/capillary related edema layer from baseline
(US.sub.Tourniquet) compared to the different time intervals after
removal of the tourniquet measured by ultrasound at all four
sites.
22TABLE 22 Duration of Mean Percent Decrease in Thickness of
Pretibial Tissue/Capillary Related Restoration of Edema Layer after
Removal of Tourniquet* Venous Drainage Proximal Third of Distal
Third of Medial Malleolus (in hr) Tibia (in %) Mid-Tibia (in %)
Tibia (in %) (in %) 0.5 17.3 19.6 5.4 41.2 1 31.8 37.1 10.7 41.8
*data averaged for both volunteers.
[0374] To assess the sensitivity of the technique in relation to
the size of the leg, anatomical regions were measured. The
circumference of the calf was measured in both volunteers at each
measurement site using a tape measure. Based on measurements of the
circumference, the radius R of the calf was calculated for each
site as:
R=C/2.pi. [Eq. 8],
[0375] where C is the circumference of the calf at a given
measurement site.
[0376] Table 23 shows circumference and radius of the calf in both
volunteers for all four measurement sites.
23 TABLE 23 Calf Circumference (in mm) Radius (in mm) Anatomic Site
Subject 1 Subject 2 Subject 1 Subject 2 Prox. Third of 366 380 58.2
60.5 Tibia Mid-Tibia 334 345 53.1 54.9 Distal Third of 228 260 36.3
41.4 Tibia Medial Malleolus 250 260 39.8 41.4
[0377] Based on the data presented in Tables 21-23, percent change
in thickness of the pretibial tissue/capillary related edema layer
relative to the radius or the circumference of the calf at the
different measurement sites was calculated for measurements
obtained after application and after removal of the tourniquet.
Percent increase after application of the tourniquet relative to
the radius was calculated for each individual as:
%
Increase.sub.Edema/Radius={.vertline.(US.sub.ts-US.sub.PreTourniquet).ve-
rtline./R}.times.100 [Eq. 9].
[0378] Percent increase after application of the tourniquet
relative to the circumference was calculated for each individual
as:
%
Increase.sub.Edema/circumference={.vertline.(US.sub.ts-US.sub.PreTourniq-
uet).vertline.C}.times.100 [Eq. 10].
[0379] Similarly, percent decrease after removal of the tourniquet
relative to the radius was calculated for each individual as:
%
Decrease.sub.Edema/Radius={.vertline.(US.sub.ts-US.sub.Tourniquet).vertl-
ine./R}.times.100 [Eq. 11]
[0380] Percent decrease after removal of the tourniquet relative to
the circumference was calculated for each individual as:
%
Decrease.sub.Edema/circumference={.vertline.(US.sub.ts-US.sub.Tourniquet-
).vertline./C}.times.100 [Eq. 12]
[0381] Table 24 shows the mean percent increase in thickness of the
pretibial tissue/capillary related edema layer relative to the calf
radius averaged over both volunteers at the different time
intervals after application of the tourniquet. The method described
herein is quite sensitive, as it can detect changes in calf radius
less than about 1.0 to 1.5% of the calf radius. Larger changes of
about 5 or 10 percent or greater can also be measured as described
herein.
24TABLE 24 Mean Percent Increase in Thickness of Pretibial
Tissue/Capillary Related Duration of Edema Layer after Application
of Tourniquet Relative to Calf Radius* Impaired Venous Proximal
Third of Distal Third of Medial Malleolus Drainage (in hr) Tibia
(in %) Mid-Tibia (in %) Tibia (in %) (in %) 0.25 1.2 1.6 1.5 0.7
0.5 2.6 1.9 2.6 0.6 1 3.9 3.6 2.0 2.8 *data averaged for both
volunteers.
[0382] Table 25 shows the mean percent increase in thickness of the
pretibial tissue/capillary related edema layer relative to the calf
circumference averaged over both volunteers at the different time
intervals after application of the tourniquet. The method described
herein is quite sensitive, as it can detect changes in calf
circumference less than about 0.2 to 0.5% of the calf
circumference. Larger changes of about 5 or 10 percent or greater
can also be measured as described herein.
25TABLE 25 Mean Percent Increase in Thickness of Pretibial
Tissue/Capillary Related Duration of Edema Layer after Application
of Tourniquet Relative to Calf Circumference* Impaired Venous
Proximal Third of Distal Third of Medial Malleolus Drainage (in hr)
Tibia (in %) Mid-Tibia (in %) Tibia (in %) (in %) 0.25 0.2 0.3 0.2
0.1 0.5 0.4 0.3 0.4 0.1 1 0.6 0.6 0.3 0.5 *data averaged for both
volunteers.
[0383] Table 26 shows the mean percent decrease in thickness of the
pretibial tissue/capillary related edema layer relative to the calf
radius averaged over both volunteers at the different time
intervals after removal of the tourniquet.
26TABLE 26 Duration of Mean Percent Decrease in Thickness of
Pretibial Tissue/Capillary Related Restoration of Edema Layer after
Removal of Tourniquet Relative to Calf Radius* Venous Drainage
Proximal Third of Distal Third of Medial Malleolus (in hr) Tibia
(in %) Mid-Tibia (in %) Tibia (in %) (in %) 0.5 1.6 1.6 0.5 3.1 1
3.0 3.0 1.0 3.2 *data averaged for both volunteers.
[0384] Table 27 shows the mean percent decrease in thickness of the
pretibial tissue/capillary related edema layer relative to the calf
circumference averaged over both volunteers at the different time
intervals after removal of the tourniquet.
27TABLE 27 Duration of Mean Percent Decrease in Thickness of
Pretibial Tissue/Capillary Related Restoration of Edema Layer after
Removal of Tourniquet Relative to Calf Circumference* Venous
Drainage Proximal Third of Distal Third of Medial Malleolus (in hr)
Tibia (in %) Mid-Tibia (in %) Tibia (in %) (in %) 0.5 0.3 0.3 0.2
0.5 1 0.5 0.5 0.2 0.5 *data averaged for both volunteers.
[0385] The results presented in Tables 11-15 and Table 21
demonstrate that ultrasound is a sensitive technique to detect
interstitial fluid shifts and quantitate the amount of interstitial
fluid. Ultrasound also appears to be extremely useful for early or
rapid detection of changes in capillary related interstitial fluid.
Significant increases in interstitial fluid can be detected as
early as 15 minutes after alteration of venous drainage. The mean
percent increase in thickness of pretibial capillary related edema
15 minutes after impairment of venous drainage was 22.3% at the
proximal tibia and 37.0% at the mid-tibia (Table 21). After 1 hour
of impaired venous drainage, the tissue thickness in the mid-tibia
measured by ultrasound had almost doubled. Clinical examination,
i.e. combined visual inspection and manual palpation, did not
detect any changes during the 15 minutes and 30 minutes observation
periods. Only a slight change (grade 1) could be detected at the 1
hour interval (Table 15). These results demonstrate that ultrasound
is substantially more sensitive than clinical examination in
detecting interstitial fluid shifts, which can be seen with venous
insufficiency and cardiac disease, as well as other disease states
and therapeutic interventions.
[0386] When the tourniquet was removed (Tables 16-20 & 22), the
model can clinically correspond to therapeutic intervention, e.g.
administration of cardiac or other drugs. Significant changes could
be observed as early as 30 minutes after removal of the tourniquet.
Thirty minutes after removal of the tourniquet, the mean decrease
in pretibial interstitial fluid layer thickness amounted to 17.3%
in the proximal third of the tibia and 19.6% in the mid-tibia
(Table 22). Clinical examination, however, showed no change even 1
hour after removal of the tourniquet confirming that clinical
examination is unreliable in assessing the presence and the amount
of edema (Table 20). These results show that, unlike clinical
examination, ultrasound, can be used for early or continuous
monitoring and quantification of the efficacy of therapeutic
interventions in medical conditions that lead to interstitial
edema.
[0387] The data presented in Tables 24-27 indicate that ultrasound
is extremely sensitive in detecting subtle shifts in interstitial
fluid. The changes in thickness of the soft-tissue/edema layer that
were detected with ultrasound ranged between 0.5 and 3.9% when
compared to the radius of the calf and between 0.1 and 0.6% when
compared to the circumference of the calf.
Example 3
Ultrasonographic Measurement of Thickness of Pretibial Edema in a
Model of Capillary Related Edema Secondary to Abnormal Colloid
Osmotic Pressure and/or Renal Failure
[0388] This example documents that ultrasound can be used in vivo
to detect subtle changes in interstitial fluid. The example shows
that changes in pretibial interstitial fluid layer thickness relate
directly to the volume of interstitial fluid. Two healthy
volunteers aged 36 and 34 years were examined with ultrasound. The
distance between the medial knee joint space and the medial
malleolus of the left calf was measured in each individual. Using
these measurements, the mid-region of the anterior tibia was
identified for ultrasound measurements. The measurement site was
marked on the skin with a pen. A baseline measurement of tissue
thickness was obtained with ultrasound at the marked site in both
individuals prior to intervention. Tissue thickness was defined as
the distance from the probe/skin to the soft-tissue/bone interface.
The soft-tissue/bone interface was prominently displayed on the
B-scan images as a bright, echogenic reflector.
[0389] The measurement site was then cleaned with iodine solution
for disinfection. A 10 cc syringe was filled with 1% Xylocaine
solution (Astra Pharmaceuticals, Westborough, Mass. 01581). A
sterile 25 Gauge needle was attached to the syringe and small
volumes of Xylocaine were injected into the pretibial soft-tissues.
The total injected volume was recorded. After each injection, an
ultrasonographic measurement of pretibial interstitial fluid layer
thickness was obtained. Injected volumes were 0.5 cc, 1.5 cc, and
2.5 cc.
[0390] Table 28 shows the ultrasound measurement of the thickness
of the pretibial edema layer in the region of the mid-tibia after
local injection of 1% Xylocaine solution for different injection
volumes.
28TABLE 28 Ultrasound Measurements of Thickness of Amount of Fluid
Pretibial Edema Layer (in mm) injected (in cc) Subject 1 Subject 2
0* 2.6 2.4 0.5 7.2 4.8 1.5 9.0 6.8 2.5 9.5 7.6 *measured prior to
injection.
[0391] Once 2.5 cc of 1% Xylocaine solution had been injected,
injection was stopped and serial ultrasound measurements of
pretibial fluid/edema layer thickness were obtained immediately
after injection, and 30 min, 1 hour, 1.5 hours, and 2 hours after
injection.
[0392] Table 29 shows the ultrasound measurement of the thickness
of the pretibial edema layer in the region of the mid-tibia for
different time intervals after injection of 2.5 cc 1% Xylocaine
solution.
29TABLE 29 Time Interval Ultrasound Measurements of Thickness of
since Injection of Pretibial Edema Layer (in mm) 2.5 cc (in hr)
Subject 1 Subject 2 0* 9.5 7.6 0.5 5.5 5.0 1 5.0 5.7 1.5 4.4 4.5
2.0 -- 4.3 *measured immediately after completion of injection; --:
not obtained.
[0393] Table 30 shows the percent decrease in thickness of the
pretibial edema layer measured by ultrasound in the region of the
mid-tibia for different time intervals after injection of 2.5 cc 1%
Xylocaine solution.
30TABLE 30 Percent Decrease in Thickness of Time Interval Pretibial
Edema Layer* since Injection Subject 1 Subject 2 (in hr) (in %) (in
%) 0.5 42.1 34.2 1 47.4 25.0 1.5 53.7 40.8 2.0 -- 43.4 *data
compared to baseline thickness measured immediately after
completion of injection; --: not obtained.
[0394] The data presented in Table 28 indicate that ultrasound is a
very sensitive technique in detecting very small changes in
interstitial fluid volume. Injection of as little as 0.5 cc
resulted in an ultrasonographic change in the thickness of the
pretibial soft-tissue/edema layer of 100% and greater. These
results demonstrate that ultrasound has very high sensitivity in
measuring subtle interstitial fluid shifts. Moreover, as seen in
Table 28, ultrasonographic measurement of pretibial interstitial
fluid layer thickness correlated well with the volume of injected
fluid. This demonstrates that ultrasonographic measurement of the
thickness of the interstitial fluid layer in the pre-tibial area as
well as potentially other anatomic regions represents a new
diagnostic parameter that relates directly to the interstitial
fluid volume. The data presented in Tables 29 and 30 show that
ultrasound cannot only be used to detect edema, but also to monitor
interstitial fluid longitudinally over time and to assess
resolution of edema, for example secondary to medical
treatment.
[0395] Publications
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[0397] All documents and publications, including patents and patent
application documents, are herein incorporated by reference to the
same extent as if each publication were individually incorporated
by reference.
* * * * *