Note: Descriptions are shown in the official language in which they were submitted.
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SYSTEMS AND METHODS FOR USING DYNAMIC VASCULAR ASSESSMENT
TO DISTINGUISH AMONG VASCULAR STATES AND FOR INVESTIGATING
INTRACRANIAL PRESSURE
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims priority to United States Provisional Application No.
60/664,295, filed March 23, 2005, and is a continuation-in-part of co-pending,
commonly
assigned United States Patent Application No. 10/442,194 filed on May 21,
2003, which is
a continuation-in-part application of United States Patent Application No.
09/966,367 filed
on October 1, 2001 (now U.S. Patent No. 6,656,122) which claims priority to
U.S.
Provisional Patent Application Nos. 60/236,661, 60/236,662, 60/236,663,
60/236,875, and
60/236,876, all filed Sep. 29, 2000, and U.S. Provisional Application Nos.
60/263,165 and
60/263,221, both filed Jan. 23, 2001. The above applications are expressly
incorporated
herein by reference in their entirety
This application is a continuation-in-part application claiming priority to co-
pending, commonly assigned United States Patent Application No. 10/442,194
filed on May
21, 2003, which is a continuation-in-part application of United States Patent
Application No.
09/966,3 67 filed on October 1, 2001 and also claims priority to United States
Provisional
Application No. 60/664,295, filed March 23, 2005. The above applications are
expressly
incorporated herein by reference in their entirety.
BACKGROUND OF THE INVENTION
Technical Field. The present invention relates generally to systems and
methods for assessing vascular health and for assessing the effects of
treatments, risk factors
and substances, including therapeutic substances, on blood vessels, especially
cerebral blood
vessels, all achieved by measuring various parameters of blood flow in one or
more vessels and
analyzing the results in a defmed matter. In addition, the present invention
further pertains to
collecting, analyzing, and using the measurement of various parameters of
blood flow in one or
more vessels to establish protocols for and to monitor clinical trials.
Further, the present
invention relates to an automated decision support system for interpreting the
values of various
parameters of blood flow in one or more vessels in assessing the vascular
health of an
individual.
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Background Information. Proper functioning of the vascular system is
essential for the health and fitness of living organisms. The vascular system
carries
essential nutrients and blood gases to all living tissues and removes waste
products for
excretion. The vasculature is divided into different regions depending on the
organ systems
served. If vessels feeding a specific organ or group of organs are
compromised, the
organs and tissues supplied by those vessels are deleteriously affected and
may even fail
completely.
Vessels, especially various types of arteries, not only transmit fluid to
various
locations, but are also active in responding to pressure changes during the
cardiac cycle. With
each contraction of the left ventricle of the heart during systole, blood is
pumped through the
aorta and then distributed throughout the body. Many arteries contain elastic
membranes in
their walls which assist in expansion of the vessel during systole. These
elastic membranes
also function in smoothing pulsatile blood flow throughout the vascular
system. The vessel
walls of such arteries often rebound following passage of the systolic
pressure waveform.
In auto-regulation, cerebral blood vessels maintain constant cerebral blood
flow by either constricting or dilating over a certain mean arterial blood
pressure range so
that constant oxygen delivery is maintained to the brain. Vascular failure
occurs when the
pressure drops too low and the velocity starts to fall. If the blood pressure
gets too high
and the vessels can no longer constrict to limit flow, then breakthrough,
hyperemia
breakthrough, and loss of auto-regulation occur. Both of these conditions are
pathologic
states, and have been described in the literature in terms of mean arterial
pressure and
cerebral blood flow velocity. But there are outliers that could not be
explained based on
that model. The failure of the model is that it relies upon systemic blood
pressure; the
pressure of blood in the brain itself is not being measured directly. The
resultant pressure
curve has an S-shaped curve.
The force applied to the blood from each heart beat is what drives it forward.
In physics, force is equivalent to mass times acceleration. But when blood is
examined on a
beat to beat, variation, each heartbeat delivers about the saine mass of
blood, unless there is
severe loss of blood or a very irregular heart rhythm. Therefore, as a first
approximation, the
force of flow on the blood at that particular moment is directly proportional
to its acceleration.
Diseased blood vessels lose the ability to stretch. The elasticity or stretch
of the blood vessel is very critical to maintaining pulsatile flow. When a
muscle is
stretched, it is not a passive relaxation. There is a chemical reaction that
happens within
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the muscle itself that causes a micro-contracture to increase the
constriction, so that when
a bolus of blood comes through with each heartbeat, it stretches the blood
vessel wall, but
the blood vessel then contracts back and gives the kick forward to maintain
flow over
such a large surface area with the relatively small organ of the heart. This
generates a
ripple of waves, starting in the large vessel of the aorta and working its way
through the
rest of the vessels. As vessels become diseased, they lose the ability to
maintain this type
of pulsatile flow.
Further, if vessels are compromised due to various factors such as narrowing
or stenosis of the vessel lumen, blood flow becomes abnormal. If narrowing of
a vessel is
extensive, turbulent flow may occur at the stenosis resulting in damage to the
vessel. In
addition, blood may not flow adequately past the point of stenosis, thereby
injuring tissues
distal to the stenosis. While such vascular injuries may occur anywhere
througliout the body,
the coronary and cerebral vascular beds are of supreme iinportance for
survival and well-
being of the organism. Narrowing of the coronary vessels supplying the heart
may decrease
cardiovascular function and decrease blood flow to the myocardium, leading to
a heart attack.
Such episodes may result in significant reduction in cardiac function and
death.
Abnormalities in the cerebral vessels may prevent adequate blood flow to
neural tissue, resulting in transient ischemic attacks (TIAs), migraines and
stroke. The blood
vessels which supply the brain are derived from the internal carotid arteries
and the vertebral
arteries. These vessels and their branches anastomose through the great
arterial circle, also
known as the Circle of Willis. From this circle arise the anterior, middle and
posterior
cerebral arteries. Other arteries such as the anterior communicating artery
and the posterior
communicating artery provide routes of collateral flow through the great
arterial circle. The
vertebral arteries join to form the basilar artery, which itself supplies
arterial branches to the
cerebellum, brain stem and other brain regions. A blockage of blood flow
within the anterior
cerebral artery, the posterior cerebral artery, the middle cerebral artery, or
any of the other
arteries distal to the great arterior circle results in coinpromised blood
flow to the neural tissue
supplied by that artery. Since neural tissue cannot survive without normal,
constant levels of
glucose and oxygen within the blood and provided to neurons by glial cells,
blockage of
blood flow in any of these vessels leads to death of the nervous tissue
supplied by that vessel.
Strokes result from blockage of blood flow in cerebral vessels due to
constriction of the vessel resulting from an embolus or stenosis. Strokes may
also arise
from tearing of the vessel wall due to any number of circumstances.
Accordingly, a
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blockage may result in ischemic stroke depriving neural tissue distal to the
blockage of
oxygen and glucose. A tearing or rupture of the vessel may result in bleeding
into the brain,
also known as a hemorrhagic stroke. Intracranial bleeding exerts deleterious
effects on
surrounding tissue due to increased intracranial pressure and direct exposure
of neurons to
blood.
Regardless of the cause, stroke is a major cause of illness and death. Stroke
is the leading cause of death in women and kills more women than breast
cancer. Currently,
more than three quarters of a million people in the United States experience a
stroke each
year, and more than 25 percent of these individuals die. Approximately one-
third of
individuals suffering their first stroke die within the following year.
Furthermore, about
one-third of all survivors of a first stroke experience additional strokes
within the next three
years.
In addition to its terminal aspect, stroke is a leading cause of disability in
the
adult population. Such disability can lead to pennanent impairment and
decreased function
in any part of the body. Paralysis of various muscle groups innervated by
neurons affected
by the stroke can lead to confinement to a wheel chair, and muscular
spasticity and rigidity.
Strokes leave many patients with no ability to communicate either orally or by
written
means. Often, stroke patients are unable to think clearly and have
difficulties naming
objects, interacting with other individuals, and generally operating in
society.
Strokes also result in massive expenditures of resources throughout society,
and place a tremendous economic burden on affected individuals and their
families. It is
estimated that the annual total costs in the United States economy alone is
over $30 billion
per year, with the average acute care stroke treatment costing approximately
$35,000. As the
population increases in age, the incidence of stroke will rise dramatically.
In fact, the risk of
stroke doubles with ever succeeding decade of life. Since the life expectancy
of the
population has increased dramatically during the last 100 years, the number of
individuals
over 50 years old has risen precipitously. In this population of individuals
living to ages
never before expected, the potential for stroke is very high indeed.
Accordingly, the fmancial
and emotional impact of cerebral vascular damage is expected to dramatically
increase during
the next several decades.
Despite the tremendous risk of stroke, there are presently no convenient and
accurate methods to access vascular health. Many methods rely on invasive
procedures,
such as arteriograms, to detennine whether vascular stenosis is occurring.
These invasive
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techniques are often not ordered until the patient becomes symptomatic. For
example,
carotid arteriograms may be ordered following a physical examination pursuant
to the
appearance of a clinical symptom. Performing an arteriogram is not without
risks due to
introducing dye materials into the vascular system that may cause allergic
responses.
Arteriograms also use catheters that can damage the vascular wall and dislodge
intraluminal
plaque, which can cause an embolic stroke at a downstream site.
Many methods and devices available for imaging cerebral vessels do not
provide a dynamic assessment of vascular health. Instead, these imaging
procedures and
equipment merely provide a snapshot or static image of a vessel at a
particular point in time.
Cerebral angiography is conventionally held to be the "gold standard" of
analyzing blood
flow to the brain. But this invasive method of analysis only provides the
shape of the vessels in
an imaging modality. To obtain the same type of flow criteria from an
angiogram as one
obtains from the present invention would entail extraordinary efforts and
multiple dangerous
procedures.
Instruments have been developed to obtain noninvasive measurements of
blood velocity in anterior arteries and veins using Doppler principles. In
accordance with
known Doppler phenomenon, these instruments provide an observer in motion
relative to a
wave source a wave from the source that has a frequency different from the
frequency of
the wave at the source. If the source is moving toward the observer, a higher
frequency
wave is received by the observer. Conversely, if the wave source is moving
away from the
observer, a lower frequency wave is received. The difference between the
emitted and
received frequencies is known as the Doppler shift. This Doppler technique may
be
accomplished through the use of ultrasound energy.
The operation of such instruments in accordance with the Doppler principle
may be illustrated with respect to Figures 1 to 4. In Figure 1, the ultrasound
probe 40 acts as
a stationary wave source, emitting pulsed ultrasound at a frequency of, e.g.,
2 MHz. This
ultrasound is transmitted through the skull 41 and brain parenchyma to a blood
vessel 42. For
purposes of illustration, a blood cell 43 is shown moving toward the probe and
acts as a
moving observer. As illustrated in Figure 2, the blood cell reflects the pulse
of ultrasound
and can be considered a moving wave source. The probe receives this reflected
ultrasound,
acting as a stationary observer. The frequency of the ultrasound received by
the probe, fl is
higher than the frequency, fo, originally emitted. The Doppler shift of the
received wave
can then be calculated. Figures 3 and 4 show the effect on a pulse of
ultrasound when blood
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flows in a direction away from the probe. In this case, the received
frequency, f2, reflected
from the blood cell, is lower than the emitted frequency fo. Again, the
Doppler shift can be
calculated.
The Doppler effect can be used to determine the velocity of blood flow in the
cerebral arteries. For this purpose, the Doppler equation used is the
following:
F _2FfVcosO
d TT
~/
where
Fd = Doppler frequency shift
Ft = Frequency of the transmitter
V = Velocity of blood flow
O= Angle of incidence between the probe and the artery
Vo = Velocity of ultrasound in body tissue
Typically, Ft is a constant, e.g., 2, 4 or 8 MHz, and Vo is approximately 1540
meters second (m/s) in soft body tissue. Assuming that there is a zero angle
of incidence
between the probe and the artery, the value of cos 0 is equal to 1. The effect
of the angle
Q is only significant for angles of incidence exceeding 30 .
In exemplary instruments, ultrasonic energy is provided in bursts at a pulse
repetition rate or frequency. The probe receives the echoes from each burst
and converts
the sound energy to an electrical signal. To obtain signal data corresponding
to reflections
occurring at a specific depth (range) within the head, an electronic
gate'opens to receive the
reflected signal at a selected time after the excitation pulse, corresponding
to the expected
time of arrival of an echo from a position at the selected depth. The range
resolution is
generally limited by the bandwidth of the various components of the instrument
and the
length of the burst. The bandwidth can be reduced by filtering the received
signal, but at
the cost of an increased length of sample volume.
Other body movements, for example, vessel wall contractions, can also
scatter ultrasound, which will be detected as "noise" in the Doppler signal.
To reduce this
noise interference, a high pass filter is used to reduce the low frequency,
high amplitude
signals. The high pass filter typically can be adjusted to have a passband
above a cutoff
frequency selectable between, e.g., about 0 and about 488 Hz.
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Many health care providers rarely have such flow diagnostic capabilities at
their disposal. For example, health care providers may be situated in remote
locations such
as in rural areas, on the ocean or in a battlefield situation. These health
care providers need
access to analytical capabilities for analysis of flow data generated at the
remote location.
Health care providers facing these geographic impediments are limited in their
ability to provide the high quality medical services needed for their
patients, especially on an
emergency basis. Further, both physicians and individuals concerned for their
own health are
often limited in their ability to consult with specialists in specific medical
disciplines.
Accordingly, a system that facilitates access of physicians in various
locations to
sophisticated medical diagnostic and prognostic capabilities concerning
vascular health is
needed. Such access would promote delivery of higher quality health care to
individuals
located throughout the country, especially in reniote areas removed from major
medical
centers.
There is also a need for a system whereby patient vascular data can be
transmitted to a central receiving facility, which receives the data, analyzes
it, produces a
value indicative of the state of vascular health, and then transmit this
information to another
location, such as the originating data transmitting station, or perhaps
directly to the health
care provider's office. This system should provide access to sophisticated
computing
capabilities that would enhance the accuracy of health care providers'
diagnostic and
prognostic capabilities concerning vascular health. This system should be able
to receive
high volumes of patient data and rapidly process the data in order to obtain
diagnoses and
prognoses of disease. Such a system could be used for diagnosis and prognosis
of any
disease or condition related to vascular health.
There is a further need for a system that facilitates the ability of a health
care
provider to conveniently and rapidly transmit vascular flow data parameters
obtained from a
patient to a location where consistent, reproducible analysis is performed.
The results of the
analysis can then be transmitted to the health care provider to facilitate
accurate diagnosis
or prognosis of a patient, to recommend treatment options, and to discuss the
rainifications
of those treatment options with the patient.
There is also a need for a system that enables health care providers to
measure the rate and type of developing vascular disease, and to recommend
interventions
that prevent, minimize, stabilize or reverse the disease.
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There is a further need for a system that enables health care providers to
predict the vascular reaction to a proposed therapeutic intervention, and to
modify the
proposed therapeutic intervention if a deleterious or adverse vascular
response is anticipated.
Physicians often prescribe therapeutic substances for patients with conditions
related to the
cardiovascular system that may affect vascular health. For example,
hypertensive patients
may be prescribed beta-blockers with the intent of lowering blood pressure,
thereby
decreasing the probability of a heart attack. Patients frequently receive more
than one
therapeutic substance for their condition or conditions. The potential
interaction of
therapeutic substances at a variety of biological targets, such as blood
vessels, is often poorly
understood. Therefore, a non-invasive method that can be used to assess the
vascular effects
of a substance, such as a tlierapeutic substance, or a combination of
therapeutic substances is
needed. A clear understanding of the vascular effects of one or more
substances on blood
vessels may prevent prescriptions of substances with undesirable and
potentially lethal effects,
such as stroke, vasospasm and heart attack. Accordingly, what is needed is a
system and
method that can be used for repeated assessment without deleterious effects of
potential
vascular effects of a substance, or combination of substances, in a patient
population during a
clinical trial. Such clinical studies may also reveal dosages of individual
substances and
combinations of substances at specific dosages that provide desirable and
unexpected effects
on blood vessels.
Furthermore, a system and method that can provide an assessment of the
vascular healtli of an individual is needed. Also needed is a system and
method that may be
used routinely to assess vascular health, such as during periodic physical
examinations.
This system and method preferably is non-invasive and provides information
concerning
the compliance and elasticity of a vessel. Also needed is a system and method
that may be
used to rapidly assess the vascular health of an individual. Such systems and
methods
should be available for use in routine physical examinations, and especially
in the
emergency room, intensive care unit or in neurological clinic: What is also
needed is a
system and method which can be applied in a longitudinal manner for each
individual so
that the vascular health of the individual may be assessed over time. In this
manner, a
problem or a disease process may be detected before the appearance of a major
cerebral
vascular accident or stroke.
In addition, there is a need for a system and method for assessing whether
treatments, risk factors and substances affect blood vessels, particularly
cerebral blood vessels,
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so that their potential for causing vascular responses may be determined. By
determining the
vascular effects of treatments, risk factors and substances, physicians may
recommend that a
patient avoid the treatment, risk factor and/or substance. Alternatively,
desirable vascular
effects of a treatment, therapeutic intervention and/or substance may result
in administration
of the treatment, therapeutic intervention and/or substance to obtain a
desired effect.
In addition, there is also needed a system and method for assessing the
efficacy of a treatment, including conducting a procedure, carrying out a
therapy, and
administering a pharinaceutical substance, in treating vascular disorders, so
that
identification of those treatments most efficacious in the treatment of
vascular disorders can
be determined and employed to restore vascular health.
As required by federal regulations, treatments, including drugs and other
therapies intended for treating individuals, have to be tested in people.
These tests, called
clinical trials, provide a variety of information regarding the efficacy of
treatment, such as
whether it is safe and effective, at what doses it works best, and what side
effects it causes.
This information guides health professionals and, for nonprescription drugs,
consumers in
the proper use of medicines. In controlled clinical trials, results observed
in patients being
administered a treatment are compared to results from similar patients
receiving a different
treatment such as a placebo or no treatment at all. Controlled clinical trials
are the only
legal basis for the United States Food and Drug Administration ("FDA") in
determining
that a new treatment provides "substantial evidence of effectiveness, as well
as confirmation
of relative safety in terms of the risk-to-benefit ratio for the disease that
is to be treated."
It is important to test drugs, therapies, and procedures in those individuals
that the treatments are intended to help. It is also important to design
clinical studies that
ask and answer the right questions about investigational treatment. Before
clinical testing is
initiated, researchers analyze a treatment's main physical and chemical
properties in the
laboratory and study its pharmacological and toxic effects on laboratory
animals. If the
results from the laboratory research and animal studies show promise, the
treatment sponsor
can apply to the FDA to begin testing in people. Once the FDA has reviewed the
sponsor's
plans and a local institutional review board - typically a panel of
scientists, ethicists, and
nonscientists that oversees clinical research at medical centers - approves
the protocol for
clinical trials, clinical investigators give the treatment to a small number
of healthy
volunteers or patients. These Phase 1 studies assess the most common acute
adverse effects
and examine the size of doses that patients can take safely without a high
incidence of side
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effects. Initial clinical studies also begin to clarify what happens to a drug
in the human
body, e.g., whether it's changed, how much of it is absorbed into the
bloodstream and
various organs, how long it is retained within the body, how the body rids the
drug, and the
effect(s) of the drug on the body.
If Phase 1 studies do not reveal serious problems, such as unacceptable
toxicity, a clinical study is then conducted wherein the treatment is given to
patients who
have the condition that the treatment is intended to treat. Researchers then
assess whether
the treatment has a favorable effect on the condition. The process for the
clinical study
simply requires recruiting one or more groups of patients to participate in a
clinical trial,
administering the treatment to those who agree to participate, and determining
whether the
treatment helps them.
Treatments usually do not miraculously reverse fatal illnesses. More often,
they reduce the risk of death but do not entirely eliminate it. This is
typically accomplished
by relieving one or more symptoms of the illness, such as nasal stuffiness,
pain, or anxiety.
A treatment may also alter a clinical measurement in a way that physicians
consider to be
valuable, for example, reduce blood pressure or lower cholesterol. Such
treatment effects
can be difficult to detect and evaluate. This is mainly because diseases do
not follow a
predictable path. For example, many acute illnesses or conditions, such as
viral ailments
like influenza, minor injuries, and insomnia, go away spontaneously without
treatment.
Some chronic conditions like arthritis, multiple sclerosis, or asthma often
follow a varying
course, e.g., better for a time, then worse, then better again, usually for no
apparent reason.
Heart attacks and strokes have widely variable death rates depending on
treatment, age, and
other risk factors, making the "expected" mortality for an individual patient
hard to predict.
A further difficulty in gauging the effectiveness of an investigational
treatment is that in some cases, measurements of disease are subjective,
relying on
interpretation by the physician or patient. In those circumstances, it's
difficult to tell
whether treatment is having a favorable effect, no effect, or even an adverse
effect. The
way to answer critical questions about an investigational treatment is to
subject it to a
controlled clinical trial.
In a controlled trial, patients in one group receive the investigational
treatment.
Those in a comparable group, the control group, receives either no treatinent
at all, a placebo
(an inactive substance that looks like the investigational drug), or a
treatment known to be
effective. The test and control groups are typically studied at the same time.
Usually, the same
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group of patients is divided into two sub-groups, with each subgroup receiving
a different
treatment.
In some special cases, a study uses a "historical control," in which patients
given the investigational treatment are compared with similar patients treated
with the
control treatment at a different time and place. Often, patients are examined
for a period of
time after treatment with an investigational treatment, with the investigators
comparing the
patients' status both before and after treatment. Here, too, the comparison is
historical and
based on an estimate of what would have happened without treatment. The
historical
control design is particularly useful when the disease being treated has high
and predictable
death or illness rates. It is important that treatment and control groups be
as similar as
possible in characteristics that can affect treatment outcomes. For example,
all patients in a
specific group inust have the disease the treatment is meant to treat or the
same stage of the
disease. Treatment and control groups should also be of similar age, weight,
and general
health status, and similar in other characteristics that could affect the
outcome of the study,
such as other treatment(s) being received at the same time.
A principal technique used in controlled trials is called "randomization."
Patients are randomly assigned to either the treatment or control group rather
than deliberately
selected for one group or the other. An iinportant assumption, albeit a
seriously flawed one,
is that when the study population is large enough and the criteria for
participation are
carefully defined, randomization yields treatment and control groups that are
similar in
important characteristics. Because assignment to one group or another is not
under the
control of the investigator, randomization also eliminates the possibility of
"selection bias,"
the tendency to pick healthier patients to get the new treatment or a placebo.
In a double-
blind study, neither the patients, the investigators, nor the data analysts
know which patients
got the investigational drug.
Unfortunately, careful definition of selection criteria for matching
participation in clinical trials has not been conventionally available.
Vascular health, and
more particularly cerebrovascular health, has been a criterion that has been
difficult, if not
impossible, to assess for possible clinical trial participants. Thus, there
remains a need in
the art for the ability to truly randomize clinical trials by choosing trial
participants with
matched vascular and cerebrovascular characteristics.
Moreover, an important aspect of clinical trials is to assess the risk of
adverse effects of a given treatment. This can be difficult for adverse
effects that manifest
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themselves only long after the short run of a clinical trial has run its
course. Unfortunately,
vascular effects, and more particularly cerebrovascular adverse effects, are
difficult, if not
impossible, to assess during the course of a clinical trial. Thus, there
remains a need in the
art for the ability to accurately assess adverse effects brought about by a
treatment upon
vascular and cerebrovascular health characteristics.
There is also needed a system and method for assessing the efficacy of a
treatment, including conducting a procedure, carrying out a therapy, and
administering a
pharmaceutical substance or combinations thereof in treating vascular
disorders, so that
identification of deleterious treatments can be determined and no longer be
prescribed.
Further, there is a need for a system and method for assessing the impact of a
treatment, including conducting a procedure, carrying out a therapy, and
administering a
pharmaceutical substance, or combinations of pharmaceutical substances, upon
vascular
health, so that the impact of a treatment which have an effect upon vascular
health can be
ascertained.
SUMMARY OF THE INVENTION
The present invention provides a solution to the above described
shortcomings by providing a system and method for assessing the vascular
health of an
individual. This system and method is inexpensive, rapid, non-invasive, and
provides
superior data concerning the dynamic function of the vasculature. Accordingly,
this system
and method may be used in a wide variety of situations including, but not
limited to,
periodic physical examinations, in an intensive care unit, in an emergency
room, in the field
such as in battlefield situations or at the scene of an emergency on the
highway or in the
country, and in a neurological clinic. The use of this system and method
enables physicians
to evaluate individuals not only for their current state of vascular health,
but also to detect
any deviations from vascular health by evaluating specific parameters of
vascular function.
In addition to use during routine physical examinations, the present system
and method may be used to evaluate individuals with the risk factors for
cerebral vascular
malfunction. Such risk factors include, but are not limited to a prior history
of stroke, a
genetic predisposition to stroke, smoking, alcohol consumption, caffeine
consumption,
obesity, hypertension, aneurysms, arteritis, transient ischemic episodes
(TIAs), closed head
injury, history of migraine headaches, prior intracranial trauma, increased
intracranial
pressure, and history of drug abuse.
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In addition to providing a system and method for evaluating individuals with
high risk factors, the present system and method also provides a mechanism for
selecting
patient groups for clinical trials and monitoring patient populations in
specific clinical groups.
For example, a patient population of individuals at high risk of stroke may be
evaluated
systematically over time to determine whether ongoing vascular changes may
indicate an
incipient cerebral vascular event, such as stroke. In this manner, it may be
possible to predict
the occurrence of a first stroke, thereby preventing the stroke. In another
embodiment, the
present invention provides a mechanism for monitoring individuals who have
experienced a
stroke.
In yet a further embodiment of the present invention, the vascular reactivity
of an individual to various substances, including but not limited to drugs,
nutrients, alcohol,
nicotine, caffeine, hormones, cytokines and other substances, may be
evaluated. Through
the use of this system and method, research studies may be conducted using
animals or
humans to evaluate the effects of various substances on the vascular system.
By performing
the noninvasive, low cost and efficient tests of the present invention,
valuable information
concerning the potential vascular effects of a substance may be collected and
assessed
before the substance is medically prescribed. Furthermore, vascular effects of
dosages of
individual substances and combinations of substances at different dosages may
be
evaluated-in selected clinical populations using the system and method of the
present
invention. Accordingly, the present invention provides a system and method for
performing
non-invasive clinical research studies to evaluate potential vascular effects
of substances, or
combinations of substances, at selected dosages and in selected patient
populations.
In another embodiment, the present invention may be applied to specific
populations of individuals who have had specific illnesses to determine
whether application
of a substance may produce undesirable effects in that population. For
example, a population
of diabetic individuals may react differently to a specific substance such as
a drug than a non-
diabetic population. Further, a population of hypertensive individuals may
react differently to
a specific substance, such as a catecholaminergic agonist drug or an ephedrine-
containing
natural extract, than a non-hypertensive population. The use of the present
invention permits
an assessment of vascular reactivity in any individual or any population,
whether it be a
population of individuals with specific diseases, conditions or prior
exposures to various
therapies.
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By means of the present invention, a method of assessing vascular health in a
human or an animal is provided. In one embodiment, this assessment method
comprises the
steps of obtaining information concerning flow velocity within a vessel;
calculating a mean
flow velocity value for the vessel; calculating a systolic acceleration value
for the vessel;
and inserting the mean flow velocity value and the systolic acceleration value
into a schema
for further analysis of the calculated values. Such schema can consist of
multiple
arrangements of such values, including but not limited to diagrams, graphs,
nomograms,
spreadsheets and databases, thereby permitting operations such as mathematical
calculations, comparisons and ordering to be performed that include the
calculated values.
In one embodiment, the assessment method may further comprise calculating
a pulsatility index. With the pulsatility index calculated, the assessment
method of is able
to plot the pulsatility index, the systolic acceleration value, and the mean
flow velocity
value for the vessel in a 3-dimensional space, wherein the plot of the
pulsatility index, the
systolic acceleration value, and the mean flow velocity value in 3-dimensional
space
produce a first characteristic value for the vessel. This first characteristic
value for the
vessel may then be compared to other first characteristic values obtained from
measurements of flow velocity collected from similar vessels from other humans
or animals
to determine whether the vessel is in an auto-regulation mode.
The assessment method may further comprise collecting information
concerning an additional variable, transforming the information into a value,
and plotting
the value in n-dimensional space together with the pulsatility index, the
systolic acceleration
value, and the mean flow velocity value to produce a second characteristic
value for the
vessel. The second characteristic value can then be compared to second
characteristic
values obtained from measurements of flow velocities collected from similar
vessels from
other humans or animals to determine whether the vessel is in an auto-
regulation mode.
The vessel of the assessment method as described above can be an intracranical
vessel. Further, the vessel can be an artery. The artery can be one that
supplies the central
nervous system. Further, the artery can be selected from the group consisting
of the common
carotid, internal carotid, external carotid, middle cerebral, anterior
cerebral, posterior cerebral,
anterior communicating, posterior communicating, vertebral, basilar,
ophthalmic, and branches
thereof.
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The information collected in the assessment method described above
concerning flow velocity can be gathered using ultrasound energy. This
gathering of flow
velocity information can furtlier be gathered by use of a Doppler probe.
The effects of a substance on a vessel can be determined by applying the
assessment method as described above both before and after administering the
substance.
This substance can be a drug. The drug may be a vasoactive drug. The substance
may be
suspected of having vascular activity.
The assessment method described above may be utilized in the instance
wherein the human or the animal is suspected of having or has a vascular
disease or a
condition that affects vascular function. The huinan or the animal can be
analyzed at a time
of normal and at a time of abnormal health.
The present invention further provides for a method of assessing vascular
effects of a treatment in a liuman or an animal. This method includes the
steps of collecting
a first set of information concerning flow velocity within a vessel;
administering the drug;
collecting a second set of information concerning flow velocity within the
vessel;
calculating a mean flow velocity value for the vessel; calculating a systolic
acceleration
value for the vessel; and inserting the mean flow velocity value and the
systolic acceleration
value into a schema for analysis of the calculated values.
The step of administering a treatment in the vascular effects assessment
method can be selected from the group consisting of administering a drug,
conducting a
procedure, and carrying out a therapy. When the administration comprises
administering a
drug, the drug may include a statin. The statin administered can include
Atorvastatin
calcium.
The steps of collecting the first set of information and collecting the second
set of
information in the vascular assessment method described above can be performed
using
ultrasound energy. More specifically, the collection steps can be performed
using a Doppler
probe.
The present invention further provides. for a method of assessing vascular
effects of a treatment in a human or an animal. The treatment can include
conducting a
procedure, carrying out a therapy, and administering a drug. This method
includes the steps
of collecting a first set of information concerning flow velocity within a
vessel; obtaining a
first mean flow velocity value before administration of the treatment;
obtaining a first
systolic acceleration value before administration of the treatment;
administering the
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treatment; collecting a second set of information concerning flow velocity
witliin the vessel;
obtaining a second mean flow velocity value following administration of the
treatment;
obtaining a second systolic acceleration value after administration of the
treatment;
comparing the first mean flow velocity value and the second mean flow velocity
value; and
comparing the first systolic acceleration value and the second systolic
acceleration value to
determine if the treatment had a vascular effect.
The method of assessing the vascular effects of a treatment as described above
may further include the steps of calculating a first pulsatility index from
the first set of
information; calculating a second pulsatility index from the second set of
information;
plotting the first pulsatility index, the first mean flow velocity value, and
the first systolic
acceleration value to produce a first characteristic value for the vessel;
plotting the second
pulsatility index, the second mean flow velocity value and the second systolic
acceleration
value to produce a second characteristic value for the vessel; and comparing
the first
characteristic value and the second characteristic value to determine if the
drug had a vascular
effect.
The step of administering a treatinent in the method of assessing vascular
effects of a treatment as described above can be selected from the group
consisting of
administering a drug, conducting a procedure, and carrying out a therapy. When
the
administration includes administering a drug, the drug can include a statin.
When a statin is
administered, the statin can include Atorvastatin calcium.
The steps of collecting the first set of information and collecting the second
set of information in the method of assessing vascular effects of a treatment
as described
above can be performed using ultrasound energy. More specifically, the
collection can be
performed by means of a Doppler probe.
The method of assessing vascular effects of a treatment as described above
may be used when the human or the animal has a risk factor for a stroke. The
human or the
animal may have received at least one medication before collecting the first
set of information.
The method of assessing vascular effects of a treatment as described above
may be used to determine if the drug may cause undesirable vascular effects in
the human
or the animal receiving the medication.
The method of assessing vascular effects of a drug as described above can be
used when the human or the animal has a vascular disease or a condition that
affects vascular
function.
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In another embodiment of the present invention, a method of assessing
vascular effects of a treatment in humans or animals is provided. The method
of accessing
the vascular effects includes assigning individual humans or animals to
different groups for
each human or animal by performing the steps of obtaining a first set of
information
concerning flow velocity within a vessel; obtaining a first mean flow velocity
value before
administration of the drug; obtaining a first systolic acceleration value
before administration
of the treatment; administering the treatment; obtaining a second set of
information
concerning flow velocity within the vessel; obtaining a second mean flow
velocity value
following administration of the treatment; obtaining a second systolic
acceleration value
after administration of the treatment; comparing the first mean flow velocity
value and the
second mean flow velocity value; comparing the first systolic acceleration
value and the
second systolic acceleration value to determine if the treatinent had a
vascular effect; and
statistically analyzing data for each individual before and after
administration of the
treatment.
The administration of the treatment in the method of assessing vascular
effects of a treatment by assigning individual humans or animals to different
groups as
described above can be selected from the group consisting of administering a
drug,
conducting a procedure, and carrying out a therapy. When the administration of
a drug is
selected, the drug may include a statin. The statin can be Atorvastatin
calcium.
The data collection step in the method of assessing vascular effects of a
treatinent by assigning individual humans or animals to different groups as
described above
can be performed using ultrasound energy. Further, the data collection step
can be
performed using a Doppler probe.
The method of assessing vascular effects of a treatment by assigning
individual humans or animals to different groups as described above can
further include
statistically analyzing data within each group before and after administration
of the
treatment.
In one embodiment, the present invention further provides for a method of
screening for adverse effects of a treatment. The screening method includes
the steps of
applying the treatment to a number of individuals; monitoring the
cerebrovascular blood
flow of such individuals after applying the treatment; and identifying adverse
effects to
cerebrovascular blood flow in such individuals arising after applying the
treatment.
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The data regarding cerebrovascular health status obtained by the screening
method of the present invention can include both the mean flow velocity value
for intracranial
blood vessels of the individuals and systolic acceleration value for
intracranial blood vessels
of the individuals. The intracranial vessels can be arteries. The arteries can
be selected from
the group consisting of is the common carotid, internal carotid, external
carotid, middle
cerebral, anterior cerebral, posterior cerebral, anterior communicating,
posterior
communicating, vertebral, basilar, and branches thereof. The data obtained may
also include
a pulsatility index.
The screening method permits quantitative data regarding the
cerebrovascular blood flow of a number of individuals to be obtained. The
quantitative data
obtained may be collected by the use of ultrasound energy. Further, a Doppler
probe can be
used to collect the data regarding cerebrovascular health status.
The screening method treatment applied can include at least one treatment
selected from the group consisting of administering a drug, conducting a
procedure, and
carrying out a therapy.
When the treatment selected is administration of a drug, the drug or
substance can be a vasoactive drug, or a drug suspected of having vascular
activity
The screening method for adverse effects of a treatment on a vessel as
described above may be applied both before and after administration of the
treatment.
The screening method for adverse effects of a treatment on a vessel as
described above may be applied on individuals suspected of having or actually
having a
vascular disease or a condition that affects vascular function.
The present invention comprises measurements of parameters of vascular
function. Specifically, the present invention uses energy including, but not
limited to,
sound energy and any form of electromagnetic energy, to determine the rate of
movement
of cells through vessels. While not wanting to be bound by the following
statement, it is
believed that red blood cells account for the majority of cells detected with
this technique.
In a preferred embodiment, ultrasound energy is utilized.
According to the present invention, a sample volume of red blood cells is
measured utilizing sound energy. Because not all blood cells in the sample
volume are
moving at the same speed, a range or spectrum of Doppler shifted frequencies
are reflected
back to the probe. Thus, the signal from the probe may be converted to digital
form by an
analog-to-digital converter, with the spectral content of the sampled Doppler
signal then
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calculated by computer or digital signal processor using a fast Fourier
transform method.
This processing method produces a velocity profile of the blood flow, which
varies over the
period of a heartbeat. The process is repeated to produce a beat-to-beat flow
pattern, or
sonogram, on a video display. The instrument can be configured to analyze
multiple
separate frequency ranges within the spectrum of Doppler signals. Color coding
may be
used to show the intensity of the signal at different points on the spectral
line. The intensity
of the signal represents the proportion of blood cells flowing within that
particular velocity
range. The information displayed on the video screen can be used by a trained
observer to
determine blood flow characteristics at particular positions within the brain
of the individual
being tested, and can be used to detect anomalies in that blood flow such as
the presence of
a blockage or restriction, or the passage of an embolus through the artery,
which introduces
a transient distortion of the displayed information. The instrument can also
include a
processing option that provides a maximum frequency follower or envelope curve
displayed
on the video screen as the white outline of the flow spectrum.
In another preferred embodiment, coherent light in the form of lasers may be
employed. In yet another embodiment, infrared or ultraviolet radiation may be
employed.
In one preferred embodiment, the system and method of the present
invention permits a determination of vascular health based on an analysis of
two blood flow
parameters, mean flow velocity and systolic acceleration.
Earlier studies have analyzed how blood velocity correlates with blood flow
to the brain. Flow is a concept different from velocity; flow is the quantity
per unit time
delivered to a certain region of the brain. This is partially dependent on
velocity.
Accordingly, the earlier studies demonstrate a one-to-one relationship between
flow and
velocity. Therefore, mean flow velocity is a very good indicator of cerebral
blood flow.
Thus, conventionally, this theory has been relied upon to determine blood flow
to the brain.
There is a second calculated number called the pulsatility index, which is the
resistance of
blood flow downstream, which others have also measured. Still, there is a need
to examine
any combination of flow parameters to assess vascular health or auto-
regulation.
In a more preferred embodiment of the present invention, transcranial
Doppler is used to obtain the velocity measurements described above.
Application of a
selected form of energy to cells within the vessels permits a calculation of
the flow rate of
the cells within the vessels. By measuring specific parameters involved in the
flow of cells
through vessels, a data analysis may be performed.
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One parameter of relevance to the present invention is mean blood flow
velocity (Vm). The value of this parameter is given by the equation
V. = Vs -Vd +Vd
3
where
Vs = peak systolic velocity, and
Vd = end diastolic velocity.
A second parameter of relevance to the present invention is the pulsatility
index (P). The value of this parameter is given by the equation
P=Vs -Vd
,
Vm
where
V,Y, = mean blood flow velocity
Vs = peak systolic velocity, and
Vd = end diastolic velocity.
Another parameter of relevance to the present invention is systolic
acceleration. This variable is determined by measuring the flow velocity at
the end of
diastole, measuring the flow velocity at peak systole, and then dividing the
difference
between these measures by the length of time between the end of diastole and
the time of
peak systolic velocity. This is an index of systolic acceleration. The value
of this
parameter is given by the equation -
14 = Vs - Vd
tS - td
where
ts = time at VS and td = time at Vd
Vs = peak systolic velocity, and
Vd = end diastolic velocity.
In one preferred embodiment of the present invention, a characteristic
signature for each vessel is defined by plotting the systolic acceleration
against the mean
flow velocity. With mean flow velocity plotted on the y-axis and systolic
acceleration
plotted on the x-axis, a vessel may be represented as a point on this graph.
The present invention reveals that vessels are in a state of normal auto-
regulation when their vascular state values fall within the auto-regulating
regions of the
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above described graph. A point on the graph represents a vascular state of a
vessel. It has
also been determined that when the value for an individual vessel falls within
other regions
of the graph outside the zone of auto-regulation, serious problems have either
occurred or
may be ongoing. Accordingly, the present invention permits not only a
determination of the
location of each individual vessel on such a graph, but also provides insight
into the
vascular health of a vessel in view of its deviation in distance and/or
direction from what
may be considered within the normal range of such vessels.
In another preferred embodiment of the present invention, another
characteristic signature for each vessel is defined by plotting the systolic
acceleration
relative to the mean flow velocity and the pulsatility index. With mean flow
velocity
plotted on the y-axis, pulsatility index plotted on the z-axis, and systolic
acceleration plotted
on the x-axis, a vessel may be represented as a point in this 3-dimensional
space.
The present invention further reveals that vessels are in a state of normal
auto-regulation when their values fall in certain regions of this 3-
dimensional space. The 3-
dimensional plot provides a characteristic shape representing a cluster of
points, wherein
each point represents the centroid from an individual's specific vessel. It
has further been
determined that when the value for an individual vessel falls in other regions
of the 3-
dimensional space outside the zone of auto-regulation, serious problems have
either
occurred or may be ongoing. Accordingly, the present invention permits not
only a
determination of the location of each individual vessel on such a graph, but
also provides
insight into the vascular health of a vessel in view of its deviation, either
in distance and/or
direction, from what may be considered within the normal range of such
vessels.
By means of the present invention, it has been determined that each cerebral
vessel has a characteristic state and signature represented in a 3-dimensional
graph. The
characteristic state and signature for one vessel of an individual can be
represented as a
point in the vascular state diagram, and the characteristic states and
signatures for a
population of the same vessel type can be represented by a set of points
described as a
mathematical centroid. This value for the centroid is obtained through those
analyses
described above. The present invention reveals that individual vessels,
especially individual
cerebral vessels, display a clustering of points in 3-dimensional space that
defines a shape.
It is to be understood that other variables may be employed in addition to
systolic
acceleration, mean flow velocity, and pulsatility index to provide additional
information
concerning specific vessels. When additional variables are employed, the data
may then be
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plotted in a 4-dimensional or more dimensional space. Analysis of a specific
centroid value for a
vessel from an individual, in terms of its distance from the mean value for
centroids for the same
named vessel taken from other individuals, provides a basis for assessing the
significance of
differences between normal and abnormal vessels and enables predictions of
abnormality.
Accordingly, the present invention is not limited to 3-dimensional space.
Further, individual
vessels may be represented in n-dimensional space, wherein each dimension may
be a relevant
clinical parameter. For example, additional dimensions or variables may
include, but are not
limited to, age, clinical history or prior stroke, risk factors such as
obesity, smoking, alcohol
consumption, caffeine consumption, hypertension, closed head injury, history
of migraine
headaches, vasculitis, TIAs, prior intracranial trauma, increased intracranial
pressure, history of
drug abuse, steroid administration including estrogen and/or progesterone,
lipid deposition,
hyperlipidemia, parathyroid disease, abnormal electrolyte levels, adrenal
cortical disease,
atherosclerosis, arteriosclerosis, calcification, diabetes, renal disease,
prior administration of
therapeutic agents with vascular effects, prior administration of therapeutic
agents with effects on
the release or reuptake of norepinephine at postganglionic sympathetic nerve
endings, prior
administration of therapeutic agents with effects on the release or reuptake
of acetylcholine at
postganglionic parasympathetic nerve endings, vascular denervation, shock,
electrolyte levels, pH,
pO2, pCO2, or any combination thereof.
The present invention permits analysis of all the vessels of an individual.
These analytical methods provide an index of the vascular health of the
individuals,
especially the compliance of individual vessels. In a preferred embodiment,
the present
invention permits analysis of a vessel's ability to auto-regulate. Any such
vessel may be
analyzed provided it can be located with the device used to analyze blood
flow. Both
arteries and veins may be analyzed with the system and method of the present
invention.
Regarding arteries, both cerebral and non-cerebral vessels may be analyzed.
For example,
the common carotid, internal carotid artery, external carotid artery and other
extracranial
arteries may be evaluated. Further, analysis of the cerebral vessels of an
individual can be
performed with the system and method of the present invention, including the
vessels
contributing to the great arterial circle and their primary branches. The
present invention
further permits analysis of individual cerebral vessels from individuals in
different groups,
for example, groups within specific age ranges or at specific ages, groups
considered
healthy, groups which may fall into a clinically defined group, such as
diabetics, groups of
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individuals who share common risk factors such as obesity, groups of
individuals exposed
to similar substances, such as nicotine, or pharmaceuticals, such as beta
blockers.
The present invention includes a system having the capability for a variety of
communication mechanisms such as access to the Internet that provides accurate
prediction
of the future occurrence of vascular disease, vascular disease diagnosis,
determination of
the severity of vascular disease, and/or vascular disease prognosis. The
present invention
provides one or more highly sophisticated computer-based databases trained to
diagnose,
prognose, determine the severity of and predict the future occurrence of
vascular disease,
and provide increased accuracy of diagnosis and prognosis.
The system of the present invention can operate by receiving patient vascular
data
from another location through a receiver or data receiving means, transmitting
the data into a
computer or through several computers containing vascular data for that
specific vessel or
numerous vessels in normal and/or diseased states, comparing the patient's
vascular data to the
database to produce one or more results, and transmitting the one or more
results to another
location. The other location may be a computer in a remote location, or other
data receiving
means.
In one embodiment of an automated decision support system for interpreting the
values of various parameters of blood flow in one or more vessels in assessing
the vascular
health of an individual according to the present invention, at least three
different modules are
presented, each interactive with the other. These modules include a module for
accessing data,
a module for interfacing with a user, and module for processing patient data,
or reasoning
module.
The data access module provides access and storage methods for transcranial
Doppler and clinical data inputted by a user, and for inferences from the
reasoning engine.
This data may be stored by any method known to those skilled in the art,
including but not
limited to storage on a network server, or storage in a file on a personal
computer. The data
access module is able to respond to a variety of commands, including but not
limited to a
command to initialize the module, one to retrieve patient data, a command to
save patient
data and/or graphs, a command to delete patient data and/or graphs, a command
to retrieve a
list of patients, and a command to query the database.
The user interface module performs various functions, including but not
limited to processing user input to be sent to the data access module, running
commands for
the reasoning module, querying about patient data for the data access module,
and querying
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about inference results from the reasoning module. The user interface module
may further
be designed to display patient data for at least one patient received from the
data access
module and concept instances received from the reasoning module. The user
interface
module can also be designed to display clinical and demographic data for a
patient, raw
transcranial Doppler velocimetry data, and an analysis of a patient's
hemodynamic state.
The analysis of the patient's hemodynamic state includes, but is not limited
to the condition
of each artery, any global conditions detected, and an assessment of the
patient's risk for
stroke. The user interface preferably provides a user the ability to drill
down from a
patient's assessment of the risk for stroke in order to determine how
conclusions were
reached.
The reasoning interface module performs various functions, including but
not limited to accepting commands to process patient data for inferred
concepts, searching
for instances of particular concepts or evidence of a given concept instance
in a concept
graph, and saving the concept graph or loading an old concept graph. The
reasoning
interface can be further broken down into at least two other modules - an
analysis module
for performing analysis of the data inputted, including but not limited to any
user input,
saved concepts and/or data, clinical data, and transcranial Doppler data; and
an interface
module for hiding the details of the interaction of the analysis module with
the other
modules. The interface module allows other modules to access data and concept
graphs
residing in the analysis module without exposure to the analysis interface.
Preferably, those
files created by the reasoning module are stored by the data access module.
According to the present invention, patient data includes all data derived
from transcranial Doppler readings and all clinical data. Preferably, patient
data is accessed
and stored as a single block of data for each patient, referenced by a unique
patient ID.
In one embodiment of the present invention, transcranial Doppler data and
clinical data is inputted by a user at the user interface. Once the input has
been completed,
the user can either save the data to a file for later access, or can
immediately analyze the
data before saving it. In either instance, patient data is retrieved by the
reasoning module
from the data access module. Both modules retrieve patient data based on
patient ID.
Preferably, a user is able to retrieve a list of all patients saved in a file
in order to be able to
select a particular patient's data to view, edit, or analyze. Preferably,
although not
necessary, the set of parameters sent to the data access module includes a
user ID.
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The analysis module is able to provide one or more classes of service. For
example, the module includes methods for commanding the analysis module,
including
commands for initializing, starting, running and stopping the module. Another
class of service
provided by the module may include methods for setting and/or retrieving
concept attribute
values.
As defined by the above described modules, the present invention is able to
provide the sequences for an automated decision support system for
interpreting the values of
various parameters of blood flow in one or more vessels in assessing the
vascular health of an
individual. These sequences include but are not limited to saving patient
data, analyzing
patient data, loading an analysis to an analysis page, and retrieving evidence
from a concept
graph.
By means of the above described modules, the present invention is able to
provide the software design for an automated decision support system for
interpreting the values
of various parameters of blood flow in one or more vessels in assessing the
vascular health of an
individual.
With the use of the above described modules, the present invention is able to
provide the use cases for an operational prototype for an automated decision
support system
for interpreting the values of various parameters of blood flow in one or more
vessels in
assessing the vascular health of an individual. These use cases, or user
interface commands,
include but are not limited to entering new patient data, loading existing
patient data,
viewing clinical data, viewing transcranial Doppler velocimetry, analyzing
patient data,
viewing analyses, and gathering the evidence behind an analysis.
In a preferred embodiment of the present invention, there is provided a
process by which the vascular health assessment can be carried out remotely,
allowing for
interrogation of a patient's vascular health at one location, while processing
the patient's
data information obtained by ultrasound measurements of the cerebral vascular
health state
from various flow parameters is done at another location. This process is
preferably
managed in a stepwise fashion using a decision matrix developed to obtain the
appropriate
data set given the patient's particular situation at the time. Therefore, the
process can be
remotely managed and the data can be remotely processed.
For example, a technician or physician would assist a patient by applying to
the patient's head an appropriate device that would obtain the necessary
transcranial
Doppler data, or alternatively, a probe would be placed at appropriate windows
on the skull
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to obtain the Doppler data. The vascular health data would then be collected
and
transmitted to another device that would perform the vascular health
assessment. The data
would then be processed and an interpretation generated, as well as potential
recommendations for additional measurements. The assessment process itself
could be
done one test at a time in batch mode, or it could be done continuously on an
online system.
The interpretation and potential recommendations can then be relayed to
another location,
this location can be any of several choices, including the location of the
patient, the location
of the health care provider, or the location where the diagnosis will be
communicated.
In executing the analysis, the analyst, e.g., a computer or assessor, would
perfonn the analysis and, preferably, do a comparison to a reference
population. The reference
population could be the group of patients evaluated that day or it could be
the population that is
appropriate in some other respect. In any case, it is important to consider
the reference
population and to have a current data set on the reference population because
the predictive
value would be affected by the underlying prevalence of individuals in that
particular reference
group.
It will be appreciated that the transmission of the vascular health
information
from the measurement device to the vascular health assessor and the
transmission of the
interpretation of vascular health to a communication location can be
accomplished through
a variety of communicationlinks, including, modem, cable modem, DSL, T1, and
wireless
transmission. The transmissions could be batch or continuous.
It will be appreciated that in a client-server informatics embodiment, some
assessment functions might reside on the client side while others would reside
on the server
side, the ratio of what is placed on each being a function of optimal
bandwidth, computer
speed and memory. Other considerations include remote transmission of the
data, either in
stepwise manner or in a batch mode, through a computational device attached to
the
ultrasound probe.
The present invention further includes a system, combined with access to the
Internet and other communication mechanisms, that provides substantially
accurate
prediction of the future occurrence of vascular disease, vascular disease
diagnosis,
determination of the severity of vascular disease, and/or vascular disease
prognosis. The
present invention further provides one or more highly sophisticated computer-
based
databases trained to interrogate, diagnose, prognose, determine the severity
of and predict
the future occurrence of vascular disease, and provide increased accuracy of
diagnosis and
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prognosis. The present invention also provides a sensitive tool to assess
subtle differences
in flow characteristics following exposure to substances such as drugs in a
clinical
environment.
The present invention may also be combined with a file system, such as an
electronic file system, so that the individual patient's vascular data file,
the results from the
analysis of vascular flow characteristics, may be stored in the patient file.
In this manner, the
health care provider or patient may have rapid access to information in the
patient file. Changes
in vascular health since previous visits to the health care provider may be
determined quickly,
thereby indicating whether vascular disease progression has changed or, if
recoinmended,
interventional strategies or therapeutics are effective. The present invention
also provides
pliysicians with the ability to rapidly advise patients concerning recommended
additional
diagnostic testing and available treatment options following receipt of
information from the
computer-based database about the prediction of the future occurrence of
vascular disease,
disease diagnosis, determination of the severity of vascular disease, and/or
vascular disease
prognosis.
It is therefore an object of the present invention to provide a new method for
assessing vascular health.
It is further an object of the present invention to provide a method for
routine
evaluation of cerebral vascular health.
Yet another object of the present invention is to evaluate the vascular health
of individuals at risk for disease.
Still another object of the present invention is to provide a method for
monitoring patients who have experienced a vascular problem, such as stroke.
Another object of the present invention is to provide a method for evaluating
the response of vessels to treatment(s), including conducting procedures,
carrying out
therapies, and administering substances.
A specific object of the present invention is to evaluate the vascular
response
to substances in individuals at risk of cerebral vascular pathology.
Yet another object of the present invention is to evaluate the vascular
response to treatment(s), including conducting procedures, carrying out
therapies, and
administering drugs which may be used in a therapeutic manner.
Another object of the present invention is to provide ongoing evaluation of
the
vascular health of patients following stroke, closed head injury, contra coup
lesions, blunt force
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trauma, transient ischemic attacks, migraine, intracranial bleeding,
arteritis, hydrocephalus,
syncope, sympathectomy, postural hypotension, carotid sinus irritability,
hypovolemia, reduced
cardiac output, cardiac arrhythmias, anxiety attacks, hysterical fainting,
hypoxia, sleep apnea,
increased intracranial pressure, anemia, altered blood gas levels,
hypoglycemia, partial or
complete carotid occlusion, atherosclerotic thrombosis, embolic infarction,
carotid
endarterectomy, oral contraceptives, hormone replacement therapy, drug
therapy, treatment
with blood thinners including coumadin, warfarin, and antiplatelet drugs,
treatment with
excitatory amino acid antagonists, brain edema, arterial amyloidosis,
aneurysm, ruptured
aneurysm, arteriovenous malformations, or any other conditions which may
affect cerebral
vessels. In addition, changes in vascular flow following aneurysm rupture can
also be
monitored.
It is another object of the present invention to evaluate drugs or other
substances suspected to have vascular activity.
Yet another object of the present invention is to evaluate drugs with
suspected vascular activity in individuals known to be at risk of vascular
disease.
Another object of the present invention is to evaluate substances, such as
drugs, suspected of having vascular activity in individuals following stroke.
Yet other object of the present invention is to provide a non-invasive method
to evaluate substances, such as drugs, suspected of have vascular activity in
individuals
with no apparent vascular problems.
Another object of the present invention is to provide a non-invasive method
to evaluate different dosages of substances, such as drugs, suspected of have
vascular
activity in individuals.
Still another object of the present invention is to provide a non-invasive
method to evaluate different combinations of substances, such as drugs,
suspected of have
vascular activity in individuals.
Yet another object of the present invention is to provide a non-invasive
method to evaluate different combinations of selected dosages of substances,
such as drugs,
suspected of have vascular activity in individuals.
A further object of the present invention is to evaluate the vascular health
of
specific vessels or vascular beds following vascular insult in another region
of the cerebral
vasculature. In this manner, the capacity of other vessels to properly auto-
regulate and
distribute collateral blood flow may be assessed.
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An advantage of the present invention is that it is not invasive.
A further advantage of the present invention is that it is rapid and
inexpensive to perform.
Another advantage of the present invention is that the characteristics of each
cerebral vessel may be established as a baseline in order to monitor the
vascular health of
the individual over time, especially during routine physical examination,
following a
vascular insult or injury, or exposure to drugs.
Yet another advantage of the present invention is that analysis of individual
vessels and their deviation from a normal value for a corresponding vessel in
another
individual may indicate specific medical conditions. Treatment of those
medical conditions
may then be evaluated with the present invention to determine whether the
treatment was
effective on the specific vessel being evaluated.
Accordingly, it is an object of the present invention to provide a system for
efficient delivery of information concerning the vascular health of an
individual.
Yet another object of the present invention is to provide a system which
health care providers can utilize to provide more precise and accurate
prediction of the
future occurrence of vascular disease, diagnosis of vascular disease,
determination of the
severity of vascular disease and prognosis of vascular disease.
An object of the present invention is to provide a system which health care
providers can utilize to provide more precise and accurate prediction,
diagnosis and
prognosis of vascular diseases, and associated treatment options, such
diseases including,
but not limited to, cerebrovascular disease.
It is further an object of the present invention to provide a computer-based
database that may receive vascular flow data from an input device, interpret
the vascular
flow data in view of existing data for the same vessel or vessels in normal or
disease states,
produce a value(s) that provides useful information concerning vascular health
and then
optionally transmit the information to another location.
It is yet another object of the present invention to provide a system that
delivers to the health care provider a complete patient report within a short
time interval.
It is another object of the present invention to provide point-of-care
analytical capabilities linked through communication means to local or remote
computers
containing a computer-based database that may receive vascular flow data from
an input
device, interpret the vascular flow data in view of existing data for the same
vessel or
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vessels in normal or disease states, produce a value that provides useful
information
concerning vascular health, and then optionally transmit the information to
another location.
Such output values may be transmitted to a variety of locations including the
point-of-care
in the health care provider's office that transmitted results from the point-
of-care flow
measuring device. The present invention provides accurate, efficient and
complete
information to health care providers using in order to enhance affordable and
quality health
care delivery to patients.
These, and other objects, features and advantages of the present invention
will
become apparent after a review of the following detailed description of the
disclosed
embodiments.
BRIEF DESCRIPTION OF THE FIGURES
Figures 1 to 4 are illustrative views showing the manner in which ultrasonic
pulses are applied to the head of an individual to obtain information on the
velocity of blood
flowing in an intracranial blood vessel;
Figures 5a to 5d provide schematic representations of transcranial Doppler
ultrasound analyses in which velocity is indicated on the y-axis and time is
provided on the
x-axis;
Figure 6 is a schematic representation of a 2-dimensional nomogram in
which mean flow velocity is indicated on the y-axis and systolic acceleration
is provided on
the x-axis;
Figure 7 shows the nomogram of Figure 6, as well as areas of the nomograin
which indicate deviations from normal, auto-regulatory conditions;
Figure 8 shows a schematic representation of a 3-dimensional nomograin;
Figures 9a to 9d show schematic representations of a 2-dimensional
nomogram in which mean flow velocity is indicated on the y-axis and systolic
acceleration
is provided on the x-axis of a patient who presented with slight feelings of
unsteadiness;
Figure 10 is a block diagram of an illustrative system architecture of a
preferred embodiment of the invention;
Figure 11 is a concept graph of left extracranial frontal artery concepts of a
preferred embodiment of the invention;
Figure 12 is a concept graph of left intracranial frontal artery concepts of a
preferred embodiment of the invention;
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Figure 13 is a concept graph of riglit intracranial frontal artery concepts of
a
preferred embodiment of the invention;
Figure 14 is a concept graph of right extracranial frontal artery concepts of
a
preferred embodiment of the invention;
Figure 15 is a concept graph of posterior artery concepts of a preferred
embodiment of the invention;
Figure 16 is a concept graph of collateral flow concepts of a preferred
embodiment of the invention;
Figure 17 is a concept graph of parameter concepts of a preferred
embodiment of the invention;
Figure 18 is a concept graph of stroke candidate concepts of a preferred
embodiment of the invention;
Figure 19 is a concept graph of small vessel disease concepts of a preferred
embodiment of the invention;
Figure 20 is a concept graph of data concepts of a preferred embodiment of
the invention;
Figure 21 is a concept graph of arterial condition concepts of a preferred
embodiment of the invention;
Figure 22 is a concept graph of arterial condition concepts of a preferred
embodiment of the invention;
Figure 23 is a block diagram for an application service provider architecture
of a preferred embodiment of the invention;
Figure 24 is an illustration of a logon page of a preferred embodiment of the
invention;
Figure 25 is an illustration of a user startup window of a preferred
embodiment of the invention;
Figure 26 is an illustration of a transcranial Doppler data window of a
preferred embodiment of the invention;
Figure 27 is an illustration of a hemodynamic analysis window of a preferred
embodiment of the invention;
Figure 28A depicts the global vascular status of a subject basedon data from a
number of vessel at the initial onset of symptoms associated with an increase
of intracranial
pressure;
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Figure 28B depicts a shift in vascular status in individual vessels as the
subject's symptoms have progressively worsened;
Figure 28C depicts a dramatic globalized shift in vascular status of
individual vessels after the subject's symptoms have increase to the point of
requiring
hospitalization;
Figure 28D depicts a return of vascular status to a near normal state after
treatment to decrease intracranial pressure;
Figure 29 demonstrates that traditional blood flow tests would not detect the
intracranial pressure changes occurring in the subject that were observable
using
transcranial based dynamic vascular assessment;
Figure 30 is a schematic representation of correlated MFV and SA data from
the two series of subjects presented in Table 8;
Figure 31 is a bar graph of Trendelenberg PI data for the two series of
subjects from Table 8;
Figure 32 is a schematic representation of correlated PI and SA data from the
two series of subjects presented in Table 8; and
Figures 33 depicts 19 intracranial vessel segments available for evaluation by
the invention;
Figures 34 depicts 19 intracranial vessel segments available for evaluation
by the invention
Figure 35 depicts the effects on flow at vascular regions proximate to a
region of
stenosis and the resultant changes in flow behavior;
Figure 36 depicts a plot of a DCI (also referred to as DWI) versus time and
the
threshold level drop in the DCI (also referred to as DWI) that indicates the
onset of
vasospasm;
Figure 37 depicts a plot of DFI versus DCI (also referred to as DWI) over time
following a vascular event and the transition between hyperemia and vasospasm;
and
Figure 38 depicts IVUS measured effects on flow at vascular regions proximate
to a
stenotic vessel region and the resultant changes in flow behavior.
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DETAILED DESCRIPTION OF THE INVENTION
This application expressly incorporates herein by reference in their entirety
co-pending and commonly assigned United States Patent Applications Nos.
09/966,366,
09/966,368, 09/966,360, and 09/966,359, all filed on October 1, 2001.
The present invention provides a novel system and method for evaluating
vascular health. This invention may be used to evaluate individuals for risk
of cerebral
vascular disease. The invention may also be used for evaluating vascular
health in individuals
following a vascular insult or stroke. The present invention may also be used
for assessing
the effects of individual substances and combinations of substances on
cerebral vessels.
As noted above, the present invention comprises measurements of
parameters of vascular function. Specifically, the present invention uses
energy including,
but not limited to, sound energy or any form of electromagnetic energy, to
determine the
rate of movement of cells through vessels. In a preferred embodiment,
ultrasound energy is
utilized.
Description of Flow Data Acquisition and Analysis
According to the system and method of the present invention, a noninvasive
instrument is utilized to obtain measurements of blood velocity in
intracranial arteries and
veins using Doppler principles. Since body movements such as vessel wall
contractions are
detected as "noise" in the Doppler signal scattering ultrasound, a high pass
filter is used to
reduce these low frequency, high amplitude signals. The high pass filter
typically can be
adjusted to have a passband above a cutoff frequency selectable between 0 and,
e.g., 488 Hz.
Because not all blood cells in the sample volume are moving at the same speed,
a range or spectrum of Doppler-shifted frequencies are reflected back to the
probe. Thus, the
signal from the probe may be converted to digital form by an analog-to-digital
converter, and
the spectral content of the sampled Doppler signal calculated by a computer or
digital signal
processor using a fast Fourier transform method. This processing method
produces a velocity
profile of the blood flow, which varies over the period of a heartbeat. The
process is repeated
to produce a beat-to-beat flow pattern, or sonogram, on a video display. The
instrument can be
configured to analyze multiple separate frequency ranges within the spectrum
of Doppler
signals. Color coding may be used to show the intensity of the signal at
different points on the
spectral line. The intensity of the signal will represent the proportion of
blood cells flowing
within that particular velocity range. The information displayed on the video
screen can be
used by a trained observer to determine blood flow characteristics at
particular positions within
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the brain of the individual being tested, and can detect anomalies in such
blood flow, for
example, the possible presence of a blockage or restriction, or the passage of
an embolus
through the artery which introduces a transient distortion of the displayed
information. The
instrument can also include a processing option which provides a maximum
frequency
follower or envelope curve which is displayed on the video screen as the white
outline of the
flow spectrum.
Figures 5a to 5d illustrate Doppler waveform definitions provided by a
system according to the present invention. Figure 5a is a graph, providing the
results of a
transcranial Doppler ultrasound analysis in which velocity is indicated on the
y-axis and
time is provided on the x-axis. The peak systole velocity is indicated in the
Figure.
Figure 5b is a graph providing the results of a transcranial Doppler
ultrasound analysis in which velocity is indicated on the y-axis and time is
provided on the
x-axis. The end diastole velocity is indicated in the Figure.
Figure 5c is a graph providing the results of a transcranial Doppler
ultrasound analysis in which velocity is indicated on the y-axis and time is
provided on the
x-axis. The mean flow velocity is indicated in the Figure.
Figure 5d is a graph providing the results of a transcranial Doppler
ultrasound analysis in which velocity is indicated on the y-axis and time is
provided on the
x-axis. The systolic upstroke time or acceleration is indicated in the Figure.
The present invention provides a plot on a two-dimensional graph of the
systolic acceleration and mean flow velocity. Referring back to the auto-
regulation model,
one now fmds that the auto-regulation curve more accurately describes the
vascular health of
a system. Addition of a third dimension, the pulsatility index, provides a
three-dimensional
plot, that gives a much more accurate look at how blood is flowing in that
particular
subsection of the vessel. Thus, the present invention combines different blood
flow
parameters to give a nomogram or a graphical representation of how blood is
flowing within
the brain itself.
The present invention permits the interrogation of cerebral vessels to
determine the state of vascular health or disease by examining the flow
parameters for a
vessel and comparing then with a normal value. This also permits a clinical
trial to be run
since an entire population can be interrogated with this relatively quick and
noninvasive
technique, thereby obtaining readings not only for each individual patient,
but also for the
population. In addition, one can monitor the flow dynamics of the group as a
whole over
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time and determine if either the non-treatment group becomes more diseased or
if the
treatment group stabilizes, improves, or has a lower rate of disease, all
determined by
clinical measurements. Thus, the present invention provides a very sensitive
blood flow
interrogation tool for the brain to determine whetlier a drug is going to be
safe or effective
for use in patients.
Using an ultrasound probe, one can determine the velocity of blood. The
relationship of the velocity of blood at two separate points within the points
will provide the
flow parameters of the present invention. Analyzing the relationship of the
three parameters
in each individual segment in relationship to a normal population can
determine the state of
disease of that particular segment of vessel. Further, assessing all the
segments of vessels in
the brain as a whole, one can determine the interconnections and the states of
abnormal flow
into whole regions of the brain. The more regions of the brain at risk, the
higher the stroke
risk for the patient. Thus, the present invention permits one to quantitate
stroke risk in
patients.
According to the present invention, values for various transcranial Doppler
sonography measurements for a number of patients are collected into a database
of the present
invention. The database may further provide ranges of transcranial Doppler
sonography
measurements for various cerebral arteries. Figure 6 provides a nomogram of
the values for
mean flow velocity on the y-axis and systolic acceleration on the x-axis for
transcranial
Doppler ultrasound analyses of the ophthalmic artery in a number of
individuals. It will be
appreciated that the majority of the data points are grouped in the lower left-
hand side of the
nomogram. These represent the values corresponding to vascular health. The
aberrant points
found in the upper left-hand portion of the nomogram correspond to a state of
vascular
disorder, specifically, vasodilation. In addition, the aberrant points found
in the lower right-
hand portion of the nomogram also correspond to a state of vascular disorder;
however, here
these points correspond to stenosis. These observations are provided in Figure
7.
In another preferred embodiment, the system and method of the present
invention permits a determination of vascular health based on an analysis of
three blood
flow parameters, mean flow velocity, systolic acceleration, and pulsatility
index. For
example, Figure 8 provides a nomogram of the values for mean flow velocity on
the y-axis,
systolic acceleration on the x-axis, and pulsatility index on the z-axis for
transcranial
Doppler ultrasound analyses of a cerebral artery in a number of individuals.
It will be
appreciated that the majority of the data points are grouped in a centroid
located in the first
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octant (x > 0, y> 0, z> 0) close to the origin of the nomogram. If plotted as
the logarithm
of the value, these exhibit a normal distribution. The normal range of the log
of these
values represent the values corresponding to the vascular health of the
reference population.
Thus, the present invention permits the construction of any and all reference
populations
based on the data collected from the reference population. The data set is the
ideal
reference set because the reference population can be defined in any manner,
e.g., those
patients who are exhibiting a certain set of symptoms or desired
characteristics.
The aberrant points found distal to the origin and having a large mean flow
velocity (y value) in the nomogram correspond to a state of vascular disorder,
specifically,
vasodilation. In addition, the aberrant points found distal to the origin and
having a large
systolic acceleration (x value) in the nomogram also correspond to a state of
vascular
disorder; however, here these points correspond to stenosis.
The measurements, gathered on a substantial number of individuals to date,
demonstrate that the observed values for a nornial population show
statistically normal
distributions of values for the three parameters, mean blood flow, systolic
acceleration, and
pulsatility index. Scrutinized by means of standard multivariate statistical
methods, such as
tests of significance, multivariate distances, and cluster analysis, the
observed values for all
three parameters all show a statistically normal distribution.
An aspect of a preferred embodiment of the present invention is the collection
of data by means of transcranial Doppler sonography. As discussed previously,
instrumentation for conducting transcranial Doppler sonography is commonly a 2
MHz
pulsed Doppler and a spectrum analyzer, in which the examiner interrogates the
intracranial
vessels without the aid of an image. Such a technique is referred to as
freehand, blind, or
non-imaging transcranial Doppler sonography. Recently, duplex ultrasound
systems
incorporating B-mode imaging and color and power Doppler have been einployed
to perform
transcranial Doppler studies. However, despite advances in duplex ultrasound
technology,
freehand transcranial Doppler sonography is commonly performed because the
technique can
be equally accurate and the instrumentation less expensive and more portable
when compared
to the duplex ultrasound.
Although freehand transcranial Doppler sonography can be characterized as
operator dependent, the technique is objective and reproducible. The operator,
in conducting
transcranial Doppler sonography, considers the relevant anatomy, natural
cranial windows, and
recognized examination techniques. Specifically, an understanding of the
extracranial arterial
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circulation contributing to the intracranial flow, the intracranial arterial
circulation, carotid
arteries, vertebral arteries, basilar artery, and their common anatomical
variations is a
prerequisite.
Additionally, in conducting the examination the examiner must also identify
the vessel. Such identification is often premised upon the acoustical window
being utilized,
the depth of the volume sample, the direction of the blood flow relative to
the transducer,
the relative velocity, and spatial relationships.
The examiner must also recognize that there are three acoustical windows or
regions over the cranium where the bone is either thin enough or through which
there are
natural openings to allow sufficient ultrasound energy to be passed into and
back out of the
skull to permit performance of a transcranial Doppler examination, i.e., the
signal-to-noise
ratio is adequate at the "window." However, enhanced phase array detectors may
provide
sufficiently improved signal-to-noise ratio that a "window" may not be
necessary. The three
acoustical windows are the transtemporal window located superior to the
zygomatic arch over
the temporal bone; the transorbital window where the transducer is oriented
directly over the
closed eyelid in a direct anteroposterior direction with a slight angulation
toward midline; and
the transforamenal window located midline over the back of the neck
approximately 1 inch
below the palpable base of the skull. It is to be understood that other
windows may be used
for other approaches using sound or other electromotive forces for detection
of cell movement
within vessels. It will be recognized that many texts provide sufficient
instruction to
examiners so as to enable them to perform optimal transcranial Doppler
sonography. One
such text is L. Nonoshita-Karr and K.A. Fujioka, "Transcranial Doppler
Sonography
Freehand Examination Techniques," J. Vasc. Tech., 24, 9 (2000), which is
incorporated
herein by reference.
In another preferred embodiment of the present invention, ultrasound beam
alignment is controlled rapidly and automatically in two dimensions. Devices
that scan
aziinuth angle rapidly while varying elevation angle in small increments have
been used for
3-dimensional image construction, but lack speed in controlling elevation. In
the analogous
area of laser scanning, it is common to steer a light beam in two dimensions
using a pair of
orthogonally-rotating mirrors driven by galvanometer movements. The double
mirror
approach does not work as well with ultrasound, however. The size and
cumbersomeness of
a pair of galvanometer driven mirrors is a disadvantage in medical
applications, especially for
limited space uses such as transesophageal and transrectal probes. Another
design constraint
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is that the wavelengths of diagnostic ultrasound waves are much larger than
optical
wavelengths, of necessity, since attenuation of ultrasound waves rises steeply
with decreasing
wavelength. As a rule of thumb, ultrasound wavelength cannot be much less than
1% of the
maximum depth to be imaged, with an even larger wavelength required for
imaging through
tissues with high attenuation. With relatively large wavelengths, diffraction
effects make it
impossible to produce very thin collimated beams that can be steered by small
mirrors, as
with lasers.
For sharp focusing of ultrasound, a relatively large aperture is needed to
avoid angular dispersion by diffraction. A well focused near field ultrasound
beam has the
shape of a converging cone connecting to a diverging cone through a short
focal neck,
representing a small depth of near-optimum focus in the target area.
Resolution
approaching a practical minimum spot diameter of a little under two
wavelengths at the
focus demands an included cone angle on the order of 60 . If the originating
end of the
columnar beam is made smaller while maintaining a fixed focus depth, then
diffraction
causes the focal neck to become thicker, sacrificing resolution at optimum
depth for an
increased depth range of relatively good focus. To achieve fine focus with a
double mirror
apparatus, the mirrors must be comparatively large, increasing the difficulty
of attaining fast
angular response.
Typical electromechanical ultrasound image scanners employ multiple
transducers on a rotating head, or an ultrasound mirror rotationally vibrating
at an angular
resonance - approaches that achieve desired azimuth scanning by sacrificing
the possibility
of precise angular servo-control in a non-scanning mode.
In radar, phased arrays permit rapid scanning and abrupt alignment changes
in two dimensions from a fixed transmit/receive surface. A comparable approach
is
applicable to medical ultrasound. One dimensional ultrasound phased arrays are
finding
increasing use, and limited control of alignment in a second dimension is
beginning to
appear. In one preferred embodiment, a stepper motor is used to rotate the
scanning plane
of a one-dimensional phased array through small incremental steps in order to
construct a 3-
dimensional digital image. This approach requires that the target and the
ultrasound
scanner be mechanically stabilized so that frames of a slow scan are in
precise registration.
A phased array with dual sets of electrodes that permit beam steering in
either of two
selected scanning planes can be used. For example, a system that employs a one
dimensional ultrasound array can achieve controllable alignment and focus
depth in a plane,
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for use in range-gated pulsed Doppler to characterize the flow velocity
profile over the
cross-section of an artery. The device is also useful to quantify angular
relationships,
through comparing Doppler velocities at different axial locations along an
artery, so that the
relationship between Doppler frequency shift and flow velocity can be
determined
accurately.
In many emerging ultrasound applications, visual image scanning takes on a
supporting role of identifying structures and defining their positions, in
preparation for
analytic measurements in a small region, which is concerned with measuring
flow velocity
profiles over the dimensions of an artery and over time, to characterize
volumetric flow and to
detect the flow disturbances caused by stenotic lesions. Using fixed aligmnent
defocused
beams or beams electromechanically aligned with respect to two axes,
ultrasound can be used
to track the time-varying positions of organ surfaces generating specular
reflections, for the
purposes of vibration tracking and diameter pulsation tracking, in a system to
determine blood
pressure, intraocular pressure and mechanical tissue properties. One preferred
embodiment
would consist a non-focusing 2-axis ultrasound aiming device, consisting of an
ultrasound
transducer disk stacked on a short magnet cylinder and the transducer-magnet
pair mounted in
a 2-axis gimbal bearing, consisting of pins and engaging bearing cups on the
ring and the
magnet, with flexible wires connecting the gimbaled part to fixed housing.
Surrounding the
gimbal is a torroidal ferromagnetic core in four sections, with four windings
on the four 90
quadrants of the core. Opposite windings are interconnected, giving two
electrical circuits
that generate two orthogonal magnetic fields crossing the gimbaled transducer-
magnet pair.
The gimbaled part tilts in response to the two applied fields, aiming the
ultrasound beam.
In this aiming device, the axially-poled center magnet is inherently unstable
in its center alignment, being attracted to point across the torroid. To
stabilize alignment,
the torsional restoration of the connecting wires must overcome the magnetic
instability.
Alignment direction is determined open-loop by the balance of mechanical and
magnetic
forces, without direct sensing for servo-control. In an uncompensated open-
loop control
situation, if the net alignment restoration is weak, then settling is slow,
and if restoration is
made stronger, then the steady power needed to maintain off-center alignment
becomes
excessive. A compensated open-loop controller whose action takes into account
the known
dynamic properties of a particular design, i.e., inertia, angular spring
coefficient, damping,
and electromagnetic coupling strength, can speed response. The term "pole-zero
compensation" is often applied to this kind of a controller, since LaPlace
pole-zero analysis
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is commonly used to design the controller transfer function. To speed
responses, the
controller transfer function cancels electromechanical low frequency zeroes
with poles and
low frequency poles with zeroes, generally replacing the poles removed with
new poles as
far to the left of the origin as is practical within bandwidth constraints.
Something much needed and unavailable in existing designs is fast
mechanical alignment capability together with alignment sensing and error
feedback for
rapid, fast settling changes in alignment. In areas of alignment tracking and
analysis of
echo features and their movements or velocities, particularly for extended
monitoring in
unanesthetized subjects, there is need for a combined ability to scan rapidly
for image
presentation and to fine-tune 2-dimensional beam alignment under continuous
software
control, to maintain alignment dynamically on a tissue structure subject to
extended
monitoring.
In the area of combined scanning and fixed beam alignment monitoring, a
phased array device that switches readily between B-Mode image scanning and
Doppler
tracking at a specified alignment within the image plane can be employed. A
device like
this, with phased array speed, can alternate between scanning sweeps and brief
periods of
Doppler data gathering at a fixed alignment in a time-multiplexed mode,
achieving relative
continuity of both image and Doppler data. Electronic alignment control is
restricted to a
single axis, while manual control is needed for the second axis. One can also
employ a dual
beam ultrasound device, using one beam for tracking data from a fixed target
and the other
beam for ongoing scanning to aid the operator in maintaining alignment on the
desired
target. Again, the other axis of alignment is controlled manually.
For many applications it is advantageous to achieve a device small enough
so that it can be affixed directly to the subject's body and ride body
motions, rather than
obtaining measurements in a clinical setting. The advantages of the present
invention in
fulfilling these and other needs will be seen in the following specification
and claims.
Description of Data Telemetry
The present invention provides an integrated system which combines several
unique technologies to assist physicians in the control, management and
delivery of
improved, efficient and timely medical care for patients. Key components of
this integrated
system include, but are not limited to, (1) a processor which may include, but
is not limited
to, a desktop personal computer, a laptop computer, or a multi-user server
system; (2) an
output device for displaying information from the processor, such as monitors,
printers,
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liquid crystal displays, and other output devices known to one skilled in the
art; and
optionally including (3) analyzers for assessing a patient's clinical profile.
Such analyzers
may be used for analyzing flow characteristics of a vessel or number of
vessels.
All patient data may be placed in a form, such as a digitized form or other
computer readable and communication acceptable form, and transmitted to
another location.
In one embodiment, the computer-based database may be located in the office of
the health
care provider, perhaps in the computer in a physician's office. In another
einbodiment, the
computer-based database may be located in a centralized hospital facility, in
a emergency
room/service, in a clinical chemistry laboratory, or in a facility dedicated
solely to housing
and maintaining the computer-based database. In yet another embodiment, the
computer-
based database may be located in a home computer. In a further embodiment, the
computer-based database may be portable for uses such as on a battlefield, in
rural areas
and at events.
Another component in the system of the present invention includes a
transmission device such as a modem or other communication device known to one
of skill
in the art. Such devices include, but are not limited to satellites, radios,
telephones, cables,
infrared devices, and any other mechanism known to one of skill in the art for
transmitting
information. The transmission device modem transmits information to the
central
computer-based database. In a preferred embodiment, modems are used for
computer
access to the Internet. Such communication means may be essential for
transmission of
patient information from assessment of vascular flow parameters, from the
health care
provider's point of care, such as an office, to another facility housing the
computer-based
database. It is to be understood that the facility housing the computer-based
database may
be located locally, in the same office, the same building, or across town, or
at a remote
location such as in another city, state, country, or on a ship, plane or
satellite.
The computer-based system may be configured to take advantage of data
communications technologies and distributed networks, which makes it possible
to deliver
data to virtually anywhere in the world in an efficient and timely manner.
This system in
accordance with the present invention is capable of transferring clinical
vascular flow data
from a remote source to a central server via one or more networks. The central
server hosts
the computer-based database and related components. Accordingly, the central
server is
operable to analyze the received laboratory and clinical vascular data using
an expert
system, in order to produce information related to diagnoses, prognoses,
decision supports,
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clinical data analyses and interpretations. The resulting information may then
be delivered
from the central server to one or more remote client stations via one or more
networks. The
entire process of transferring data from a remote source to a central server,
analyzing the
data at the central server to produce information, and transferring the
information to a
remote client site may thus be performed on-line and in real time.
In automated decision support system for interpreting the values of various
parameters of blood flow in one or more vessels in assessing the vascular
health of an
individual, the data which are collected on an individual vessel are analyzed
individually for
each patient and then are also analyzed as an ensemble over that patient. In
other words, all
the vessels and their respective paraineters, their respective health states,
are compared to
one another and an overall system analysis is made. The points of data in n-
dimension
states describing the health state of a vessel are tracked over time so as to
determine a
starting point and a velocity. The velocity in this case would be a direction
of change as
well as a rate of change in n-dimensional space. In more conventional terms,
if
noncompliance was detected in a vessel as one of the dimensions in n-
dimensional space,
then after a treatment one might see that number which represents
noncompliance, or a
degree of noncompliance migrate in a certain direction - for example, toward
compliance -
as the vessel becomes more compliant with the treatment intended to make it
more
compliant. The significance of that change will be assessed by looking at the
velocity of
health state movement in dimensional space across all of the individual's
cerebral
vasculature.
The movement from the baseline of any single vessel point may be hard to
assess for statistical significance. However, there are statistical tools
which are appropriate
for analyzing the movement of the health states of all of the vessel points
simultaneously. An
example of that would be the Wilcox Test, which allows comparison of a group
of non-
parametric values to ascertain whether the variables are statistically
different from one
another or not. Other tests may be appropriate given the data set. However,
fundamentally
the process is to quantitate the health state of each vessel of an individual
in a n-dimensional
space and determine the significance of change and the direction of change,
such that if the
directions and the degrees of change are, when considered together,
significant, it can then be
concluded that the treatment is effective. In an individual case it is also
possible to stop
treatment and confirm that the effect being observed was in fact due to the
drug by observing
a reversal of the same.
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When comparing a clinical trial treatment group to a control group, the
process
can be similar to what is being done with the individual. There, it is a
matter of assessing
whether or not the numbers quantitating particular characteristics of the
vessel health state with
regard to each of the dimensions in dimensional space can be construed to be
significant. A
discussion of the statistical analysis employed here is found in Jerrold H.
Zar, Biostatistical
Analysis, Prentice Hall, Inc. New Jersey, pp. 153-161, which is incorporated
herein by
reference.
One way in which the system of the present invention is trained is one
wherein the software quantitates the rationale being used by the expert. In
such a system,
during this process the expert and the system come to mirror each otlier. In
the process the
expert is very specific, concrete and quantitative regarding the data
analysis. In its turn, the
software maintains a detailed bookkeeping of the analytical process. Thus, the
software
system and the expert each begin to diversify their respective roles in the
development of
this knowledge. The purpose of the software is to capture the expert's
analysis.
According to the expert system of the present invention, characteristics of
various functions for an automated decision support system for interpreting
the values of
various parameters of blood flow in one or more vessels in assessing the
vascular health of
an individual are provided. These characteristics can be derived from various
functions, for
example, transcranial Doppler readings at a left anterior carotid artery or
basal artery test
point, flow parameters for various arteries, a summary of patient data, a
summary of clinical
test(s) perforined on a patient, the presence of vasodilators and/or
vasoconstrictors in a
patient, a stenotic pattern or pattern indicating constriction of an artery at
a particular test
point, a vasodilation pattern or pattern indicating dilation of a blood
vessel, a
noncompliance pattern or pattern indicating loss of compliance in an artery
such as in the
example of hardening of the artery, a normal pattern or pattern indicating a
blood vessel
with norinal radius, a global vasoconstriction or reversible stenosis of
vessels in the brain,
global vasodilation or dilation of all cranial blood vessels, a pseudo-
normalized pattern of
constriction or dilation at an arterial test point, a pseudo-normalized
pattern of loss of
compliance in an artery, stenosis of a vessel due to blockage, dilation of an
artery to
compensate for loss of flow elsewhere, permanent dilation of an artery,
noncompliance or a
state in which a vessel's walls have lost flexibility, collateral flow through
an artery or via
reversal of flow, and/or patient risk assessment for any type of stroke.
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Parameters for determining the various functions can include, but are not
limited to, identification of the person taking the Doppler reading, the date
of the reading,
patient identification, a patient's sex, a patient's ethnic group, a patient's
date of birth, a
patient's drug usage including specific drugs, Doppler values, Doppler times,
acceleration,
flow direction, reading depth, the mean and/or standard deviation of the flow
velocity in a
vessel, the mean and/or standard deviation of the systolic acceleration in a
vessel, the
pulsatility index of a vessel. These parameters can be static values, inputted
or retained
within a database, or calculated ones. Other calculated parameters may include
the
calculation of the belief of whether there are vasodilators or
vasoconstrictors present in the
patient, which may be based upon the presence of vasoactive substances such as
caffeine
and/or methylxanthine. An example of another calculated parameter may include
the belief
of the severity of the constriction of an artery at a particular test point,
which may be
characterized as none, minimal, moderate or severe. An example of another
calculated
parameter of the present invention may include the belief of dilation of a
blood vessel,
which may be characterized as none, hyperemic, normal or pathological. An
example of
another calculated parameter of the present invention may include the belief
of loss of
compliance in an artery, which may be characterized as none, normal or
pathological. An
exainple of another calculated parameter of the present invention may include
the belief of a
blood vessel with normal radius, which may be characterized as none,
hyperemic, normal or
pathological. An example of another calculated parameter of the present
invention may
include the belief of a blood vessel with a high pulsatility index, or wherein
the pulsatility
index of one vessel is higher than another, which may be characterized as true
or false. As
can be seen from the above examples, various beliefs may be calculated
according to the
expert system of the present invention based upon the function studied.
An automated decision support system according to the present invention
provides a domain ontology for interpreting the values of various parameters
of blood flow
in one or more vessels in assessing the vascular health of an individual.
These parameters
may be determined by means of a transcranial Doppler velocimetry technique,
which is a
noninvasive technique for measuring blood flow in the brain. According to this
technique,
an ultrasound beam from a transducer is directed through one of three natural
acoustical
windows in the skull to produce a waveform of blood flow in the arteries using
Doppler
sonography. The data collected to determine the blood flow may include values
such as the
pulse cycle, blood flow velocity, end diastolic velocity, peak systolic
velocity, mean flow
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velocity, total volume of cerebral blood flow, flow acceleration, the mean
blood pressure in
an artery, and the pulsatility index, or impedance to flow through a vessel.
From this data,
the condition of an artery may be derived, those conditions including
stenosis,
vasoconstriction, irreversible stenosis, vasodilation, compensatory
vasodilation, hyperemic
vasodilation, vascular failure, compliance, breakthrough, and pseudo-
normalization.
In order to best analyze a patient's risk of stroke, additional patient data
is
utilized by the automated decision support system according to the present
invention. This
data may include personal data, such as date of birth, ethnic group, sex,
physical activity
level, and address. The data may further include clinical data such as a visit
identification,
height, weight, date of visit, age, blood pressure, pulse rate, respiration
rate, and so forth.
The data may further include data collected from blood work, such as the
antinuclear
antibody panel, B-vitamin deficiency, C-reactive protein value, calcium level,
cholesterol
levels, entidal C02, fibromogin, amount of folic acid, glucose level,
hematocrit percentage,
H-pylori antibodies, hemocysteine level, hypercapnia, magnesium level, methyl
maloric
acid level, platelets count, potassium level, sedrate (ESR), serum osmolality,
sodium level,
zinc level, and so forth. The data may further include the health history data
of the patient,
including alcohol intake, autoimmune diseases, caffeine intake, carbohydrate
intake, carotid
artery disease, coronary disease, diabetes, drug abuse, fainting, glaucoma,
head injury,
hypertension, lupus, medications, smoking, stroke, family history of stroke,
surgery history,
and so forth.
The automated decision support system according to the present invention
further considers related pathologies in analyzing a patient's risk of stroke,
including but
not limited to gastritis, increased intracranial pressure, sleep disorders,
small vessel disease,
and vasculitis. In a preferred embodiment, the invention includes a decision
support system
and method for screening potential participants in a drug trial. General
references detailing
principles and terms known to those skilled in the art of decision support
systems include
(1) Schank, R.C. and Abelson, R., Scripts, Plans Goals and Understanding,
Hillsdale, NJ:
Lawrence Erlbaum Associates (1977); (2) Schank, R.C. and Riesbeck, C.K.,
Inside
Computer Understanding, Hillsdale, NJ: Lawrence Erlbaum Associates (1981); (3)
Sacerdoti, E.D., A Structure for Plans and Behaviors, New York: Elsevier
(1978); (4)
Rinnooy Kan, A.H.G., Machine Scheduling Problems, The Hague: Martinus Nijhoff
(1976); and (5) Chamiak, E., Riesbeck, C.K. and McDermott, D., Artificial
Intelligence
Programming, Hillsdale, NJ: Lawrence Erlbaum Associates (1980).
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Several terms used in disclosure of the present invention are described
generally by the following definitions accepted by those skilled in the art:
Concept Gf=aph: a knowledge representation of the dependencies between
observable data values and higher level computations and assertions made about
the data.
A concept graph can be implemented as a directed acyclic graph of concept
nodes that is a
particular type of augmented transition network (ATN).
Decision Support System: a computer program that uses a knowledge base
to assist in solving problems. Most expert systems use an inference engine to
derive new
facts and beliefs using a knowledge base.
Inference Erzgine: a computer program that infers new facts or beliefs from
known facts or beliefs using a knowledge base and a set of logical operations.
Knowledge Base: a collection of knowledge (e.g., objects, concepts,
relationships, facts, rules, etc.) expressed in a manner such that it can be
used by an
inference engine. For example, a knowledge base may include rules and facts or
assertions
as in traditional expert systems.
One preferred embodiment of a decision support system of the present
invention includes the ability to assess the hemodynamic state of a subject's
cerebrovasculature tlirough the use of transcranial Doppler measurements.
Referring to
Figure 10 the embodiment consists of three software modules: a Data Access
1010 module,
a Reasoning 1020 module, and a Graphical User Interface (GUI) module 1030. The
Reasoning 1020 module consists of two sub-modules: a situation assessment
module
comprising the PreAct DSA 1022 sub-module from Applied System Intelligence,
Inc.,
including the domain knowledge base 2362; and Reasoning Interface 1024 sub-
module.
Cognitive engines, other than DSA, may be used. The Reasoning Interface 1024
sub-
module serves to hide the details of interacting with the DSA 1022 sub-module
from other
objects. In this embodiment, these modules run sequentially as part of the
same process,
with one instance of each module.
The Data Access 1010 module provides access and storage methods for TCD
measurement/data, clinical data, and inferences from the Reasoning 1020
module. In a
preferred laptop personal computer configuration this collection of data is
stored in a file.
The GUI 1030 module processes user input to be sent to the Data Access
1010 module, runs commands for the Reasoning 1020 module, queries about
patient data
for the Data Access 1010 module, and queries about inference results for the
Reasoning
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1020 module. The GUI 1030 module also displays patient data received from the
Data
Access 1010 module and concept instances, related to the concept graph
instances received
from the Reasoning 1020 module.
The PreAct DSA 1022 sub-module accepts leaf-level concepts representing
patient data and processes them for inferred concepts such as disease. The
current concept
graph may be queried for all instances of a particular concept pattern or for
evidence
supporting a particular instance. The current graph may be saved for future
queries and saved
concept graphs may be reloaded for querying. The DSA 1022 sub-module also has
access to
the underlying knowledge base 2362. The Reasoning Interface 1024 sub-module
accepts
commands to process patient data for inferred concepts, to search for
instances of particular
concepts or evidence for a given concept instance in the active concept graph,
and to save the
current concept graph or load a saved concept graph. The Reasoning Interface
1024 sub-
module converts these commands into a command language understood by the DSA
1022 sub-
module.
This preferred embodiment makes use of the data structures found in Table 1.
DATA STRUCTURE DEFINITION
Patient ID Uniquely identifies each patient
Group ID Uniquely identifies each group of patients in the system
Contains TCD data and clinical data for a patient. This includes:
~ Data and measurement times for each vessel test point;
Patient data block ~ Demo ra hic data, e.g., date of birth, ethnic rou
g P g p;
~ Clinical data, e.g., vital signs, test results
Filename Name of a concept graph file
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Concept pattern ID Unique identifier of a concept pattern
Concept key ID Unique key of a concept in stance
Concept instance Concept instance from a concept graph. Derived concepts
include belief values.
List of concept instances List of concept instances from a concept graph
List of concept keys- - List of keys for instances of a certain pattern
Table 1
Patient data consists of data derived from TCD measurements and clinical data.
This data is used to fill in the leaf-level concepts in the concept graph.
Patient data is
accessed and stored as a single block of data for each patient, referenced by
a unique patient
ID.
TCD measurements and data may be input in a streaming fashion via a
network or direct connection or as a file. Clinical data may be input as a
file or manually
through the GUI 1030 module. After completing data input, the user may elect
to save the
data or file for later access or to analyze the data. In either case, the
Reasoning 1020
module retrieves patient data via the Data Access 1010 module. For this
purpose, the GUI
1030 module stores data in a file. Both modules retrieve patient data by
patient ID.
Additionally, in order to allow a user to select a patient's data to view,
edit, or analyze, the
interface allows the GUI 1030 module to retrieve a list of all patients saved
in a file. In
preferred embodiments, the set of parameters passed to Data Access 1010 module
functions
includes a user ID.
Inference data includes concept instances in the concept graph for a
particular patient. The DSA 1022 sub-module provides its own accessors for
loading a
concept graph from a text file and saving a concept graph to a text file. The
Data Access
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1010 sub-module is responsible for storing the file created by the Reasoning
1020 module.
Table 2 identifies commands used by the Data Access 1010 module.
COMMAND USED BY PARAMETERS RETURN
Initialize Module System layer None Success/failure
Retrieve Patient Data GUI control, Patient ID, user ID Patient data block
Reasoning
Save Patient Data GUI control Patient ID, user ID Success/failure
Delete Patient Data and GUI control Patient ID, user ID Success/failure
Concept Graph
Retrieve List of Patients GUI control User ID List of patient IDs
Store Patient Concept Graph Reasoning Patient ID, user ID, Success/failure
filename accessible by
Data Access Module
Retrieve Patient Concept Reasoning, GUI Patient ID, user ID Filename
accessible by
Graph Reasoning Module
Query Database GUI SQL Query Query result
Table 2
The GUI 1030 module accepts input from the user, converts the user's input
in to data and commands for other modules, and displays the values returned on
the screen
or in a printout. The GUI 1030 module provides for display of clinical and
demographic
data for a patient, raw TCD data and measurements, and an analysis of a
patient's
hemodynamic state. The analysis of a patient's hemodynamic state includes the
condition
of each artery for which TCD measurements are available, any global conditions
found, and
an assessment of the patient's risk for stroke. The GUI 1030 also allows a
user to drill
down from a patient's risk for stroke to determine how that conclusion was
reached.
The Reasoning Interface 1024 sub-inodule allows other modules to access the
concept stored in the DSA 1022 sub-module without being exposed to all the
details of the DSA
1022's interface. Reasoning Interface 1024 sub-module commands include those
in Table 3.
COMMAND USED BY PARAMETERS RETURN
Initialize module System layer None Success/failure
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Run module with a GUI control Patient ID, user ID Success/failure
patient's data
Get concept instances GUI control Concept pattern ID List of concepts
Get concept instance GUI control Concept pattern ID, Concept
concept key ID
Get concept evidence GUI control Concept pattern ID, List of concepts
concept key ID
Load a patient's GUI control Patient ID, user ID Success/failure
concept graph
Save a patient's GUI control Patient ID, user ID Success/failure
concept graph
Table 3
The DSA 1022 sub-module includes methods for commanding the sub-
modules, including commands for initializing, starting, running, and stopping.
The DSA
1022 sub-module also includes services for setting and retrieving concept
attribute values.
Requests for DSA 1022 sub-module data are responded to with one of three
values: 1- data found correctly; 0 - data not found but no critical error
occurred; and - 1 -
critical error, see exception log file. In addition to requesting the value of
a particular
attribute in a known concept instance, the invention can request both an index
of concepts and
a deep copy of a particular concept instance. The system also responds to: a
user request for a
list of all child concept instances of a particular concept instance; a user
request to clear all
concept instances from the concept graph (patterns will remain loaded); a user
request to save
a concept graph to a specified file name (in preferred embodiments, this file
will be saved as
an XML file); and a user request to load a saved concept graph from a
specified file name.
In a broad sense, this preferred embodiment allows as user to enter new
patient data through the GUI 1030 and save the data; load existing patient
data from a
database; view raw data, e.g., clinical data and TCD data; analyze patient
data for
inferences about the patient's hemodynamic state; view results of an analysis;
and view the
evidence used to reach a particular inference.
Upon initialization, a main program instantiates and initializes the modules
and sub-modules in the following order: Data Access 1010, Reasoning Interface
1024
(which will initialize the DSA 1022), and GUI 1030. After initialization is
complete,
control is passed to the GUI 1030. Control remains with the GUI 1030 until the
user signs
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out, at which point the main program shuts down the modules in the reverse
order of
initialization. The Reasoning Interface 1024 module shuts down the DSA 1022.
Specific operation of the GUI 1030 module can include being initialized by
one or more external commands. Operation of the GUI 1030 can further include
accepting
a user commands to sign in to the system; change the group of patients
currently being
processed (contingent upon authority of that user to have access to the data
for the new
group); create a new group; sign out of the system; create a new patient
record; process a
patient's data for inferences; edit data for a new or existing patient; save a
patient's data;
display a list of subjects in the specified group (including an indication of
whether or not a
hemodynamic analysis has been done on the patient's data; display patient data
for an
existing patient; display patient's overall risk of stroke; display an
explanation of a patient's
stroke risk, including concepts used as evidence and the ability to drill down
in to evidence
for further detailed display; and display the status of arterial flow in all
the patient/subject's
arteries for which data is available, including flow characteristics at each
test point, global
characterizations of blood flow, and the direction of blood flow.
Specific operation of the Data Access 1010 module can include serving as an
interface to an existing relational database management system; accepting
commands for
initialization, shutdown, creation of a new patient record, retrieval of the
patient data block
for a specified patient, update of a patient's data, deletion of a record,
retrieval of a concept
graph, update of a concept graph, deletion of a concept graph; and accepting a
query for a
list of all patients in the database.
Specific operation of the Reasoning Interface 1024 sub-module can include
initialization by one or more external commands; accepting commands for
processing a
patient's data, saving the analysis of the current patient's data, loading a
saved analysis, and
stop processing; and accepting queries for instances of particular concept
patterns in the
concept graph, a particular concept instance, and further explanation of a
concept instance.
Specific operation of the DSA 1022 sub-module can include initialization by
one or more external commands; and use of knowledge bases to store concept
patterns and
knowledge base algorithms used to infer concepts from leaf-level data
provided, with the
basis for the inferences being the TCD data and clinical data. The algorithms
infer the
concepts in several intermediate steps, each represented in the concept graph,
such that it is
sufficient for one skilled in the art of the problem domain to follow the
chain of reasoning.
The conditions represented in the concept graph include, but are not limited
to, vasodilation,
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hyperemic vasodilation, pathological vasodilation, non-compliance, and
irreversible
stenosis. The concept graphs provide a path for following a chain of reasoning
backwards
from a conclusion. The algorithms use a plurality of reasoning techniques,
e.g., Bayesian
reasoning, to look for supporting data in related concepts. Further operation
of the DSA
1022 sub-module can include loading knowledge bases; accepting patient data to
be
processed through transactions; allowing the user to save the concepts
resulting from an
inference and load saves concepts; and querying for instances of particular
concept patterns
in the current concept graph, particular concept instances, and further
explanation of a
concept instance. This querying can include accepting a clear command, and in
response,
clearing all concept instances from the current graph; concept patterns remain
loaded;
accepting a kill conimand to release all allocated memory and terminate; and
writing non-
fatal errors to a log file.
In another preferred embodiment, the invention is a networked based system
and method for analyzing the hemodynamic state of a subject based on TCD
measurements.
When using this embodiment; a user submits data to a centralized system for
analysis
similar to that described in the previous embodiment.
Referring to Figure 23 a block diagram illustrating the context and
relationship between modules for the preferred Application Service Provider
(ASP)
embodiment is shown. The modules run in separate process spaces. The user
interface (one
or more instances of a Web Browser 2310) and System Interface 2320 are
connected via a
network, in this case the Internet, using connection protocols known to those
skilled in the
art of computing. The System Interface 2320 Manager provides an adaptive layer
between
the web server and the remainder of the system. The Accounts Manager 2340
maintains
authorization and accounting data for each user account. The Reasoning Manager
2350
manages requests for analysis of data and queries of existing analyses. It
also maintains
connections to one or more instances of the Reasoning Module 2360. The
Reasoning
Module 2360 encapsulates a DSA component in a fashion similar to the earlier-
described
embodiment. The DSA component uses the invention's knowledge base to analyze
TCD
data and provide access to results. The Reasoning Module 2360 provides
translations to
and from the interface language use by the DSA component. The Watchdog 2370
monitors
invention performance for functioning within acceptable parameters.
The invention is accessed via the Internet through a web site, using a
standard browser 2310. Figures 24 through 27 illustrate the data available
through typical
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pages displayed at the browser in response to appropriate user actions. The
system is
entered through a login page, an example of which is illustrated in Figure 24.
In this
embodiment, the same login page is used by both users and administrators.
Based on the
identity of the account, the invention will present either the administrator
startup page or the
user startup page. The administrator startup page provides an administrator
with access to
administration functionality described below. The user startup page,
illustrated in Figure 25,
lists those patients that are associated with the user. From this point, the
user may add new
patient data, edit existing patient data or delete patient data.
The patient data page, illustrated in Figure 26, displays clinical data on a
patient and allows a user to edit this data. The patient data page also
provides access to the
TCD data tab for that patient. The TCD data tab for a patient, provides access
to TCD
measurements. The user may add new TCD measurements, view existing
measurements,
edit, or delete measurements. This page provides further access to the
hemodynamic
analysis tab, illustrated in Figure 27, for the patient. The hemodynamic
analysis tab
displays the result of an analysis of a patient's TCD data. If no analysis has
been performed
on a set of TCD readings, the user may request that such analysis be performed
from this
page.
The Knowledge base 2362 maintains the knowledge for TCD analysis. The
inventions analytical techniques'may be modified by changing these Knowledge
base 2362
files. The Patient database 2382 stores data about a patient pertinent to
analysis of his TCD
data. Each patient is assigned a unique ID by the user of the system.
Information contained
in the Patient database 2382 includes that shown in Table 4.
ITEM DESCRIPTION
User ID Unique identifier for the user of the system
Patient ID Unique identifier for this patient within this user's patients
Date of birth Patient's date of birth
Sex Patient's generic sex
Ethnic group Patient's etl-nic group
For each set of TCD readings for this patient:
Reading date Date of reading
For each reading.within a set of TCD readings
Segment ID Arterial segment from which the reading was taken
Depth Depth of the reading (mm)
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ITEM DESCRIPTION
PSV Peak systolic velocity
PSVTime Timestamp of PSV reading (sec)
EDV End diastolic velocity
EDVTime Timestamp of EDV reading (sec)
Table 4
The Patient Analysis Database 2384 stores the Reasoning 1020 module's
analysis of a set of TCD data. The analysis is stored as a file in a format
that can be read into
the Reasoning 1020 module, e.g., an extensible Markup Language (XML) file.
Information
contained in an entry in the Patient Analysis Database 2384 includes the
information in Table
5.
ITEM DESCRIPTION
User ID Unique identifier for the user of the system
Patient ID Unique identifier for this patient within this user's patients
Reading ID Patient's date of birth
Analysis Output file from the patient's concept graph
Table 5
The Authorization Database 2342 stores the IDs and passwords of authorized
users and administrators. Information contained in an entry in the
Authorization Database
2342 includes the information in Table 6.
ITEM DESCRIPTION
User ID Unique identifier for the user of the system
Password Encrypted password for the user
Account type User or Administrator
Table 6
The Transaction Log 2344 records activity of users and administrators in the
system, Information contained in the Transaction Log 2344 includes the types
found in Table
7.
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TRANSACTION NAME TRANSACTION FIELDS
Log in User ID
Timestamp
Failed log in User ID
Invalid password
Timestamp
Log out User ID
Timestamp
Add new patient User ID
Patient ID
Timestamp
Edit patient data User ID
Patient ID
Timestamp
Delete patient User ID
Patient ID
Timestamp
Analyze patient User ID
Patient ID
Reading ID
Timestamp
Display patient list User ID
Timestamp
Display patient User ID
Patient ID
Timestamp
Create new account Administrator ID
New account ID
Account type (user or administrator)
Timestamp
Delete account Administrator ID
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Account ID
Timestamp
Download Transaction Log Administrator ID
Timestamp
Download Authorization Database Administrator ID
Timestamp
Timestamp
Table 7
System Database 2390 stores data used to provision the application's process.
Examples include parameters for the IPC connections and the location of the
data files
specified in the above description.
Knowledge structures are defined and developed over the lifecycle of the
invention; both for this embodiment and for other preferred embodiments. The
knowledge
structures identify broad functionality to envision the invention's behavior.
Preferred
embodiment of the present invention use a concept graph (CNG) for knowledge
representation. The CNG, see Figures 11 through 22, contain input data to the
system and
inferred states form the input data. Arrows in the concept graph represent the
direction of
inference. The inferences culminate in the top-level Stroke Risk concept.
The system provides various functionality to authorized users, including
logging in using an existing account; setting up a new patient record; editing
an existing
patient record; requesting and obtaining an analysis of a previously entered
set of patient
TCD readings; requesting and obtaining a list of all patients for which that
user has entered
data, with the existence of an analysis indicated; requesting and obtaining a
display of
previously entered data and, if available the analysis of that data; deleting
patient data
entered by that user; deleting a TCD reading set; and logging off.
The system provides various functionality to authorized system
administrators, including logging in; creating a new account; listing all
existing accounts;
deleting an existing account; downloading transaction data; changing the e-
mail address to
which notifications are sent by the Watchdog 2370; and logging off.
Upon initialization, a main program instantiates and initializes the modules
in the following order: Watchdog 2370, System Interface 2320, Accounts Manager
2340,
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Data Manager 2380, Reasoning Manager 2350. These modules run in separate
process
spaces from the main program. Upon shutdown, a main program sliuts down the
modules
in the following order: Reasoning 1020 module, Data Manager 2380, Accounts
Manager
2340, System Interface 2320, Watchdog 2370.
The System Interface 2320 is initialized by external command. It converts data
submitted in hypertext markup language (HTML) into commands for other system
modules, and
conversely, reformats data from other system modules into outbound HTML pages
for
presentation to a user. The System Interface 2320 module maintains a list of
users currently
logged into the system and automatically logs a user off after some time of
inactivity. The System
Interface 2320 accepts a shutdown command accepts requests for system data
from other modules.
The Data Manager 2380 can be initialized by an external command, and maintains
data in persistent storage. The Data Manager 2380 is able to accept and
respond to various
commands, such as retrieve the IDs of patients entered by a particular user;
set up a new patient
record; retrieve a patient's data; modify a patient's data; store the analysis
of a particular TCDV
reading; retrieve the analysis of a particular TCDV reading; delete a
patient's records; and shut
down.
The Accounts Manager 2340 can be initialized by external cominand, and can
accept transactions to be recorded in a Transaction Log 2344. The Accounts
Manager 2340 can
accept and respond to commands such as create a new account; delete an
existing account;
validate an account ID and password (if the account ID and password are valid,
the Accounts
Manager 2340 can indicate in the reply whether this account is a regular user
or an
administrator); download the Transaction Log 2344; download the Authorization
Database
2342; and shut down.
The Reasoning Manager 2350 can be initialized by an external command.
Upon initialization, the Reasoning Manager 2350 initializes one instance of
the Reasoning
1020 module. The Reasoning Manager 2350 maintains connections to all existing
instances
of the Reasoning 1020 module. The Reasoning 1020 modules run in a separate
process
space from the Reasoning Manager 2350. The Reasoning Manager 2350 initialize
additional instances of the Reasoning 1020 module or delete instances of the
Reasoning
1020 module as necessary to optimize the system load.
The Reasoning Manager 2350 is able to accept and respond to various
commands such as analyze a patient's data. The patient's data is assumed to be
accessible
through the Data Manager. The Reasoning Manager 2350 retrieves the data from
the Data
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Manager, loads it into a particular Reasoning 1020 module, and issues a
command to the
Reasoning 1020 module to analyze the data. The Reasoning Manager 2350 is
further able to
accept and respond to other various commands such as query a patient's
analysis for a particular
concept instance. In this instance, the Reasoning Manager 2350 loads the
analysis into a
Reasoning 1020 module, if necessary, and sends a query to the Reasoning 1020
module. The
Reasoning Manager 2350 is further able to accept and respond to other various
commands such
as query a patient's analysis for all instances of a particular concept
pattern. In this instance, the
Reasoning Manager 2350 loads the analysis into a Reasoning 1020 module, if
necessary, and
sends a query to the Reasoning 1020 module. The Reasoning Manager 2350 is
further able to
accept and respond to other various commands such as query a patient's
analysis for further
explanation of a concept instance. If necessary, the Reasoning Manager 2350
loads the analysis
into a Reasoning 1020 module and sends a query to the Reasoning 1020 module.
The Reasoning
Manager 2350 is further able to accept and respond to other various commands
such as shut
down. When shutting down, the Reasoning Manager 2350 preferably shuts down all
instances
of the Reasoning 1020 module.
Reasoning 1020 module is initialized by an external command. No other
commands are processed until the module is initialized. The Reasoning 1020
module
Applied System Intelligence, Inc.'s PreAct DSA 1022 module to store and
analyze data
using a concept graph. The Reasoning 1020 module uses a knowledge bases
independent
of the PreAct library to store the concept patterns and necessary algorithms.
These
knowledge base 2362s are loaded after the module is initialized. The
algorithms use
various reasoning techniques, e.g., Bayesian reasoning, to propagate belief
values through
the graph. Sample concept graphs can be found at Figures 11 through 22. The
Reasoning
Module 2360 provides accessors to input patient data into the concept graph.
The Reasoning Module 2360 accepts and responds to various commands such as
clear the current concept graph; analyze a patient's data (preferably, the
module sends a
notification when the analysis is complete); save the analysis of the current
patient's data
(preferably, the module sends a notification when the save is complete); load
a saved patient
analysis; and stop.
The Reasoning 1020 module can accept and respond to one or more queries
for all instances of a particular concept pattern in the concept graph; a
particular concept
instance; and further explanation of a concept instance. The Reasoning 1020
module is
further able to write non-fatal errors to a log file.
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The Watchdog 2370 includes an off-the-slielf module chosen to be initialized
by
an external command which will set all necessary parameters; to send a
notification to a specified
set of e-mail addresses when the available disk space drops below a preset
level; to send a
notification to a specified set of e-mail addresses when the system load
exceeds a preset level; and
to accept and respond to a command to change the set of e-mail addresses to
which notifications
are sent.
An exemplary network architecture of an exemplary system in accordance
with the present invention is described below. The exemplary system comprises
one or
more client stations, a central server and a communications link. The one or
more client
stations function as remote access points to the central server. A client
station may be
located in a laboratory, a physician office and/or at any other appropriate
site. A client
station may be configured for transmitting and/or receiving information to or
from the
central server in either an interactive mode or a batch mode.
Client stations may comprise any type of computer-like device that is capable
of
sending and/or receiving data. For example, a client station may comprise a
desktop computer,
a laptop computer, a hand-held device, or the like. A client station may also
comprise a
laboratory instrument having functionality for collecting raw data (such as
patient vascular data),
and for transferring that raw data to the central server via the
communications link. A client
station may also comprise a device for receiving raw data from a laboratory
instrument, such as
a flow analytical device, or a device holding data transmitted from a flow
analytical device, and
then passing that data to the central server via the communications link.
These and other
examples of client station configurations will be apparent to those of
ordinary skill in the art.
A first client station may be configured to transmit raw data to the central
server via the communications link and a second client station may be
configured to receive
processed data (results) from the central server via the communications link.
A client
station may implement various user interfaces, printing and/or other data
management tasks
and may have the ability to store data at least temporarily.
The communications link may comprise a dedicated communications link, such
as a dedicated leased line or a modem dial up connection. Alternately, the
communications link
may comprise a network, such as a computer network, a telecommunications
network, a cable
network, a satellite network, or the like, or any combination thereof. The
communications link
may thus comprise a distributed network and/or one or more interconnected
networks. In an
exemplary embodiment, the communications link may comprise the Internet. As
should be
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apparent to those of skill in the art, the communications link may be land-
line based and/or
wireless. Communications over the communication link between the client
station and the
central server may be carried out using any well-known method for data
transmission, such as
e-mail, facsimile, FTP, HTTP, and any other data transmission protocol.
The central server comprises the computer-based database of vascular
information. The central server implements analytic and interpretive
algorithms. It will be
apparent to those of skill in the art, however, that the communication station
and the
computation station may be implemented in a single computer. The configuration
of an
exemplary central server will be described in greater detail below.
A system in accordance with an exemplary embodiment of the present
invention may operate in an interactive mode or a batch mode. In the
interactive operating
mode, data samples are processed one by one interactively. For example, in an
interactive
processing mode, a user connects to the central server through a client
station. A data
sample to be processed is then sent from the client station to the central
server. The
processed data (result file) is returned from the central server to the client
station, where it
may be printed and/or archived. After the result file is received at the
client station, a
subsequent data sample may then be transmitted from the client station to the
central server.
An exemplary system configured for an interactive processing mode is now
described. A client station may be configured for execution of a communication
browser
program module and one or more printing and/or archiving program modules. As
is known in
the art, a convenient and effective communication link for facilitating
interactive operations is
the Internet. Communication browsers are also known as World Wide Web browsers
or Internet
browsers.
The components of the central server may be distributed among two stations,
a communications station and a computation station. Configured for an
interactive
processing mode, the communications station may comprise a communications
server, such
as a standard http server, for interacting with the communication browser
executed at the
client station. Communications between the communications server and the
communication browser may occur using html pages and computer graphics
interface (CGI)
programs transferred by way of TCP/IP.
Substances
In one preferred embodiment of the present invention, vascular reactivity to
substances may be evaluated. Substances include, but are not limited to,
alcohol, nicotine,
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foodstuffs, extracts of plants, nutraceuticals, and drugs. Many drugs are
known to have effects on
the vascular system. A non-limiting list of classes of drugs and drugs known
to have affects on
the vascular system includes the following: beta adrenoreceptor antagonists;
calcium channel
antagonists; angiotensin I converting enzyme inhibitors; alpha adrenoreceptor
antagonists;
cholesterol antagonists; angiotensin II 1 antagonists; HMGCoA reductase
inhibitors; thrombin
inhibitors; adrenoreceptor antagonists; endothelin A receptor antagonists;
NMDA antagonists;
platelet aggregation antagonists; NMDA antagonists; platelet aggregation
antagonists; sodium
channel antagonists; 5-hydroxytrypltamine la agonists; AMPA receptor
antagonists; GPIIb IIIa
receptor antagonists; lipase clearing factor stimulants; potassium channel
agonists; potassium
channel antagonists; 5-alpha reductase inhibitors; acetylcholine agonists;
dopaminergic agonists;
endopeptidase inhibitors; estrogen antagonists; GABA receptor agonists;
glutamate antagonists;
peroxisome proliferator-activated receptor agonists; plasminogen activator
stimulants; platelet-
derived growth factor receptor kinase inhibitors; prostacyclin agonists;
sodium/hydrogen
exchange inhibitors; vasopressin 1 antagonists; 15-lipoxygenase inhibitors;
acetyl CoA transferase
inhibitors; adenosine Al receptor agonists; aldose reductase inhibitors;
aldosterone antagonists;
angiogenesis stimulants; apoptosis antagonists; atrial peptide antagonist;
beta tubulin antagonists;
bone formation stimulants caspase inhibitors; CC chemokine receptor 2
antagonists; CD18
antagonists; cholesterol ester transfer protein antagonists; complement factor
inhibitors;
cyclooxygenase inhibitors; diuretics; DNA topoisomerase ATP hydrolyzing
inhibitors; elastase
inhibitors; endothelial growth factor agonists; enkephalinase inhibitors;
excitatory amino acid
antagonists; factor Xa inhibitors; fibrinogen antagonists; free radical
scavengers; glycosylation
antagonists; growth factor agonists; guanylate cyclase stimulants; imidazoline
Il receptor
agonists; immunostimulants; iminunosuppressants; interleukin 1-beta converting
enzyme
inhibitors; interleukin 8 antagonists; LDL receptor function stimulants; MCP-1
antagonists;
melanocortin MC-4 antagonists; mineralocorticoid antagonists; nerve growth
factor agonists;
neuropeptide Y antagonists; oxygen scavengers; phosphodiesterase inhibitors;
potassium sparing
diuretics; proline hydroxylase inhibitors; prostaglandin El agonists;
purinoreceptor P2T
antagonists; reducing agents; thromboxane A2 antagonists; thyroid hormone
function agonists;
transcription factor inhibitors; vasopressin 2 antagonists; and vitronectin
antagonists, among
others.
In addition, other agents are suspected of having vascular activity. These
agents are include, but are not limited to, danaparoid sodium, nitric acid
scavengers,
clomethiazole, remacemide, TP10, cerivastatin, nimodipine, nitrendipine, BMS-
204352,
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BIII-890, dipyridamole +ASA, fradafiban, irampanel hydrochloride,
lefradafiban, aptiganel,
sipatrigine, NRTs, cromfiban, eptifibatide, nematode anticoagulant protein
NAPc2, UK-
279276, Flocor, DMP-647, ASA, GPI-6150, dermatan sulfate, NOS inhibitors,
ancrod,
PARP inhibitors, tinzaparin sodium, NOX-100, LDP-01, argatroban, fosphenytoin,
tirilazad
mesylate, dexanabinol, CPC-21 1, CPC-1 11, bosentan, clopidogrel hydrogen
sulfate,
nadroparin, ticlopidine, NS-1209, ADNF III, vinconate, ONO-2506, cilostazol,
SUN-
N4057, SR-67029i, nicardipine, YM-337, and YM-872.
The present invention may be utilized following administration of the drug
through acceptable methods of administration to evaluate the effects on
vessels. It is to be
understood that the present invention may be practiced with regard to
different vessels,
including but not limited to, vessels in the extremities, in the coronary
circulation, and
extracranial and intracranial cerebral vessels. In a preferred embodiment, the
extracranial
and intracranial cerebral vessels are examined with the present invention.
Measurements may be taken before administration of the drug, and at
specific times following administration of the drug to determine the effect of
the drug on
vascular reactivity. In this manner, each individual subject and each
individual vessel acts
as its own control to assess the effects of that drug on that specific vessel.
All cerebral vessels may be analyzed to determine whether the drug has
differential effects on different cerebral vessels. By performing such an
analysis over numerous
individuals, valuable data may be obtained concerning the vascular effects of
a specific drug.
Furthermore, by choosing individuals from different groups, such as (a)
individuals with no
known pathology, (b) individuals with no known pathology in specific age
groups, (c)
individuals with known pathology in a specific disease group, (d) individuals
with known
pathology in a specific disease group in a specific age range or in a specific
stage of the
progression of the disease, and (e) individuals in a specific disease group
currently receiving
specific therapeutic mediations.
Through application of the present invention to individuals from the desired
group, valuable information may be obtained concerning the effects of
different disease
processes, or prior or co-administration of other drugs, on the vascular
effects of the test
drug in different individuals, at different ages, and in different conditions.
It will be appreciated that a preferred embodiment of the present invention
allows for the assaying of the efficacy of a treatment comprising collecting
data regarding
cerebrovascular health status of a number of individuals serving as patients
in the clinical trial;
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grouping the patients into at least two groups of patients such that patients
with a similar
cerebrovascular health status are grouped together; applying the treatment to
the at least two
groups of patients; monitoring outcomes of the treatment for each of the at
least two groups of
patients; and determining the efficacy of the treatment based on the outcomes
of the treatment
for each of the at least two groups of patients. In a preferred embodiment of
the present
invention, the data regarding cerebrovascular health status comprises mean
flow velocity value
for at least three cerebrovascular vessels of the individuals and systolic
acceleration value for at
least three cerebrovascular vessel s of the individuals. In another preferred
embodiment of the
invention, the data regarding cerebrovascular health status further comprises
calculating a
pulsatility index.
Another preferred embodiment of the present invention provides a method of
screening for adverse effects of a treatment comprising: applying the
treatment to a number
of individuals; monitoring the cerebrovascular blood flow of such individuals
after applying
the treatment; and identifying adverse effects to cerebrovascular blood flow
in such
individuals arising after applying the treatment. In a preferred embodiment,
quantitative
data regarding the cerebrovascular blood flow of a number of individuals is
obtained. In a
still further preferred einbodiment of the present invention, the data
regarding
cerebrovascular health status comprises mean flow velocity value for at least
three
cerebrovascular vessels of the individuals and systolic acceleration value for
at least three
cerebrovascular vessels of the individuals. In still a further preferred
embodiment, the data
regarding cerebrovascular health status further comprises calculating a
pulsatility index.
It will be appreciated that the present invention allows for the creation of
matched groups with a suite of blood vessel issues, e.g., plaque and general
vasculitis,
among others. The present invention also provides for the creation of matched
groups with
a particular circulatory problem, e.g., stenosis in a particular vessel,
inadequate profusion of
small blood vessels in posterior of brain, migraines, and apnea, among others.
Under conventional approaches to clinical trials, one cannot identify
participants with such problems, much less match participants wherein both
groups have
essentially the saine severity and incidence of the pathology being examined.
Thus, the
conventional approach to clinical trials (1) address much less specific
conditions, e.g.,
overall stroke risk, rather than the precise severity and incidence of the
pathology being
examined, (2) include individuals who show no disease/deterioration, and (3)
include
individuals who are likely to suffer immediate catastrophic failure. Despite
numerous
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attempts to conduct clinical trials related to primary stroke prevention where
there is no
previous history of stroke or acute cardiac event, this problem has remained
unsolved until
now.
EXAMPLE 1: Effects of Propranolol on Vascular Reactivity
Propranolol, also known as Inderal, is prescribed routinely for individuals
with hypertension, one of the major risk factors for stroke. In order to
assess the effects of
propranolol on vascular reactivity, a transcranial Doppler analysis was
performed on the
cerebral vessels of a 46 year old hypertensive man. Propranolol was then
administered at
an oral dosage of about 40 mg. Another transcranial Doppler analysis was
performed
approximately two hours after administration of the propranolol. Changes in
specific
vessels were compared to pre-administration readings. By analyzing pre- and
post-
administration vessel dynamics, an indication of the effect of the beta
adrenergic blocker,
propranolol, on dynainics of flow in specific cerebral vessels is obtained.
EXAMPLE 2: Analysis of the Effects of Plavix on Cerebral Vessels
Plavix is a member of a class of drugs known as blood thinners or anti-
platelet drugs. Plavix is often prescribed following stroke to minimize
platelet aggregation
and clot formation. However, one of the major dangers of Plavix is
intracranial hemorrhage.
Therefore, when using Plavix to prevent or minimize the possibility of a
stroke due to
infarction, one may increase the possibility of a hemorrhagic stroke.
Accordingly, properly
selecting the appropriate patient for Plavix is critical for maintenance of
vascular health.
A 63 year old male with a history of hypertension experiences a first stroke
in the left middle cerebral artery resulting in deficits in the right hand,
leg, and some deficits
in motor speech. These are the symptoms upon presentation in the neurological
clinic.
Transcranial Doppler analysis of all cerebral vessels is performed in addition
to analyzing
the common carotid artery and the internal carotid artery. The analysis
reveals alterations in
vascular flow in the internal carotid artery just distal to the bifurcation of
the common
carotid artery. A stenotic area is observed. Further, additional flow
abnormalities are
detected in the left middle cerebral artery, consistent with the patient's
presentation of right-
sided motor paralysis. Transcranial Doppler analysis reveals excellent
collateral flow to the
contralateral hemisphere and no deficits in the left anterior cerebral and
left posterior
cerebral arteries.
The physician considers prescription of Plavix together with a calcium
channel blocker. Transcranial Doppler analysis was performed at monthly
intervals. By
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analyzing changes in the individual cerebral vessels as a function of Plavix
+/- calcium
channel blocker administration, the physician observes no effect on the
cerebral vessels.
The physician subsequently administers a higher dose. Again, transcranial
Doppler analysis
is performed on all cerebral vessels. The physician observes marked changes in
the
vascular dynamics of the vessel studied as the pulsatility index decreases and
the auto-
regulation curve left-shifts toward normal. The physician, based on these
results,
determined a proper dosage of the vasoactive medication for the patient.
The patient is then monitored on a monthly basis after the initial
prescription
of Plavix in order to determine whether vascular changes are occurring which
necessitate
alteration in the therapy.
EXAMPLE 3: Assessment of Cerebral Vascular Status During
Battlefield Situations
A 21 year old paratrooper jumps from an airplane to reach the battlefield
below.
While parachuting to the surface, his parachute becomes entangled in the
branches of a large
tree. The serviceinan hears gunfire in the vicinity of his location and, in an
attempt to free
hiinself, cuts one of the lines connecting the parachute to his harness. He
falls to the earth but
his head strikes a major branch of the tree during descent. The servicenian is
found
unconscious by a field medic. After determining that no cervical fracture is
present, the medic
removes the serviceman to a field hospital. Transcranial Doppler is performed
by the medic
trained in such techniques. The data is acquired and transmitted by an uplink
satellite
cominunication to a battlefield command center hospital. Prior data on the
serviceman is
compiled during routine physical examination at the time of induction into the
service. The
new transcranial Doppler data is compared to the prior data. The results
indicate dramatic
changes in auto-regulation of the left anterior cerebral artery. This is
caused by vasospasm due
to a subarachnoid hemorrhage from blunt force trauma at the fronto-parietal
suture. There is
also a subdural hematoma. The field physician suspects this possibility in
view of the
contusions evident in the region of this suture. The results of the
comparative analysis of the
cerebral vessels are transmitted to the field physician who then performs an
emergency
craniotomy in the region of the left fronto-parietal suture. Following release
of pressure on the
brain and stabilization of the patient, a transcranial Doppler analysis is
performed immediately
post surgery, and at 12 and 24 hours thereafter. The results indicate that the
left anterior
cerebral artery flow dynamics are changing and the characteristic of this
vessel moves from the
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lower right quadrant on the plot of flow velocity versus systolic acceleration
toward the region
of norinal auto-regulation.
Another scenario is development of spasm or post-traumatic hyperemia at
24 C with clinical deterioration. Transcranial Doppler analysis was performed
at the field
hospital. Worsening vasospasm was found and the treatment altered in response.
EXAMPLE 4: Application of Transcranial Doppler Analysis in the
Emergency Room
A 23 year old is admitted into the emergency room in a state of extreme
agitation and mania. While the medical staff is attempting to obtain a blood
workup and
waits for the results of the analysis, the patient suddenly falls unconscious.
Blood pressure
is observed to drop precipitously. Transcranial Doppler analysis is performed
on the
cerebral vessels of the patient. The results indicate a shifting to the lower
left of the normal
regulation curve for the left middle cerebral artery. Electrocardiagraphic
analysis reveals
atrial fibrillation. Blood chemistry reveals that the patient took a large
dosage of cocaine
together with amphetamine. The results of the transcranial Doppler analysis
are consistent
with induction of cerebral vascular failure which was secondary to a heart
attack due to
extreme vessel constriction of the coronary vasculature.
EXAMPLE 5: Case Study of a Female Who Presented With Unsteady
Gait
A 62 year old female presented in the neurological clinic complaining of
slight feelings of unsteadiness during walking. Transcranial Doppler analysis
was
performed and the different cerebral vessels were analyzed. The initial
nomogram
schematic representation of a 2-dimensional nomogram of the transcranial
Doppler
sonography data, in which mean flow velocity is indicated on the y-axis and
systolic
acceleration is provided on the x-axis, is provided in Figure 9a. Shortly
thereafter, the
patient's symptoms worsened, however, no definitive diagnosis was yet
established.
Transcranial Doppler analysis was performed a second time and the transcranial
Doppler
sonography data was represented in a second nomogram provided in Figure 9b.
The results
were compared to the first test and showed a clear shifting to the right on
the flow velocity
versus systolic acceleration plot.
Next, the patient was hospitalized in critical condition and yet no diagnosis
had been established. The technician performed another transcranial Doppler
test and the
transcranial Doppler sonography data was represented in a third nomogram
provided in
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Figure 9c. A dramatic shifting to the right of many of the vascular points was
observed. A
cisternogram revealed hydrocephalus, so a shunt was inserted. The neurologist
concluded
that an increased intracranial pressure had exerted a deleterious effect on
the cerebral
vessels displacing them from the normal auto-regulation zone. Following
surgery, a fourth
transcranial Doppler analysis was performed and the transcranial Doppler
sonography data
was represented in a fourth nomogram provided in Figure 9d. The results showed
a clear
return toward baseline, i.e., a left shifting in the characteristic data
points for the vessels
analyzed toward their prior location at the time of the second test.
This example demonstrated that the results froin the transcranial Doppler
analysis, a non-invasive and highly accurate test, provided valuable
information for the
neurologist to select an appropriate course of action thereby probably
preventing a massive
increase in intracranial pressure resulting in an occlusive stroke and
probable death. These
results also provided an indication of the onset of the life-threatening
changes that occurred
between tests 2 and 3.
EXAMPLE 6: Use of Transcranial Doppler to Analyze Blunt Force
Trauma in an Athlete
During a soccer match, a 17 year old high school student receives a severe
blow
to the forehead when he and an opponent jumped together to head the ball. The
student
becomes unconscious but is then revived with smelling salts. After the game,
he complains of
changes in his vision. He is taken to the emergency room and a transcranial
Doppler analysis is
performed. The results of the analysis are compared to a transcranial Doppler
analysis
performed at the beginning of the soccer season. Transcranial Doppler analysis
shows a slight
change in the flow dynamics of the left posterior cerebral artery indicating
hyperemia or
increased flow often observed in patients with cerebral contusions. Twenty-
four hours later the
patient's mental state deteriorates and a CT scan only reveals subarachnoid
blood. A repeat
transcranial Doppler analysis shows vasospasm of the same artery. An
interventional
neuroradiologist is called into the case and performs angioplasty. Following
the procedure,
transcranial Doppler analysis is perfonned periodically over a 6 week period.
The results are
compared to the transcranial Doppler profile at the time of admission to the
emergency room
and also to the normal readings obtained at the beginning of the. soccer
season. The results
show a gradual return to the normal flow patterns for the left posterior
cerebral vessel.
EXAMPLE 7: Use of Transcranial Doppler to Analyze Blunt Force
Trauma in the Vascular Effects of a Drug
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A pharmaceutical company has developed a new substance which it suspects
may have antihypertensive activity by inducing partial dilation of blood
vessels. The
company selects a patient population of individuals with normal blood
pressure, a
population with mild hypertension, and a population with severe hypertension.
Sub-
populations are constructed based on age (fourth, fifth and six decades of
life) and sex.
The cerebral vessels of all patients are analyzed using transcranial Doppler
analysis, as described in the present invention, two hours before and two
hours following
oral administration of 25 mg of the test substance. Blood pressure was
monitored at"30
minute intervals for the two hours before aiid two hours following oral
administration of the
new substance. The results demonstrate no discernable effect in the
normotensive and
mildly hypertensive group, and a significant anti-hypertensive effect in the
severely
hypertensive patients in all age groups tested. Analysis of the data obtained
with
transcranial Doppler revealed a decreased flow velocity in the vessels of the
great arterial
circle.
Significant variation is detected in the data set from the female test groups
in
the fifth and sixth decades of life. Further questioning of these individuals
revealed use of
antimenopausal hormone replacement therapy through combined administration of
estrogen
and progesterone. Removal of data contributed from these individuals
dramatically
decreases variance in these test groups. The pharmaceutical company initiates
a new study
to examine the potential interactions of the test substance with estrogen,
progesterone, or a
combination of estrogen, and progesterone, in normotensive, mildly
hypertensive, and
severely hypertensive females in premenopausal and postmenopausal groups,
further
subdivided by history of hormone replacement therapy or exposure to oral
contraceptives.
The invention as disclosed above is also applicable as both a system and
method for assessing and treating hydrocephalus. Specifically, the invention
provides a
system and method for identifying critical variables affecting the
intracranial space,
including increased intracranial pressure (ICP), and is capable of being used
to distinguish
patients suffering from one of several forms of hydrocephalus from the normal
population.
Hydrocephalus is a condition characterized by increased intracranial pressure
resulting in decreased intracranial blood flow. Raised intracranial pressure
puts additional
external force on vessels, compressing small vessels such as terminal
capillaries and/or the
capillaries of the vaso-vasorum, which supplies blood to arterial walls.
Diminished flow to
the vaso-vasorum reduces the ability of the smooth muscle of an arterial wall
to relax,
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thereby diminishing the compliance of the conductance vessels. The combination
of
diminished compliance and increased impedance limits vascular performance.
Specifically,
this flow limitation affects the deeper brain structures fed by deep
penetrating arteries such
as those in the periventricular space. This decrease in flow
characteristically results in
edema formation at the ventricular horns which is believed to be a watershed
ischemic
event.
Very little is known in most cases about the cause of hydrocephalus. It has
been observed to affect patients with a variety of conditions including, for
example,
meningitis or intracranial hemorrhage (e.g. subarachnoid hemorrhage) and it
has been
speculated that it can be precipitated by certain metabolic disorders or
general inflammatory
states. It may also affect people, particularly the elderly, who exhibit no
preexisting
condition. The hydrocephalus condition often seen in the elderly is known as
Normal
Pressure Hydrocephalus (NPH).
NPH is a neurological disorder. While its exact cause is unknown, there are
several competing theories as to its cause. The main postulated theory is that
NPH results from
increased intracranial pressure on brain tissue due to improper or inefficient
reabsorption or
clearance of accumulated cerebrospinal fluid. Spinal fluid is generated at a
rate of half a liter a
day and must be reabsorbed. Given that the cranium represents a fmite space,
an equilibrium
must exists between fluids entering and leaving that space otherwise the
pressure within will
increase. Modern studies indicate that the generation and reabsorption of
spinal fluid is an active
process, as opposed to a passive one. As such, it is predisposed to
deterioration and breakdown
from various causes that can lead to an accumulation of excess fluid and a
resulting increase in
intracranial pressure. A second theory asserts that the increased intracranial
pressure associated
with NPH is caused by disease of the small vessels in the brain leading to
cortical atrophy (i.e.
diminished flow to the small vessels leading to a relative enlargement of the
ventricles). It is also
possible that NPH results from a combination of these theories-- a concurrent
vascular change
due to transient spinal fluid accumulation when a patient is recumbent at
night that is associated
with diminished venous flow outside of the cranium resulting in a blood volume
build-up within
the cranial vascular space causing a relative increase in pressure. Data
derived from the
invention speaks conclusively to the fact that NPH is the result fluid
accumulation that in turn
creates vascular disorder. The invention has fiu ther enabled the specific
characterization (i.e.
monitoring and diagnosis) of that vascular disorder throughout the onset,
treatment and follow-
up care of NPH.
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Considerable confusion exists in modern medicine distinguishing these two
suspected root causes of NPH. Conventional imaging studies show nothing more
than an
increase in the space occupied by cerebrospinal fluid. These studies, however
cannot
comment directly on the behavior of the fluid. That is, MRI or CAT scans can
only show
concurrent fluid dilation associated with brain atrophy. These "causes"
standing alone,
however, are commonly interpreted as nothing more than age-related changes
instead of
treatable causes of another condition (i.e., NPH).
Further complicating accurate diagnosis of NPH is that it is characterized by
the "classical symptom triad" of incontinence, dementia and unsteadiness of
gait, though
other symptoms are often present or more prevalent. These symptoms can often
be
mistakenly attributed to other causes. As a result, NPH is frequently
misdiagnosed because
it historically requires a high index of suspicion on the part of the treating
physician. Once
suspected, NPH is difficult to definitively assess and diagnose accurately.
Conventionally,
confirming a diagnosis of NPH entails performing an invasive procedure, known
as a
cisternogram, comprising injection of a radioactive tracer substance into the
subdural space
(i.e., the cerebrospinal fluid space) and monitoring the uptake of the tracer
at particular
points in the cranium using a nuclear detector at 24, 48 and 72 hour intervals
after the initial
injection in an effort to semi-quantitate the clearance of that radionuclide
tracer. Other
methods of diagnosing hydrocephalus and NPH include repeated lumbar puncture
testing,
which is the withdrawal of anywhere from 20 to 40 cc's of spinal fluid to see
if a patient
gains clinical improvement. The most marked improvements being in gait and
mentation.
Continuous pressure monitoring of the spinal fluid pressure can also be
performed via an
indwelling catheter. However, this methodology is performed only at those
institutions
having specialized critical care units dedicated to this task. Furthermore,
this method
entails a very high risk of infection (i.e., a meningitis).
While a cisternograin or other clinical study can be indicative of NPH
condition,
alone they typically cannot defmitively diagnose a patient with NPH because
they do not
sufficiently exclude other causes of the observed symptoms. The only
definitive diagnostic
procedure entails a major invasive neurosurgical procedure. The presence of
the symptoms
alone, however, usually does not warrant performing such a procedure.
Accordingly, it has
been notoriously difficult to both accurately and quickly assess and diagnose
NPH.
Finally, by the time the classic triad of symptoms appears in a patient
sufficient to arouse the suspicions of the treating physician, considerable
injury to the
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central nervous system has already occurred. Given that the central nervous
system has
very little capacity for damage repair, especially in the elderly, it is
highly desirable to have
a system capable of being used to both preventively monitor patients before
symptoms
become evident and to quickly and accurately diagnosis a patient once the
symptoms have
been expressed.
The use of the dynamic vascular analysis (DVA) (also referred to as DCA or
Dynamic Cerebrovascular Analysis) methodology described above has been
uniquely
applied for the diagnosis and evaluation of hydrocephalus, including NPH, both
before and
after surgical correction. It has been used to track the natural history and
progression of the
onset of NPH. It has also been used to generate a reference database useful
for future
diagnoses that includes a variety of intracranial pressure data such as
natural history NPH
data, supine data, Trendelenberg (head down tilt of approximately 15 degrees).
Finally, the
invention provides a reliable, non-invasive, portable, inexpensive method for
diagnosing
and monitoring hydrocephalus and, in particular, NPH.
In accordance with an embodiment of the invention, a representative
DVA/hydrocephalus protocol involves interrogation with a fixed TCD
probe/device, as
depicted in Figures 1-4, such that the artery being studied is continuously
monitored.
Alternatively, other forms of emissive and reflective wave technology, such as
laser technology,
can be utilized. Monitoring occurs with the patient placed in a Trendelenberg
position of
varying degrees (optimally between -15 and -20 ). followed by data collection
at 30, 60, 90
and 120 seconds intervals. Following analysis in the Trendelenberg position,
the patient is
brought to the supine position. Again, data is collected at 30, 60, 90 and 120
second intervals.
In a norinative patient state there will be no statistically significant
change in flow dynamics of
the vessel being interrogated. Patients experiencing global intracranial
change (i.e.,
experiencing increasing intracranial pressure) will demonstrate dramatically
changing and
shifting flow dynamics between hyperdynamic states characterized, in part, by
stiffening of the
vessel, increasing acceleration and slight impedance increases but with very
little change of the
velocity.
While in the Trendelenberg position the relationship between the middle
cerebral and the ophthalmic artery is observed for the patient. There will be
a reversal of
the impedance index relative to a norinal baseline state in a patient
experiencing increased
intracranial pressure associated with hydrocephalus. It is also helpful to
similarly diagnose
increased intracranial pressure prior to evaluating the subject in the
Trendelenberg position.
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The protocol is also applicable after a patient has undergone an intracranial
shunting procedure.
One cominon shortcoming of most diagnostic systems relates to the lack of
sensitivity and specificity associated with the differential diagnosis of
various conditions (i.e.
increased intracranial pressure and/or flow variations) that may explained by
any number of
physiological phenomenon. The invention has enabled observation of the
abnormal flow
characteristics in patients suffering from hydrocephalus which are especially
apparent during a
tilt table (Trendelenberg) test. The fundamental feature of the test is the
ability to detect and
observe a homogenous global increase in both the pulsatility index and flow
acceleration, thus
enabling discrimination between homogenous and heterogeneous effects from
global intracranial
events. For example, a global event could be global inflammation which would
typically cause a
patchy distribution when the TCD data was correlated (i.e., a heterogeneous
event) or it could be
a metabolic disorder affecting all vessels homogeneously without necessarily
excluding any
particular region. These metabolic disorders may include, for example, Fabry
Disease or
Diabetes.
One example of an application of the invention involved an elderly patient
who represents the first documented natural history study of the development
of increasing
intracranial pressure. In other words, it represented the first progressive
study of the onset
of NPH. Figures 28A-28D illustrate this progressive study. It was observed
that the onset
of NPH over time was characterized by global blood flow accelerations in the
cerebral
vasculature, as well as an increase in the pulsatility index. There was also
an observed
reversal in the impedance index of the middle cerebral artery to ophthalmic
artery
relationship. Typically in a normal state, the ophthalmic artery is considered
an end artery
and has higher impedance values (or index of pulsatility) than the middle
cerebral artery
which is considered a conductance artery. If an impedance reversal occurs, the
impedance
is greater in the conductance vessel than the end artery. Furtherinore, when
an impedance
reversal occurs, it exists bilaterally in the cranium. As such, it is probable
that the reversal
is a result of increased intracranial pressure. Figure 29 demonstrates that
traditional blood
flow tests would not have detected the intracranial pressure changes occurring
in the subject
that were observable using transcranial-based dynamic vascular assessment.
As an extension of the above study, Table 8 contains inean flow velocity,
systolic
acceleration and pulsatility index data for two series of subjects suffering
from increased
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intracranial pressure obtained by TCD when the subjects were moved from a
supine to a head-
down tilt position. Figures 30-32 illustrate this same data after being
subjected to DVA analysis.
Group Mean Flow Velocity Systolic Acceleration Pulsatility Index
41 693 1.72
59 1537 1.78
Series 1 64 1138 1.64
61 1372 1.91
55 1327 2.01
59 1932 1.94
52 437 0.76
54 458 0.90
52 473 0.81
54 451 0.83
58 656 0.84
Series 2 56 467 0.76
55 390 0.70
55 428 0.76
46 539 0.95
54 614 0.74
47 478 0.75
43 593 0.79
Table 8.
Once calculated, the TCD data was analyzed by Dynamic Vascular Analysis
(DVA), as described above. The DVA for each subject comprised a) a
simultaneous
consideration of the TCD values (peak systolic velocity(PSV), end diastolic
velocity (EDV),
peak systolic time (PST), end diastolic time (EDT), mean flow velocity (MFV),
systolic
acceleration (SA), pulsatility index (PI), the natural logarithm of the SA
(LnSA)) for each of the
established 19 vessel segments within the cerebral vasculature; b) a
comparison of the TCD
values against a reference database to quantify the degree of variance from
mean values; and c)
a series of indices (blood flow velocity rations) derived from the TCD values
that are
representative of the vascular status/performance/health of each the 19 vessel
segments. The
derived indices include:
1. Acceleration/Mean Flow Velocity Index (VAI) (Systolic Acceleration value
divided by the Mean Flow Velocity value and/or reciprocals thereof);
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2. Velocity/Impedance index (VPI) (Mean Flow Velocity value divided by the
Pulsatility Index value and/or reciprocals thereof); and
3. Acceleration Impedance Index (API) (Systolic Acceleration value divided by
the Pulsatility Index value and/or reciprocals thereof).
The 19 intracranial vessel segnients considered are depicted in Figures 33
and 34. The vessel segments depicted in Figures 33 and 34 represent the left
and right
vertebral artery (VA), basilar artery (BA), posterior cerebral artery/PCA t
(towards) (P1),
posterior cerebral artery/PCA a (away) (P2), internal carotid artery/ICA t
(towards) (Cl),
middle cerebral artery (M1), anterior cerebral artery (Al), anterior
communicating artery
(ACOM), carotid siphon (towards) (C4), carotid siphon (away) (C2), and the
ophthalmic
artery (OA).
The data revealed that patients suffering from hydrocehalus had higher than
normal PSV values for the M1 and Cl segments. These patients also exhibited a
PI
increase in the Ml, A1, Cl and C2 segments as well as an increase in the SA in
the M1, A1
and C4 segments. The LnSA was also increased in the Ml, Al and C4 segments.
Conversely, the acceleration-impedance ratios were diminished in the M1, A1
and Cl
segments. The velocity-impedance ratio was also decreased in the A1 segment.
The
invention further disclosed that increased PI is predictive of hydrocephalus
in the Al and
C 1 segments. Increased SA in the C4 segment is also an indicator of
hydrocephalus.
Finally, a collective increase in SA, PI and LnSA in the Ml segment was also
predictive. It
has been concluded based on this data that observation in blood flow changes
in the C 1
segment provides the most effective indicators and predictors of
hydrocephalus. Blood
flow data derived from the Ml and Cl segments is also well suited for
predicting and
monitoring hydrocephalus.
The invention has been particularly adapted for use in evaluating and
assessing hydrocephalus and NPH. The methodology for doing so involves
measuring one
or more points in the c,erebrovasculature by TCD and performing a DCA analysis
in either
or both the supine and Trendelenberg positions on patients suspected of having
or at risk of
experiencing increased intracranial pressures associated with hydrocephalus
and NPH.
The invention has further application than the direct detection and
monitoring of patients with hydrocephalus. For example, there currently exists
a
programmable shunt system. A shunt is a tube placed in the fluid space in the
brain that
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drains into the belly cavity and which usually passes through a pressure
control valve. The
valve activates the shunt to drain after a preset intracranial pressure level
is reached.
Continuous drainage is undesirable because creates the risk of over-drainage
and the
formation of a causing a subdural hematoma. The programmable shunt system was
developed whereby the shunt is initially set at a high opening pressure and
progressively
adjusted according to clinical effect. The difficulty with such a process is
that it usually
takes two to tliree weeks to observe an adequate clinical effect in order to
change the
pressure setting of the shunt system. The invention enables observation of any
dynamic
shift in vessel performance long before there is a clinical change in the
patient. In fact, the
invention enables almost instantaneous changes in vessel performance. It is
thus possible to
make adjustments to these types of shunting systems much more quickly and
accurately.
For example, a monitoring physician can utilize the invention as an indicator
of when to
reduce the valve opening pressure level without go so low as to risk patient
development of
a subdural hematoma. It also enables the physician to optimize the
normalization of
cerebral perfusion over a two or three day period rather than a several month
period because
it eliininates the need to follow the traditional process of adjusting the
pressure level
followed by a several week wait to observe a clinical effect.
The device is also of practical value to makers and distributors of shunts and
related devices. The invention enables makers and sellers of such devices
because in
enables better product development and marketing practices and in turn
facilitates
expansion of product markets. For example, the invention could be given to a
care facility
as part of a contract to exclusively purchase shunts from a particular
manufacturer or
distributor.
It is also envisioned that the invention will be used a screening device at
hospitals, nursing homes and other care facilities. Specifically, it will help
facilitate resource
management by enabling administrators and treating physicians to forecast
demand for,
among other things, intracranial shunts, as well as the staff needed for
implanting the same.
The invention further facilitates more effective monitoring and tracking of
patients with
known intracranial conditions that predispose them to suffering intracranial
pressure increases.
These patients would include, for example, those having experienced or
disposed to
experiencing a hemorrhagic stroke or patients with altered mental status
suspected to be
related to increased intracranial pressure. Further, because the invention is
disposed to being
operated both as a monitor and/or remotely, it can be operated from a central
location within a
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care facility (e.g., a nurses station), thus enabling one person to
simultaneously monitor a
number of patients.
The invention is well suited to the development and optimization of drugs,
treatments and therapies of NPH. That is, the invention can be readily
utilized to evaluate
the effects of various hydrocephalus treatment methodologies by monitoring
patients both
pre- and post-treatment. Furthermore, the treatment data can be further
combined with
longitudinal patient data to particularly tailor patient treatment regimens.
Finally, as will be appreciated by those skilled in the art, the invention as
a
methodology for diagnosing and treating hydrocephalus can be further applied
in an
automated fashion, locally or remotely, via telecommunications line or simple
local bedside
test. As with any diagnostic test, the present invention is intended in at
least one
embodiment to be a fully-automated, remotely-controlled diagnostic system for
the
detection and monitoring of increased intracranial pressure.
In a controlled study, it has been discovered that the invention is also
applicable as both a system and method for assessing and treating dementia.
Specifically,
in a study of 56 patients with a diagnosis of dementia, Alzheimer's type, and
39 age-
matched controls, it has been observed that the invention can identify
critical variables that
affect intracranial blood flow that in turn cause dementia.
Participants were categorized into either the patient or control group based
on
several factors. Members of the patient group had a pre-existing diagnosis of
dementia and had
below average performance on the Mini Mental Status Exam (MMSE). The control
group was
selected from friends and family of the dementia patients based on the absence
of a dementia
diagnosis, no reported history of cognitive impairment, and an above average
score on the
MMSE.
Study subjects were evaluated using TCD, though other forms of emissive
and reflective wave technology, such as laser technology, can alternatively be
utilized.
TCD measurements were conducted in a small 10'X10' dimly lit room and asked to
sit in a
recliner-style chair using traditional TCD methodologies. TCD measurements
were
obtained non-invasively and provided blood flow velocity data of the major
arteries
supplying blood to the brain. Waveforms were obtained from several cranial
windows.
The transtemporal windows were used bilaterally to view segments of the middle
cerebral
arteries, anterior cerebral arteries, internal carotid artery, and the
posterior cerebral arteries.
The transophthalmic windows were used bilaterally to view segments of the
ophthalmic
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arteries as well as the internal carotid arteries. The transoccipital window
was used to view
the right and left vertebral arteries as well as several depths of the basilar
artery. A sweep
speed of 4 seconds per screen was used yielding 3-7 quality waveforms per page
based on
the participant's heart rate. The display screen was saved when the
technologist identified
at least one waveform on which a clear diastolic trough and a systolic peak
could be
measured on one waveform that was among several contiguous waves. The vessels
were
insonated at well-established depths corresponding to the 19 established
vessel segments.
Analysis of the TCD data comprised software-assisted determination of time
and velocity. Specifically, the TCD technologist placed the computer cursor on
the end-
diastolic trough immediately prior to the up-sloping and second cursor at the
ensuing peak
systole. The x- and y-axis values for each cursor position yielded,
respectively, the time and
velocity. From this data, the peak systolic velocity, peak systolic tinie, end
diastolic velocity,
and end diastolic time values were determined. Using traditional TCD formulae,
this data was
used to calculate the Mean Flow Velocity, Systolic Acceleration, and
Pulsatility Index values
for each subject.
Once calculated, the TCD data was analyzed by Dynamic Vascular Analysis
(DVA), as described above. The DVA for each subject comprised a) a
simultaneous
consideration of the TCD values (MFV, SA, and PI) from a single wave form for
each of
the established 19 vessel seginents within the cerebral vasculature; b) a
comparison of the
TCD values collected from a single wave against a reference database to
quantify the
degree of variance from mean values; and c) a series of indices (blood flow
velocity rations)
derived from the TCD values that are representative of the vascular
status/performance/health of each the 19 vessel segments depicted in Figures
33 and 34.
The derived indices include:
1. Acceleration/Mean Flow Velocity Index (Systolic Acceleration value
divided by the Mean Flow Velocity value and/or reciprocals thereof);
2. Velocity/Impedance index (Mean Flow Velocity value divided by the
Pulsatility Index value and/or reciprocals thereof); and
3. Acceleration Impedance Index (Systolic Acceleration value divided by the
Pulsatility Index value and/or reciprocals thereof).
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The data revealed that the patients suffering from dementia had a decrease in
mean flow velocity and a corresponding increase in the pulsitility index
within the Ml, Al,
C1, C2, C4, VA, BA, P1 and the P2 vessel segments. Except for a decrease in
the basilar
artery, it was observed that the systolic upstroke acceleration was unchanged
in the patient
group relative to the control groups.
The blood flow velocity ratios were also determined to be important to the
evaluation of the patients suffering from dementia. First, the
acceleration/velocity ratio, an
indicator of the kinetic energy transfer into forward blood flow, was
increased in the Ml, Al,
Cl, C2, C4, VA, BA, P1 and the P2 vessel segnlents. Conversely, the
acceleration
impedance ratios, indicating the result of downstream impedance force on the
forward force
of blood flow, and the velocity impedance ratio, indicating the effect of
downstream
impedance force on the forward mean flow velocity and a surrogate marker for
relative blood
flow, were diminished in the Ml, A1, Cl, C2, C4, VA, BA, P1 and P2 vessel
segments of the
dementia patients.
The holocephalic diminution of mean cerebral blood flow velocities in a
number of vessel segments in the dementia subjects (relative to the control
group) is
consistent with previous cerebral blood flow studies demonstrating diminished
cerebral
perfusion in dementia (i.e. changes in mean cerebral blood flow velocities
have been
associated with diminished cerebral blood flow). The discovery that systolic
upstroke
acceleration remains unchanged in patients suffering from dementia is
significant when
related to the global diminishing blood flow velocities otherwise associated
with this
condition. If diminished blood flow to the cerebrum is secondary effect of
global low blood
flow, then the cerebral vessels should dilate to compensate for the
diminishing force of flow
up to the point of autoregulation failures. Under this "traditional" scenario,
systolic
acceleration should exhibit a continual to decline. The present invention,
however, has
demonstrated the opposite effect in patients suffering from dementia (i.e.
declining mean
flow velocities did not correspond.to a change in systolic upstroke
acceleration). In other
words, the invention has been used to specifically quantify and demonstrate
that in patients
affected by dementia, a static forward force on blood flow has, over time,
less direct effect
on the forward movement of the blood. The invention expresses this effect on
blood flow
as the acceleration-velocity ratio which is reflective of the amount of
kinetic energy
required for forward blood movement. The invention has demonstrated that the
acceleration-velocity ratio is increased in all vessels, except the ophthalmic
arteries, in
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patients suffering from dementia. This discovery is buttressed by the observed
increases in
the pulsatility index in the Ml, Al, Cl, C2, C4, VA, BA, Pl and the P2 vessel
segments.
In sum, the assumption that dementia is an apoptotic process secondary to
toxic substance deposition, is inconsistent with the data developed by the
invention; if
dementia is the result of atrophy or the loss of brain tissue, the amount of
work (i.e., kinetic
energy) needed to move blood forward should be decreased. The invention has
demonstrated conclusively, therefore, that dementia is at least in large part
a direct function
of blood flow dynamics as opposed to the result of the deterioration brain
matter.
Accordingly, the invention provides a reliable and efficient means for
diagnosing and
assessing patients suffering from dementia as well as monitoring and
optimizing treatments
and regimens designed to combat the onset and progression of the condition.
The invention as disclosed above is also applicable as both a system and
method for distinguishing and assisting in the treatment among various
vascular states,
including, for example, vascular narrowing resulting from vasospasm (or other
similar,
quicker-onset structural vascular changes) from stenotic conditions (which are
characterized
by slower onset periods during which time it is possible for the vasculature
to adapt to such
changes in order to try and maintain normal physiological performance) each of
which can
result in hyperemic (or other physiological changes). In particular, the
invention provides a
methodology of differentiating among various vascular states and conditions
and, in particular,
facilitates characterizing the transition between vasospasm (i.e., a
structural condition) and a
hyperemic state (i.e., a physiological condition) using, among other things,
TCD technology.
The ability to differentiate such vascular states (that may otherwise be
indistinguishable until
after a vascular event) is particularly applicable in, for example,
subarachnoid bleed from a
ruptured aneurysm.
Vascular disease processes can affect the tone of a vessel or create points of
blockage along the vessel (e.g., from inflammation from surrounding blood
related to a
bleed, inflammation in a vessel or atherosclerosis). Various methodologies
exist today for
assessing static vascular function (more commonly referred to as endothelial
function).
These tests generally measure the response to a physiological stimulus such as
breatli
holding or hyperventilation. Arterial blockages, however, are normally
evaluated
functionally from induced changes in mean flow velocity (for example by
Transcranial
Doppler ("TCD") ultrasound) or structurally by angiographical evaluation of
the arterial
segment (showing only a cross section silhouette of a vascular narrowing).
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Stenosis is defined as a vessel narrowing caused by inflammation, external
compression, or arteriosclerosis within an arterial segment. In this regard,
the structural vessel
changes (e.g., narrowing due to vasospasm, inflammation, calcification or a
bleed) result in
physiological (or function) changes such as hyperemia or pressure/flow changes
in associated
vessel segments. These physiological changes due to structural changes in turn
are manifested
in clinical conditions, features or symptoms (e.g., dementia, unsteady gait,
etc.). Thus, there is
structure-function relationship between the anatomical changes within
particular vessel
segments and the function blood flow characteristics that result therefrom. In
this regard, any
stenosis (i.e., narrowing) can cause relative hyperemia and vasospasm that is
manifest
functionally as a supraphysiological (extreme) hyperemia. For example,
vasospasm causes
stenosis, represented by supraphysiologic stenosis hyperemia (i.e., a
supraphysiological change
defined as a change beyond that expected from physiological compensation due
to a process
beyond that segment). Such is characteristic of disease that originates in the
segment being
measured rather than beyond the segment in surrounding segments. It should
also be kept in
mind that when there is atherosclerotic stenosis secondary to inflammatory
changes at any
particular point or vessel segment, there usually exist similar changes
elsewhere in the vascular
system (i.e., both proximate and distal to that point) that produce other
stenotic segments. The
most common form of stenosis is atherosclerotic narrowing. Further, there will
likely be
compensatory changes occuring in adjacent and more distant segments of the
vascular system.
The most common form of stenosis is atherosclerotic narrowing. In the
coronaries and elsewhere, stenosis is assessed by a variety of methods. In the
coronaries, for
example, stenosis is measured primarily by angiography. As discussed above,
however,
angiography provides only a cross section silhouette of a vascular narrowing.
As such,
angiographic analysis is highly susceptible to being inaccurate (at times) due
to the asymmetry
of the narrowing within the artery (i.e., when the projection of view is
changed, it may appear
that the narrowing is either nonexistent or much smaller than would be
measured
physiologically).
Stenotic events and conditions resulting in significant flow alteration due to
structural changes (i.e., narrowing), including those needing therapeutic
intervention, are defined
not only by changes within a vessel segment (as measured by DVA indices), but
also by
coinpensatory changes in the physiological states of adjacent segments. In
other words, a
segment that is stenotic (narrowed) manifests a physiological state that may
be characterized by
DVA indices and further corroborating information may be gathered by
inspecting the
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physiological state of the adjancent segments (in the same vesssel) . The set
of segments that
together evidence the significance of the narrowing may be defined by the
stenotic segment
considered together with the adjacent segments: (1) pre-stenotic segment, (2)
the stenotic segment
and (3) the post-stenotic segment. If dealing with a critical stenosis, the
physiologic states in these
3 segments will be, respectively, a distal Perfusion-Inipedance Mismatch
("PIIVIlVI") in the pre-
stenotic region, a hyperemic breakthrough at the site of stenosis in order to
conserve volume and
pressure of flow, and a proximal PIlVIlVI in the post stenotic region.
PIMM is defined as the imbalance of force vectors such that the impedance
vector contributes more to the balance than the forward force vector. The net
result of this
condition is a reduction in forward flow. There may be two reasons for
PI1VIlVI to occur.
The first possible reason is a"proximaP' PIMM incurred by a drop in proximal
perfusion
pressure as a result of a significant stenosis. The second possible cause is a
"distal" PIMM
resulting from the increase in the impedance vector that induces the
imbalance. Distal
PIMM also occurs when significant small vessel disease is present. A
combination of both
types of PIMM can significantly inhibit forward movement of blood and when it
is present
in a post stenotic region it likely indicates a state of compensatory flow
from other vessels.
Traditionally, neurological critical care defines two distinct types of
cerebral
vascular events. The first event is an ischemic flow or low flow. The second
event is a
vessel rupture (most commonly an aneurysm resulting from an over-dilated
vessel). When
a patient suffers or bleeds from an aneurysm, it typically occurs is in the
subarachnoid space
(i.e., a subarachnoid hemorrhage). The initial response to a subarachnoid
hemorrhage is a
neurologic injury accompanied by loss of consciousness.
Patients surviving the initial event, however, frequently also have a
secondary
response to the hemorrhage. In particular, it is well documented that in the
early phases of
recovery, patients go into a state of hyperemia. Hyperemia is defined as a
pathological
increase in blood flow volume that exceeds the metabolic needs of the tissue
being served by
that vessel.
Another secondary response, often occurring five to ten days after the initial
event, is the development of vasospasm. Vasospasm is defined as the pathologic
constriction of
the muscles to the vessel causing a significant narrowing lead'uig to a
secondary ischemic or
low flow stroke. Prevention and treatment of vasospasm (and more importantly
prevention of
the clinical or morbid state associated with vasospasm) primarily include
hypertension and
hypervolemic therapy. Thus, patients suffering a subarachnoid hemorrhage are
frequently
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given a medication regimen that includes mendicants for preemptively treating
hemodilution,
hypertension, and hypervolemia ("HIIH therapy"). These therapies endeavor to
increase
vascular volume with fluid infusion and by raising the patient's blood
pressure artificially with
pharmacological agents. In the course of raising the patient's blood pressure
and/or increasing
the blood volume, however, it is possible to induce the state of cerebral
hyperemia. Thus,
treatment of one condition (vasospasm) may unintentionally induce the other
(hyperemia). As
such, it is important to be able to distinguish between physiological
hyperemia resulting from
HHH therapy and/or minimal vasospasm following a hemorrhage (i.e.,
physiological conditions
or states) from blood flow diminution from progressive vasospasm and vessel
narrowing (i.e.,
structural conditions).
As can be seen from the foregoing discussion, it becomes very importa.nt to be
able
to distinguish between naturally occurring hyperemia, therapy-induced
hyperemia and whether that
hyperemia is actually becoming a vasospasm. The practicality of making such
distinctions,
however, is difficult to accomplish by traditional methodologies. For example,
the current
treatinent modalities for evaluating vasospasm include transporting a patient
to an angiogeaphy
suite and performing angioplasty on the spastic lesion. Similarly, premature
treatment of an
apparent vasospastic condition (i.e., by HIH therapy) may actually increase a
patient's risk of
hypereinic swelling from the initial vascular event or cerebral edema. As
such, it is critical to
determine if and when a patient is transitioning from a hyperemic state to the
early stages of
vasospasm. Conversely, instituting HHH therapy too late after the onset of
vasospasm is of little or
no value, as it provides no difference to the clinical outcome. In this
regard, unnecessarily
beginning HHH therapy too far after the onset of vasospasm may be detrimental
to the patient's
health in view of the well-known incidence of induced congestive heart failure
among certain older
(i.e., middle age and older) patients undergoing aggressive hypertensive
and/or hypervolemic
therapy.
Thus, the timing and use of hypertensive and/or hypervolemic therapy
following a subarachnoid hemorrhage depends largely on being able to better
define when a
patient is transitioning from a hyperemic state to vasospasm. Currently,
making such
determinations employs comparison of peak systolic velocity ratios (derived
from TCD
ultrasound among other methodologies) of an intracranial vessel versus the
extracranial
carotid artery. This comparison is referred to as the Lindegaard ratio. This
analysis,
however, is not accurate; some studies have shown that the Lindegaard ratio is
no better
than 50% predictive for identifying the transition from hyperemia to
vasospasm.
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Other methodologies have been explored but have not come into widespread
use for evaluating and differentiating among vascular states. On such
methodology involves
measuring blood pressure waves with a catheter being pulled through a point of
narrowing
within the corner artery. Similarly, some efforts have been directed to
conducting vascular
assessments using intravascular ultrasound ("IVUS"). These studies, however,
have focused
almost entirely on the use of the resultant ultrasound images and/or to
evaluate the
physiological responses to the injection of vasodilators (e.g., adenosine) in
order to calculate
an anomaly defined ratio called the coronary flow volume reserve or the
arterial flow volume
reserve.
As discussed below, DVA can be used to quantitatively distinguish the
transition from a hyperemic state to vasospasm (which can vary dynamically and
dramatically on a day-to-day or even moment-to-moment basis in a neurocritical
care unit).
It should be further understood, however, that the physiological principals
described herein
may be extended and/or applied to differentiate other forms of vascular
stenosis.
DVA involves the analysis of the Transcranial Doppler data (TCD). As
applied to evaluating and differentiating among vascular states and
conditions, DVA can
include TCD and/or Intravascular Ultrasound ("IVUS") data (collectively
"ultrasound
data") that is collected and evaluated (via software) as a function of time
and velocity.
Among the factors that can be measured and considered when evaluating and
differentiating
among vascular states are (a) a simultaneous consideration of the ultrasound
data values
(peak systolic velocity (PSV), end diastolic velocity (EDV), peak systolic
tiine (PST), end
diastolic time (EDT), mean flow velocity (MFV), systolic acceleration (SA),
pulsatility
index (PI), the natural logarithm of the SA (LnSA)) for each of the
established 19 vessel
segments within the cerebral vasculature; (b) a comparison of the ultrasound
data values
against a reference database to quantify the degree of variance from mean
values; and (c) a
series of indices (blood flow velocity ratios) derived from the ultrasound
data values that
are representative of the vascular status/performance/health of each the 19
vessel segments.
As discussed above, the 19 intracranial vessel segments considered are
depicted in Figures 33 and 34. The vessel segments depicted in Figures 33 and
34 represent
the left and right vertebral artery (VA), basilar artery (BA), posterior
cerebral artery/PCA t
(towards) (P1), posterior cerebral artery/PCA a (away) (P2), internal carotid
artery/ICA t
(towards) (C1), middle cerebral artery (Ml), anterior cerebral artery (A1),
anterior
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communicating artery (ACOM), carotid siphon (towards) (C4), carotid siphon
(away) (C2),
and the ophthalmic artery (OA).
The derived indices include:
1. Dynamic Compliance Index (DCI) (also referred to as the Dynamic Work
Index (DWI) or Acceleration/Mean Flow Velocity Index (VAI)) = (the
natural logarithm of the Systolic Acceleration value divided by the Mean
Flow Velocity value and/or reciprocals thereof). Thus, the DCI relates to the
force of flow to the mean flow velocity and describes kinetic efficiency of a
segment in moving blood forward.
2. Dynainic Flow Index (DFI or Velocity/Impedance Index (VPI)) = (Mean
Flow Velocity value divided by the Pulsatility Index value and/or reciprocals
thereof). Thus, the DFI relates the mean flow velocity to the impedance
(pulsatility index) and describes how capacitance volume affects flow
through the conductance vessel; and
3. Dynamic Pressure Index (DPI or Acceleration/Iinpedance Index (API)) _
(the natural logarithm of the Systolic Acceleration value divided by the
Pulsatility Index value and/or reciprocals thereof). Thus, the DPI relates the
force of flow to impedance and describes the effect of capacitance
vessel volume on the force of flow.
A pathologically compromised blood vessel (whether by stenosis or
atheromatous disease) is defined according to three physiological segments:
the pre-
stenotic segment immediately proximal to the point of stenosis, the stenotic
segment and the
post-stenotic segment immediately distal to the point of stenosis. The
physiologic states
within these three segments include the Perfusion-Impedance Mismatch (PIMM) in
the pre-
stenotic segment, a hyperemic breakthrough at the site of stenosis (in order
to conserve
volume and pressure of flow) and a proximal PIMM in the post stenotic segment.
As discussed above, PIMM is defined as the imbalance of force vectors, such
that the impedance vector contributes overwhelms the forward force vector such
that there
is a net reduction in forward flow. Within the pre-stenotic segment, PIMM
results from a
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drop in proximal perfusion pressure due to the downstream effects of a
stenosis. Within the
post-stenotic segment, a PIMM results from an increase in the impedance vector
and likely
indicating a compensatory flow from other vessels. The stenotic segment is
defined as a
segment of relative hyperemic breakthrough. In particular, the stenotic
segment exhibits an
increased forward flow due to a narrowed artery that is unable to expand (or
"stretch")
because the elastic properties of the artery are diminishing. Thus, there is a
dramatic
increase in velocity through the segment to maintain flow.
Figure 35 outlines the flow effect with the areas proximate to a stenotic
vessel segment. In Figure 35, it is observed that within the pre-stenotic
segment (labeled
"PIMM (distal)") and the post-stenotic segment (labeled "PIMM (proximal)")
there is a
drop in both DFI and DPI while there is an increase in DCI (also referred to
as the DWI).
Siinultaneously, within the stenotic segment, there is an increase in the DFI
and DPI but a
decrease in the DCI (also referred to as the DWI).
DVA has been used to determine that the DCI (also referred to as the DWI) is a
marker of the elastic properties determining compliance of a given blood
vessel segment. In
particular, it has been preliminarily observed that the transition from a
hyperemic state (due to
HHH therapy but which may also be due to early narrowing) to vasospasm can be
characterized
as a function of DCI (also referred to as the DWI) as measured by DVA (i.e.,
that there will be a
quantifiable point for defining the point at which a vessel transitions from
hyperemia to
vasospasm). Figure 36, depicts a plot of DCI (also referred to as the DWI)
versus time. In
Figure 36, it is observed that over time there exists a threshold DCI (also
referred to as the
DWI) value below which a patient having experienced a vascular event
transitions from a
hyperemic state to vasospasm (the pathologic changes in the DCI (also referred
to as the DWI)
index indicating the transition from hyperemia to vasospasm can be defined as
compliance
uncoupling or elastic uncoupling). In this regard, as a patient starts
transitioning from a
hyperemic state to vasospasm (based on analysis of the patient's blood flow
vectors), timely
and advanced notice can be provided to the management team so as to institute
various
appropriate intravenous and other therapies. These therapies may include the
use of certain
intravascular dilating agents concurrently with angioplasty and/or other
pharmacological
therapy.
In one embodiment of the invention, DVA-measured changes in DCI (also
referred to as the DWI) can be used to evaluate and differentiate among
various vascular
states among patients in a neurocritical care unit.
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In another embodiment of the invention, DVA-measured changes in DCI
(also referred to as the DWI) can be used in clinical trials to further
develop quantitative
metrics and end-points defining hyperemic conditions, vasospasm and the
transition
point(s) between such states as well as to better define the scope and timing
of intervention
with pharmaceuticals and devices. For example, when a subarachnoid hemorrhage
occurs
in the basal vessels to the brain, they essentially deplete any nitrous oxide
and/or dilating
capacity, hence leading to the severe tightening or spasm of this vessel.
Under such
circumstances, treatment with a stent would be appropriate. Figure 37 depicts
a plot of DFI
versus DCI (also referred to as the DWI) of a patient over time following a
vascular event
and the transition between hyperemia and vasospasm. In Figure 37, it is
observed that on
the first day following the vascular event, the affected vessel has a very low
DCI (also
referred to as the DWI), which suggests that extremely "stiff' or inflexible
vessels. As a
result, there is a corresponding high forward flow velocity (on the order of
15 standard
deviations from normal). This state corresponds to vasospasm. After several
days, the
vessel begins to "relax" and flow velocity is diminished. Thus, the vessel
begins
transitioning back to a hyperemic state. Several days later, the vessel
segment continues to
experience a diminishing flow. This data suggests that changes in the DCI
(also referred to
as the DWI) are reflective of the amount of elastic properties of a particular
vessel and are
thus indicative of the transitions between hyperemia and vasospasm. In
particular, it
appears that when the DCI (also referred to as the DWI) value drops below a
certain value it
is indicative of an absolute loss of elastic properties and significant
stiffening of that
segment of vessel.
In another embodiment of the invention, DVA-measured changes in DCI
(also referred to as the DWI) can be used to monitor continuous metrics of
clinical trial
participants that can be readily correlated with specific therapeutic and/or
safety procedures.
Similarly, direct monitoring of continuous quantitative inetrics can be used
in conjunction
with surrogate markers to align dichotomous endpoints. In this way, a
continuous metric
such as DVA can predict a dichotomous outcome with sufficient reliability that
a clinical
trial can be run quickly and with improved efficiency.
In accordance with another embodiment of the invention, DVA-measured
changes in DCI (also referred to as the DWI) can be used to manage the
incidence of induced
hyperemia occurring after a stenting procedure by enabling staged (or stepped)
stent
expansion. Pathological hyperemia refers to the breakthrough increase in flow
following any
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revascularization (i.e., stenting) procedure. Downstream vessels are
particularly susceptible
to such effects because they may have become weakened or atrophied (e.g.,
decreased
elasticity) due to minimal performance demands during the time period (which
may cover
many years) in which flow has been diminished.
In accordance with another embodiment of the invention, the vascular states
can be represented by algorithms incorporated into a computer(s) that can
access a server
and/or communicate over a communications network such as the Internet. Such
algorithms
can also be implemented in a computerized platform coupled to a detection
system capable
of generating and/or receiving flow data including, for example, TCD
ultrasound and/or
other Doppler ultrasound devices.
In accordance with another embodiment of the invention, conventional free-
hand Doppler techniques can be used with the invention to evaluate arterial
segments (e.g.,
manual adjustment of the gating of the reflected sound to ascertain the depth
of the
measurement and also by positioning the three dimensional space).
In accordance with another embodiment of the invention, robotic or self-
directing TCD device may be used. In particular, robotic TCD devices employing
a robotically
adjusted coinputer guided probe can be utilized to continuously maintain a
lock on a particular
target position being measured. An exainple of such a probe includes a
mechanical robotic
probe for use in a neurocritical care unit that can be strapped to the head of
a patient and that
allows for continuous monitoring of TCD data signaling the development of a
vasospasm.
Alternatively, a robotic probe can be used that is capable of self-adjusting
to
sample different depths along one artery or to scan an area in order to obtain
data from
several different arteries during the course of an analysis. The data
collected can then be
processed using DVA to provide continuous visual and auditory readouts
regarding a
patient's evolving vascular state.
In accordance with another embodiment of the invention, DVA-measured
changes in DCI (also referred to as the DWI) can be measured using thin wire
intravascular
ultrasound (IVUS) procedures. For example, a thin wire IVUS device can be
pulled across a
stented vascular region whereby it passes through the pre-stenotic, stenotic
and post-stenotic areas.
As depicted in Figure 38, when data is evaluated following such a procedure,
three distinct
vectors representing the net effect on flow can be observed. This type of data
is also particularly
important as part ot among other things, diversion procedures and studies.
Diversion procedures
and studies entail shunting (e.g., insertion of a tube, such as in a
ventriculostomy procedure or
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other similar procedure, to relieve pressure in an intracranial space) a
blocked vessel and
monitoring a second ancillary vessel that shares a common blood supply and
determining whether
the increase in flow in the blocked vessel (e.g., due to a stent implantation)
impacts flow in the
non-blocked vessel.
EXAMPLE 8: DVA ANALYSIS OF VASOSPASM
DVA was used to acquire data from 14 subjects who had subarachnoid
hemorrhage with vasospasm. All of the subjects were, at different times, on
HHH therapy
though not necessarily at the time of their initial TCD analyses. Some of the
subjects were
not on HHH therapy at the time they had their TCD study. Others were on triple
H therapy
and some of the subjects had multiple TCD studies after they went into spasm
and after the
spasm was resolved. Thus, DVA analysis was performed at multiple critical
states along
this disease pathway (i.e., care pathway) of initial bleed without triple H,
hemorrhagic
stroke with triple H, hemorrhagic stroke with vasospasm, and then the
resolution of
vasospasm (i.e., pre-spasm pre-hyperemia, pre-spasm post-hyperemia, and then
spasm and
then post-spasm).
The results of the DVA analysis on these subjects were as follows:
1. First, it was observed that the patients who were developing hyperemia were
experiencing elevations of their DFI and DPI accompanied by a slight
reduction in the DCI (also referred to as the DWI). This data distinguishes
these patients from those who were not receiving the triple H therapy.
2. Second, it was observed that DVA could reliably distinguish those subjects
in vasospasm from those who were not and/or those who were receiving just
triple H therapy if their DFI and DPI scores, particularly the DFI, reached
approximately 8 standard deviations above normal and that the DCI
(also referred to as the DWI) was approximately 2 standard deviations below
normal. This profile of high DFI scores and low DCI (also referred to as the
DWI) scores represents secondary supraphysiological heinodynamic changes
that indicate substantial vascular narrowing
As discussed above, the DVA process makes measurements in a three parameter
nomogram on a segment-by-segment basis. These measurements can be done in
absolutely any
segment of the body whatsoever, in any arterial or even venous segment of the
body or the heart.
For vasospasm, which is a primary vascular condition (which means that it is
single point
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condition within the vessel being measured but that has an upstream and/or
downstream flow
effect). As a primary condition, vasospasm is an intrinsic disease process of
a single or several
vessel segments, but it is a segmental disease. In the case of vasospasm, you
have a disease in
the arterial system in the brain that does produce collateral uncompensated
hemodynamic
changes (i.e., surrounding segments in the ensemble compensate, or not, for
the primary
intravascular segmental level legion). The surrounding segments, however, do
not need to be
measured in order to characterize vasospasm provided that the threshold
criteria described
above are met. Namely, a vasospasm is characterized by DVA has a flow index of
approximately 8 standard deviations or greater with the compliance index of
approxinnately 2 or
lower.
The situation for vasospasm can be contrasted with a secondary vascular
condition involving a disease (e.g., dementia) that has a systemic flow
effect, and which is
therefore characterized and can only be measured by the observing the
relationship
between particular vessels and segments therein and then correlating such
information so as
to develop an ensemble patter specific for the disease.
Various preferred embodiments of the invention have been described in
fulfillment of the various objects of the invention. It should be recognized
that these
embodiments are merely illustrative of the principles of the invention.
Numerous
modifications and adaptations thereof will be readily apparent to those
skilled in the art
without departing from the spirit and scope of the present invention.
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