U.S. patent application number 10/167625 was filed with the patent office on 2003-04-03 for calibrated measurement of blood vessels and endothelium after reactive hyperemia and method therefor.
Invention is credited to Insull, William JR., Raines, Jeffrey K..
Application Number | 20030065270 10/167625 |
Document ID | / |
Family ID | 23062919 |
Filed Date | 2003-04-03 |
United States Patent
Application |
20030065270 |
Kind Code |
A1 |
Raines, Jeffrey K. ; et
al. |
April 3, 2003 |
Calibrated measurement of blood vessels and endothelium after
reactive hyperemia and method therefor
Abstract
Calibrated method characterizing blood flow in a patient's limb
during reactive hyperemia episode utilizes a blood pressure cuff,
establishes a predetermined, near diastolic, pressure in the cuff
during the episode, continually senses the pressure cuff and
periodically changes the internal volume of the cuff by a
predetermined volumetric amount to calibrate the system with a
calibration pressure pulse. The method may determine the condition
of blood vessels and endothelium by determining, for each
calibration cycle, a blood volume peak and comparing the peak with
peak volume values for healthy blood vessels and endothelium
(potentially waveform analysis). The method, implemented as a
system, inflates, during pre-test, the cuff to a suprasystolic
pressure, and establishes the near diastolic pressure in the cuff
during the episode. A sensor generates a pressure signal and a
subsystem periodically changes the volume during calibration such
that a corrected and calibrated blood volume signal is
calculated.
Inventors: |
Raines, Jeffrey K.; (Coral
Gables, FL) ; Insull, William JR.; (Houston,
TX) |
Correspondence
Address: |
FLEIT, KAIN, GIBBONS, GUTMAN & BONGINI, P.L.
Suite 100
750 S.E. Third Avenue
Ft. Lauderdale
FL
33316-1153
US
|
Family ID: |
23062919 |
Appl. No.: |
10/167625 |
Filed: |
June 12, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10167625 |
Jun 12, 2002 |
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09672544 |
Sep 28, 2000 |
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09672544 |
Sep 28, 2000 |
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09277914 |
Mar 29, 1999 |
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6152881 |
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Current U.S.
Class: |
600/504 |
Current CPC
Class: |
A61B 5/022 20130101;
A61B 5/7239 20130101; A61B 5/0295 20130101; A61B 5/742 20130101;
A61B 5/02141 20130101; A61B 5/02007 20130101; A61B 5/026
20130101 |
Class at
Publication: |
600/504 |
International
Class: |
A61B 005/02 |
Claims
What is claimed is:
1. A calibrated method for characterizing blood flow in a limb of a
patient during reactive hyperemia with a blood pressure cuff bound
about said limb comprising the steps of: establishing a
predetermined, near diastolic, pressure in said blood pressure cuff
during the reactive hyperemic episode; substantially continually
sensing the pressure in said blood pressure cuff during the
reactive hyperemic episode; during the reactive hyperemic episode,
periodically changing a volume of said blood pressure cuff by a
predetermined volumetric amount and substantially concurrently
sensing a resultant change in the pressure as a calibration
pressure pulse; calculating pulsatile blood volume by correcting
the sensed pressure with the ratio of the predetermined volumetric
amount and calibration pressure pulse.
2. A calibrated method for characterizing blood flow as claimed in
claim 1 wherein the step of sensing the pressure includes sensing a
pressure pulse due to blood flow through the patient's arteries and
the step of periodically changing said volume of said blood
pressure cuff by a predetermined volumetric amount includes the
step of changing said volume based upon a periodic presence of a
predetermined plurality of sensed pressure pulses.
3. A calibrated method for characterizing blood flow as claimed in
claim 2 wherein the periodic presence of a predetermined plurality
of sensed pressure pulses defines a cyclic calibration routine for
calculating a plurality of pulsatile blood volumes during the
reactive hyperemic episode.
4. A calibrated method for characterizing blood flow as claimed in
claim 3 including the step of selecting at least one of said sensed
pressure pulses during each cyclic calibration and calculating said
pulsatile blood volume based thereon, said step of calculating a
plurality of pulsatile blood volumes during the reactive hyperemic
episode including the step of utilizing said at least one of said
sensed pressure pulses for each said cyclic calibration.
5. A calibrated method for characterizing blood flow as claimed in
claim 4 including the step of reducing motion artifacts by
averaging one from the group of a predetermined number of sensed
pressure pulses in each cyclic calibration and a predetermined
number of pulsatile blood volumes in each cyclic calibration.
6. A calibrated method for characterizing blood flow as claimed in
claim 4 including the step of correlating an episodic time with
each cyclic calibration.
7. A calibrated method for characterizing blood flow as claimed in
claim 6 wherein said pulsatile blood volume is a wave and the
method includes the step of calculating a plurality of peak values
for the pulsatile blood volume during the reactive hyperemic
episode.
8. A calibrated method for characterizing blood flow as claimed in
claim 7 including the step of graphically presenting said plurality
of peak values for the pulsatile blood volume with respect to the
correlated episodic time for substantially the entire reactive
hyperemic episode.
9. A calibrated method for characterizing blood flow as claimed in
claim 3 wherein the step of changing said volume based upon a
periodic presence of a predetermined plurality of sensed pressure
pulses includes the step of counting sensed pressure pulses.
10. A calibrated method for characterizing blood flow as claimed in
claim 9 wherein the step of changing said volume based upon
counting a periodic presence of a predetermined plurality of sensed
pressure pulses includes the step of counting at least three
substantially similar pressure pulses and subsequently changing
said volume with said predetermined volumetric amount.
11. A calibrated method for characterizing blood flow as claimed in
claim 10 including the step of ignoring a second predetermined
plurality of sensed pressure pulses subsequent to changing said
volume with said predetermined volumetric amount.
12. A calibrated method for characterizing blood flow as claimed in
claim 11 wherein said steps of counting at least three
substantially similar pressure pulses, subsequently changing said
volume with said predetermined volumetric amount, and ignoring a
second predetermined plurality of sensed pressure pulses subsequent
to changing said volume defines a cyclic calibration period.
13. A calibrated method for characterizing blood flow as claimed in
claim 8 wherein the step of changing said volume based upon a
periodic presence of a predetermined plurality of sensed pressure
pulses includes the step of counting sensed pressure pulses.
14. A calibrated method for characterizing blood flow as claimed in
claim 13 changing said volume based upon counting a periodic
presence of a predetermined plurality of sensed pressure pulses
includes the step of counting at least three substantially similar
pressure pulses and subsequently changing said volume with said
predetermined volumetric amount.
15. A calibrated method for characterizing blood flow as claimed in
claim 14 including the step of ignoring a second predetermined
plurality of sensed pressure pulses subsequent to changing said
volume with said predetermined volumetric amount.
16. A calibrated method for characterizing blood flow as claimed in
claim 15 wherein said steps of counting at least three
substantially similar pressure pulses, subsequently changing said
volume with said predetermined volumetric amount, and ignoring a
second predetermined plurality of sensed pressure pulses subsequent
to changing said volume defines a cyclic calibration period.
17. A calibrated method for characterizing blood flow as claimed in
claim 16 including the step of obtaining said patient's diastolic
blood pressure prior to said reactive hyperemic episode and
utilizing one of said patient's diastolic pressure and a
predetermined, step-down diastolic pressure in the step of
establishing said predetermined pressure in said blood pressure
cuff during the reactive hyperemic episode.
18. A calibrated method for characterizing blood flow as claimed in
claim 17 including the step of occluding blood flow through the
limb of said patient for a predetermined time period prior to the
step of establishing said predetermined pressure in said blood
pressure cuff thereby creating said reactive hyperemic episode in
the limb of said patient.
19. A calibrated system for characterizing blood flow in a limb of
a patient during reactive hyperemia with a blood pressure cuff
bound about said limb comprising: means, coupled to said blood
pressure cuff, for inflating, for a predetermined pre-test time,
said blood pressure cuff to a suprasystolic pressure and thereafter
establishing a predetermined, near diastolic, pressure in said
blood pressure cuff during the ensuing reactive hyperemic episode;
a sensor, pneumatically coupled to said blood pressure cuff,
substantially continually sensing the pressure in said cuff and
generating a pressure signal during the reactive hyperemic episode;
means, coupled to said blood pressure cuff, for periodically
changing a volume of said blood pressure cuff by a predetermined
volumetric amount during the reactive hyperemic episode; means,
coupled to said sensor, for generating a calibration pressure pulse
signal based upon a resultant change in the pressure signal during
the periodic change of volume; means for calculating a blood volume
signal by correcting the sensed pressure signal with a ratio of the
predetermined volumetric amount and said calibration pressure pulse
signal.
20. A calibrated system for characterizing blood flow during
reactive hyperemia as claimed in claim 19 including means for
quickly releasing said suprasystolic pressure in said blood
pressure cuff prior to establishing said predetermined, near
diastolic, pressure in said cuff.
Description
[0001] This is a continuation of patent application Ser. No.
09/672,544, filed Sep. 28, 2000, now pending, which was a
continuation of U.S. patent application Ser. No. 09/277,914, filed
Mar. 29, 1999.
[0002] The present invention relates to the calibrated measurement
of blood vessels, particularly arterial blood vessels, and the
physiologic change of the endothelium, resulting from the
generation of nitric oxide (NO), after reactive hyperemia and a
method therefor.
BACKGROUND OF THE INVENTION
[0003] Researchers have observed that endothelial dysfunction is an
early event in the pathogenesis of cardiovascular disease. The role
of endothelium in maintaining cardiovascular health is fairly well
documented. Endothelial dysfunction and coronary artery disease
(CAD) are also linked to hypertension, hypercholesterolemia
diabetes mellitus and cigarette smoking. Dietary and lifestyle
modification, in addition to anti-oxidant vitamin supplementation,
have been demonstrated to have a beneficial affect on endothelial
function. Clinical Implications of Endothelial Dysfunction, C.
Pepine, Clinical Cardiology, Vol. 21, November, 1998, pp. 795-799.
Other researchers have observed that the vascular endothelium, the
cells lining the interior portion of arteries, plays a fundamental
role in several processes related to hemostasis thrombosis. These
researchers have proposed that endothelial function may provide
guidance to developing new strategies for coronary disease
prevention and treatment. Nontraditional Coronary Risk Factors and
Vascular Biology: The Frontiers of Preventive Cardiology, by P.
Ridker et al., J. of Investigative Medicine, Vol. 46, No. 8,
October, 1998, pp. 348-350. At present, the full range of different
diseases associated with endothelial dysfunction remains to be
determined, the nature of the abnormalities defined and measured,
and the effects of potential treatments evaluated.
[0004] To some degree, the health and the condition of the
endothelium is also related to the ability of that cellular layer
to generate and transmit nitric oxide (NO) as a biomarker
throughout the tissues of the arterial wall. Most recently, Nobel
Prize winners Robert F. Furchgott, Ferid Murad and Louis J. Ignarro
have linked the production and transmission of NO through the
endothelium as being the primary indicator associated with vascular
dilation. Previously, researchers theorized that vascular dilation
was triggered by an agent named "endothelium-derived relaxing
factor" or EDRF. With the association established by Furchgott,
Murad and Ignarro, researchers now believe that NO is the dominant,
if not exclusive EDRF and is directly related to the health and
condition of the endothelium and the ability of the endothelium to
dilate the arteries of a person. The Nature of Endothelium-Derived
Relaxation Factor, R. Furchgott, Nov. 16, 1998, at the "www"
website hscbklyn.edu/pharmacology/- furch.htm; Research Interests:
nitric oxide; cyclic gmp, cell signaling, second messengers,
regulatory biology, molecular pharmacology, F. Murad, Nov. 15,
1998, at the "http" website girchz.med.uth.tmc.edu/faculty/fmura-
d/index.cfm; and, Nitric Oxide and Cyclic GMP Signal Transduction
Mechanisms, L. Ignarro, Nov. 15, 1998, at the "www" website
nuc.ucla.edu/html-docs/faculty-docs/ignarro.html. Accordingly,
current research now indicates that NO is generated by the
endothelium and is transmitted through the endothelium and that NO
is a biomarker for vascular dilation.
[0005] Medical professionals have, in the past, sought to determine
the health of a patient's vascular system by monitoring the
physiological conditions or characteristics of the arteries in a
patient's limb after reactive hyperemia. Reactive hyperemia occurs
in a patient after a mayor artery has been blocked off or closed by
a blood pressure cuff inflated slightly above systolic pressure for
approximately five minutes. The limb, downstream from the blocked
artery, suffers anoxia or severe hypoxia. Upon a sudden release of
the blood pressure cuff, the endothelial cells lining the interior
of the arterial wall react by generating NO and by dilating. This
vascular dilation and expansion results in the expansion of
resistive arterial vessels and associated muscles significantly
downstream from site of the previously collapsed artery. The
resistive arterial vessels enlarge based upon the NO biomarker,
transmit NO through other parts of the endothelium and may cause
reactive hyperemia in the limb. Reactive hyperemia is a
significantly greater flow of blood through an artery, vein or limb
as compared with normal blood flow therethrough. Blood flow is a
characteristic of the artery and is typically a quantitative
measurement of blood volume with respect to time (e.g. ml per
minute). Generally, the phenomenon of reactive hyperemia lasts up
to 10 minutes before return to pre-test pulse volume values.
[0006] Some medical professionals utilize pulse volume recorders to
measure the peak pressure (mmHg) in the arteries immediately after
the release of the blood pressure cuff and ischemia. However, these
researches measure only the peak pressure during the reactive
hyperemia and typically do not continuously measure blood volume or
blood flow or the pulsatile blood volume change through the
arteries in the limb during the entire reactive hyperemia episode,
i.e., until return to the pre-episode state. The methods of pulse
volume measurements have not been standardized by a national
consensus panel of investigators.
[0007] Other researchers studying the effect of reactive hyperemia
on a vascular system utilize ultrasound imaging techniques to
capture an image of the brachial artery (the artery which is
blocked to achieve reactive hyperemia in the arm of the patient)
and measure the changing diameter of the brachial artery.
Technicians measure the diameter of the artery before the ischemia
(prior to reactive hyperemia and closure of the vascular system) by
capturing electronic ultrasonic images. Subsequently, technicians
attempt to detect and measure the largest expansion of the diameter
of the brachial artery after ischemia and during the reactive
hyperemia episode. These medical professionals then compute (with
simple geometric equations) the expansion of the artery and the
volume change of the artery. However, the use of an ultrasound
image to measure the expansion of the brachial artery during
reactive hyperemia has many technical problems that may jeopardize
the measurement's accuracy and precision.
[0008] Researchers have observed that the brachial artery diameter
typically expands about 0.3 mm during reactive hyperemia.
Reproducibility of Brachial Ultrasonography and Flow-Mediated
Dilation (FMD) for Assessing Endothelial Function, by K. L. Hardie,
et al., Australian New Zealand Journal of Medicine, 27, pp.
649-652, 1997 (this study revealed arterial diameter of 3.78 mm at
rest; 3.89 mm during reactive hyperemia). Other studies show
diameters of 3.92 mm at rest increasing to 4.13 mm during reactive
hyperemia. Noninvasive Assessment of Endothelium-Dependent
Flow-Mediated Dilation of the Brachial Artery, by A. Uehata et al,
Vascular Medicine 2, pp. 87-92, 1997. Studies have shown that the
effect of nitroglycerin treatment during reactive hyperemia
increases the expansion of the arterial diameter by about 11%.
Flow-Induced Vasodilation of the Human Brachial Artery is Impaired
in Patient [over] 40 years of Age with Coronary Artery Disease, by
E. Lieberman, et al., American Journal of Cardiology, 78, pp.
1210-1214, 1996. Nitroglycerin is converted into NO and this
additional NO stimulates vascular dilation. This study has
indicated that young people, without any indication of coronary
artery disease (healthy individuals), exhibit an increase in the
diameter of the brachial arterial on the order of 6.2%. In
contrast, young people with coronary artery disease exhibit an
arterial diameter increase of only 1.3%. This same study measured
arterial diameters utilizing ultrasonic techniques and revealed
measurement errors of plus or minus 1.1% for the diseased
population typical (arterial expansion of 1.3%). Errors of 0.7%
were noted during the ultrasonic measurement of the brachial
arteries in the healthy population (typical arterial change of
6.2%). Accordingly, these studies show a coefficient of error or
variation of almost 30% with utilization of ultrasonic techniques.
These errors are caused by the acquisition of the electronic image
data capturing the expansion of the brachial artery during reactive
hyperemia, the measurement of the electronic image and the
introduction of arithmetic errors into the calculation of the
arterial diameter.
[0009] Currently, many researchers utilize ultrasonic techniques to
noninvasively detect the increase of the diameter of the artery
during reactive hyperemia. The use of ultrasonic imaging techniques
has many problems. For example, the ultrasound technician operator
must carefully place the ultrasound scanning head on and above the
brachial artery at a certain x-y and z position relative to the
patient's skin. The ultrasound head is typically placed a few
inches above the crease in the patient's elbow. If the operator
places the ultrasound head at a different location on another
patient or if the operator places the ultrasound head at a
different location on the same patient at a different clinical
testing time, the data obtained during these inter-patient and
intra-patient tests is not consistent. Further, the ultrasound
operator must place the ultrasound head on the patient, move the
ultrasound head longitudinally up and down the patient's arm, move
the head laterally side to side about the arm and rotate the angle
of the ultrasound head relative to the surface of the skin in order
to obtain a clear electronic image of the brachial artery. This
involves multiple eye-hand coordination by the operator since the
operator views the image while he or she moves the ultrasound head
over the patient's arm. Further, after the operator correctly
positions and obtains a clear electronic image, the operator must
then issue (a) a cuff release command to begin the reactive
hyperemia and (b) a record command to the ultrasound equipment
which begins recording the image. The ultrasound operator may also
be required to move electronic calipers on the captured electronic
image at the same time as he or she is capturing additional images
in order to measure the expanded diameter of the brachial artery
during reactive hyperemia. Specifically, the ultrasound operator
quickly releases the blood pressure cuff which occluded the
brachial artery for about five (5) minutes and initiates reactive
hyperemia in the limb. During the first minute after cuff release,
the ultrasound operator carefully positions the ultrasound head on
the skin of the patient. During the next thirty seconds, the
operator captures the ultrasound image of the expanded diameter of
the brachial artery as a recorded electronic image and measures the
increase of the arterial diameter. This measurement normally
includes the use of electronic calipers on the display screen. In
the third sixty second period, the operator continues to
electronically monitor and store the image of the brachial artery
as the arterial diameter reduces in size during the latter portions
of the reactive hyperemia episode.
[0010] After the ultrasound operator captures this electronic
image, the operator or other health professional can view or
re-play the stored electronic image and seek to identify the
largest expansion of the diameter of the brachial artery.
Accordingly, it is difficult to obtain this data with ultrasound
equipment, to replicate the test on the same patient, to replicate
the same test on a different patient, to interpret the electronic
image and to quantify the amount of arterial expansion.
[0011] These problems with respect to ultrasound imagery and the
interpretation of the captured image have inhibited researchers
from reproducing earlier experiments and confirming experiments
conducted by other researchers and combining or correlating data
from various studies. The current lack of standardization of
methods prevents definitive studies among investigators.
[0012] Further, since ultrasonic imagery measures only an increase
in the diameter of an artery, any error introduced by this
measurement is amplified since it is squared in the mathematic
formulas for the area A of a circle and the volume V of a tubular
structure such as an artery. The equation for area A follows:
A=(1/4).pi.d.sup.2 Eq. 1
[0013] The equation for the volume V of a cylinder follows.
V=(1/4).pi.d.sup.2l Eq. 2
[0014] The length of the ultrasound head is utilized to estimate
the length l of the generally cylindrical arterial vessel. This
formula establishes the volume of the arterial segment and the
change in volume of the arterial segment during reactive hyperemia.
Accordingly, any error introduced into the measurement of the
diameter d of the artery is squared by the volumetric formula Eq. 2
and the system operator can only estimate the length l of arterial
segment based upon the size of the ultrasound head. This estimate
of length l also introduces another element of error into the
measurement of the volumetric change of the blood vessel during
reactive hyperemia.
[0015] U.S. Pat. Nos. 5,718,232 and 5,630,424 to Raines, et al.
describe a calibration system for measuring segmental blood volume
changes in arteries and veins for pulse volume recorders. The pulse
volume recorders described in Raines '232 and Raines '424 add or
subtract a predetermined volume (approximately 1 ml) to or from the
volume of the pneumatic blood pressure cuff system at each cuff
pressure over a plurality or multiple levels of induced cuff
pressure. Basically, Raines '232 and Raines '424 seek a solution to
the problem that the pneumatic response of the blood pressure cuff
system due to blood pressure pulse waves changes at each discrete
level of induced cuff pressure (the response delta P changes at
each cuff lever Pcuff 40, 50, 60, 70, 80, and 90 mmHg.). In order
to measure and calibrate the blood pressure system at each discrete
cuff level, the predetermined volumetric amount is added or
withdrawn from the pneumatic system at that induced cuff pressure
level. By measuring the pressure change at the time of the
volumetric calibration pulse, the resulting pressure wave signal is
a calibration pressure pulse. The sensed pressure wave signal at
the induced cuff pressure is converted into a corrected blood
volume signal using the ratio of the volumetric calibration pulse
versus the calibration pressure pulse. This is a direct measurement
of blood volume and a basis for blood flow at the induced pressure
level.
[0016] Specifically, the Raines '232 and the Raines '424 patents
utilize a blood pressure cuff placed around the limb of a patient.
The blood pressure cuff was pumped up or inflated to certain
predetermined cuff levels such as 40, 50, 60, 70 mmHg through 120
mmHg. At each discrete cuff pressure level Pcuff, the system was
calibrated in order to obtain a corrected blood volume signal
change at each cuff pressure level. After the corrected blood
volume data was obtained, a ratio was generated between blood
volume change in relation to the pressure change at the selected
induced cuff pressure in order to determine the maximum value of
the blood volume versus the sensed pressure differential. The
maximal ratio of blood volume change versus blood pressure change
at a particular cuff pressure provides an indication of the onset
and the degree of atherosclerosis in humans as well as provides an
indication of the health or condition of the vascular system and
particularly of the peripheral vascular system. The contents and
substance of U.S. Pat. Nos. 5,718,232 and 5,630,424 to Raines et
al. is incorporated herein by reference thereto. The relationship
between atherosclerosis and the maximal ratio of delta V over delta
P (peak arterial compliance) is disclosed in U.S. Pat. No.
5,241,963 to Shankar. The content of U.S. Pat. No. 5,241,963 is
incorporated herein by reference thereto.
OBJECTS OF THE INVENTION
[0017] It is an object of the present invention to provide a
calibrated measurement system to measure the dilation of blood
vessels in a patient's limb and to measure the endothelium after
reactive hyperemia.
[0018] It is an additional object of the present invention to
provide a calibrated measurement system to measure the dilation of
arterial blood vessels and to indirectly measure the endothelium's
production of NO and the arterial dilation response to the NO after
reactive hyperemia. Also, it is an object of the present invention
to measure those items before and after the administration of other
agents producing similar alterations of arterial reactions.
[0019] It is another object of the present invention to provide a
method for obtaining a calibrated measurement of blood vessels and
endothelium after reactive hyperemia.
[0020] It is an object of the present invention to provide a
clinical diagnostic and evaluation method for obtaining a
calibrated measurement of the change of volume of arterial blood
vessels and endothelium after production of reactive hyperemia.
[0021] It is a further object of the present invention to provide
an internal calibration system for measuring the dilation of blood
vessels and the effects on the endothelium during the entire
reactive hyperemia episode.
[0022] It is additional object of the present invention to capture
pressure pulse data (which may be waveform and/or tabular data),
periodically calibrate the pneumatic system, and calculate the
blood volume data and waveform, if necessary, and the blood flow (q
versus t) during the entire reactive hyperemia episode. The data
capture and processing is preferably, essentially continuous,
however, the processing may be conducted during a post-examination
time or off-line rather than in real time, during the reactive
hyperemia (RHT) test.
[0023] It is another object of the present invention to provide
multiple and periodic calibrations of the pneumatic system during
the entire reactive hyperemia episode.
[0024] It is an additional object of the present invention to
provide a pneumatic system which automatically initiates the quick
pressure release of the blood pressure cuff pneumatic system,
quickly achieves a predetermined diastolic or near diastolic cuff
pressure in the blood pressure cuff pneumatic system and monitors
and calibrates pressure pulse waves during substantially all of the
reactive hyperemia episode.
[0025] It is an additional object of the present invention to
measure the effects of reactive hyperemia on all the blood vessels
(primarily arterial blood vessels) and endothelium of the patient
rather than simply the brachial artery of the patient. Further, the
RHT test may be conducted on the major distal portion of each of
the four limbs of the patent. This technique potentially enhances
the quality of test's overall results.
[0026] It is a further object of the present invention to plot, map
and/or record calibrated blood volume data and/or the blood flow
data during substantially all of the reactive hyperemia episode in
order to correlate the health and condition of the endothelium and
the coronary artery system based upon the effects of the reactive
hyperemia on the limb of patient.
[0027] It is another object of the present invention to compare
normal blood volume data and normal waveforms showing the pulsatile
component of blood flow during substantially all of the reactive
hyperemia episode with other data and waveforms from patients
exhibiting healthy blood flow and cardiovascular disease and
coronary artery disease in order to provide a noninvasive method
and noninvasive system to measure coronary artery disease based
upon the response and condition of the endothelium during reactive
hyperemia.
[0028] It is another object of the present invention to
automatically perform a reactive hyperemia test on a plurality of
patients and/or a number of reactive hyperemia tests on a single
patient with a high degree of accuracy, precision and repeatability
in order to reduce interpatient and intrapatient errors. This
objective greatly enhances the creation of definitive studies among
investigators.
[0029] It is a further object of the present invention to provide
measurements of pulse waveform and blood volume and to
automatically gather that data with a minimum of error and bias. As
explained herein, prior art techniques utilizing ultrasound
machines and imaging techniques involve a considerable degree of
operator intervention and hence, result in an unacceptable amount
of operator error in the reported results.
[0030] It is another object of the present invention to provide
frequent and continuous measurement of the pulse volume response
which enables detection of inter-test and/or interpatient
differences, the magnitude of the responses that may be associated
with the time-based phases of hyperemic response, i.e., the maximum
response occurring in the early, mid-range, late or prolonged
response.
SUMMARY OF THE INVENTION
[0031] The calibrated method for characterizing blood flow in a
limb of a patient during reactive hyperemiautilizes a blood
pressure cuff. The method establishes a predetermined, diastolic or
near diastolic pressure in the blood pressure cuff during the
reactive hyperemic episode, continually senses the pressure in said
blood pressure cuff during the reactive hyperemic episode, and
periodically changes the internal volume of said blood pressure
cuff by a predetermined volumetric amount. This volumetric change
establishes a calibration cycle. The method concurrently senses a
resultant change in the pressure as a calibration pressure pulse
and calculates pulsatile blood volume through the blood vessel by
correcting the sensed pressure with the ratio of the predetermined
volumetric amount and calibration pressure pulse. A calibrated
method for determining the condition of blood vessels and
endothelium includes determining, for each calibration cycle, a
respective peak value for the blood volume, and comparing the peak
blood volume values for the plurality of calibration cycles
encompassing the reactive hyperemia episode with peak blood volume
values for healthy blood vessels and endothelium during reactive
hyperemia. The comparison is preferably made with acquired blood
volume data or waveform and stored data or waveform showing peak
blood volume values for healthy blood vessels and the
characterization of the endothelium during reactive hyperemia.
[0032] The calibrated system for characterizing blood flow includes
a computerized electronic and pneumatic system which inflates, for
a predetermined pre-test time, the blood pressure cuff to a
suprasystolic pressure and thereafter establishes the diastolic or
near diastolic pressure in the cuff during the ensuing reactive
hyperemic episode. A sensor substantially continually senses the
pressure in the cuff and generates a pressure signal, particularly
a pressure pulse signal. A subsystem periodically changes the
volume of the blood pressure cuff by a predetermined volumetric
amount in a calibration cycle. A calibration pressure pulse signal
is generated based upon a resultant change in the pressure signal.
A blood volume signal is generated by correcting the sensed
pressure signal with a ratio of the predetermined volumetric amount
and the calibration pressure pulse signal. A calibrated system for
determining the condition of blood vessels and endothelium includes
the aforementioned elements and a computerized system for
determining, for each calibration cycle, a respective peak blood
volume value and for comparing the acquired peak blood volume
values with a plurality of predetermined peak blood volume values
representing healthy blood vessels and endothelium during reactive
hyperemia. Typically, these are graphically presented and displayed
as waveforms. Alternatively, data table presentations are provided
to the operator.
BRIEF DESCRIPTIONS OF THE DRAWINGS
[0033] Further objects and advantages of the present invention can
be found in the detailed description of the preferred embodiments
when taken in conjunction with accompanying drawings in which:
[0034] FIG. 1 diagrammatically illustrates a computer system and
the major functional components of an electronic and a pneumatic
system for the calibrated measurement of blood vessels and
endothelium after reactive hyperemia and method therefor in
accordance with the principles of the present invention;
[0035] FIG. 2 diagrammatically illustrates an electronic and
pneumatic system for generating cuff pressures, calibrating the
cuff pressures and capturing pressure pulse wave data in accordance
with the principles of the present invention;
[0036] FIG. 3 diagrammatically illustrates an alternate pneumatic
system to obtain calibrated signals and pulse pressure waveforms in
accordance with the principles of the present invention;
[0037] FIG. 4 diagrammatically illustrates another embodiment of
the pneumatic system to obtain the calibrated measurements
described herein and the pressure pulse waveforms in accordance
with the principles of the present invention;
[0038] FIG. 5 diagrammatically illustrates an arterial system which
is monitored to measure the health of the endothelium, the
transmission of nitric oxide NO and which provides an indicator of
the health and condition of the patient's cardiovascular
system;
[0039] FIGS. 6a, 6b and 6c diagrammatically illustrate the method
of achieving reactive hyperemia and dilation of the brachial
artery;
[0040] FIG. 7 diagrammatically illustrates a plot or graph of blood
volume (V) or blood flow (Q) vs. time t which documents the
reactive hyperemia episode in the patient's limb (time t may be
illustrated in real time but not necessarily to scale);
[0041] FIG. 8 diagrammatically illustrates a plot or graph of the
pulsatile component of blood volume V during reactive hyperemia
(with episodic time t being discontinuous);
[0042] FIG. 9 diagrammatically illustrates blood flow Q (quantity
versus time) and a number of waveform profiles showing a normal
blood vessel flow and endothelial reaction after hyperemia
(waveform W.sub.1), a rapid recovery waveform profile (W.sub.2), a
diminished recovery waveform profile (W.sub.3) and a diminished and
prolonged recovery waveform profile (W.sub.4) which indicates
various coronary arterial conditions and diseased states and
vascular conditions and problems as compared with the normal
waveform profile (W.sub.1);
[0043] FIG. 10 diagrammatically illustrates a plurality detected
pressure pulse waveforms P.sub.t, the resultant calibration pulse
(t.sub.4) and further diagrammatically illustrates the pressure
pulse waveform P.sub.n in accordance with the principles of the
present invention;
[0044] FIG. 11 diagrammatically illustrates a plurality of pressure
pulse waveforms P.sub.t and a periodic calibration pulse for the
pressure waveforms in accordance with the principles of the present
invention;
[0045] FIGS. 12a, and 12b diagrammatically illustrate the system
capturing a large plurality of pressure wave forms P.sub.t, several
periodic calibration pulses or cycles and the computation and
illustration of blood volume waveforms V.sub.n at various times
during the reactive hyperemia episode; and
[0046] FIG. 13 diagrammatically illustrates one configuration of a
user interface display.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0047] The present invention relates to a calibrated measurement of
blood vessels and endothelium after reactive hyperemia and a method
therefor. Particularly, volume and flow through the arterial blood
vessels is measured by the method and the apparatus.
[0048] FIG. 1 diagrammatically illustrates the basic components of
a computer or an electronic system 10 and a pneumatic system 12
used in connection with the calibrated measurement of blood vessels
and the endothelium after reactive hyperemia. Due to the continual
reduction in price, improvement in quality and integration of
electronic and computer components, FIG. 1 diagrammatically
illustrates functional elements of the invention. Accordingly, the
claims appended hereto are meant to cover the future integration of
electronic components. Pneumatic system 12 includes a blood
pressure cuff 14 that is adapted to be wrapped around the upper arm
16 of a patient. Particularly, since it is important to correctly
locate cuff 14 on upper arm 16, cuff 14 may include a label with
written instructions instructing the operator to place cuff edge 18
a certain distance from elbow crease 20 of the patient's limb. The
objective is to locate the cuff, on a regular basis, at a standard,
specified and constant location or distance above the antecubital
crease or fold. The pneumatic system described herein preferably
utilizes a blood pressure cuff which is designated as the
"standard" or predetermined cuff used for all the machines and used
in connection with all methods described herein. The use of
"standard" or a single type of cuff results in the establishment of
a constant sized occlusion or blockage of the arteries in the limb
of the patient. The relative dimensional sizes of the components in
FIG. 1 are not accurate. As explained in detail later, cuff 14 is
wrapped around upper arm 16, inflated for a 5 minute period to
collapse the arteries and veins in limb segment 16, thereby
achieving ischemia in the limb and the downstream portions of the
limb. Blood pressure cuff 14 is inflated, deflated and controlled
based upon pneumatic and electronic components on system board 22.
System board 22 is explained in detail later in connection with
FIGS. 2-4.
[0049] The computer system 10 includes a keyboard or keypad 24 (and
may further include a mouse, trackball or other pointing device,
not shown), a main CPU box 26, a display screen or monitor 28, and
a memory system 30. Memory system 30 includes hard drive 32, floppy
drive 34, removable drive 36 and possibly a ZIP drive or comparable
removable tape drive (not shown). A CDROM writer may also be used
to write data to a CDROM. The computerized system 10 also includes
a microprocessor 38, an input/output unit 40 and, in a preferred
embodiment, a modem 42. The modem enables connection to the
Internet. Input/output unit 40 may be connected to a computer
network 44 (local area network or wide area network) and/or a
printer 46.
[0050] Microprocessor 38 utilizes computer programs stored in
memory 30, which includes hard drive 32, floppy drive 34 and
removable drive 36, as necessary, as well as random access memory
RAM and read only memory ROM (included in memory 30). The
microprocessor obtains, processes and stores data with the
assistance of the memory 30 and under the control of programs
stored in memory 30. Microprocessor 38 controls various peripheral
equipment via input/output unit 40. These peripherals include
display 28, modem 42, printer 46 and network card or board 44. The
input/output unit 40 also controls keyboard 24 and any associated
mouse or other operator input control. Microprocessor 38 is
connected to these various electronic components and to the system
electronic/pneumatic unit 22 via a bus 48.
[0051] FIGS. 2-4 diagrammatically illustrate various pneumatic and
electronic systems to measure the dilation of blood vessels and
actions of the endothelium with reactive hyperemia as well as to
create the reactive hyperemia in the patient's limb. FIG. 2
diagrammatically illustrates the preferred embodiment. However, the
systems in FIGS. 3-4 may be utilized to achieve substantially the
same results.
[0052] In FIG. 2, a pump P 50 is pneumatically connected to valves
52 and 54 via line or tube 77. Main valve 52 is pneumatically
connected via line 83 to blood pressure cuff coupling 56. Pressure
sensor 58 is also pneumatically linked to line 77, pump 50 and
valves 52, 54. Sensor 58 monitors the air or other pressure in the
blood pressure cuff system. This pressure sensor substantially
continually monitors pressure based upon a pre-programmed sampling
rate. Although unlikely, a hydraulic system may be utilized rather
than a pneumatic blood pressure cuff system. This hydraulic
embodiment is unlikely because of the wide acceptance of pneumatic
blood pressure cuff systems by the medical community.
[0053] Main valve 52 has a primary pneumatic output that is further
pneumatically linked to a resistive pneumatic element 59. The
positioning of main valve 52 may be changed such that resistive
element 59 is at its input. Piston system 60 is pneumatically
coupled at an intermediate position relative to resistive element
59 and secondary valve 54. Piston system 60 includes piston head 62
which is biased forward by spring 64 mechanically acting on stop
66. The face of piston 62 effects the volume of chamber 68 in
piston system 60. The backside of piston head 62 is effected and
acted on by the air pressure in the backside chamber 69. This air
pressure in backside piston chamber 69 is controlled by secondary
valve 54 which is pneumatically linked to the backside of the
chamber.
[0054] Main valve 52 and secondary valve 54 both include exhaust
ports 53, 55. Ports 53, 55 may be quick action valves.
[0055] Pump 50, main valve 52 and secondary valve 54 are controlled
by electronic signals supplied by and supplied through signal
conditioner 70. Signal conditioner 70 is an interface between the
valves and the balance of the electronic system. The signal
conditioner 70 may be incorporated into the other electronic
devices or may include several discrete electrical components. The
pump drive signals and valve control signals are generated by a
microcontroller 72 in accordance with programs stored in memory 74.
Memory 74 may include random access memory, read only memory or may
be incorporated into computer system memory 30. Further,
microprocessor 72 and memory 74 may be replaced with programmable
logic or erasable programmable read only memory (EPROM) or
programmable read only memory (PROM) as appropriate. In the
preferred embodiment, the electronic and pneumatic system board 22
includes an on-board microprocessor and an on-board memory in order
to generate pump control and valve control signals via signal
conditioner 70 to main valve 52, pump 50 and secondary valve
54.
[0056] Pressure sensor 58 is electronically monitored by analog to
digital A/D converter 76. The output of A/D converter 76 is
connected to microprocessor 72 and memory 74 and also to the main
computer bus 48. It should be noted that microprocessor 72 and
memory 74 may be replaced by and integrated with main
microprocessor 38 and memory 30 in computer system 10. This
integration may depend upon the speed of microprocessor 38 and
multi-tasking capability of that microprocessor as well as the cost
of an on-board microprocessor 72. Pressure data signals may be
temporarily stored in on-board memory 74 dependent upon the
architecture of the electrical hardware and software.
[0057] In operation, the electronic and pneumatic system
illustrated in FIG. 2 operates in the following manner. Main valve
52 closes. Secondary valve 54 is opened and exhausts any pressure
in pneumatic lines 77 and 79 by venting the subsystem to the
ambient pressure environment via exhaust port 55. Secondary valve
54 then closes and pump 50 is activated. Main valve 52 is opened.
Pump 50 is commanded to inflate cuff 14 (FIG. 1) to a suprasystolic
pressure level which effectively collapses or occludes all the
arteries in the upper arm 16 of the patient. A suprasystolic
pressure is a pressure greater than the patient's highest level of
blood pressure in his or her vascular system. In one working
embodiment, the supra-systolic pressure is 20 mmHg above the
previously obtained systolic pressure of the patient. The pressure
in the pneumatic system (pneumatic line 77 and cuff 14) is
substantially continually monitored by sensor 58, A/D converter 76
and ultimately microprocessor 72. A duplicate monitoring of the
pressure signal may be implemented with main processor 38. In the
event of a failure (mechanical, pneumatic or patient voluntary or
involuntary interruption), microprocessor 72 stops pump 50 and
opens main valve 52 and/or secondary valve 54 thereby venting
pressure from the pneumatic system (line 77 and cuff 14) via
exhaust port 55 and/or 53.
[0058] During normal operation, pump 50 is activated to pump up and
pneumatically inflate cuff 14 until all the arteries in limb 16
collapse thereby blocking any blood flow through those arteries
into the downstream portion of limb 16.
[0059] This condition is maintained for 5 minutes to achieve
ischemia or extreme hypoxia in the patient's limb. This is a
predetermined pre-test time period which is a standard used by most
clinical investigators. This time may be shortened or lengthened
based upon further experimentation. Pump 50 is turned OFF when
pressure sensor 58 (and associated electronics) detects a
predetermined suprasystolic pressure level in the pneumatic blood
pressure cuff system (line 77, 83 and blood pressure cuff 14). The
suprasystolic pressure level is generally specified at a level 20
mmHg above the subject's systolic pressure but other elevations may
be used.
[0060] When the pneumatic blood pressure cuff system reaches the
suprasystolic pressure (established either by (a) a predetermined
value programmed into microprocessor 72 and memory 74 or programmed
into main microprocessor 38 and memory 30 or (b) a predetermined
level above the patient's systolic pressure), a timer or clock is
initiated in the appropriate memory under the control of the
appropriate microprocessor. Currently, the timers are maintained by
main microprocessor 38 and memory 30. Upon the expiration of the
predetermined time period (5 minutes), microprocessor 72 and memory
74 (under the ultimate control of main microprocessor 38 but the
specific control of processor 72) commands main valve 72 to open
its exhaust port 53 to quickly release pressure from the pneumatic
system established by blood pressure cuff 14.
[0061] This quick release feature is one feature of the present
system. An additional quick release exhaust valve may be added to
the system if necessary (not illustrated). The further quick
release system would be pneumatically coupled on line 83. The
electronic output of pressure sensor 58 is monitored by
microprocessor 72 until the pressure reaches the diastolic level or
a near diastolic level. This quick release of cuff pressure is
required in order to rapidly achieve reactive hyperemia in limb
segment 16 and the downstream portions of that limb segment. As
described in greater detail hereinafter, the calibrated system and
the calibrated method in accordance with the principles of the
present invention periodically calibrate the pneumatic system while
acquiring pressure wave pulse data during reactive hyperemia.
[0062] The predetermined diastolic or near diastolic pressure level
at which main valve 52 (or alternately valve 54) closes is
determined in whole or in part upon the patient's diastolic or low
blood pressure level. In one working embodiment, the predetermined
pressure is 5 mmHg less that the measured diastolic pressure. Prior
to initiating the test described herein, the medical professional
obtains, via conventional methods or otherwise, the patient's
diastolic (low level) and systolic (high level) blood pressures. A
typical diastolic/systolic blood pressure (BP) is 120/60 mmHg.
Normal systolic pressure in the range of 90-140 mmHg is reasonable.
Diastolic pressure of 60 mmHg plus or minus 10 mmHg is reasonable.
Since the diastolic pressure should be about 60 mmHg, the presently
described system may be pre-set to close the exhaust valve during
the quick release operational module at 60 mmHg. However another
version, the system operator may be prompted to (a) obtain the
patient's diastolic/systolic blood pressure/(BP); and (b) input
that BP data into the system. In this event, the system may utilize
the input diastolic pressure plus or minus a pre-set value (e.g. 5
mmHg) rather than the pre-set pressure of 60 mmHg. The term "near
diastolic" is meant to cover these three variations.
[0063] In a further enhancement, the system may be configured to
directly measure both BP data points prior to initiating reactive
hyperemia in the patient. Electronic systems controlling and
monitoring pneumatic systems to acquire and store diastolic and
systolic blood pressure data are known in the biomedical industry.
In a working embodiment, (a) the operator measures BP via
conventional audio methods, (b) the operator inputs this data into
the system, (c) the system inflates the cuff to 5 mmHg less then
the measured diastolic pressure, (d) calibrates the data, (e)
measures and computes V.sub.m and Q.sub.p (discussed later herein)
and (f) then occludes the artery and initiates the hyperemia
reactive test described in detail hereinafter.
[0064] Either of these pre-test procedures may be utilized to
obtain, record and utilize a diastolic pressure level, or a pre-set
value offset from diastolic pressure, as a predetermined base cuff
pressure level. As explained later, the predetermined base pressure
is easily convertible into a predetermined base blood volume level
V and a predetermined base blood flow level Q. The term "level" as
used herein is equivalent to the terms "data" or "value." The term
"limb" or "arm" can refer to any of the body's limbs.
[0065] The system and method may also be modified to measure the
physiologic condition of the blood vessels by monitoring blood
pressure, pressure pulses, and hence blood volume, at a
predetermined level above or below the patient's diastolic pressure
(e.g. diastolic minus 5 mmHg.).
[0066] Returning to a brief description of the operation of the
calibrated system and method, during each calibration cycle,
secondary valve 54 is opened to vent pneumatic line 79 and exhaust
the pressure from line 79 through exhaust port 55. Valve 54 may be
able to independently vent line 79 separate from line 77. When the
pressure is vented from pneumatic line 79, the pressure is reduced
in back chamber 68 of piston unit 60.
[0067] At an earlier time, pneumatic line 79 and back chamber 69
held the same pressure as pneumatic line 77 and blood pressure cuff
subsystem 14.
[0068] At the calibration trigger time, established by
microprocessor 72 and memory 74 (optionally processor 38),
secondary valve 54 vents pneumatic line 76 to the ambient
environment via exhaust port 55. This also vents the pressure from
back chamber 69. Piston head 62 then moves backwards against the
biasing force of spring 64 a predetermined volumetric amount.
Rearward movement of piston head 62 is caused by the pressure
differential between chambers 68 and 69 (lines 81-83 and 79). This
predetermined movement changes the internal volume in the pneumatic
system (established by pneumatic lines 81, 83 and blood pressure
cuff 14) by a predetermined volumetric amount.
[0069] The biasing force of spring 64 and the movement of piston
head 62 within chambers 68, 69 is carefully preset such that when
piston head 62 moves and expands chamber 68, the expansion
increases the volume of the pneumatic system (lines 81, 83 and
pressure cuff 14) a predetermined volumetric amount. In a currently
preferred embodiment, the volume change in the pneumatic system is
0.68 ml. Volume is added to the cuff system. In a different
embodiment, volume may be subtracted from the cuff system by
forcing piston head forward in chamber 68.
[0070] As explained in detail later, this volumetric calibration
amount V.sub.cal is added at several times during the reactive
hyperemia episode to the cuff system in order to recalibrate the
system pursuant to realtime derived timing requirements. The timing
requirements are keyed to the sensed pressure pulses. Frequent
recalibration of the system is thought to be necessary for optimal
accuracy and precision while repeatedly measuring small changes in
the pressure pulse waveform. The pneumatic and electronic data
acquisition system may drift thereby corrupting the data
acquisition and processing. The system measures blood pressure
pulse changes. More specifically, the system responds to blood
pressure pulse volume changes in the arterial system in the
patient's limb. Typically, the diameter of the brachial artery in
an arm changes 1.3% to 6.2% during these blood pressure pulses.
[0071] Periodic recalibration avoids and eliminates the problems
regarding pneumatic and electronic signal drift. Also, it has been
established by preliminary testing that the response and the
performance of the pneumatic system changes (a) during the
hyperemia test (i.e., over time); (b) based upon the cuff pressure
in the pneumatic system and (c) due to pneumatic and mechanical
limitations in the current equipment. For example in one working
embodiment, it is not possible to precisely and continuously
maintain diastolic or near diastolic (5 mmHg below diastolic)
pressure in the pneumatic system for 5-10 minutes hyperemic
episode. This "leakage" or pneumatic drift may be due to many
factors (e.g., the specific cuff used in the present experiments,
the cuffs linkage to the pneumatic coupler on the PC board, the
pneumatic system mounted on the PC board (unlikely, but possible),
the type or quality of valves, pump or calibration cylinder used on
the PC board). Some of these factors may be eliminated by improving
the quality of the components or improving the interfit or
mechanical interfaces between the components. However, it is
unlikely that all pneumatic drift (presently on the order of about
plus or minus 2-5 mmHg over five to ten minute hyperemic time
frame) will be eliminated. Even if such drift is reduced by closer
manufacturing tolerances and quality assurance programs, the
projected high utilization rate of the machine (7-10 patients per
day) and life cycle durability of the machine (grossly currently
estimated at 3-5 years), it is inevitable that the "wear and tear"
on the machine will cause pneumatic signal drift. Frequent and
repeated calibrations during the RHT test significantly reduce, if
not eliminate, this drift problem since pulse signals are captured
based upon calibration triggers.
[0072] In U.S. Pat. No. 5,718,232 to Raines, et al., it is known
that at each discrete induced cuff pressure level (50 mmHg, 60
mmHg, 70 mmHg . . . 120 mmHg), the pneumatic system provides a
slightly different response to the blood flow through the patient's
arteries (measured by blood pressure pulse data) than at other
pressure cuff levels. The system response at 60 mmHg is different
than the system response at 90 mmHg.
[0073] In the present invention, it is thought that since the
response of the brachial arterial diameter during reactive
hyperemia diminishes from 6.2% (a healthy arterial diameter
response) to 1.3% (a diseased arterial diameter response), the
periodic calibration of the pneumatic system measuring blood
pressure pulse waves is necessary to obtain correct blood volume
pulse wave data V during the entire 5-10 minute reactive hyperemia
episode. The episode may last 10 minutes and the calibrated testing
method described herein can be easily expanded to cover the longer
10 minute RHT test.
[0074] Further, the utilization of the internal calibration system
described and claimed in connection with the present invention
enables the medical community to gather blood volume pulse data and
waveforms in a standardized, constant, reproducible and an
automatic manner. By acquiring this blood volume pulse wave data
utilizing standard calibration techniques, both repetitive
calibration during the reactive hyperemia episode and the
standardized nature of the calibration (withdrawing or injecting
predetermined volumes from the pneumatic cuff system), further
measurements of brachial artery dilation and performance and
condition of the endothelium can be reproduced with different
patient groups at many medical facilities by many researchers. The
standardized collection of data will greatly advance the study of
NO, endothelial reaction and blood vessel activity during reactive
hyperemia.
[0075] One of the major drawbacks in the study of the health and
condition or physiologic characterization of the endothelium and
the effects of nitric oxide NO is the utilization of ultrasound
data. Ultrasound techniques measure the diameter of the brachial
artery during reactive hyperemia. As discussed in detail above,
ultrasound data include operator errors, visual data acquisition
errors and interpretation errors. The present data acquisition
system is better for several reasons. Operator error is minimized
because the instructions are on the cuff label and use of the
method and the machine is simplified. Hand-eye coordination to
acquire an image signal is eliminated. Operator placement of
electronic calipers about an electronic ultrasound image to measure
arterial diameter is eliminated. Lastly, blood volume change is
directly measured without resort to visual measurements and
compounding computational errors. Also, the present invention is
absolutely non-invasive.
[0076] Since the present invention establishes an automatic and
standardized calibration routine with volume additions or
subtractions from the pneumatic system and periodic automatic
calibration of the acquired signals during the entire reactive
hyperemic episode, the study of the health, condition and
physiologic characterization of the endothelium, the effects of NO,
and the effects of drugs on NO and on the cardiovascular system can
be easily standardized. Therefore, data can be shared among
researchers to compare and contrast the effectiveness of drugs, the
effects of lifestyle modifications, the cessation of smoking, and
the effects of diet on the endothelium and the cardiovascular
system. These are major objectives of the invention and a summary
of the problems solved by the invention described herein.
[0077] FIGS. 3 and 4 diagrammatically illustrate other types of
pneumatic systems. In FIG. 3, pump 50 is pneumatically connected to
pneumatic line 90. Pressure sensor 92 is electronically connected
to A/D converter 76 and is pneumatically connected to pneumatic
line 90. Safety relief valve 94 insures that, if an adverse or
other undesirable event occurs in the testing procedure, safety
valve 94 opens and quickly vents the pressure in the pneumatic
system to the ambient environment. Quick release valve 96 is
utilized to quickly vent air from the pneumatic system which
includes pneumatic line 90 and blood pressure cuff 14. The system
is vented via exhaust 97. Valves 98 and 99 are utilized to add a
predetermined volume into the pneumatic system. This predetermined
volume is established by pneumatic chamber or line 95.
[0078] Briefly, when the pneumatic and electronic system is
operating during the reactive hyperemia episode and the system is
collecting blood pressure pulse wave data (see FIG. 10), the
calibration steps include (a) opening valve 99 and exhausting the
pressure in pneumatic line 95 while valve 98 is closed; (b) closing
valve 99; (c) opening valve 98 at the calibration time thereby
exposing the volume in chamber 95 (a calibrated volume V.sub.cc) to
the pneumatic system which includes pneumatic line 90 and blood
pressure cuff 14; (d) detecting the pressure change P.sub.CAL with
sensor 92; (e) computing the corrected blood volume pulse waveform
based upon the ratio of the predetermined volume V.sub.cc added to
the pneumatic system and the measured pressure calibration data
P.sub.CAL and taking that ratio into account when computing the
blood volume pulse waveform V.sub.n with the current diastolic
pressure P.sub.d established as a base line. This computation of
the blood volume pulse waveform is discussed in detail later.
[0079] FIG. 4 diagrammatically illustrates another embodiment of
the pneumatic and electronic system. In this embodiment, pump motor
control 70 is coupled to motor 103a which is coupled to a positive
displacement pump output 101 (the entire unit may be called a
positive displacement pump) which is connected to pneumatic line
103. Pneumatic line 103 is connected pressure sensor 58 and main
valve 52. Cuff coupler 56 is pneumatically and mechanically
connected to blood pressure cuff 14. Main valve 52 has an exhaust
port 53 and is electronically connected to valve control 70.
[0080] In operation, motor 103a drives positive displacement pump
output 101 to initially pump up and achieve the correct air
pressure in the pneumatic system which includes pneumatic line 103
and blood pressure cuff 14 (first supersystolic, then quick
release, then diastolic pressure). In order to achieve calibration
of the system, positive displacement pump output 101 is triggered
to inject a predetermined volume V.sub.cc into the pneumatic
system. The output of PDP pump 101 and line 103 is a predetermined
volume of air. In a preferred embodiment, this injected volume is 1
ml. Sensor 58 then detects the change in the system pressure
P.sub.cal and this calibrated pressure pulse P.sub.cal is utilized
to compute the actual blood volume pulse waveform V.sub.n numerous
times over a time period which includes the reactive hyperemia
episode.
[0081] FIG. 5 diagrammatically illustrates some of the arterial
system in limb 16 of the patient. FIG. 5 will be discussed
concurrently with FIGS. 6a, 6b and 6c which diagrammatically
illustrate the ischemia and subsequent dilation of the brachial
artery during reactive hyperemia.
[0082] In FIG. 5, brachial artery 110 will be compressed and
collapsed about region 112 by a compressive force placed about limb
16 (FIG. 1) of the patient with blood pressure cuff 14. Region 112
is upstream of the brachial arterial branch 114 (near the patient's
elbow crease). In FIG. 6a, brachial artery 110 is diagrammatically
illustrated beneath epidermis skin layer 116. At rest and in a
sedentary position, brachial artery 110 of the patient has a
diameter d.sub.1.
[0083] In order to establish and record pressure pulse data and
waveforms and calculate calibrated blood volume pulse data and
waveforms, the patient should undergo certain pre-test
preparations, be placed in a certain position and maintained in a
certain condition during the test. In a preferred embodiment, the
pre-test and test conditions will be specified in a defined and a
standardized manner to establish a certain medical protocol. The
following Pre-Study Patient Condition Table provides some examples,
of a fundamental nature, of the condition of the patient prior to
conducting the test to determine the state or condition of the
endothelium with reactive hyperemia.
[0084] Pre-Study Patient Condition Table
[0085] patient sedentary and in a relaxed state
[0086] no food for more than 2 hours (possibly 12 hours) before
test
[0087] no coffee or caffeine beverages for more than 1 hour before
test
[0088] no smoking for more than 1 hour before test
[0089] It has been established by other researchers that if a
patient eats a high fat meal, e.g., a MC DONALD'S BIG MAC, within
one hour prior to an ultrasonic test to measure brachial arterial
diameter during reactive hyperemia, the patient's arteries, and
hence the data, is adversely affected by the high amount of salt,
dietary fat and cholesterol.
[0090] Other factors affect the condition of the endothelium and
the generation NO by the endothelium and the dilation of the
patient's cardiovascular system. The following table lists typical
factors.
[0091] Factors Affecting Endothelium and NO Generation
[0092] age
[0093] gender
[0094] smoking
[0095] plasma cholesterol level
[0096] disease (especially coronary artery disease and peripheral
vascular disorders)
[0097] With the acquisition of calibrated blood volume pulsatile
data, researchers may identify other factors which affect the
response of blood vessels and the endothelium during reactive
hyperemia.
[0098] The following Physiological Process Table provides a general
outline of the physiologic effects of reactive hyperemia on the
endothelium and the cardiovascular system of a patient as currently
understood by one of the inventors.
1 Physiological Process Table 1. cause anoxia or severe hypoxia in
the limb's arterial system 2. which causes an increase in NO
production by the arterial endothelium 3. which results in dilation
of the local and distal arterial system 4. which is believed to
cause a reduction in peripheral resistance in the resistive vessel
muscles 5. which is generally believed to cause an increase in
pulsatile blood flow (Q) 6. which causes a further increase
(potentially) in pulsatile blood flow (Q) (which increase may be
small or not measurable)
[0099] In summary, FIG. 6b shows the collapse of brachial artery
110 by blood pressure cuff 14. The illustrated force is shown by
arrows 117. In a preferred embodiment, ischemia in the patient's
limb is established for 5 minutes. In FIG. 6c, blood pressure cuff
14 has been quickly released and brachial artery 110 has expanded
to diameter d.sub.2. Even though significant suprasystolic pressure
has been released from blood pressure cuff 14, pressure cuff 14
exerts a small pressure 119 (diastolic or near diastolic) on the
limb 16 in order to capture physiological data regarding the
pressure pulse waveforms at the predetermined diastolic pressure.
Hence, force vector arrows 119 are smaller than vector arrows
117.
[0100] FIGS. 6a-6c are related to FIG. 5 in the following manner.
Upon collapse the brachial artery 110 due to a suprasystolic
pressure placed on region 112 about limb 16 of the patient, the
downstream portions of the limb experience anoxia or severe
hypoxia. When the suprasystolic pressure is released from the blood
pressure cuff 14 (but maintained at or near diastolic pressure),
there is a reduction in the peripheral resistance of the resistive
blood vessel muscles 120 located in distal regions of the patient's
limb, diagrammatically illustrated in FIG. 5. These resistive
vessel muscles 120 are primarily located in and about the arterials
122. The relaxation of the resistive vessel muscles 120 causes an
increase in pulsatile blood flow (identified herein as Q), and an
increase in the generation and transmission of nitric oxide (NO)
through the endothelium. This NO or chemical composition biomaker
is generated throughout the endothelium and travels therethrough
from arterials 122 upstream to a point about critical monitoring
area 112 of brachial artery 110. The NO causes dilation of the
arterial system primarily due to a relaxation of the resistive
vessel muscles 120, an increase in pulsatile blood flow Q and a
possible further increase in pulsatile blood flow. This last
increase (step 6 in the Physiological Process Table) may not be
measurable. However, it is apparent that a careful measurement of
arterial blood vessels slightly upstream of the brachial arterial
branch 114 (near the patient's elbow crease) provides a very good
indication of the health or the condition of the endothelium, the
generation and transmission of NO and the health of the
cardiovascular system during reactive hyperemia.
[0101] The present invention measures the production of NO and the
condition of the blood vessel and endothelium about the entire limb
16 rather than simply measure the diameter of the brachial artery
110 as is currently done by ultrasound techniques.
[0102] The prior art systems utilizing ultrasonic imaging only
focus on the change in diameter of brachial artery 110 during
reactive hyperemia. This change in diameter d.sub.1 to d.sub.2
(FIGS. 6a, 6c) is on the order of 0.30 to 0.33 mm. Healthy patients
without cardiovascular disease present an increase in brachial
arterial diameter of approximately 6.2% during reactive hyperemia.
Another group of patients having a history of coronary artery
disease show an increase in brachial artery diameter of 1.3%.
Accordingly, the sensitivity of the present invention, the ability
of the present invention to automatically initiate a quick cuff
release, and the standardization of the calibration pulse and the
periodic calibration of the data acquisition system during the
entire reactive hyperemia episode, all contribute to the benefits
achieved by the present invention over the pre-existing technology.
These benefits are apparent because of the small change
(approximately 0.30 mm) of the brachial artery during reactive
hyperemia. Other clinical studies using prior art technology have
revealed that the response of the endothelium and the generation of
NO can be directly correlated with the presence or absence of
coronary artery disease. Since the present invention is a
noninvasive method and system for detecting the onset and degree of
coronary artery disease, the present invention is potentially
better suited technically and practically than other invasive
methods to detect coronary artery disease. Other invasive methods
to detect these problems include cardiac catheterization and
angiographic procedures.
[0103] FIG. 7 diagrammatically illustrates a plot or a chart of
either blood volume V or blood flow Q versus time t. At time
T.sub.1, the patient's limb is compressed and the limb experiences
ischemia or extreme hypoxia (a 5 minute period). At time episodic
period T.sub.2, the system first initially quickly releases the
pressure in blood pressure cuff 14, the pneumatic and electronic
pressure sensing system settles to a predetermined diastolic
pressure, the patient's limb and arterial system generates NO and
provides initial stage data of the reactive hyperemic episode. Time
period T.sub.2 may last up to 1 minute. This is the first stage of
the reaction. In time T.sub.3, the system continues to measure the
reactive hyperemia episode and detects the condition of the
endothelium and the generation of NO through the cardiovascular
system. The initial or primarily significant data acquisition
period is the first 5 minutes after cuff pressure release (T.sub.2
plus T.sub.3). The subsequent 5 minute period T.sub.4 captures the
secondary phase data of the reactive hyperemia test (RHT Test).
2 Reactive Hyperemic Time Table T.sub.1 five (5) minutes to achieve
ischemia or extreme hypoxia T.sub.2 about one (1) minute for
physiological system to initiate first stage of reaction T.sub.2
plus T.sub.3 about five (5) minutes to monitor typical, primary
phase of reactive hyperemia episode T.sub.4 about five (5) minutes
to monitor typical, secondary phase of reactive hyperemia episode
T.sub.2 plus T.sub.3 plus T.sub.4 about ten (10) minutes
[0104] Utilizing ultrasound prior art techniques, the ultrasound
operator, in the first minute after cuff release, visually
identifies and locates the brachial artery and prepares himself or
herself for the data acquisition imaging phase. In the subsequent
60 second period, the ultrasound operator captures the image of the
greatest expansion of the diameter of the brachial artery. This
image acquisition period generally corresponds to the peak of the
blood flow waveform shown in FIG. 7. In the third 60 second period
subsequent to cuff release, the operator watches the diameter of
the brachial artery decrease. Since the diameter of the artery
reduces in size, there is a decrease in blood flow. Of course, in
the ultrasound data acquisition system, the operator only sees the
change in arterial diameter (on the order of 0.30 mm). The
ultrasound operator does not measure the change in blood flow. He
or she measures arterial diameter change. However, this blood flow
change is apparent in the sonic image because of the visually
confirmed change in arterial diameter.
[0105] The present invention actually monitors and captures
pressure pulse data and waveforms P.sub.t in real time and converts
them to calibrated blood volume pulse data and waveforms V.sub.n
with periodic calibration pulses. This direct measurement of blood
volume V and blood flow (Q) is a significant difference between the
ultrasound systems and the present invention.
[0106] FIG. 8 diagrammatically illustrates a plot or a graph of the
pulsatile component of blood flow Q.sub.p versus episode time t.
Essentially, the present invention captures pressure waveform
P.sub.t data, converts that pressure waveform data into blood
volume pulse V.sub.n data (per a calibration routine) and then, in
one embodiment, samples periodic blood volume data (preferably
obtaining the maximum or peak value V.sub.m of selected, periodic
waves V.sub.n). The peak value of blood volume V.sub.m in relation
to episodic time is one type of measurement to show the condition
of the blood vessel. Another measurement is the resulting
calculation of pulsatile blood flow Q.sub.p. FIG. 9 is blood flow
plotted data. In this embodiment in FIG. 8, the height or peak m of
the blood volume pulsatile signal V is plotted versus episode time
t. At time t.sub.1, the blood pressure cuff has been released, the
system is settled (about 20 seconds) and data acquisition begins. A
settling period may be necessary due to the pneumatic quick release
of air pressure. A plurality of blood volume peak data points
V.sub.m are obtained and plotted and mapped. Mapping may be to a
data table (V.sub.m and episodic time) or graphically stored
(V.sub.m versus t). At time t.sub.2, the maximum blood volume peak
V.sub.m is computed by the system and preferably displayed to the
operator, health professional or physician. At time t.sub.3, the
patient's cardiovascular system has reached the end of the reactive
hyperemia episode.
[0107] In FIG. 8, the plot of V.sub.m with respect to time t may
not be absolutely precise. The reactive episodic time t may be
replaced by pulse wave number n. In other words if the patient has
a heart rate of 60 beats per minute and the test lasts 3 minutes (a
short version of the test), 180 blood pressure waves or data are
available. The signal settle period may be one minute. Sixty (60)
waves are discarded at initial settling stage period T.sub.1. As
explained later, six (6) wave cycles are utilized for each
calibration window or cycle. As an alternative embodiment, three
(3) of the six waves in each calibration window are averaged to
reduce motion artifacts. In one initial working embodiment, only
one wave or data value from each calibration cycle is initially
utilized. Accordingly from the 120 wave segment (180 waves less 60
waves for signal settling), 20 corrected wave signals or data
V.sub.n are available. The peak values V.sub.m are computed. Since
the patient's heart rate may not be precisely 60 beats per minute
(it may be 59, 62, 58), the system may plot V.sub.m versus pressure
or volume wave number 61, 67, 74, 81, 88, 95 . . . etc. In a
working embodiment, V.sub.m versus episodic time is mapped to a
data table and to a graphic, waveform display. Blood flow Q.sub.p
is calculated by (a) integrating the V.sub.n pulsatile waveform
with respect to time (after the signal settling period), adding the
integrated signal data and dividing the sum by a standard time
period (the result being flow Q.sub.p in ml per minute).
[0108] However, FIG. 8 is accurate with respect to blood volume
flow Q.sub.p versus episodic time t if time t is measured from the
quick cuff release time. In this event, there is a "discontinuity"
in the graph because the graph in FIG. 8 does not show ischemia
time T.sub.1 (FIG. 7). Further, time t.sub.1 begins at time period
T.sub.2 in FIG. 7. Time is also discontinuous in FIG. 7. Since the
physician or health professional is primarily interested in the
V.sub.m data and the shape, height, size and other waveform
characteristics of V.sub.m from time t.sub.1 to time t.sub.3 and
the time t.sub.4, the time-based discontinuity due to ischemia is
not significant. If wave number is used rather than time, no
discontinuity would be present.
[0109] With respect to FIG. 8, a basal blood flow level Q.sub.p has
been established based upon the calibrated and summed blood volume
pulsatile data. This basal level is obtained prior to initiating a
reactive hyperemia in the patient's limb. The basal blood volume
level is also obtained electronically prior to the test. V.sub.m is
the peak value of the corrected blood volume pulse wave V.sub.n at
predetermined times. In an initial working embodiment, five V.sub.m
data points are acquired, calibrated, processed and calculated from
the pulsatile pressure wave data during the 60 second period after
a 20 second signal settlement period (after t.sub.1). The signal
settlement period may be adjusted as necessary to match equipment
limitations. Shorter settle periods are preferred. An additional
seven V.sub.m data points or values are obtained and processed
during the remaining portion of the five minute reactive hyperemia
test (short RHT test). For example, V.sub.m data is obtained at
about 110 seconds after release, at 140 seconds, 170 seconds, 200
seconds, 230 seconds, 260 seconds, and 290 seconds after release of
t.sub.1 (FIG. 8). Data tables for V.sub.m at those times are mapped
electronically by waveform data acquisition and processing
techniques.
[0110] In FIG. 9, the pulsatile component of blood flow Q.sub.P
versus episodic time t for several patients is plotted atop each
other. Essentially, FIGS. 8 and 9 show individual and collective
recovery profiles for reactive hyperemia tests, respectively. These
recovery profiles or recovery waveforms W provide good
physiological data regarding the health or the condition of the
endothelium, the generation of NO by the patient and the
cardiovascular health of the patient.
[0111] Ultrasound studies have established that if patients with
cardiovascular disease utilize nitroglycerin, this increases NO in
the patient's system and the expansion of the brachial arterial
diameter during reactive hyperemia changes from 3.78 mm to 3.89 mm.
Accordingly, the recovery profile waveforms in FIGS. 8 and 9 also
provide an indication of the effectiveness of drugs, e.g.
nitroglycerin, in the patient as well as the generation of NO and
the transmission of NO through the arterial bed.
[0112] It has been proposed, based upon the present invention, that
the recovery waveform profiles w.sub.1, w.sub.2, w.sub.3 and
w.sub.4 shown in FIG. 9 mostly likely show a normal state (waveform
w.sub.1), a rapid recovery (waveform w.sub.2), a diminished
recovery (waveform w.sub.3), and a diminished prolonged recovery
(waveform w.sub.4). Of course, deviations or changes from the
normal recovery profile waveform w.sub.1 provide an indication of
the health and condition of the cardiovascular system of the
patient under study.
3 Exemplary Waveform Classification Table W.sub.1 normal recovery
profile W.sub.2 rapid recovery W.sub.3 diminished recovery W.sub.4
diminished and prolonged recovery
[0113] Further, the recovery profile waveform may be analyzed with
various mathematical algorithms. For example, the researcher could
compare the sequential calibrated blood volume pulse waveform
V.sub.n at 30 second intervals after signal settlement period (for
a 3 minute reactive hyperemia episode, 6 blood volume pulse
waveforms V.sub.n are studied inclusive of initial stage T.sub.1
but after signal settlement) and review the rise and fall of the
peak values V.sub.m for the six waveforms. Running averages of
blood volume pulse waveforms (e.g. computing a three (3) wave
average V.sub.n--Ave during successive six wave calibration
periods) could be taken and compared against each other. The
researcher could average three waveforms V.sub.n--Ave prior to the
calibration pulse (in a six wave calibration cycle) and analyze the
running peak values V.sub.m--Ave over the 3-5 minute reactive
hyperemia episode. Further, the waveforms could be utilized with
weighted average (based on time t from initial stage T.sub.1) to
compare the blood volume data V.sub.m with respect to episodic
time. Blood flow Q.sub.p at different episodic times may be
compared. The following Waveform Analysis Table may provide some
guidance.
4 Waveform Analysis Table periodic, selected peak values or data
V.sub.m running average peak values, e.g. average 3 V.sub.m
(V.sub.m - Ave) episode analysis, use V.sub.m - Ave as data points
V.sub.t, V.sub.t2, V.sub.t3, V.sub.tn weighted average calculation
of V.sub.m based on time of acquisition leading slope of V.sub.n
(or trailing slope) at selected episodic times t.sub.1 t.sub.2
leading slope V.sub.m or Q.sub.p (or trailing slope) during episode
gross value of slope (peak V.sub.m or Q.sub.p versus time from base
to peak (t.sub.1 - t.sub.2)) integrated value of corrected V.sub.n
waveform (from t.sub.1F to t.sub.1B)(FIG. 10) integrated value Of
V.sub.m and/or Q.sub.p waveform (FIG. 8) first, second or third
derivatives of V.sub.m waveform or Q.sub.p at selected episode
times
[0114] FIG. 10 diagrammatically illustrates one method for
calibrating the blood pressure pulse wave P.sub.t and generating
and calculating blood volume pulse waveform V.sub.n.
[0115] In lower region 210, the system displays (on a monitor)
pressure pulse waveforms P.sub.t. At a time prior to t.sub.0, the
system experiences discontinuities and transients due to pneumatic
and electronic settlement based on the quick release of pressure
from blood pressure cuff 14. A 20 second signal settlement period
is used in a working embodiment. Subsequent to time to, the system
begins monitoring the waveforms P at t.sub.1, t.sub.2, t.sub.3, and
particularly the system detects the foot of the wave at t.sub.1f,
the peak of the wave at t.sub.1p, and the base of the wave at
t.sub.1b.
[0116] This detection of wave features is done by standard
mathematical algorithms analyzing the waves during real time
acquisition of data, that is, the pressure pulse waveform P. First,
second and third derivatives of the acquired data signal may be
utilized to locate waveform features. In the embodiment shown in
FIG. 10, the system determines when three substantial identical
pressure pulse waveforms P.sub.t have been received (based on peak
height or integrated valve or otherwise) and then, after
predetermined time period from detecting the initial slope of the
third waveform at t.sub.3, the system generates a calibration
pneumatic pulse V.sub.cc at time t.sub.4. The calibration volume
V.sub.cc may be triggered by detecting and counting other waveform
features.
[0117] As described earlier in connection with the preferred
embodiment, this volume change is achieved by cylinder head moving
and expanding chamber 68 a predetermined amount V.sub.cc. See FIG.
2. This predetermined volume V.sub.cc is added to the pneumatic
system and generates a measurable change in the pressure signal
which is the calibration pressure pulse P.sub.cal. The system then
computes the actual blood volume pulse V.sub.n in accordance with
the following equation.
V.sub.n divided by P.sub.dia equals Vcc divided by P.sub.cal. Eq.
3
[0118] The calibrated and measured blood volume pulse waveform
V.sub.n is obtained by multiplying the measured or pre-set
diastolic pressure P.sub.dia by the ratio of the V.sub.cc and
P.sub.cal. The calibration volume V.sub.cc is currently 0.68 ml but
may be set at 1 ml. Accordingly in display region 212, the system
displays the recorded pressure wave P.sub.n. Alternatively, the
system may display the measured and corrected blood volume pulse
waveform V.sub.n. In this situation, there is a time-based
discontinuity in the display due to the signal processing of
V.sub.n with P.sub.cal. Additionally, the system may illustrate the
calibration pulse P.sub.cal.
[0119] Subsequent to the calibration pulse at time t.sub.4, the
pneumatic and electronic system may require a one or two wave
period to settle in order to remove any transients caused by the
calibration pulse V.sub.cc. The system ignores this second
plurality of pressure waves at t.sub.5 and t.sub.6 in the
calibration cycle.
[0120] In FIG. 11, one embodiment of the present system is
illustrated. In FIG. 11, the calibration pulses are generated at
times t.sub.4 and t.sub.11 during a six cycle calibration period.
In other words, the system acquires and records, in real time,
pressure pulse waveforms P at times t.sub.1, t.sub.2 and t.sub.3,
fires a calibration pulse V.sub.cc after waveform at t.sub.3
(calibration at time t.sub.4), enables the system to settle with
waveforms P at times t.sub.5, t.sub.6 and time t.sub.7 (which
post-calibration waveform data may be discarded), then acquires and
records the next three pressure pulse waveforms P at times t.sub.8,
t.sub.9 and t.sub.10 and subsequently fires a calibration volume
V.sub.cc at time t.sub.11 into the system. Therefore, the
calibration pulse is issued during a six pressure pulse waveform
cycle, the system discards three subsequent post-calibration
pressure pulse waveforms and saves and records the previous three
pressure pulse waveforms immediately prior to the calibration
pulse. Of course the system may record all pressure pulse waveform
data but only utilize one, two or three pre-calibration waves to
calculate data point V.sub.m in each calibration cycle per FIG. 8.
The currently preferred embodiment records 12, five second strips
of data during the long, ten minute RHT test.
[0121] If the initial, critical data period for the reactive
hyperemia episode lasts 5 minutes and if the patient's heart beats
60 beats per minute, 300 pressure pulse waveforms are acquired, 20
are discarded during the quick release signal settlement period (20
seconds) about 140 pressure pulse waveforms are discarded in the
post calibration cycles, and about 140 are available for processing
as calibrated blood volume pulse waveforms data V.sub.n in the
method and system. This data provides approximately 140 potentially
available data points V.sub.m and computation plot Q.sub.p versus
episodic time shown in FIG. 8.
[0122] FIGS. 12a-12b diagrammatically show the decreasing pulse
height for the pressure pulse waveforms P.sub.t. The following
Exemplary Timing Table describes FIGS. 12a-12b.
5 Exemplary Timing Table t < t.sub.0 prior to t.sub.0, system is
subject to transients due to the quick cuff release and is unstable
and unsettled t.sub.0 system is settled and wave counter started,
record waveform function ON t.sub.1 to t.sub.3 three (3) generally
similar pressure waves P.sub.t identified t.sub.1F foot of waveform
P.sub.1 at t.sub.1 t.sub.1 waveform marker and wave count N
incremented t.sub.1P peak of waveform P.sub.1 t.sub.1B base of
waveform P.sub.1 t.sub.2 waveform P.sub.2 detected and wave count N
incremented t.sub.3 waveform P.sub.3 detected and counted t.sub.4
calibration volume change V.sub.cc -- system measures pressure
change P.sub.CAL due to calibration change V.sub.cc -- system
computes blood volume waveform V.sub.n based on calibration --
displays V.sub.n or P.sub.n t.sub.5-t.sub.6 system settles and
recovers from calibration event t.sub.8-t.sub.10 system confirms
three (3) generally similar pressure waves P at t.sub.8, t.sub.9
and t.sub.10 t.sub.11 calibration event -- system computes the
tenth blood volume data point V.sub.10 based on calibration event
at t.sub.11 and waveform P at t.sub.10 -- note this assumes system
captured and calibrated V.sub.1, V.sub.2, V.sub.3, . . . V.sub.9
during 9 P.sub.r waves where r is number of P waveforms per
calibration cycle t.sub.15-t.sub.17 system confirms three good P
waves t.sub.18 calibration event - compute and display V.sub.12
based on calibration t.sub.18 and P at t.sub.17 t.sub.22-t.sub.24
confirm similar waveforms t.sub.25 calibrate and compute V.sub.32
with cal pulse t.sub.25 and P at t.sub.24 -- display
[0123] The signal processing routines described herein may be
changed. For example, to obtain an average blood volume pulse
waveform V.sub.n--Ave, the embodiment locates a common waveform
feature on each wave, e.g. the leading edge (first derivative and
slope detection), and overlays multiple, predetermined waveforms
atop each other. Another averaging technique includes computing the
peak value V.sub.m, then averaging a predetermined number of peak
values together to obtain V.sub.m--Ave. The averaging may be done
on pressure waves P prior to calculating blood volume V. In the
calibration routine, other calibration windows or cycles may be
utilized. Herein, a six (6) waveform cycle is utilized. However, a
four (4) or a ten (10) correction and calibration cycle may be
appropriate. Further, rather than using a three (3) wave average, a
six (6) wave average may be appropriate.
[0124] With respect to the wave number and episodic time charts in
FIGS. 8 and 9, if a six (6) wave calibration cycle is selected and
a three (3) wave average is utilized (using waveform overlays as
the averaging algorithm), the system counts the wave numbers N to
track the calibration cycles and to compute V.sub.n--Ave as
processed signal overlays. A correlation between episodic time and
wave count is maintained by the processor and memory. Additionally,
the computerized system starts a timer at the initial state T.sub.2
(FIG. 7) and keeps a running list or map of the wave number N and
the episodic time (t.sub.1 t.sub.2 t.sub.3 t.sub.4 in FIG. 8).
After calibrating with six (6) wave cycles for five (5) minutes,
correcting the pressure pulse waves P.sub.n and obtaining blood
volume pulse waves V.sub.n, averaging to obtain V.sub.n--Ave, and
calculating averaged peak values V.sub.m--Ave, the resulting 50
data points V.sub.m--Ave are then mapped to the corresponding
reactive hyperemia episodic time with the stored time versus
waveform number N. The system plots V.sub.m--Ave versus episodic
time t as waveforms shown in FIGS. 8 and 9. The system also maps a
data table with the averaged peak and episodic time. The episodic
time may be at selected t.sub.1f or t.sub.1b or at calibration time
t.sub.4 for each calibration cycle. See FIG. 10, waveform base,
foot, peak or trailing base. Other episodic time markers may be
selected.
[0125] The display routines may also be modified from those
described and illustrated above. For example, rather than display
blood pressure pulse P.sub.n in display window 212 of FIG. 10,
FIGS. 12a and 12b show the corrected and computed blood volume
pulsatile waveform V.sub.n. If blood volume wave V.sub.n is
illustrated, the displayed wave will have a time discontinuity
between the inverted V-shaped wave V.sub.n and the measured
calibration pressure pulse (a negative waveform) P.sub.cal.
Basically V.sub.n is a computed value from P.sub.n as corrected by
the ratio V.sub.cc versus P.sub.cal.
[0126] Further, the system may sequentially show acquired and
processed signals after the signal settle time frame (20 sec.) as
follows: P.sub.n with P.sub.cal for 30 sec.; initial V.sub.n waves
at episodic times 32 seconds, 44 seconds, 56 seconds, 68 seconds,
80 seconds, 92 seconds (the first "clear data acquisition" time
frame 60 sec. episodic period); secondary V.sub.n at about episodic
times 122 seconds, 152 seconds (a V.sub.n data waveform in the
second 60 sec. episodic clear time frame period); tertiary V.sub.n
at about episodic times 182 seconds, 212 seconds, 302 seconds and
332 seconds (V.sub.n data wave in the third 60 sec. episodic clear
time period); the fourth and fifth V.sub.n representing fourth and
fifth episodic periods; and blood flow Q.sub.p versus episodic time
t (FIG. 8) for 60 sec. during or after reactive hyperemia test. Of
course, blood flow Q.sub.p versus episodic time t is both a data
table and a waveform plot of 50 data points computed from V waves
during real time acquisition period T.sub.2 and T.sub.3 and t.sub.4
(FIG. 7).
[0127] Also, the computer system generates electronic and print
versions of the reactive hyperemic test results as necessary.
[0128] Blood volume and blood flow both characterize the condition
of the patient's arterial system, the condition of the endothelium,
the generation and transmission of NO and the action of drugs on
those biological systems. Blood flow is a volumetric quantity of
blood with respect to time. Typically, blood volume is measured in
ml per minute. Blood flow is mathematically obtained from the
V.sub.n waveform correlated to time. "Pulsatile" refers to the
"pulse" caused by the heart pumping blood through the system.
"Pulsatile" refers to the signal, flow or volume in excess of the
basal value or rate. Waveform data is relatively easily converted
into a data table once a constant time period has been selected.
Similarly, data from a time based and mapped table can be
reformatted as a wave or other time-based presentational display or
print-out. "Mapping" involves the step or function of correlating
data valves to a certain time frame and time period data. "Mapping"
occurs both in a data table and a waveform illustration.
[0129] In an initial working embodiment, the system operates as
follows:
6 Exemplary Process Table 1. Gather and store patient data and risk
profile data 2. Obtain brachial BP when the patient is supine (e.g.
120/80) 3. Inflate cuff to slightly less than diastolic pressure
(80 - 5 = 75 mmHg) 4. System calibrates, measures and stores base
line P, V, V.sub.m and Q.sub.p 5. Inflate cuff to suprastolic (120
+ 20 = 140 mmHg) 6. Occlude arterial system for five (5) minutes 7.
Quickly deflate to slightly less than diastolic pressure (80 - 5 =
75 mmHg) 8. Let electronic and pneumatic system settle (about 20
seconds) 9. Periodically calibrate, measure P.sub.n and V.sub.m and
calculate V.sub.m and Q.sub.p data points (about 5 data point
acquisitions and computations) for primary episodic data
acquisition time (first 60 seconds). Store data. Display as
necessary. Correlate to episodic time. 10. Repeat step 9 for
remaining four (4) minutes of the short reactive hyperemic test
(short RHT). Gather and calculate seven or eight additional data
points V.sub.m and Q.sub.p (based on P.sub.n and V.sub.n) over the
test period. 11. Generate data table V.sub.m versus episodic time
and Q.sub.p versus t. Print- out. Plot graph. Display. Print-out.
12. Generate comparison data table with healthy RHT waves and data.
Repeat with waveform.
[0130] In a further enhancement, a carefully manufactured bellows
with a predetermined volumetric size may be used rather that
cylinder piston system 60.
[0131] In a subsequent working embodiment (the currently preferred
embodiment, subject to revision following a plurality of patent
studies), the system operates as follows:
7 Exemplary Process Table (Revised) 1. Gather and store patient
data and risk profile data. Display upon entry into system. 2.
Obtain brachial BP when the patient is supine (e.g. 120/80) by
traditional methods. 3. Start test. Inflate cuff to slightly less
than diastolic pressure (80 - 5 = 75 mmHg). 4. System calibrates,
measures and stores base line P, V, V.sub.m and Q.sub.p Display. 5.
Inflate cuff to suprastolic (120 + 20 = 140 mmHg) via machine. 6.
Occlude arterial system for five (5) minutes. Display and possibly
audibly announce a five minute countdown to cuff/pressure release.
Provide early warning to patient immediately prior to cuff pressure
release, "Do not move during RHT test." 7. Quickly deflate cuff to
slightly less than diastolic pressure (80 - 5 = 75 mmHg). 8. Let
electronic and pneumatic system settle (about 20 seconds). 9.
Capture data. Periodically calibrate, measure P.sub.n and V.sub.n
and cal- culate V.sub.m and Q.sub.p data points (average j number
of signals to obtain e number of averaged signals during predefined
time segment (quintiles) during 5 min. short test or 10 min. long
RHT test. See Phase Process Table below for values of j and e) for
primary episodic "clear data acquisition" time (subsequent to the
20 sec. signal settle time). Store data. Display as necessary.
Correlate to episodic time. Display. 10. Repeat step 9 for
remaining test period (10 min. test) Gather and calculate data
points V.sub.m and Q.sub.p (based on P.sub.n and V.sub.n) over the
test period. Calculate Qp (ratio); Qp (phase); Vm (ratio); Vm
(phase); and V (exp) )explained below). 11. Generate data table
V.sub.m versus episodic time and Q.sub.p versus t. Print- out. Plot
graph. Display. Print-out. 12. Generate comparison data table with
healthy RHT waveform or data. Repeat with waveform.
[0132] One configuration of the user interface for present
invention is diagrammatically illustrated in FIG. 13. This display
shows the name of the patient, the name of the clinic or doctor
conducting the test, and the current pressure reading from the
pneumatic system in the upper horizontal region of the interface.
Beneath this information bar is a data table (on the left-hand
side) and a bar chart (on the right) showing the results of the
test. During the test, portions of this data and bar chart are
displayed such that the technician conducting the test obtains
real-time feedback regarding the quality and quantity of data
captured by the system. Beneath the RHT Test Data Table is a
computational table, a display showing blood pressure data and the
real time waveform display of pressure pulsatile signals (with a
calibration pulse therein).
8 RHT DATA TABLE (SHORT RHT TEST) (abbreviated) Time (min) Pcuff Pm
Pcal Vm Qp Baseline 68 1.05 1.29 0.53 4.69 0.3 79 1.75 1.39 0.82
9.06 0.5 77 1.85 1.37 0.88 8.95 0.7 78 1.90 1.38 0.90 8.71 0.9 75
1.83 1.35 0.88 8.22 1.1 76 1.91 1.36 0.91 8.59 1.4 76 1.93 1.36
0.92 8.58 1.7 76 1.84 1.36 0.88 8.56 2.1 79 1.79 1.39 0.84 6.68 2.6
74 1.66 1.34 0.80 7.97 3.1 78 1.76 1.38 0.83 8.00 3.6 73 1.24 1.33
0.60 6.32
[0133] In addition to the tabular display of the RHT Data Table,
the system, in a current embodiment, displays the following
computations shown below in the Computational Display Table.
9 COMPUTATIONAL DISPLAY TABLE Qp Max Ratio = 1.90 T (0-2 min)
(1.sup.st quintile) Vm Max Ratio = 1.70 T (4-6 min) (3.sup.rd
quintile) V(Exp) = 33.88 ml
[0134] The computational display includes the variables set forth
below.
10 VARIABLE TABLE Qp Max Ratio [a label] = x T (y min) (z quintile)
where x = blood flow maximum value in ml per minute; where y = the
time frame corresponding to max. blood flow Qp; and, where z = the
quintile corresponding to max. blood flow Qp. Vm Max Ratio [a
label] = r T (n min) (u quintile) where r = blood volume maximum
value in cc; where n = the time frame corresponding to max. blood
volume Vm; and, where u = the quintile corresponding to max. blood
volume Vm. V(Exp) [a label] = k ml. where k = computational value
of total blood volume measured during the entire RHT test (whether
5 min. (short test) or 10 min. (long test)).
[0135] The RHT test may measure and monitor reactive hyperemia for
the initial five (5) minutes of the hyperemic episode (typically
capturing primary phase RHT data) or may measure and monitor
reactive hyperemia for the full ten (10) minutes of the hyperemic
episode. Researches do not have sufficient information at this time
to determine the exact length of the RHT test. In any event, the
operational aspects of the RHT test are substantially similar.
Multiple and frequent calibrations are taken to gather and correct
the raw blood pressure pulse data and compute blood volume
pulsatile data and flow. The theories described herein are
applicable to RHT tests ranging from at least three (3) minutes
subsequent to the quick release of the suprasystolic cuff pressure
to about ten (10) minutes post cuff pressure release. The claims
appended hereto are meant to cover these test time frames.
[0136] The following Phase Process Table refers to a long, ten (10)
minute RHT test wherein the 10 minute data acquisition period is
subdivided into fifths or quintiles. Other data acquisition
segments may be established following clinical evaluations of a
reasonable number of patients. The term "phase" refers to the time
or episodic time of data acquisition.
11 PHASE PROCESS TABLE (LONG RHT TEST) Measurement RHT Testing
Phase Time Plotted Value (Qp and Vm) BL Baseline Baseline T (0-2
min) (1.sup.st quintile) 0.5 min, 1 min Average (3 measurements) 2
min T (2-4 min) (2.sup.nd quintile) 3 min, 4 min Average (2
measurements) T (4-6 min) (3.sup.rd quintile) 5 min, 6 min Average
(2 measurements) T (6-8 min) (4.sup.th quintile) 7 min, 8 min
Average (2 measurements) T (8-10 min) (5.sup.th quintile) 9 min, 10
min Average (2 measurements)
[0137] The blood volume signals or the raw pressure pulse signals
are averaged in this currently preferred embodiment of the
invention. Averaging (a) reduces involuntary motion artifact
corruption of the data (large movement by the patient requires
electronic signal processing to detect and block-out or ignore the
resulting signals which are aberrations of the true pressure pulse
signals); and (b) smooths the signals. Data values may be averaged
or waveform data may be averaged. In the currently preferred
embodiment of the invention, wave peak data values are averaged.
Mathematically, it does not matter whether pressure pulse data
values or blood volume peak data values are averaged. Other
averaging factors (rather than the 3 point and 2 point average) may
be utilized. However, the time based accuracy of the pulsatile data
deteriorates if higher averaging values are utilized by the data
acquisition system.
[0138] The Computational Display Table shown and described above is
obtained from the following computations:
Qp(Ratio)=Qp(Max)/Qp(BL(baseline)). Eq. 4
Qp(Phase(time of
occurrence))=1.sup.st,2.sup.nd,3.sup.rd,4.sup.th,5.sup.th period
Eq. 5
[0139] where 1.sup.st=T(0-2 min) etc. and where Qp max. is
found.
Vm(Ratio)=Vm(max)/Vm(BL) Eq. 6
Vm(Phase)=1.sup.st,2.sup.nd,3.sup.rd,4.sup.th,5.sup.th quintile
time periods Eq. 7
V(Exp)=((Qp(1.sup.st).times.2)+(Qp(2.sup.nd).times.2)+(Qp(3.sup.rd).times.-
2)+(Qp(4.sup.th).times.2)+(Qp(5.sup.th).times.2)-(Qp(BL)).times.10
min. Eq. 8
[0140] The last formula for V (exp) refers to blood volume
expansion or the capacitive value of the arterial system. During
reactive hyperemia, the arterial system expands, captures a greater
amount of blood volume than normally and temporarily stores that
blood volume. This is similar to a capacitor which stores
electrical energy for a time. In the arterial system, this stored,
excess blood volume is dissipated over time from the peak or
maximum value Vmax. The total blood volume generated, captured,
stored and dissipated during the entire reactive hyperemic episode
is indicative of the health and physiologic characteristic of the
arterial system and the endothelium. At the present time,
researchers do not know wether the phase of the signal (a time
based analysis) or a total flow or volume or a combination of this
data is most significant.
[0141] The present working embodiment utilizes a ten minute test
period after the five minute occlusion period. The episodic test
period is divided into six (6) testing phases. To generate the
aforementioned data, the electronic system electronically stores
signals representing 12, five second strips of pressure waveforms.
If necessary, the electronic system could store waveform signals
for the entire 10 minute episodic test period. Simple data
processing techniques are utilized herein due to the novelty of the
test in the medical community.
[0142] An important advantage of the present invention is the
simplicity of operation. The technician asks the patient a series
of simple questions (Do you smoke cigarettes? etc.), inputs the
data into the system, takes the blood pressure of the patient by
conventional methods, records this BP data into the system, wraps
the cuff around the patient's arm, and presses a START key. The
system thereafter operates in an automatic fashion.
[0143] FIG. 13 also illustrates the baseline (BL) maximum blood
volume Vm (ml), and the basal blood flow Qp (ml/min). In the
current, revised working embodiment, the RHT test is divided into
quintiles. Maximum blood volume Vm (averaged) and blood flow is
shown in each quintile with a bar graph. An important data
comparison feature is the difference between the baseline values
and the values in each quintile. The display may be altered to show
differences rather than actual values. Also, the bar graph may be
replaced with a waveform display. The waveform may be generated by
datapoints at the top of each bar in the bar graph plot. A waveform
smoothing routine may be used to better illustrate the compiled
data.
[0144] The claims appended hereto are meant to cover modification
and changes within the scope and spirit of the present
invention.
* * * * *