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BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to the measurement of pressure within a liquid
containing vessel. More particularly, the invention relates to a method
for measuring pressure within the cardiovascular system of a living test
subject.
2. Prior Art
The measurement of pressure within a liquid containing vessel such as the
cardiovascular system of a living being can be performed by any of a
number of methods. Catheterization and direct measurement of pressure is
one wholly accurate method. Systemic blood pressure may also be measured
externally of the test subject as by attaching a blood pressure cuff about
a portion of the subject's body and listening for Korotkoff sounds,
measuring the Doppler shift of the artery wall with fluctuating pressure,
measuring the derivative of the instantaneous pressure at the cuff, and
the like. Other methods of making such blood pressure determinations are
discussed in, for example, "The Direct and Indirect Measurement of Blood
Pressure" by L. A. Geddes, Yearbook Medical Publishers, Inc., Chicago,
Ill., 1970.
The direct catherization method of measuring blood pressure has the
advantage of being useable any place within the cardiovascular system, to
the extent that irreversible physical damage and shock is not caused by
the catheterization technique. The various techniques which require the
use of a cuff can generally be used only on parts of the body where the
cuff can be readily attached, for example, an arm, a leg, a finger, or the
like. And, this approach is only amenable to the systemic circulation, for
example, it cannot be used to measure pulmonic arterial pressure. Further,
with small infants such as premature babies, it may be impossible, at
times, to properly attach such a cuff. Hence, these techniques, while
finding wide usefulness, are not useful to provide certain desired data
such as the differences in blood pressure in different portions of the
cardiovascular system, and the measurement of blood pressures in small
infants, although the latter can be accomplished, at times, with special
cuffs.
An attempt has previously been made to utilize the fact that when
ultrasonic signals are reflected from microbubbles of known size, the
frequency of the reflected signal will be a function of the pressure in
the liquid in which the bubbles exist. If such bubbles are in a
cardiovascular system of a living being, the frequency of the reflected
signals from the bubbles will vary over a heartbeat in response to the
variation in pressure within the cardiovascular system. This technique has
been found, however, to be difficult to practice, because the ultrasonic
signals have set up standing waves with the microbubbles, at times, at a
node, and because the frequency of the signals has needed to be swept,
which in combination with the existence of standing wave nodes has led to
the detection of false signals. Thus, while one has been able in the past
to inject preformed microbubbles into the cardiovascular system, and to
reflect ultrasonic signals from these bubbles as they pass a desired
position in that system, for example, the main pulmonary artery, the
ultrasonic reflection system has not provided a signal which as a
practical matter can be utilized for accurate measurements of blood
pressure.
It is also known, as set out in copending U.S. Pat. application Ser. No.
36,098, of E. Glenn Tickner and Ned S. Rasor, to measure instantaneous
blood flow rate in a cardiovascular system using microbubbles of uniform
size in the system and to enhance ultrasonic images by injection of such
microbubbles.
It would be highly desirable to provide a method for measuring pressure
within a liquid containing vessel, particularly within the cardiovascular
system of a living being, which method could measure the pressure in the
system at different points therein and could be readily utilized with
infants as well as adults. It would particularly be advantageous if such a
system would allow measurement of pressure within the heart itself,
without the necessity of performing a relatively risky catheterization and
insertion of a pressure detector into the heart from a vein or artery. It
would also be useful if blood flow rate and/or ultrasonic image
enhancement could be provided with particularly advantageous
signal-to-noise ratios.
SUMMARY OF THE INVENTION
The invention relates to a method of determining the pressure within a
liquid containing vessel. As a first step, a solid precursor for at least
one bubble is added to the liquid. The precursor is retained in the liquid
for a sufficient time to form at least one bubble and to generate a sonic
signal. A characteristic of the sonic signal which is representative of
the pressure in the liquid is measured. Thereafter, the pressure in the
liquid is determined from the measured characteristic.
The invention provides a very advantageous method for measuring pressure
within the cardiovascular system of a living being. This method is also
useful with other liquid containing vessels without modification thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention will be better understood by reference to the figures of the
drawing wherein like numbers denote like parts throughout and wherein:
FIG. 1 illustrates, schematically, operation of an embodiment in accordance
with the present invention;
FIG. 2 illustrates microbubble generating material useful in a method in
accordance with the present invention;
FIG. 3 illustrates formation of microbubble generating material useful in
the practice of the present invention; and
FIG. 4 illustrates, schematically, electrical circuitry for determining the
pressure in a liquid.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
Adverting to FIG. 1, there is shown therein in a generally schematic
representation a heart 10 which forms a portion of a cardiovascular system
12, part of which is shown in FIG. 1, of a living test subject. In the
representation of FIG. 1, blood flows from the superior vena cava 14 into
the right atrium 16, then into the right ventricle 18, on to the main
pulmonary artery 20, and then on via the left pulmonary artery 22 and the
right pulmonary artery 24 to the remainder of the cardiovascular system
12.
In accordance with the present invention a solid bubble precursor, such as
the various particles 26 seen in FIGS. 1 and 2, are added to the blood 28
which fills the cardiovascular system 12. These particles 26 are carried
along with the blood flow in the manner just described. Generally the
particles 26 would be injected into the blood stream a slight distance
upstream of the heart 10 and then would be carried therethrough by the
blood flow.
The particles 26 serve as microbubble precursors in a method which will be
explained. The term "bubble" is used to denote bubbles of any size. The
term "microbubble" as used herein refers to bubbles which generate
ultrasonic signals on their formation. Briefly, the solid microbubble
precursors or particles 26 will generally comprise a hollow interior space
30 (See FIG. 2) completely enclosed therein by an outer surrounding wall
32. The outer surrounding wall will generally be of a saccharide
composition. A particular preferred composition is approximately 80%
sucrose and 20% lactose. The hollow space 30 will generally be filled with
a gas which is of a pressure above the pressure which exists within the
cardiovascular system 18. Such compositions as have just been described
for the particles 26 can be formed generally as described in U.S. Pat. No.
3,012,893, issued Dec. 12, 1961 to L. Kremzner and W. A. Mitchell. It is
important to the present invention, however, that the amount of gas in the
hollow space 30 of each one of the particles 26 of the present invention
be generally the same so that when the outer wall 32 of each particle 26
dissolves sufficiently to allow the gas to escape from the hollow space
30, the resulting microbubbles formed in the cardiovascular system will be
of a uniform size. FIG. 2 shows the particles 26 dissolving as they flow
from left to right in the cardiovascular system.
It has been found that if particles 26 are made in accordance with the
teachings of the aforementioned U.S. Pat. No. 3,012,893, sufficient
uniformity of amount of gas entrapped in the hollow space 30 is not
attained. However, it also has been found that if a viscous sugar solution
31, of the composition set out in that patent, is flowed through a tube 33
as shown in FIG. 3, with the temperature of the sugar solution being held
just a few degrees above the solidification point thereof, and if an end
35 of the tube exits into a pressurized cooled zone 36 which is at a
temperature below the solidification temperature of the viscous sugar
liquid, and if a gas such as carbon dioxide is introduced generally
centrally into the flowing liquid via a capillary tube 39, with an end 37
of the capillary tube 39 being at or near an end 35 of the tube 33, then
as the sugar quickly solidifies, the amount of carbon dioxide or other gas
trapped in each of the resulting quickly solidified microbubble precursor,
or particles, 26 is substantially equal. Generally, the entire apparatus
is kept at a elevated pressure, for example 5 to 50 atmospheres. A
vibrator 41 is placed adjacent the tube 33 to create dynamic (Rayleigh)
instability whereby particles 26 are produced having as few as possible
hollow spaces 30 per particle. Generally, about thirty hollow spaces 30
have been formed per particle 26, although less, most preferably one, is
preferred.
Generally, the amount of gas entrapped within each one of the particles 26
is controlled so that when a microbubble is produced therefrom, it will be
generally within a range from about 325 microns to about 0.5 micron in
diameter. More preferably, the microbubbles would have a diameter below
about 150 microns and above about 1.0 micron. Microbubbles of about 25
microns in size have been found to be very suitable for use in the method
of the present invention.
The particles 26 can be added to the cardiovascular system over a period of
time, if desired, so as to provide measurements of blood pressure over one
or more heartbeats. Further, the microbubble precursor 26 can be added as
a particle containing several microbubbles therein, which particle may be
broken up by the agitation action occurring within the heart 10.
Generally, however, it would be preferable to use a plurality of particles
26, each of which contains, generally, a single hollow space 30 filled
with an equal quantity of gas. Large aggregates of precursor 26 can be
ground up to provide smaller particles having only one or a few hollow
spaces 30, or particles 26 can be used having up to about fifty such
hollow spaces 30. It is noted that even if all of the particles 26 are
added at a single time, their time of arrival at any particular position
in the cardiovascular system 12 will generally not be quite identical
because of the agitation taking place within the heart 10 and other
portions of the cardiovascular system 12.
The particles 26 are retained in the blood 28 for a sufficient time to form
the desired microbubbles. On formation of a microbubble, a transient
ultrasonic signal having a large amplitude is generated since the
microbubble expands outwardly very rapidly and alternately contracts and
expands until it attains its equilibrium size and shape at the lesser
pressure which exists within the cardiovascular system 12, as compared
with the higher pressure within the hollow space 30. The ultrasonic signal
is then generated by this alternate expansion and contraction (compression
wave).
It follows that a plurality of ultrasonic signals are generated as a
function of time as the various microbubbles are formed on dissolving of
the various particles 26 or on dissolving of portions thereof.
A characteristic of the ultrasonic signal which is generated is measured,
which characteristic is representative of the pressure in the blood 28. In
accordance with the present invention, this characteristic is generally
the frequency of the ultrasonic signal which has been generated. Normally,
a measurement will be made of the frequency generated by the formation of
the microbubbles as a function of time. From this measurement, the
pressure in the blood 28 is determined.
Basically, the ultrasonic signal generated is picked up by an ultrasonic
sensitive transducer 34 attached to a living being opposite the position
at which the particles 26 are dissolving. In the particular embodiment
shown in FIG. 1, the transducer 34 is on the chest 25 of the test subject
generally opposite the main pulmonary artery and the pressure being
determined is that within the main pulmonary artery.
Briefly, as each microbubble is formed by dissolving of at least part of
the wall 32 to expose the hollow space 30 or as the wall 32 thins
sufficiently to cause the pressurized bubble 30 to fracture it, the
microbubble expands to beyond its equilibrium size then contracts to below
its equilibrium size, and alternately expands and contracts until it
finally attains substantially its equilibrium size and shape. The
frequency of the signal thereby detected by the transducer 34 is a
function of the pressure in the cardiovascular system 12 opposite the
positioning of the transducer 34. Briefly, the pressure is directly
proportional to the frequency as detected. The output from the transducer
34 is conventionally converted from a frequency versus time representation
to a voltage versus time representation. In the simplest instance, this
would be via analog signal processing means 38 as shown in FIG. 4.
Considering now a specific example of the signal processing means 38
suitable for converting the output signals from transducer 34 to a display
or recording of pressure and pressure variations, if any, within the
subject, reference should be made to FIG. 4. In response to an individual
microbubble, transducer 34 generates an electrical output, depicted by
waveform 34a in FIG. 4, which as previously discussed has a frequency
indicative of the ambient pressure in the region of the microbubble. The
waveform 34a of the transducer 34 is amplified by an amplifier 40 and
transmitted through a band pass filter 42 to the input of a zero crossing
detector 44. Band pass filter 42, which may be of known construction,
suppresses wave trains having frequencies above or below those
characteristic of the microbubbles and thus suppresses spurious data which
could detract from the accuracy of the system.
Zero crossing detector 44 is of the known form which produces an output
voltage, indicated by waveform 44a in FIG. 4, having a magnitude which is
a function of the frequency of the input waveform. Thus the output of zero
crossing detector 44 is a voltage having a magnitude indicative of the
frequency of the sonic vibrations detected by transducer 34 in response to
current microbubble production in the subject.
The output of zero crossing detector 44 is transmitted to one input of a
differential amplifier 46, the other input of which receives a reference
voltage from a sample and a hold circuit 48 to be hereinafter discussed in
more detail. Differential amplifier 46 transmits that portion of the
waveform 44a which exceeds the reference voltage level to an integrating
circuit 50 which may, for example, be an R-C network having a resistor 52
through which the output signals 46a of amplifier 46 are transmitted to a
terminal 54. An integrating capacitor 56 and a second resistor 58 are
connected in parallel between terminal 54 and ground. Integrating circuit
50 averages the amplitudes of the input waveforms 46a which are being
received at any given time to produce an output voltage 50a which varies
in accordance with variations of the average frequency of the waveforms
34a being generated by transducer 34. Where this average frequency varies
over a period of time, as in the case of the blood pressure of a medical
patient, for example, the output voltage 50a of integrating current 50
varies correspondingly.
Output voltage 50a from terminal 54 may be transmitted to any of a variety
of display and/or receiving devices depending on the requirements of the
specific usage of the invention. For example, the output of integrating
circuit 50 may be connected to the input of a chart recorder 60 of the
known form which produces a continuous graph on paper or the like
corresponding to variations of an input voltage. The output voltage 50a
from integrating circuit 50 may also be transmitted to the Y sweep
frequency terminal of an oscilloscope 62 while a repetitive ramp signal is
applied to the X sweep frequency terminal to generate a visible graphical
display of pressure variations. Alternately or concurrently the output of
integrating circuit 50 may be applied to a volt meter 64 suitably
calibrated to indicate pressure. The various display or recording devices
60,62 and 64 discussed above may be used individually or jointly and other
forms of voltage indicator or recording device may also be used. As will
be apparent, the output of integrating circuit 50 may also be stored by
analog or digital means for later playback and display.
Sample and hold circuit 48, which provides the reference input to a
differential amplifier or comparator 46, serves to maintain a reference
signal. It also enhances accuracy of the data by eliminating that portion
of the output signals 44a from zero crossing detector 44 which may result
from background noise detected by transducer 34 or which may result from
variations in ambient conditions that alter the frequency of the output
wave trains 34a from transducer 34 in ways which are not indicative of the
actual pressure which it is desired to measure. For example, the blood
pressure of a medical patient may be affected by variations of barometric
pressure and this will affect the frequency of the output wave trains 34a
of transducer 34 although this component of the detected data is not
medically significant. In order to remove these components of the pressure
signals, or other components which may not be significant in other usages
of the invention, sample and hold circuit 48 has an input which may be
selectively connected to the output of integrating circuit 50 through a
switch 66. Prior to making the measurement of the pressure which is to be
detected, and prior to the initiation of microbubble production, switch 66
is temporarily closed to provide an input voltage to sample and hold
circuit 48. The magnitude of such input voltage at that time is indicative
of the background noise and background pressure effects. Sample and hold
circuit 48 is of the form which detects the background input voltage while
switch 66 is closed and then stores that data after the switch 66 is
opened. After switch 66 is opened and the desired pressure measurement is
in progress, hold circuit 48 applies the stored background voltage signal
to the reference input of amplifier 46. Differential amplifier 46 then
reduces the amplitudes of the output signals from zero cross detector 44
by an amount proportional to the magnitude of the background voltage
signal to remove the unwanted components from the pressure readings.
The signal processing system 38 as described above is of an analog form for
purposes of example. As will be apparent to those skilled in the art, the
output of amplifier 40 may be transmitted to an analog to digital
converter and the several subsequent functions of the system as described
above may then be performed by equivalent digital data processing means,
although a digital to analog converter must then be provided at the inputs
to the display or recording devices 60,62,64 unless such devices are of
the form which contain such converters internally or are digital devices
themselves.
Calibration of the system against particles 26 which dissolve in a liquid
of a known pressure, for example atmospheric pressure, provides a direct
readout of main pulmonary artery 20 pressure against time since the
frequency measured is determined from the equation:
P.sub.Pulmonary Artery =(f.sub.meas -f.sub.o)/K
where K is a function of the particular gas in hollow space 30 and the
diameter of the microbubble produced by release of that gas, f.sub.0 is
the frequency at ambient pressure, and P.sub.Pulmonary Artery is the
pressure in the pulmonary artery at any time.
It should be pointed out that while the preferred gas is carbon dioxide,
other gases can also be included in place of the carbon dioxide or in
addition thereto. Other gases which are useful include nitrogen, oxygen,
argon, xenon, air, methane, freon, ether and even carbon monoxide, so long
as it is used in an amount that will not be harmful. It is of course
important that whatever gas is utilized not be harmful to a living test
subject when it is dissolved in the cardiovascular system.
The aforementioned and described method is useful for determining blood
pressure, particularly in the main pulmonary artery, but also in other
portions of the cardiovascular system. Such determination can be made
without the utilization of a blood pressure cuff and without injuriously
catheterizing the test subject.
The microbubbles, as formed in the manner just described, also serve to
provide an enhanced ultrasonic image which provides useful diagnostic data
to a physician. Also, substantially instantaneous blood flow rate can be
determined by examining the ultrasonic image produced as described above
and generated opposite a location in a patient's cardiovascular system.
Both the positions and generally simultaneous velocities, when the
microbubbles are of generally a uniform size, are measured to provide a
determination of such blood flow rate. The velocity can be determined by
observing the positions of the various microbubbles as a function of time.
Previously mentioned copending application Ser. No. 36,098 describes such
methods utilizing microbubbles in general, in more detail and that
application is hereby incorporated herein by reference thereto.
While the invention has been described in terms of its use in a
cardiovascular system, it should be apparent that it is also useful
without modification to measure pressure in any liquid containing vessel.
Other aspects, objects, and advantages of this invention can be obtained
from a study of the drawings, the disclosure and the appended claims.
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