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BACKGROUND AND SUMMARY OF THE INVENTION
This invention relates generally to a system for the continuous withdrawal
of blood and more particularly to a system for continuously withdrawing
and collecting blood from a subject for a selected period. In order to
analyze various properties of materials contained in blood, it is
necessary that the blood be withdrawn from the subject. In some instances
the blood concentration of material changes rapidly and markedly under
physiological and pathological conditions. Values obtained from a single
blood specimen, or even multiple blood specimens drawn in quick
succession, will not reflect adequately the variations in concentration of
the material.
For example, the integration of the concentration curves of hormones has
been obtained previously by withdrawing numerous blood samples from a
subject, measuring the concentration in each sample, and then calculating
the average concentration. Use of this method results in inaccuracies in
data collected and calculated as well as resulting in inconvenience and
trauma to the subject due to the numerous blood withdrawals.
In an attempt to overcome these disadvantages, complex systems have been
developed. For example, in one system, a pump withdraws blood continuously
through an indwelling intravenous catheter and infuses by still another
pump a heparin solution into the withdrawn blood through a small catheter
inserted into an extracorporal portion of the indwelling catheter to
prevent clotting in the withdrawal system. Obviously, the indwelling
catheter must be larger than the infusion catheter and, therefore, is
limited to indwelling in veins of considerable size. Also, two pumps are
required and they must be closely synchronized. This and other similar
systems require intricate arrangements and types of equipment which result
in long periods of immobilization of the subject whose blood is being
withdrawn.
Additionally, it is frequently necessary to determine the in vivo
concentration of the diffusible fraction of certain materials in the
blood. If the blood is withdrawn from the subject to measure, for example,
the concentration of the diffusable part of any hormone, drugs or other
material in the blood of the subject, the diffusible fraction, which may
be 100% thereof, frequently changes once the blood is outside of the body.
Therefore, intravenous sensing, rather than the analysis of withdrawn
blood, is necessary to obtain accurate results.
In many systems where blood is withdrawn from a subject and conducted
through various tubes and component parts of an analyzing system, the
tubes and parts can be used only for relatively brief periods without
clotting of the blood therein. This reduces the opportunity for long range
blood withdrawal and the attendant advantages thereof.
It becomes apparent, then, that a need exists for a non-thrombogenic system
for withdrawing blood from a subject over a relatively long period. In
addition, there is a need for a non-thrombogenic system for permitting the
determination of the in vivo concentration of various materials in blood.
Additionally, there is an advantage in the portability of this combined
system.
It is, therefore, an object of this invention to provide a system for the
withdrawal of blood from a subject over and extended period of time to
permit continuous analysis of the blood.
Another object of this invention is to provide a sensing system for
permitting the continuous determination of the in vivo concentration of
the diffusible fraction of certain materials in the blood as well as the
continuous determination of the in vivo concentrations of non-diffusible
materials in blood.
Yet another object of this invention is to provide a sensing system for
permitting the continuous determination of the in vivo concentration of
glucose in the blood.
Still another object of this invention is to provide a non-thrombogenic
system which permits the continuous withdrawal of blood through a single
catheter over an extended period of time.
Another object of this invention is to provide a nonthrombogenic system
which will permit the measurement outside the system of the integrated
concentration of a material in blood.
Still another object of this invention is to provide a portable system for
the continuous withdrawal of blood from a mobile subject.
Other objects and attendant advantages of this invention will become more
readily apparent and understood from the following detailed specification
and accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a pictorial view showing components of a system for withdrawing
blood from a subject.
FIG. 2 is a pictorial view showing the system of FIG. 1 attached to a
subject.
FIGS. 3, 4 and 5 are pictorial views showing various steps for inserting a
catheter of the system of FIG. 1 into the vein of a subject.
FIG. 6 is a pictorial view showing a sensing system attached to the system
of FIG. 1.
FIG. 7 is an exploded pictorial view of the sensing chamber of the sensing
system of FIG. 6.
FIG. 8 is a pictorial view of a variation of the sensing system depicted in
FIGS. 6 and 7.
DETAILED DESCRIPTION OF THE INVENTION
Referring now to FIG. 1, a blood withdrawal system 10 includes a disposable
needle assembly 12. The needle assembly 12 includes a seventeen gauge
needle 14 mounted in a needle hub 16. A plastic sleeve 18 is attached at
one end thereof to an extension of the needle hub 16. The other end 20 of
the sleeve 18 is open.
The system 10 further includes a nineteen gauge catheter 22 composed of a
radiopaque material. The catheter 22 is free at one end and is connected
to a plastic tube 26 having a larger diameter which, in turn, is connected
at its opposite end to another plastic tube 28 having a still larger
diameter. The connected sections of the catheter 22 and tubes 26 and 28
are joined securely by glue.
Thereafter, the internal walls of the catheter 22 and the tubes 26 and 28
are treated to preclude clotting of blood ultimately passing therethrough.
This treatment is accomplished in a two-step process. Initially, by using
a 50/50 mixture of toluene and petroleum ether, a 5% solution of
tridodecylmethyl-ammonium chloride is made. This solution is shaken with
200 milligrams of heparin in 100 milliliters of water. After the emulsion
is separated, the supernatant portion of this mixture is drawn into the
catheter 22 and tubes 26 and 28 and is left in place for 2 hours. After
this, the solution is emptied and filtered, air is drawn through the
catheter 22 and tubes 26 and 28 for 24 hours, thus drying the solution
that has impregnated the internal walls of the catheter and the tubes.
This is accomplished at room temperature. Thereafter, a solution of 200
milligrams of heparin in 50% methyl alcohol and 50% water is drawn through
the catheter 22 and tubes 26 and 28 and is left for 3 to 5 hours,
withdrawn, and the passageway thereafter air dried by suction for twelve
hours as previously described. This impregnation-coating treatment permits
a non-thrombogenic use of the catheter 22 and tubes 26 and 28 for at least
a 24 hour blood withdrawal period.
Of course, other non-thrombogenic materials besides heparin could be
employed for the impregnation, and instead of impregnation, coating is
suitable under some circumstances and using some non-thrombogenic
materials. Also, synthetic materials that have an anti-coagulant (such as
heparin) incorporated therein during manufacture, may be utilized for all
blood engaging portions of the system.
It is to be noticed that great success has been encountered in coating
tubes with very narrow internal diameters due to the drying of the wetted
internal surfaces with air sucked through them rather than the
conventional method of vacuum oven drying.
A housing 30 is formed having strap holders 32 and a hinged door 34. The
housing 30 contains a rotating milking device 36 which functions as a pump
or as a means for controlling the rate of withdrawal of blood from a
subject 50 (FIG. 2). An on-off switch 38 and a timer-control knob 40 are
part of a circuit (not shown) which determines when energy from a battery
42 is applied to the milking device 36. The housing 30 and the various
components contained therein are similar to a pump such as a Model ML-6-3
available from Sigmamotor, Inc., of Middleport, N.Y. In the Model ML-6-3,
the milking device 36 includes a grooved member into which a flexible tube
is positioned. An eccentric roller is rotated at a prescribed rate and
engages the flexible tube to milk a fluid in the tube therethrough at a
prescribed rate.
The housing 30 is formed with a compartment for containing a plastic bag 44
haing a tubular port 46. An intermediate section of the tube 28 is
positioned about the grooved member of the milking device 36 within the
housing 30 as illustrated in FIG. 1, and fastened in this position by use
of a screw 84. The remaining end of the tube 28 is inserted into the port
46 to facilitate the eventual collection of withdrawn blood. It should be
noted that the plastic bag 44 is only representative of a blood collection
facility and could include other facilities such as, for example, test
tubes. The eccentric wheel of the milking device 36 can then be rotated at
a prescribed rate to withdraw blood from the subject 50.
Referring to FIG. 2, straps 48 are used to secure the housing 30 to the
subject 50. The tubes 26 and 28 are positioned through the clothing of the
subject 50 so that the catheter 22 is positioned along the inside of one
arm of the subject.
Referring to FIGS. 3, 4 and 5, a peripheral vein 52 is a lower portion of
the arm of the subject 50 is selected and the adjacent skin area 54 is
sterilized. The hollow needle 14 is then inserted into the vein 52 as
illustrated in FIG. 3. Catheter 22 is disposed with the forward end
thereof extending partly into needle 14 and the other end extending
through opening 20 of the plastic sleeve 18, the catheter being shown
during the inserting operation in FIG. 3.
From the position shown in FIG. 3, the catheter 22 is moved as illustrated
in FIG. 4 through the opening of the needle 14 so that the forward end of
the catheter is moved into the vein 52. As illustrated in FIG. 5, the
needle 14 is withdrawn from the vein 52 and backed over the catheter 22 to
the position shown. The removal of the neelde 14 is accomplished in such a
manner that the forward end of the catheter 22 remains in the vein 52 of
the subject 50.
A plastic clamp 24 (FIGS. 1 and 5) is clamped about the exposed, pointed
tip of needle 14 and placed against the skin of the subject 50. Adhesive
tape 56 is wrapped about the arm of the subject and the clamp 24 as shown
in FIG. 2. The plastic sleeve 18 is then removed from the hub 16 of the
needle and adhesive tape 56 is wrapped about the arm of the subject and
the needle 14 and the needle hub 16. This permits complete portability of
the housing 30 and the contents thereof, the indwelling catheter 22 and
tubes 26 and 28. The subject 50 is free to move about and engage in normal
movement.
The milking device 36 is operated by selective positioning of the on-off
switch 38 and the speed regulator 40. The speed regulator 40 can be set
for various speeds of the milking device 36 of the blood withdrawal system
10. For example, the system 10 can be adjusted to continuously and slowly
withdraw blood from the subject 50 at a constant rate, e.g., 1 milliliter
per hour for 24 hours. Alternatively, the blood can be withdrawn at a rate
of 2 milliliters per minute.
The internal heparin treatment of the walls of the catheter 22 and tubes 26
and 28 eliminates any need for heparin infusion into the withdrawn blood
and, consequently, for additional pumping and infusion facilities. This
enhances the lightweight aspects of the system 10 which improves its
portability.
The portability of the system 10 permits normal activity, including sleep,
for the subject 50 while the blood is being withdrawn from the subject
during the blood-withdrawal period. The blood withdrawn continuously over
the extended period of up to 24 hours by use of the system 10 permits
analysis of the blood with more accurate results than are attainable with
methods where the subject is immobilized or where there are numerous,
separate blood withdrawals.
Referring to FIG. 6, the system 10 can be modified to include a
microdiffusion chamber 64 located between patient 50 and the blood
collection facility, e.g., plastic bag 44. A sensor system is used to
sense the concentration of diffusible materials in the blood and
electrically sends a signal over a wire 62 to a recording device 58. The
sensor and the recording device 58 can be, for example, a device available
from the Space Science Division of Whitaker Corporation, Waltham, Mass.
The recording device 58 is contained within a housing which includes a
clip 60 to facilitate the attaching of the housing to the waist strap 48
as illustrated in FIG. 2. This permits portability of the microdiffusion
chamber 64 and associated equipment.
Referring to FIG. 7, the microdiffusion chamber system 64 includes two
plastic housing sections 66 and 68 which are joined together and held by
screw fasteners such as fastener 70. The tube 28 is connected to either
opening in the chamber 64, liquid flowing from the patient through chamber
66 as shown by arrow 82 and onto the collection device 44. The sections 66
and 68 are formed with chambers 72 and 74, respectively. A sensor probe
76, which is connected to the wire 62, extends into the chamber 74. A
sealing gasket 78 and a silicone rubber or cellulose acetate diffusion
membrane 80, for example, are positioned between the sections 66 and 68
such that the gasket 78 seals the interface of the two sections and the
membrane separates the two chambers 72 and 74. It will be understood that
membrane 80 may be made from materials other than silicone rubber or
cellulose acetate. Membrane 80 may be porous, containing one or more pores
which may vary in size from submicronic to pinhole size. Alternatively,
depending on what is being analyzed and the nature of the sensor probe,
membrane 80 may be eliminated.
The probe 76 may be the type referred to as a glucose sensor in an article
in "Industrial Research" published on Sept. 21, 1972 and appearing on page
27 thereof. It will be understood that probe 76 may alternatively be of
the type to detect other diffusible materials in blood, e.g., calcium ion
and hydrogen ion. This probe 76 responds by the generation of electrical
energy in relation to the concentration of diffusible materials in the
blood. Previously, a probe of this type had to be inserted intravenously
in order to obtain the electrical impulses necessary for measuring the
concentration of diffusible materials in the blood. In the use of the
microdiffusion chamber system 64 illustrated in FIGS. 6 and 7, a diluent
containing heparin is contained in chamber 74. An example of a suitable
diluent would be a buffer solution. As blood passes through the chamber
72, some of the heparin present in chamber 74 will diffuse through the
membrane 80 to thereby render the membrane non-thrombogenic. Also,
diffusible materials in the blood will diffuse through the membrane 80
into the chamber 74 and will eventually lead to equilibration of the
concentration of diffusible materials in the chamber 74 and in venous
blood. By use of the sensor probe 76, detection and measurement of the
concentration of such materials in the chamber occur and permit the
measurement of diffusible materials in vivo. Thus, the sensor probe 76
need not be inserted intravenously of a subject, but can still detect and
measure the same properties of the withdrawn blood as if the blood were
within the subject. It is also possible to remove the contents of chamber
74 and measure directly the concentration of the diffusible materials
therein.
FIG. 8 depicts a variation of the sensing system of FIGS. 6 and 7. Tube 28,
the internal surface of which has been coated with heparin in accordance
with the present method contains blood from a subject which is urged by
milking device 85 into mixing chamber 86. The internal surface of mixing
chamber 86 may be coated with heparin, but it need not be. Tube 88, one
end of which is connected to mixing chamber 86, has its opposite end
positioned in reservoir 90. Reservoir 90 contains a diluent, e.g., a
buffer solution, which is urged through tube 88 into mixing chamber 86 by
milking device 92. The blood and the diluent in mixing chamber 86 are
thoroughly mixed by means of a mixing means 94, which may conveniently be
a magnetic stirring bar actuated by a magnetic stirrer located outside
mixing chamber 86. Mixing device 94 may or may not be coated with heparin.
The blood and diluent mixture flows from mixing chamber 86 through tube 96
into sensing chamber 98. Sensor probe 100 extends into sensing chamber 98.
A membrane 102 made of silicone rubber, cellulose acetate or other
suitable material is disposed across the tip of sensor probe 100 to form
an enclosed cavity 104. Alternatively, a porous membrane containing one or
more pores which may conveniently vary in size from submicronic to about
pinhole size may be used. An example of such a porous membrane is a
Millipore filter. The purpose of membrane 102 in the embodiment depicted
in FIG. 8 is to act as a barrier for non-diffusible material, to act as a
damper for surges in concentration of the blood-diluent mixture, or both.
However, it will be understood that the presence of membrane 102 may not
be required in some cases, depending on the nature of the sensor probe and
the material in blood which is being analyzed. Cavity 104 contains a
diluent which may be, for example, water or a buffer solution. The blood
and diluent mixture passes through sensing chamber 98 and is conducted by
tube 106 into receiver 108 from which it is ultimately discarded.
It will be understood that, like mixing chamber 86 and mixing device 94,
the inner surfaces of tubes 96 and 106 and of sensing chamber 98 as well
as the outer surface of sensor probe 100 where it extends into sensing
chamber 98 may or may not be coated with heparin in accordance with the
present method. If all of the foregoing surfaces which come into contact
with the blood-diluent mixture are heparin-coated, only a simple diluent
need be present in reservoir 90 for mixing with the blood in mixing
chamber 86. Alternatively, if one or more of said surfaces is not coated
with heparin, it is necessary that heparin be present in the diluent in
reservoir 90 for mixing with the blood in mixing chamber 86. It will be
further understood that, if heparin is not present in the blood-diluent
mixture or if membrane 102 is not rendered non-thrombogenic with heparin,
the diluent present in cavity 104 must contain heparin which diffuses
through said membrane to thereby render it non-thrombogenic.
As the blood-diluent mixture, which may or may not contain heparin, passes
through sensing chamber 98, the diffusible fraction of materials in the
blood diffuses through membrane 102 into cavity 104 and eventually comes
into equilibrium with the concentration of said diffusible materials in
venous blood. The tip of sensor probe 100 comes into contact with cavity
104 and may, as mentioned above, be of a type to detect glucose, calcium
ion, hydrogen ion or other diffusible materials in blood. Sensor probe 100
responds by the generation of electrical energy in relation to the
concentration of the diffusible material in blood to which it is sensitive
and transmits an electrical signal over wire 110 to recording device 112.
While FIG. 8 depicts sensor probe 100 in sensing chamber 98, it will be
understood that probe 100 may alternatively be in mixing chamber 86 or,
indeed, at any point downstream from where blood and diluent, and
optionally heparin, are mixed. It will be further understood that the
blood withdrawal and sensing system of FIG. 8 may be either stationary or
portable, i.e., adapted to being strapped to the subject.
While the sensing systems and sensor probes described in FIGS. 7 and 8 are
of a type suitable for the analysis of a diffusible material such as
glucose, it will be understood that variations of the sensing systems
coming within the scope of the claims are anticipated. For example, the
membranes 80 and 102 may be eliminated depending on what is being analyzed
and the nature of the sensor probes.
In summary, the system 10 permits studies on many aspects of the blood
heretofore unobtainable due to inaccuracies which result from previous
blood collecting processes and vacillations of substances in the blood.
For example, an integrated concentration of substances in the blood is
that concentration of a substance determined on a specimen which has been
collected over an extended period of time and which represents a mean
concentration for a specified period of time. A preferable method, both in
respect to scientific accuracy and in reducing trauma to the subject, is
to determine an integrated concentration by analyzing the concentration of
a sample of blood which results from a uniform collection of blood, minute
by minute, over an extended period. The use of the system 10 to collect
the blood over an extended period, for example twenty-four hours, permits
the practice of the preferable method and thus provides a means of
attaining more significant results in blood studies.
A number of hormones and other substances are partially bound to various
proteins in blood. The biological activity of these materials is related
to the concentration of the unbound moiety rather than to their total
concentration. The unbound fraction in vitro is determined by measuring
the diffusion fraction. Results obtained by such in vitro methods are of
limited usefulness since the studies are conducted outside the body. Also,
significant changes in the equilibrium between bound and free fractions
occur because of pH changes and other in vitro changes that often are
unavoidable. The errors in measuring free concentrations of hormones in
vitro may explain a number of inconsistencies between the concentration of
the unbound biological materials, measured by presently available methods,
and their known biological activity.
The development of the small catheter 22, which will permit the
measurements of integrated concentrations of substances, and the
development of the small, non-thrombogenic diffusion chamber system 64 as
well as the sensing system depicted in FIG. 8, which can be inserted
between the catheter 22 and the extracorporal tube 28 in FIG. 6 or tube
106 in FIG. 8, will permit the determination of production rates of
various substances which have not previously been determinable and a true,
free fraction of the substance under study. The latter is possible because
one can expect an equilibrium will be established between the diffusible
fraction of materials in blood and the solution contained in the chamber
74 or cavity 104. In this type of study where the blood would constantly
come from a vein, the results obtained for the free fraction will better
reflect conditions inside the body and give more accurate data regarding
interrelationship of hormones and other substances than can currently be
determined using crude in vitro techniques.
While the invention has been herein shown and described in what is
presently conceived to be the most practical and preferred embodiment
thereof, it will be apparent to those of ordinary skill in the art that
many modifications may be made thereof within the scope of the invention,
which scope is to be accorded the braodest interpretation of the appended
claims so as to encompass all equivalent structures and systems.
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