U.S. patent number RE31,688 [Application Number 06/354,054] was granted by the patent office on 1984-09-25 for method and apparatus for continuous plasmapheresis.
This patent grant is currently assigned to Hemotherapy, Inc.. Invention is credited to Glen D. Antwiler, Jack W. Moncrief, Robert P. Popovich.
United States Patent |
RE31,688 |
Popovich , et al. |
September 25, 1984 |
Method and apparatus for continuous plasmapheresis
Abstract
A process and apparatus are provided for continuously separating
blood into plasma and cellular component fractions and returning
the latter to the subject in admixture with a makeup fluid. The
separation is effected by continuously ultrafiltering the subject's
blood at specified shear stresses and pressures employing a
membrane ultrafilter, preferably having a pore size of 0.45
microns, and a disclosed flow system.
Inventors: |
Popovich; Robert P. (Austin,
TX), Moncrief; Jack W. (Austin, TX), Antwiler; Glen
D. (Westminister, CO) |
Assignee: |
Hemotherapy, Inc. (Austin,
TX)
|
Family
ID: |
26998211 |
Appl.
No.: |
06/354,054 |
Filed: |
March 2, 1982 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
Reissue of: |
836214 |
Sep 23, 1977 |
04191182 |
Mar 4, 1980 |
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Current U.S.
Class: |
604/6.01;
210/195.2; 210/321.65; 210/651 |
Current CPC
Class: |
A61M
1/3496 (20130101); A61M 1/3603 (20140204); A61M
1/3431 (20140204) |
Current International
Class: |
A61M
1/34 (20060101); A61M 1/36 (20060101); A61M
001/03 () |
Field of
Search: |
;210/195.2,321.3,433.2,434,651,927 ;128/214 ;422/44 ;604/6 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
"The Effects of Membrane Diffusion and Ultrafiltration Properties
on Hemodialyzer Design and Performance", Popovich et al, Chemical
Engineering Progress, vol. 67, No. 114, pp. 105-115 (1971). .
"Transfer of Chemical Species Through a Protein Gel", Dorson et
al., vol. XVII, Trans. Amer. Soc. Artif. Int. Organs, pp. 287-292
(1971). .
"Plasma Exchange in Patients with Fulminant Hepatic Failure",
Buckner et al., Arch. Intern. Med./vol. 132, pp. 487-492 (Oc.
1973). .
"Characterization of Possible `Toxic` Metabolites in Uremia and
Hepatic Coma Based on the Clearance Spectrum for Larger Molecules
by the ACA Microcapsule Artificial Kidney", Change et al., vol.
XIX, Trans. Amer. Soc. Artif. Int. Organs, pp. 314-319 (1973).
.
"Initial Trials of Molecular Separation Artificial Kidney", Dorsen
et al., vol. XIX, Trans. Amer. Soc. Artif. Int. Organs, pp. 119-125
(1973). .
"Clinical Experience with Intermittent Hemodiafiltration",
Henderson et al., vol. XIX, Trans. Amer. Soc. Artif. Int. Organs,
pp. 119-125 (1973). .
"Plasma Fractionation in the United States", Ness et al, JAMA, vol.
230, No. 2, pp. 247-250 (Oct. 14, 1974). .
"Microemboli-Free Blood Detoxification Utilizing Plasma
Filtration", Castino et al., Amer. Soc. Artif. Int. Organs, pp.
637-644 (1976). .
"Investigation of Factors Controlling the Rate of Plasma Filtration
with Microporous Membranes", Lysaght et al., AICHE 83rd National
Meeting, Houston, Texas, Mar. 20-24, 1977. .
Buckner et al., "Plasma Exchange with NCI-IBM Blood Cell
Separator", Rev. Fr Etud Clin Biol vol. 14: 803-805, Oct. 1969.
.
Graw, Jr. et al., "Plasma Exchange Transfusion for Hepatic Coma New
Technique", Human Tumor Cell Bio. Br., Natl. Cancer Inst.;
Jan.-Feb. 1970, Transfusion pp. 26-32. .
"Membrane Separation", Osborn et al., T884,001, Def. Pub.,
published 3/09/71, 884 O.G. 433..
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Primary Examiner: Lander; Ferris H.
Attorney, Agent or Firm: Arnold, White & Durkee
Claims
We claim:
1. An apparatus for the continuous separation of blood into a
cellular component fraction and a plasma fraction comprising:
(a) an ultrafiltration cell comprising a filter membrane having a
pore size of from about 0.1 to about 1.0 microns in diameter, said
membrane separating said cell into filtering and filtrate chambers,
said filtering chamber comprising an inlet and an outlet, and said
filtrate chamber comprising an inlet and an outlet;
(b) a blood input pumping means for pumping blood directly from a
blood vessel to the inlet of said filtering chamber and delivering
a flow of whole blood parallel to said filter membrane in depths of
from about 0.1 mm to about 1.0 mm measured perpendicularly from the
face of said membrane, and at rates sufficient to obtain a shear
rate at the membrane interface of from about 10 dynes/cm.sup.2 to
about 1000 dynes/cm.sup.2 ;
(c) a pumping means to direct a portion of said plasma fraction
flowing from the outlet of said filtrate chamber in a flow from the
inlet to the outlet of said filtrate chamber and parallel and in
the same direction as the flow of whole blood passing through said
filtering chamber.
2. The apparatus of claim 1 and further comprising recycle pumping
means connected between the input and output of said filtering
chamber for recycling a portion of the cellular component fraction
from the outlet of said filtering chamber to the inlet of said
filtering chamber to obtain the desired shear rate within said
filtering chamber at whole blood flow rates which are not great
enough to provide said shear rates.
3. The apparatus of claim 1 and further comprising a plasma pumping
means connected to the outlet of said filtrate chamber.
4. The apparatus of claim 3 and further comprising pressure sensing
means connected between the outlet of said filtrate chamber and
said plasma pumping means for sensing the pressure in said filtrate
chamber.
5. The apparatus of claim 4 and further comprising pressure
regulating means interconnected to said pressure sensing means and
said plasma pumping means for regulating the operation rate of said
plasma pumping means in response to variations of filtrate chamber
pressures as sensed by said pressure sensing means.
6. The apparatus of claim 3 and further comprising replacement
fluid pumping means connected to the inlet of said filtering
chamber for delivering a volume of replacement fluid to said
filtering chamber at volumetric rates substantially equal to the
volume of plasma fraction leaving said filtrate chamber.
7. The apparatus of claim 6 wherein said replacement fluid pumping
means and said plasma pumping means are interconnected so as to
operate at substantially the same rate and thereby provide for the
addition of a replacement fluid to said filtering chamber at the
same rate as the plasma fraction is being removed from said
filtrate chamber by said plasma pump.
8. The apparatus of claim 1 and further comprising drip cell means
for removing entrapped gases from the blood being separated, a
first said drip cell means communicating with the inlet of said
filtering chamber and a second drill cell means communicating with
the outlet of said filtering chamber.
9. The apparatus of claim 8 and further comprising pressure
indicating means, a first said pressure indicating means
communicating with the inlet of said filtering chamber and a second
said pressure indicating means communicating with the outlet
thereof.
10. The apparatus of claim 1 and further comprising pressure
indicating means communicating with the inlet of said filtrate
chamber.
11. The apparatus of claim 1 and further comprising flow
restriction means communicating with the outlet of said filtering
chamber for regulating the rate of flow from said outlet and
thereby the pressure within said filtering chamber.
12. The apparatus of claim 1 wherein said filter membrane has a
pore size of about 0.45 microns and is fabricated from materials
selected from the group consisting of cellulose nitrate and
regenerated cellulose.
13. An apparatus for the continuous separation of blood into a
cellular component fraction and a plasma fraction comprising:
(a) an ultrafiltration cell comprising a filter membrane having a
pore size of from about 0.1 to about 1.0 microns in diameter
separating said cell into filtering and filtrate chambers, said
filtering chamber having an inlet and an outlet and said filtrate
chamber having an outlet;
(b) blood input pumping means for pumping blood directly from a
blood vessel to the inlet of said filtering chamber and delivering
a flow of whole blood parallel to said filter membrane in depths of
from about 0.1 mm to about 1.0 mm, measured perpendicularly from
the face of said membrane;
(c) recycle pumping means connected between the inlet and outlet of
said filtering chamber for recycling a portion of said blood
fraction from said outlet to said inlet the combined flow rates of
said o the outlet of said filtrate chamber for removing said plasma
fraction from said filtrate chamber;
(e) replacement fluid pumping means connected to the inlet of said
filtering chamber for delivering replacement fluid thereto at
substantially the same volumetric rate at which said plasma
fraction is being removed from said filtrate chamber via said
plasma pumping means.
14. The apparatus of claim 13 and further comprising pressure
sensing means connected between the outlet of said filtrate chamber
and said plasma pumping means for sensing pressure in said filtrate
chamber, and automatic pressure regulating means interconnected
between said pressure sensing means and said plasma pumping means
for regulating the pumping rate of said pumping means in response
to variations in pressure sensed by said pressure sensing
means.
15. The apparatus of claim 13 wherein said replacement fluid
pumping means and said plasma pumping means are interconnected so
as to operate at substantially the same rate to thereby provide for
delivery of replacement fluid to said filtering chamber at the same
volumetric rate at which said plasma fraction is removed from said
filtrate chamber.
16. The apparatus of claim 13 and further comprising drip cell
means for removing entrapped gas in blood being separated, a first
drip cell means communicating with the inlet of said filtrate
chamber and a second drip cell means communicating with the outlet
thereof.
17. The apparatus of claim 16 and further comprising pressure
indicating means, a first said pressure indicating means
communicating with the inlet of said filtering chamber and a second
said pressure indicating means communicating with the outlet of
said filtering chamber.
18. The apparatus of claim 13 wherein said filter membrane has a
pore size of about 0.45 microns and is fabricated from materials
selected from the group consisting of cellulose nitrate and
regenerated cellulose.
19. A continuous plasmapheresis process comprising:
(a) continuously withdrawing whole blood from the blood vessel of a
donor and pumping said whole blood into the filtering chamber of an
ultrafiltration cell;
(b) continuously filtering said whole blood into a cellular
component fraction and a plasma fraction by passing it in a flow
over and parallel to an ultrafilter membrane having a pore size of
from about 0.1 to 1.0 microns in diameter, and at a flow rate
sufficient to provide a shear stress at the membrane interface of
from about 10 dynes/cm.sup.2 to about 1000 dynes/cm.sup.2 at
transmembrane pressures of from about 50 mm of mercury to about 700
mm of mercury;
(c) continuously admixing said cellular component fraction with an
amount of replacement fluid substantially equal to said separated
plasma fraction; and
(d) continuously returning said cellular component fraction and
replacement fluid mixture to a blood vessel of said donor.
20. The process of claim 19 and further comprising recycling a
portion of the plasma fraction separated from said whole blood in a
flow parallel to and in the same direction as the flow of said
whole blood over said ultrafilter membrane, but on the opposite
side of said membrane from the flow of whole blood, to thereby
obtain a substantially uniform transmembrane pressure across the
entire length of said membrane.
21. The process of claim 19 and further comprising recycling a
portion of said cellular component fraction over said ultrafilter
membrane in the same direction as said flow of whole blood in a
manner such that said shear rates can be obtained at insufficient
whole blood flow rates.
22. The process of claim 19 wherein said transmembrane pressure is
from about 100 to about 400 mm of mercury.
23. The process of claim 19 wherein said ultrafiltration is
effected employing an ultrafilter membrane having a pore size of
about 0.45 microns and fabricated from materials selected from the
group consisting of cellulose nitrate and regenerated
cellulose.
24. The process of claim 19 wherein said shear stress at the
membrane interface is from about 150 dynes/cm.sup.2 to about 600
dynes/cm.sup.2. .Iadd. 25. Apparatus for plasmapheresis treatment
of a patient, comprising:
(a) an ultrafiltration cell having an inlet for receiving a flow of
whole blood, an outlet for discharging blood cellular components,
and an outlet for discharging plasma filtrate;
(b) means disposed in said ultrafiltration cell for effecting
separation of plasma and cellular components of whole blood flowing
therein;
(c) means for continuously withdrawing whole blood from a blood
vessel of a patient and supplying same to the whole blood inlet of
said cell;
(d) means coupled to the blood cellular components outlet, for
continuously receiving the separated blood cellular components and
supplying same back to the patient; and
(e) means coupled to the plasma filtrate outlet, for continuously
removing plasma filtrate therefrom. .Iaddend..Iadd. 26. The
apparatus of claim 25 further comprising:
means in fluid communication with the whole blood inlet to said
cell, for supplying a continuous flow of replacement fluid to be
admixed with whole blood incoming to the whole blood inlet.
.Iaddend. .Iadd. 27. Apparatus for plasmapheresis treatment of a
patient, comprising:
(a) an ultrafiltration cell having a filter membrane defining
filtering and filtrate chambers, said filtering chamber having an
inlet and an outlet, and said filtrate chamber having an outlet
unconnected with the filtering chamber outlet;
(b) means for continuously withdrawing whole blood from a blood
vessel of a patient and supplying same to the filtering chamber
inlet, and establishing a parallel flow across said filter membrane
at a rate sufficient to produce a shear rate at the membrane
interface that effects separation of plasma and blood cellular
components without hemolysis;
(c) means coupled to the filtering chamber outlet, for continuously
receiving the separated blood cellular components and supplying
same back to the patient; and
(d) means coupled to the filtrate chamber outlet, for continuously
removing the separated plasma fraction from the filtrate chamber.
.Iaddend..Iadd. 28. The apparatus of claim 27 further
comprising:
means in fluid communication with the filtering chamber inlet, for
supplying a continuous flow of replacement fluid to be admixed with
whole blood incoming to the filtering chamber. .Iaddend.
Description
BACKGROUND OF THE INVENTION
In one aspect the present invention relates to plasmapheresis, that
is, the separation of blood into a plasma fraction and a cellular
component fraction. In another aspect, the present invention
relates to plasmapheresis effected by ultrafiltration on a
continuous basis, that is, a process whereby blood is withdrawn
from a donor, separated into cellular component and plasma
fractions, and the cellular components returned, in admixture with
an appropriate amount of replacement fluid, to the donor at
approximately the rate at which blood is being withdrawn. In still
a further aspect, the present invention relates to an apparatus for
the continuous separation of blood into plasma and cellular
component fractions by ultrafiltration.
To appreciate the nature of the present invention, as well as the
difficulties and complications which attend the separation of blood
into cellular component and plasma fractions, a brief discussion of
the makeup of blood is useful. Approximately 45% of the volume of
blood is in the form of cellular components. These cellular
components include red cells, also referred to as erythrocytes,
white cells, also referred to as leukocytes, and platelets. Plasma
makes up the remaining 55% of the volume of blood. Basically,
plasma is the fluid portion of the blood which suspends the cells
and comprises a solution of approximately 90% water, 7% protein and
3% of various other organic and inorganic solutes. As used herein,
the term "plasmapheresis" refers to the separation of a portion of
the plasma fraction of the blood from the cellular components
thereof. Thus, plasmapheresis effected by ultrafiltration is to be
distinguished from ultrafiltration of blood into a fraction
containing cellular materials and the protein constituents of the
plasma and a fraction comprising the aqueous portion of the
plasma.
Separation of blood into a plasma fraction and a cellular component
fraction is desirable for many medical reasons. For example,
separation of blood into plasma fractions and cellular component
fractions provides for a collection of plasma alone, with the
cellular components being returned to the donor with a suitable
portion of replacement fluid. Thus, continuous plasmapheresis
provides for the collection of plasma from donors without the
removal of the cellular components of the blood. Secondly,
continuous plasmapheresis can be used therapeutically to remove
pathogenic substances contained in the plasma portion of the blood.
This can be accomplished by separating the cellular components from
the diseased plasma and returning the cellular components to the
patient in admixture with a suitable replacement fluid, or by
further fractionating the patient's plasma to remove the unwanted
substances and returning a major portion of the patient's plasma
with the cellular components. Finally, a continuous plasmapheresis
process can be employed for diagnostic purposes wherein plasma is
separated on a continuous basis from the cellular components and
analyzed to detect disease-causing substances or conditions
therein.
In the past, ultrafiltration has been used on a continuous basis as
a substitute for, or in combination with, dialysis methods in
artificial kidneys and the like and has also been employed in
batch-type plasmapheresis processes. For example, U.S. Pat. No.
3,579,441 to Brown, issued May 18, 1971, discloses a means for
purifying the blood by continuously ultrafiltering the blood to
separate macromolecular substances having molecular weights higher
than 10,000, or so, and generally at least 40,000-50,000 which
includes blood cells, fat droplets, lipids, high molecular weight
polypeptides and the like from the remaining ultrafiltered aqueous
portion of the blood. Such operations are not true plasmapheresis
processes, as defined herein, because blood is separated not into
plasma and cellular component fractions but rather into
macromolecular fractions (containing cellular components and
portions of the plasma) and a low molecular weight fraction which
contains the waste products which must be removed in an artificial
kidney-type process. Further, ultrafiltration has been used for
plasmapheresis on a noncontinuous basis. For example, U.S. Pat. No.
3,705,100 to Blatt et al., issued Dec. 5, 1972, discloses a process
and apparatus for a blood fractionating process. However, the
process and apparatus disclosed therein is for the fractionating of
blood on a batch basis, that is, on a noncontinuous basis whereby
blood is held in a reservoir and then circulated in a spiral flow
over an ultrafiltration membrane to effect separation.
In any plasmapheresis-type process effected by ultrafiltration
there are various problems which occur during the fractionating of
the blood by passing it in a parallel flow pattern over a membrane,
with a transmembrane pressure sufficient to push the plasma portion
of the blood therethrough, while allowing the cellular component
portion of the blood to remain thereon. One of these problems is
that the flow rates must be controlled fairly closely. Thus, if the
flow rate employed is too fast, turbulence will occur within the
ultrafiltration cell which may cause hemolysis and the general
destruction of cellular components. On the other hand, if flow
rates and transmembrane pressures are not controlled adequately the
cellular and macromolecular components of the blood will tend to
clog up the membrane thus significantly slowing the ultrafiltration
rate. Such clogging can also cause hemolysis to occur. While the
above stated problems attend any ultrafiltration procedure employed
to fractionate blood there are several other important problems
which attend the continuous plasmapheresis of blood wherein
cellular components of the blood are continually returned to the
patient with an amount of replacement fluid equal to the volume of
plasma extracted from the blood. Thus, one of the basic problems of
plasmapheresis is that some of the cellular components of the
blood, such as platelets for example, are very fragile and easily
destroyed and therefore must be returned to the patient undergoing
plasmapheresis within a time period shorter than the useful life
thereof. Blood which is stored in blood banks and the like
typically does not contain sufficient amounts of viable platelets,
because the blood has been outside the body longer than the useful
life thereof. Another problem attending continuous plasmapheresis
includes the tendency of blood which is being separated by
ultrafiltration to have damage occur to the clotting factors
thereof. Basically there are approximately a dozen different
clotting factors which can be affected, and, of course,
re-injecting the cellular components back into a patient's system
where the clotting factors have been adversely effected could
result in a condition similar to hemophilia. Thirdly, denaturing of
proteinaceous materials contained in the blood can be a problem if
the blood is subjected to varying conditions outside the body for
extended periods of time.
Thus, while ultrafiltration has been employed in the past either in
a plasmapheresis batch system, or in a blood fractionating process
in artificial kidney devices, there is not at present a process and
apparatus which provides for the continuous separation of blood
into plasma fractions and cellular component fractions, wherein the
cellular component fractions are continuously returned to the donor
with an effective amount of replacement fluid to thereby
continuously separate the donor's plasma for use in transfusions,
or diagnostic, or therapeutic procedures.
SUMMARY OF THE INVENTION
The process and apparatus of the subject invention provide for the
fractionation of blood into a cellular component fraction and a
plasma fraction on a continuous basis. Thus, according to the
process described herein, a blood feed conduit communicating with a
blood vessel, through a cannula formed therein, delivers whole
blood to the apparatus further described hereinbelow which includes
means for ultrafiltering and thereby separating the cellular
components of the blood from the plasma fraction thereof. The
cellular components are then returned in admixture with an
appropriate amount of replacement fluid, through a second conduit
and cannula formed in a second blood vessel of the patient or
donor. Therefore, the apparatus and process described herein
provide for the continuous separation of plasma from the cellular
components of the blood with return of the latter with an
appropriate amount of replacement fluid to the subject. The process
is hereinafter referred to as continuous plasmapheresis.
Continuous plasmapheresis is accomplished by continually
withdrawing whole blood from a blood vessel and pumping same
through an ultrafiltration chamber to effect separation of plasma
and cellular components. The blood passes in laminar flow, parallel
to the plane of the ultrafiltration membrane at flow rates
sufficient to create shear stress across the ultrafilter membrane
of from about 10 dynes/cm.sup.2 to about 1000 dynes/cm.sup.2, a
preferred range being from about 150 dynes/cm.sup.2 to about 600
dynes/cm.sup.2. The membrane has a pore size sufficient to allow
the plasma components to pass therethrough but retain cellular
components thereon. Generally pore sizes of from about 1.0 to about
0.05 microns can be employed, a preferred range being from about
1.0 to about 0.1 microns, membranes having a pore size of
approximately 0.45 microns being especially preferred.
Transmembrane pressures of from about 50 mmHg to about 700 mmHg are
employed to separate the blood into cellular component and plasma
fractions, a preferred range being about 100 to about 400 mmHg.
Transmembrane pressures of about 200 mmHg are especially preferred.
The cellular components are then admixed with a suitable amount of
replacement fluid which can be clean plasma, an aqueous solution of
dextran, normal serum albumin, normal saline, or any other suitable
plasma substitute, and the replacement fluidcellular component
mixture is then returned to the subject, on a continuous basis,
through a cannula in a second blood vessel. A single vessel can be
employed with the use of a double lumen catheter.
In order to accomplish the above process a special apparatus
basically comprising one or more ultrafiltration cells in
combination with pumping means, conduits, and pressure regulating
and sensing devices is provided. The apparatus includes an
ultrafiltration cell comprising at least one filter membrane
separating the cell into filtering and filtrate chambers. The
filtering chamber has an inlet and outlet thereto. A blood input
pumping means is connected to the inlet of the filtering chamber
portion of the ultrafiltration cell for delivering blood at a
preselected flow rate. Recycling pumping means can also be
connected via conduits between the inlet and outlet of the
filtering chamber of the ultrafiltration cell. This recycling
pumping provides for continuous movement of the blood, through the
filtering chamber of the ultrafiltration cell at a rate sufficient
to obtain the necessary shear rate when the flow of whole blood
alone is insufficient. A plasma pumping means is connected to the
outlet of the filtrate chamber for removing the plasma fraction
therefrom. Transmembrane pressure is regulated either by adjusting
the plasma pumping means, or the blood input and recycling pumping
means, or both, or by restricting flow out of the ultrafiltration
cell.
Additionally, replacement fluid pumping means, interconnected with
the plasma pumping means in a manner such that the plasma and
replacement fluid pumping means operate at substantially the same
rate, is provided, thus insuring that the amount of replacement
fluid added to the system is substantially equal to the amount of
plasma being withdrawn.
In a preferred embodiment of the subject invention, the rate of
ultrafiltration (or flux) through the ultrafilter membrane is
increased by providing a plasma recycling flow through the filtrate
chamber of the ultrafiltration cell, said flow being parallel to
that of the whole blood in the filtering chamber, to thereby
provide a constant transmembrane pressure across the entire flow
path length of the membrane.
SHORT DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic representation of one embodiment of the
plasmapheresis apparatus of the present invention; and
FIG. 2 is a schematic representation of a second embodiment of the
plasmapheresis apparatus of the present invention.
DETAILED DESCRIPTION
It has been discovered that in order to continuously separate blood
into a plasma fraction and a cellular component fraction and return
the cellular components with an appropriate amount of replacement
fluid to the patient or donor specific process conditions must be
maintained during the ultrafiltration of the blood. Specifically,
it has been discovered that by creating specific shear stresses of
the blood as it flows over the membrane of the ultrafilter at
transmembrane pressures of from about 100 to about 400 mm of
mercury and employing an ultrafiltration membrane having a pore
size of 0.45 microns fabricated from cellulose nitrate or
regenerated cellulose the prior art problems of hemolysis,
clogging, and polarization of membrane materials can be overcome
and continuous plasmapheresis obtained.
Proper shear stress over the membrane is provided by recycling a
portion of the cellular components at the outlet of the
ultrafiltration cell to the inlet of the ultrafiltration cell. In
this manner, the recycled portion admixes with the fresh incoming
whole blood and provides for flow rates through the ultrafiltration
cell in excess of those obtained from the input of the blood
pumping means alone which is delivering blood to the
ultrafiltration cell from a donor. In a preferred embodiment,
further described below, replacement fluids are also added at the
inlet of the ultrafiltration cell further increasing the volumetric
flow rate (and therefore shear stress) through the ultrafiltration
cell. Means for regulating the flow of the blood through the
filtering chamber of the ultrafiltration cell can be provided at
both the inlet and the outlet thereof so that a preferred pressure
and flow rate across the filtering side of the membrane can be
maintained.
A plasma pumping means is provided for removing plasma from the
filtrate side of the ultrafiltration cell at a rate sufficient to
insure that preferred transmembrane pressures of from about 100 to
about 400 and preferably about 200 mm of mercury are maintained. A
pressure transducer for sensing and measuring the pressure on the
filtrate side of the ultrafiltration cell is provided for
regulation purposes. The plasma pumping means is interconnected,
for example by means of a common drive shaft, with a replacement
fluid pump such that replacement fluids are added to the system at
substantially the same rate at which plasma is being withdrawn.
Thus, the volumetric flow rates in and out of the continous
plasmapheresis apparatus of the subject invention will be
essentially equal during operation. Replacement fluids are admixed
with the cellular components either by connecting the replacement
fluid conduit with the outlet from the ultrafiltration cell or the
input thereof as disclosed above. In the latter case the
replacement fluids dilute the cellular components which are
reconstituted to their normal levels in the ultrafiltration cell.
This prevents the cellular components from being densely packed
which can result in excessive hemolysis. The replacement fluids
employed can either be plasma, or a suitable substitute
therefor.
In another embodiment of the present invention a unique plasma
filtrate flow, parallel to that of the flow of blood over the
filtering side of the ultrafiltration membrane, is employed in
order to obtain relatively constant transmembrane pressures over
the entire membrane surface. This is accomplished by recycling
plasma filtrate through the filtrate chamber of the ultrafiltration
cell in the same direction and parallel to the flow of the blood
which is being ultrafiltered in the filtering chamber of the
ultrafiltration cell. By regulating the inlet and outlet pressures
of the plasma recycle such that the pressure drop across the
filtrate chamber of the ultrafiltration cell equals the pressure
drop of the blood across the filtering chamber substantially
constant transmembrane pressures are obtained. This is important
because there is a maximum allowable transmembrane pressure which
can be employed at a given shear rate without causing excessive
damage to the cellular components. The result is that
ultrafiltration rates, or fluxes, are increased in the order of
twice that when plasma filtrate is removed from the filtrate
chamber without such recycling. In the embodiment described
previously wherein plasma is simply removed from the filtrate
chamber of the ultrafiltration cell the filtrate side of the
membrane is essentially at a uniform pressure. Thus, transmembrane
pressure is high (or at the maximum) at the portion of the membrane
adjacent the blood inlet side of the filtering chamber and
progressively becomes smaller as the blood flows through the
channel toward the blood outlet of the filtering chamber. However,
by providing a pressure drop of plasma filtrate across the filtrate
side of the membrane which is equal to the pressure drop of the
blood flowing across the filtering side of the membrane the
transmembrane pressure is kept constant across the entire flow path
of the blood through the ultrafiltration cell. This allows for the
use of long filtering chamber flow paths which would otherwise be
prohibited because of excessive inlet transmembrane pressures with
concomitant cellular destruction. This is an important design
criteria for the manufacture of coil type ultrafiltration
cells.
Now referring to FIG. 1, a detailed description of the continuous
plasmapheresis process of the subject invention according to a
preferred embodiment will be described. Blood enters the processing
system of the subject invention via conduit 1 which communicates
with a blood vessel of the subject via a suitable catheter. The
conduit can comprise various types of flexible plastic tubing
including, for example, non-thrombogenic materials such as
heparinized polytetrafluoroethylene, heparinized surgical grade
silicon rubber, and the like. Generally, conduits useful in the
present invention can be flexible tubing having inner diameters of
from about 1/16 inch to about 3/8 inch so as to be sufficient to
provide the necessary flow rates required by the process of the
subject invention. The blood flow in conduit 1 will normally be
from about 20 ml/minute to about 400 ml/minute depending on the
blood vessel and the physical characteristics of the subject, if
the process is being run on a human. Therefore, the flow rate in
conduit 1 is regulated via inlet pumping means 3 which can, for
example, be a common type of pump used in medical apparatus such as
a peristaltic pump. Inlet conduit 1 can then empty into a drip cell
5 in order to insure that any entrapped gas bubbles will be removed
prior to the introduction of the blood into the ultrafiltration
cell 9 further described hereinbelow. A pressure gauge, or other
pressure indicating instrument, 7 can be employed for monitoring
the inlet pressure of the blood flow coming from inlet pumping
means 3. Inlet conduit 1 empties into ultrafiltration cell 9 which
basically comprises a filtering chamber 9a at the top portion
thereof and a filtrate chamber 9b at the lower portion thereof, the
two chambers being separated by an ultrafiltration membrane 11. The
ultrafiltration cell, more fully described hereinbelow, partially
separates the whole blood into a cellular fraction which remains on
top of the ultrafiltration membrane 11 within filtering chamber 9a
and a plasma fraction which passes through ultrafiltration membrane
11 and into filtrate chamber 9b. The concentrated cellular
components are passed from the ultrafiltration cell via outlet
conduit 13 and a portion thereof, in admixture with makeup fluid,
which has been added to the system in a manner described below, are
returned to the subject via drip cell 15 which prevents the
transmission of air bubbles to the patient and a suitable catheter
inserted in a blood vessel of the subject. A second pressure
indicating instrument 17 can be used to monitor the pressure at the
outlet end of the ultrafiltration cell.
A portion of the cellular component fraction admixed with
replacement fluid is recycled through the ultrafiltration cell via
recycle conduit 19 and recycle pumping means 21. The amount of
fluid recycled in this manner will depend upon the flow rates
desired to maintain the approximate shear rates in the particular
ultrafiltration cell employed which will generally be in a range of
from about 10 dynes/cm.sup.2 to about 1000 dynes/cm.sup.2 with a
preferred range of from about 150 to about 600 dynes/cm.sup.2.
The plasma fraction flowing into filtrate chamber 9b through
ultrafiltering membrane 11 is removed via plasma outlet conduit 23.
Plasma outlet conduit 23 communicates with pressure sensing means
25 which in turn controls the pumping rate of plasma pumping means
29. In a preferred embodiment, pressure sensing means 25 can
comprise a pressure transducer which generates an electrical signal
of varying strength in response to the pressure in plasma outlet
conduit 23. The electrical signal generated by such a transducer is
then communicated to pump control means 27 which can comprise, for
example, a rheostat which in turn is connected electrically to an
electrically driven pump (plasma pumping means 29). In this manner,
the rate at which plasma pump 29 operates can be controlled such
that the pressure in plasma outlet conduit 23 never varies from
that necessary to maintain optimum transmembrane pressures,
regardless of the rate of ultrafiltration. Preferably the pressure
in filtrate chamber 9b is kept at about atmospheric pressure at all
times. The plasma filtrate can then be removed and stored for
transfusion, subjected to diagnostic tests, or further fractionated
to remove pathogenic substances therein and returned to the subject
as either a part, or all of the replacement fluid.
A suitable replacement fluid can be pumped from a reserve thereof
(not shown) via replacement fluid pumping means 31 and replacement
fluid conduit 33 and is admixed with incoming blood in inlet
conduit 1. The amount of replacement fluid added to the system
corresponds substantially identically in volume to the amount of
fluid being removed from the system by interconnecting pumping
means 31 and pumping means 29 such that they operate at
substantially the same rate. This can be conveniently accomplished
by providing a common drive shaft for pumping means 31 and 29, for
example.
Referring to FIG. 2, a second embodiment of the present invention
will be described wherein ultrafiltration rates are increased by
providing a recycled flow of plasma parallel to, and in the same
direction as, the flow of the blood being ultrafiltered. The
schematic drawing of the process of this embodiment employs like
numbers to identify like components as described hereinabove with
reference to FIG. 1. Thus, whole blood from the subject enters the
system via inlet conduit 1, and blood inlet pumping means 3 and the
pressure thereof is indicated by pressure sensing means 7 in the
manner described above with relation to FIG. 1. The blood which is
to be filtered enters ultrafiltration cell 9 and flows in a path
parallel to ultrafiltering membrane 11 within filtering chamber 9a.
The cellular component fraction of the blood leaves ultrafiltration
cell 9 via conduit 13 and a portion thereof may be recycled as
needed via recycle conduit 19 and recycle pumping means 21.
The plasma fraction of the blood enters filtrate chamber 9b through
ultrafilter membrane 11 and leaves filtrate chamber 9b via conduit
23 at the same end of ultrafiltration cell 9 as the cellular
component fraction exits via outlet conduit 13. A portion of the
plasma leaves the system (or is returned as a replacement fluid as
disclosed above with reference to FIG. 1) via conduit 23 and a
portion thereof is recycled via plasma recycle conduit 35 and
plasma recycle pumping means 37. Thus, a portion of the plasma
filtrate is recycled into the inlet end of the ultrafiltration cell
such that a plasma flow parallel to, and in the same direction as,
the whole blood being separated in filtering chamber 9a, occurs
within filtrate chamber 9b. By adjusting the operation rate of
plasma recycle pumping means 37, the pressure drop across filtrate
chamber 9b (that is the difference in pressure between where plasma
is introduced into filtrate chamber 9b via plasma recycle conduit
35 and where the plasma is removed via plasma outlet 23) can be
controlled. Thus without affecting the blood flow rate or the shear
stress at the blood-membrane interface the transmembrane pressure
can be adjusted by controlling the plasma recycle flow rate. The
preferred mode of operation is to adjust the pressure drop across
the filtrate chamber 9b to equal the pressure drop across the
filtering chamber 9a of ultrafiltration cell 9 (that is the
difference between the pressure of the blood flow as it enters
filtering chamber 9a from inlet conduit 1 and the pressure at the
outlet of filtering chamber 9a where the fluid enters outlet
conduit 13); thereby the transmembrane pressure will be
approximately constant over the entire membrane. Pressure
indicating means 39 and pressure sensing means 25 (such as a
pressure transducer) at the inlet and outlet, respectively, of the
recycle flow loop of plasma through filtering chamber 9b can be
employed to monitor the pressure drop therebetween and adjust it in
the above described manner.
The pressure drops across the filtering and filtrate sides of the
ultrafiltration membrane can be adjusted by providing automatic
adjusting mechanisms or by manually adjusting the pressure. By
adjusting the clamp 41 on conduit 13 the preferred mode of
operation can be obtained by adjusting the pressure indicated by
pressure indicating means 17 to be approximately one half of that
of pressure indicating means 7, then, by use of plasma recycle pump
37, adjusting pressure indicating means 39 to equal the pressure
indicated by pressure indicating means 17 and maintaining the
pressure at pressure sensing means 25 at approximately atmospheric
pressure.
The ultrafiltration cell useful in the process and apparatus of the
subject invention can be any one of a number of physical
realizations. To achieve the arrangement and conditions of the
subject invention, the membrane (or membranes) needs to be placed
with respect to the filtering chamber 9a and filtrate chamber 9b so
as to provide the indicated flow rates, transverse pressures, and
pressure differences across the membrane. The membranes themselves
can be in the form of suitably supported flat sheets, rolled-up
sheets, cylinders, concentric cylinders, ducts of various
cross-section, and other configurations, assembled either singly or
in groups, and connected in series and/or in parallel within the
ultrafiltration cell 9 so as to provide the desired flow rates and
pressures. The container and the spacing material must be
constructed so that there is a continuous filtering and filtrate
chamber running the length of the membrane.
A preferred type of cell for use in the present invention comprises
generally rectangular plate members comprising flow plates, over
which the blood and filtrate flow, separated by a rectangular plate
member upon which a suitable ultrafiltering membrane has been
mounted. The result is a generally rectangular shaped filtering
chamber allowing for a flow of blood of from about 0.01 cm to about
0.1 cm in depth to flow across the ultrafilter membrane with a
filtrate chamber of approximately the same dimensions on the
opposite side of the membrane. By stacking a series of these
sandwiched rectangular membrane ultrafiltering cells to form a
composite ultrafiltration cell, flow rates can be increased or
decreased as required by the particular situation. A preferred type
of rectangular ultrafiltration plate type cell is sold by Beckman
Instruments Inc., Anaheim, California, under the trade name
Sartorius Ultrafiltration System. This ultrafiltration cell
comprises plates which have a 0.7 mm wide V-shaped parallel running
grooves allowing a liquid being passed therethrough to cover the
filtering area completely. This particular cell can use up to
fifteen separate ultrafiltering membranes providing a maximum
effected filter area of 2550 cm.sup.2.
While many membranes were investigated in order to find a suitable
membrane which will separate blood into cellular component and
plasma fractions without substantial hemolysis or clogging problems
and at a rate sufficient for the continuous operation of the
system, membranes having a pore size of 0.45 microns and fabricated
from cellulose nitrate or regenerated cellulose have been found to
provide the necessary characteristics. Suitable membranes having
these characteristics are marketed by Beckman Instruments Inc.,
Anaheim, California, under the trade name Sartorius Membranes.
The apparatus described in detail above can be operated in a
continuous manner to separate blood into a cellular component
fraction and a plasma fraction according to the following
procedure. First, the instrument is filled with heparin or another
suitable anticoagulant material in admixture with a saline
solution. Heparin or some other suitable anticoagulant is also
injected into the subject so as to prevent clogging of the system.
For an adult human from about 2,000 units to about 20,000 units of
heparin are employed for this purpose. Blood is then pumped from an
artery or vein of the subject at a rate of from about 20 to about
400 ml/minute into the systems by blood inlet pumping means 3. As
the blood goes through drip cell 5, pressure gauge 7 is used to
monitor clot formation either by visual observation of the
pressures indicated thereby or by means of an automatic system
which will warn if pressures exceed an expected normal. After the
blood has started through the membrane (or membranes if a multiple
series of parallel plate membranes are being employed) recycle is
started by starting recycle pumping means 21. For the Sartorius
cell and membranes described above, recycle flow rates must be
maintained in the range of from about 5 ml/minute/layer to about 40
ml/minute/layer in order to yield the high shear rates which are
necessary to prevent damage occurring to the blood.
In a preferred embodiment, blood is returned to a vein after
passing through a second drip chamber 15 which prevents air bubbles
fom being entrained in the return blood. Plasma, separated from the
cellular components in the blood is pumped out at exactly the same
optimal rate at which it passes through the membranes by operating
plasma pumping means 29 at rates such that the pressure in filtrate
chamber 9b is essentially equal to atmospheric.
The following examples are submitted for the purpose of
exemplifying the process and apparatus of the subject invention and
are not to be construed to be limiting in any manner. Example 1
used a Dextran solution as the replacement fluid; similar
experiments have been performed using plasma.
EXAMPLE 1
Employing an apparatus substantially the same as that depicted
schematically in FIG. 1, a dog, weighing approximately 48 lbs., was
used as an experimental subject for continuous plasmapheresis. The
tubing employed was tygon, and plastic. The pumps employed were
peristaltic-type pumps sold under the trade name of Sarns by
Travernol and Masterflex and the ultrafiltration cell employed was
the Sartorius type cell described above carrying fifteen
ultrafiltering membranes having a pore size of 0.45 microns and
manufactured from cellulose nitrate. The system was sterilized by
formaldehyde and was flushed with a sterile saline solution prior
to use. The dog was prepared for the experiment by injecting 5,500
units of heparin. The system was also flushed with heparin prior to
start-up.
The dog's right femoral artery and vein were cannulated, the former
providing the blood source and the later providing the return port.
The blood inlet pump was then turned on, with the recycle pumping
means being turned on shortly thereafter and the filtrate pumping
means being turned on shortly after filtering began. The experiment
was run for a total of 60 minutes during which time 1200 ml of
replacement fluid (6% dextran in normal saline) was pumped into the
dog and 1200 ml of plasma was separated from the dog's blood and
collected. The pressures at the indicated points throughout the
system at specified times during filtration are listed in Table
I.
TABLE I ______________________________________ Blood Venus Pressure
Inlet Inlet Recycle Return Filtrate Time to Membrane Pump Pump
Pressure Pump (min) (mm hg) (ml/min) (ml/min) (mm hg) (ml/min)
______________________________________ 10 240 100 384 10-30 23.1 20
120 80 200 10-30 13.8 40 160 80 300 10-30 18.0 60 220 80 384 10-30
24.3 ______________________________________
In Table II the initial and final concentrations of various blood
constituents are given.
TABLE II ______________________________________ Concentration of
Various Blood Constituents Initial Final
______________________________________ Red Blood Cell Count 5.9
.times. 10.sup.6 ml.sup.-1 5.1 .times. 10.sup.6 ml.sup.-1 White
Blood Cell Count 9.9 .times. 10.sup.3 ml.sup.-1 3.5 .times.
10.sup.3 ml.sup.-1 Platelet Count 118,000 ml.sup.-1 74,000
ml.sup.-1 IgG 6000 mg/dl 2920 mg/dl IgM 428 mg/dl 202 mg/dl Albumin
2.6 gm/dl 1.0 gm/dl Cholesterol 153 mg/dl 58 mg/dl Plasma
Hemoglobin 66 mg/dl 75 mg/dl
______________________________________
EXAMPLE 2
Employing an apparatus substantially the same as that depicted
schematically in FIG. 2, expired blood from a blood bank was used
in an experiment. The purpose of this experiment was to test the
feasibility of using the recirculating plasma filtrate to increase
the ultrafiltration rate without increasing the maximum
transmembrane pressure. Two layers of cellulose nitrate membrane
having a pore size of 0.45 microns were used in the Sartorius cell
which had been mechanically altered to allow for parallel flow of
the blood and filtrate. During this experiment the ultrafiltration
rate was measured at three different transmembrane pressures for
the case of recycled plasma filtrate and for the same maximum
transmembrane pressures with no recycled filtrate. At all times
during this experiment the plasma filtrate outlet pressure was
atmospheric. The experiment's data is presented in Table III,
showing the increased ultrafiltration rates obtained when recycled
plasma filtrate is used.
TABLE III ______________________________________ Blood Blood Blood
Plasma Inlet Blood Plasma Ultrafil- Inlet Outlet Inlet Pump Recycle
Recycle tration Pres- Pres- Pres- ml/ Pump Pump Rate sure sure sure
min. ml/min. ml/min. ml/min. mmHg mmHg mmHg
______________________________________ 132 48 0 .98 205 0 0 132 48
44 2.0 410 200 205 88 0 0 .46 105 0 0 88 0 32 .80 205 103 105 212 0
0 .85 290 0 0 208 0 66 2.3 600 303 300
______________________________________
Thus, in the first set of data set forth in Table III above when
the maximum transmembrane pressure was 205 mmHg and no plasma
recycle was employed the ultrafiltration rate was 0.98 ml/minute.
However, when the pressure drop in the filtering chamber was
maintained at about 210 mmHg (Blood Inlet Pressure minus Blood
Outlet Pressure) and a plasma recyle was employed to obtain a
pressure drop of 205 mmHg, the ultrafiltration rate increased to
2.0 ml/minute while flow rates remained constant.
While this invention has been described in relation to its
preferred embodiments, it is to be understood that various
modifications thereof will be apparent to one skilled in the art
upon reading the specification and it is intended to cover such
modifications as fall within the scope of the appended claims.
* * * * *