U.S. patent application number 10/408657 was filed with the patent office on 2003-12-25 for apparatus and method for in-vivo plasmapheresis using periodic backflush.
Invention is credited to Cooper, Tommy, Gorsuch, Reynolds G., Handley, Harold H..
Application Number | 20030236482 10/408657 |
Document ID | / |
Family ID | 25036273 |
Filed Date | 2003-12-25 |
United States Patent
Application |
20030236482 |
Kind Code |
A1 |
Gorsuch, Reynolds G. ; et
al. |
December 25, 2003 |
Apparatus and method for in-vivo plasmapheresis using periodic
backflush
Abstract
Apparatus and method for in-vivo plasmapheresis utilizing a
plurality of elongated hollow microporous filter fibers
periodically interrupt diffusion of blood plasma from a patient,
and, for a selected time, backflush fluid into the fibers at a
pressure and interval sufficient to cleanse the fiber pores, after
which plasma diffusion is resumed. The backflush fluid, preferably
a normal saline solution, may contain an anticoagulant such as
heparin in suitable concentration for systemic anti-coagulation or
for treating the fiber for thromboresistance.
Inventors: |
Gorsuch, Reynolds G.;
(Yountville, CA) ; Cooper, Tommy; (Friendswood,
TX) ; Handley, Harold H.; (Novato, CA) |
Correspondence
Address: |
KNOBBE MARTENS OLSON & BEAR LLP
2040 MAIN STREET
FOURTEENTH FLOOR
IRVINE
CA
92614
US
|
Family ID: |
25036273 |
Appl. No.: |
10/408657 |
Filed: |
April 4, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10408657 |
Apr 4, 2003 |
|
|
|
09754773 |
Jan 4, 2001 |
|
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Current U.S.
Class: |
604/6.04 ;
604/4.01 |
Current CPC
Class: |
A61M 1/1688 20140204;
A61M 2205/7554 20130101; A61M 1/1682 20140204; A61M 1/1678
20130101; A61M 1/3413 20130101; A61P 7/02 20180101 |
Class at
Publication: |
604/6.04 ;
604/4.01 |
International
Class: |
A61M 037/00 |
Claims
What is claimed is:
1. A method of carrying out human in-vivo plasmapheresis
comprising: implanting a filter device within a blood vessel of a
patient, said filter device comprising a plurality of elongated
hollow microporous fibers; providing a multiple lumen catheter in
fluid communication with the hollow interior of said fibers, and
diffusing plasma and toxins from the patient's blood through the
wall of said fibers into the hollow interior thereof; and
periodically interrupting said diffusion of plasma and toxins and
backflushing said fibers by directing a backflush fluid containing
an amount of anticoagulant at least sufficient to provide fiber
thromboresistance through a lumen of said catheter into said fibers
at a pressure and for an interval sufficient to substantially
cleanse the pores of said filter, and after said interval, resuming
said diffusion of plasma.
2. A method of claim 1 using a backflush fluid comprising a saline
solution containing at least 1 IU heparin per kilogram of human
patient body weight.
3. A method of claim 1 using a backflush fluid comprising saline
solution containing about 2 or more IU per kilogram of human
patient body weight.
4. A method of claim 1 using a backflush fluid comprising saline
solution having a heparin concentration of between about 25 IU per
ml and about 300 IU per ml.
5. A method of claim 1 using a backflush fluid comprising saline
solution having a heparin concentration of between about 75 IU per
ml and about 150 IU per ml.
6. A method of claim 1, 2, 3, 4 or 5 wherein the fluid is
backflushed at a pressure of between about 15 and about 100 mg Hg
for an interval of between about 5 and about 50 seconds.
7. A method of claim 4 wherein heparin concentration is sufficient
to provide systemic anti-coagulation in a human patient.
8. A method of claim 1 for inducing systemic anti-coagulation
comprising using a single bolus of backflush fluid containing
between about 50 IU and about 150 IU heparin per kilogram of
patient body weight.
9. A method of claim 1 for maintaining systemic anti-coagulation
comprising using a backflush fluid containing more than about 150
IU heparin per ml and less than about 50 IU per kilogram of patient
body weight.
10. A method of claim 1 wherein toxin-containing plasma from said
fibers is directed to plasma treatment apparatus through a second
lumen of said catheter.
11. A method of claim 1 wherein plasma from plasma treatment
apparatus is directed to a third lumen of said catheter and
returned to said patient.
12. A method of claim 6 wherein plasma from plasma treatment
apparatus is directed to a third lumen of said catheter and
returned to said patient.
13. A method of claim 6 wherein plasma from plasma treatment
apparatus is directed to a third lumen of said catheter and
returned to said patient.
Description
[0001] This application is a continuation-in-part of U.S. patent
application Ser. No. 09/754,773, filed Jan. 4, 2001
(TRANSVI.008A)
BACKGROUND OF THE INVENTION
[0002] In U.S. Pat. Nos. 4,950,224, 5,152,743, 5,151,082, 5,735,809
and 5,980,481 there are disclosed methods and apparatus for
carrying out in-vivo plasmapheresis for separating plasma from
other blood components within the body and blood vessels of a
patient. In the apparatus pumping is used to create a
trans-membrane pressure and motivate the flow of fluid from within
the in-vivo system, whereby blood plasma is pumped from the patient
to a treatment system such as a dialyzer or other apparatus in
which toxic metabolic waste in the plasma is removed. After the
plasma is treated for removal of waste products, excess fluids,
toxins, and/or other deleterious plasma proteins, the treated
plasma is returned and reintroduced to the patient's blood stream.
Methods of toxin removal from blood, as taught by the aforesaid
patents and referred to as plasma dialysis, ultrafiltration or
blood purification, are unique from and substantially superior to
conventional hemodialysis as presently practiced for both acute and
chronic kidney failure, primarily because removal of whole blood
from the patient's vasculature is eliminated from the procedure
using plasma, or portions of the plasma. The methods and apparatus
described in the aforesaid patents are incorporated herein by
reference.
[0003] In U.S. Pat. Nos. 5,224,926, 5,735,809 and 5,968,004 there
are disclosed improved filter assemblies including elongated hollow
fibers and various filter assembly designs incorporating such
hollow fibers to be used in the above-described methods and
apparatus. In U.S. patent application Ser. No. 09/549,131, filed
Apr. 13, 2000 (TRANSVI.007), there is disclosed specialized hollow
fiber membranes which are superior in biocompatibility, performance
and morphology for use in the aforesaid in-vivo plasmapheresis. In
U.S. patent application Ser. No. 09/981,783, filed Oct. 17, 2001
(TRANSVI.011A) there is disclosed a plasmapheresis filter device
and catheter assembly incorporating the aforesaid specialized
hollow fiber membranes. In U.S. patent application Ser. No.
10/219,082, filed Aug. 13, 2002 (TRANSVI.012A) there are disclosed
apparatus and methods for therapeutic apheresis using the aforesaid
specialized hollow fiber membranes, filter device and catheter
assembly. Such fibers, filter device, catheter assembly, apparatus
and methods as disclosed in the aforesaid patents and applications
are incorporated herein by reference.
[0004] In the aforesaid systems, the hollow fiber membranes
function as filters, where the primary purpose of said membranes is
separation of specific blood or plasma components from whole blood.
In such systems, the blood (permeate) flows on the outside of the
fiber and the plasma (exudate) is diffused through the fiber
membrane to the interior lumen of the hollow fiber. However, as use
is continued, performance of the fibers as filters becomes degraded
over time. For example, clogging or fouling of the filter occurs on
the surface of the filter as the pore void spaces become more
occluded with particulate matter from the permeate building up
within the pore void such that the minute volume of the exudate is
progressively degraded to the point of failure and cessation of
exudate flow. Such clogging or fouling of the filter membranes, as
well as clotting problems with prior art filter systems as
disclosed in the aforesaid application Ser. No. 09/549,131
(TRANSVI.007), causes major operational and economic problems with
current ex-vivo systems performing Continuous Renal Replacement
Therapy (CRRT) for acute and chronic kidney failure. It is reported
by Ramesh, Prasad, et al., in Clinical Neprology, Vol. 53, p. 55-60
(January 2000), that over 50% of such filters fail in 10 hours and
over 75% fail in 30 hours of usage. Because short-term filter
replacement is both undesirable and unacceptable, clogging or
fouling failure of filters used in in-vivo systems described in the
aforesaid patents would be totally unacceptable for both medical
and economic reasons.
SUMMARY OF THE INVENTION
[0005] According to the present invention, in-vivo plasmapheresis
is periodically interrupted and a backflush fluid is directed into
the interior of the hollow fibers of the filter device for a
duration and at a flow rate sufficient to substantially cleanse the
pores of the filter. After a sufficient duration, the backflush is
terminated and the plasmapheresis extraction is resumed. The
apparatus for carrying out the improvement of the invention.
includes a multiple lumen catheter having a first lumen for
directing backflush fluid into the hollow fibers, a second fluid
for directing plasma from the filter assembly, and a third lumen
for returning treated plasma to the patient. The apparatus also
includes one or more pumps for pumping the backflush fluid into the
filter assembly.
BRIEF DESCRIPTION OF THE DRAWINGS
[0006] FIG. 1 is a schematic illustration of an apparatus for
carrying out the improved method of the invention;
[0007] FIG. 2 illustrates an apparatus of the invention implanted
in a patient; and
[0008] FIG. 3 is a graph illustrating trans-membrane flux
degradation trends with and without periodic backflush of the
invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0009] As illustrated in FIG. 1, the apparatus for carrying out the
invention comprises a filter assembly 12 having a plurality of
hollow fiber membranes 14. The terminal ends of the fibers are
potted into an extraction header 16 which provides fluid
communication between the hollow interior 15 of each of the fiber
membranes and into the interior lumens of the triple-lumen catheter
20. The catheter 20 comprises a first lumen 22 for directing
backflush fluid through the header 16 into the hollow interior of
the elongated fiber membranes. A second lumen 24 directs plasma
from the filter assembly to a plasma treatment apparatus 34 to
provide ultrafiltration, dialysis, replacement, column adsorption,
or a bioreactor or other such apparatus for treating or utilizing
the plasma. A third lumen 26 directs the treated plasma back to the
patient. Providing a separate lumen (22) for backflush fluid
instead of using exudate lumen (24) for backflush eliminates
deadspace in lumen 24 and the necessity of removing and
reintroducing exudate to accommodate such backflush. The apparatus
also includes one or more positive displacement pumps. A first pump
21 pumps fluid from a source of backflush fluid 32 at predetermined
intervals and for a predetermined and selected duration as will be
explained further hereinafter. A second positive displacement pump
23 pumps plasma exudate from the filter assembly via catheter lumen
24 through the treatment apparatus 34 and back to the patient via
third catheter lumen 26. In other selected systems a third positive
displacement pump 25 is used to pump the treated plasma or plasma
component back to the patient via third catheter lumen 26. The
catheter includes an orifice 27 which directs the returned treated
plasma into the patient's blood vessel 11. Alternatively, an
apparatus may only require three pumps, using one pump for plasma
to and from the patient, a second pump for backflush, and a third
pump for removing water or for pumping dialysate through a
hemofilter.
[0010] The apparatus may also provide means for collecting and
disposing of plasma components such as toxins, excess plasma water,
etc, separated in the plasma exudate in treatment apparatus 34, and
which is not to be returned to the patient. Such means is connected
to the plasma treatment apparatus via conduct 37 and includes a
collection container 39 and a pump 28 for pumping the effluent to
be removed from the plasma exudate to the container.
[0011] The filter assembly 12, including the header and elongated
hollow microporous membrane fibers 14, is implanted in a blood
vessel 11 of the patient, preferably the vena cava, or other
suitable blood vessel as described in the aforesaid patents. A
preferred fiber membrane used in the filter assembly is disclosed
in aforesaid application Ser. No. 09/549,131. Such a membrane has a
plurality of zones between the inner and outer wall surfaces, each
zone having a different mass density than the mass density of an
adjacent zone. The membrane fiber wall may have two, three or four
or more mass density zones with a lower mass density zone at the
inner wall surface and a higher mass density zone at the outer wall
surface. Each zone is characterized by a different average moninal
pore size, with a lower mass density zone having a nominal average
pore size of between about 1 um and about 60 um and a higher mass
density zone having a nominal average pore diameter of between
about 0.3 um and about 1 um. A preferred membrane has the
capability of extracting up to 0.75 (ml/min)/(cm.sup.2.times.mm Hg)
at transmembrane pressures of between about 5 mm and about 50 mmHg.
An implanted filter assembly is illustrated in FIG. 2 and further
described in the aforesaid patents.
[0012] The backflush fluid source 32 comprises a container, bag or
other suitable source of a backflush fluid, for example, a normal
saline solution, or a source of fresh or treated plasma from which
toxins, high molecular weight proteins and/or other undesirable
contaminants have been removed. The apparatus also includes a
microprocessor/controller 38 which controls operation of the pumps
and manages the system. The microprocessor/controller is calibrated
to determine the flowrate of the pumps. The system may include one
or more pressure transducers for monitoring the pressure of fluids
within all lumens. Such transducers, not shown, may be used to
measure the transmembrane pressure thereby indicating when the
pores of the filter have become clogged to an extent to terminate
the extraction period, and initiate the backflush operation of the
apparatus. Depending on the exudate flow determined by the
microprocessor/controller and the transmembrane pressure sensed by
such transducers, the microprocessor/controller may determine the
duration of the backflush period, as well as the backflush flow
rate to be used for substantially cleansing the pores of the fiber
membrane. Pumps may also be provided having variable pressure
capabilities which may also be regulated by the
microprocessor/controller, if desired. The
microprocessor/controller 38 may be used to manage the system
through monitoring of the flows in the lumens of the catheter,
particularly the flow of the exudate through catheter 24 and the
pumping of the backflush fluid through the catheter lumen 22. Pump
25 may also be operated by the microprocessor/controller for
returning the desired amount of treated plasma to the patient.
[0013] The backflush cycle is periodic and preferably provided at a
high trans-membrane pressure and low volume, i.e., a low multiple
of the volume contained in the membrane lumens of the hollow fibers
of the filter and the extraction header. The combination of high
pressure and relatively short injection times for backflushing both
expands the membrane pores and dislodges adhered proteins, thereby
restoring pore integrity and density of the virtual filter area to
an improved performance level after each backflush cycle. Thus, the
process of the invention not only prevents degradation due to
clogging, but over time improves the yield of trans-membrane
exudate flux in terms of (ml/min)/(cm.sup.2.times.mm Hg) by
progressively adjusting and thus optimizing the backflush
parameters. Backflush pressures used are between about 15 and about
100 mm Hg which are substantially less than the trans-membrane
pressure which is deemed safe since the burst pressures of the
membranes are greater than 760 mm Hg.
[0014] As previously noted, the pumps used in the apparatus of the
invention are positive displacement roller pumps. Thus, the fluid
flows for both exudate extraction via catheter lumen 24 and
backflush fluid injection via catheter lumen 22 are functions of
the diameter of the tubing used and the pump revolutions per
second. The microprocessor/controller is calibrated to the
parameters of the tubing diameter and pump revolutions, thereby
equating fluid volume pumped to the time of operation. For example,
the setting of the parameters for the control and regulation of the
pumps may be empirically determined for equating the volume and
time for exudate extraction and backflush injection functions of
the apparatus. By way of example, such parameters found to be
useful for plasmapheresis have been empirically determined for an
exudate extraction period of between about 240 and about 600 sec,
and a backflush duration of between about 5 and about 50 sec,
thereby yielding a preferred backflush fluid flow of between 5 and
45 ml/min. The settings for such parameters are determined by
catheter design and by blood flow conditions around the filter and
plasma extraction membrane. Again, it is desired and preferred to
deliver a minimum amount of saline backflush fluid for cleansing
the hollow fiber membrane pores. Moreover, the volume of the
backflush injection bolus must be greater than the dead space
volume of the catheter extraction header, the inner lumen of the
hollow fibers, and the interstitial space in the membrane walls. In
addition to the dead space volume, a certain amount of saline is
needed to wash out the material that fouls the membrane. The volume
of this washing fluid is dependent upon the surface area of the
membrane and may be expressed as a bolus flux in ml/cm.sup.2. By
way of example, a bolus flux used for in-vivo and in-vitro tests is
0.03 ml/cm.sup.2. Again, the injection bolus volume is determined
from the dead space volume and the membrane surface areas set by
the catheter design.
[0015] The time between backflush periods may be determined by how
quickly the membrane becomes clogged. Unnecessarily short intervals
between backflushes results in higher average backflush flow rates,
thereby reducing the amount of plasma removed. On the other hand,
where backflush intervals are overly long, plasma flow rates
decline due to filter fouling. For example, an empirically
determined interval between backflushes of 300 sec has been found
to be useful for existing catheter designs.
[0016] The flow rate for backflush fluid injections is determined
by pressure limitations of the catheter, the effect of flow
velocity for substantially cleansing or clearing the membrane, and
the amount of backflush or bolus volume required. A rise in
pressure is a result of resistance to flow due to clogged membranes
and is a function of the backflush flow rate, membrane surface
area, and level of membrane clogging. The flow rate is also limited
by the amount of pressure that the inner lumen of the catheter and
fibers can withstand without failure. As previously noted, the
velocity or pressure of the backflush fluid must be sufficient to
dislodge the clogging material in all of the membrane surface. It
has been found that with 16 ml/min and a surface area of 40
cm.sup.2, by using a backflush pressure of 15 mm Hg, all of the
membrane is sufficiently and substantially cleared. The duration of
the backflush bolus may also be lengthened or shortened to adjust
the backflush flow volume. While the period between backflush
intervals and the flow rate are closely related to membrane
clearing requirements, the duration is not, thereby making it an
obvious choice for adjustment of bolus volume. For example, a
catheter with a dead volume of 1.5 ml and a surface area of 40
cm.sup.2 requires a bolus volume of 2.7 ml. A plasma extraction
period of 300 sec and a flow rate of 16 ml/min results in a
backflush duration of about 10 sec. The average backflush flow rate
is computed to be 0.54 ml/min.
[0017] The clogging or fouling of the filtration membrane is a
function of the flow rate of exudate through the extraction filter
assembly, the size of which, i.e., cm.sup.2 of membrane surface
area, is dictated by the clinical application to be served.
Generally, the more advanced disease state of organ failure to be
served requires greater exudate flow rate and a greater membrane
surface area, resulting in earlier degradation of extraction
performance and requiring a more aggressive program for backflush
cleansing of the membrane. Thus, for example, treatment of advanced
acute renal failure (ARF) and end stage renal disease (ESRD)
requires substantially higher fluid extraction rates for optimum
clinical results as compared to fluid management systems for
treating congestive heart failure (CHF).
[0018] A comparison of a system using backflush components and
methods of the invention with a system having no backflush is
illustrated in the graph of FIG. 3, and based on actual test
results which have been repeated over time. The results show marked
improvement using apparatus and method of the invention.
[0019] As previously described, useful backflush fluid may be a
normal saline solution. The backflush fluid may also contain other
desirable components. For example, it may be efficacious to
incorporate anticoagulants in the backflush fluid to provide
systemic anticoagulation, or to provide localized anticoagulation
protection to the fibers for reducing or inhibiting thrombosis or
clotting at or near the fiber surface and within the fiber wall
itself. Some very useful fiber polymers will not have heparin
retaining sites, while other useful polymers may include active
anti-thrombogenicity, for example, polymers with heparin
receptores. Where such anti-thrombogenic properties are not
permanent, for example, where heparin is not permanently bound to
the polymer, backflushing with heparin containing fluid will
replenish the membrane with anticoagulant for continued
thromboresistance throughout the in-vivo plasmapheresis. Desired
and useful concentrations of heparin in the backflush fluid will be
determined by those skilled in the art. Useful amounts of heparin
in a backflush fluid such as a normal saline solution for treating
the fibers for thromboresistance are of at least 1 IU and
preferably 2 IU or more per kilogram of human patient body weight
for backflushing at 5 minute intervals. For treating the fibers for
continuing thrombosresistance, heparin concentrations of between
about 25 IU and 300 IU per ml and preferably between about 75 IU
and about 150 IU per ml of backflush fluid may be used. The
backflush fluid may also be used to induce systemic
anti-coagulation. For example, a single backflush 2.5 ml bolus
containing between about 25 IU and about 150 IU and preferably
between about 50 IU and about 100 IU per kilogram of human patient
body weight should be sufficient to induce systemic
anti-coagulation. Moreover, systemic anti-coagulation may be
maintained using heparin backflush concentrations somewhere between
the aforesaid fiber treatment and systemic inducement
concentrations. However, other concentrations of heparin may be
used where desired or as determined or prescribed, depending on
backflush intervals, duration, and other process and backflushing
variables such as described herein.
[0020] Medical applications of systems using the aforesaid
invention include fluid management for patients in decompensated
congestive heart failure and prevention of pre-renal kidney failure
and acute respiratory distress syndrome, treatment of refractive
congestive heart failure and acute renal failure, as well as
therapeutic apheresis systems for immune system disease and blood
component therapy, edema, management systems for ascites,
lymphedema, and selective systemic edema, post surgical and
traumatic edema, tissue engineering applications including
bioreactors and hybrid bio-organs, and dialysis systems for end
stage renal disease. Other uses and applications will be
appreciated by those skilled in the art.
* * * * *