Note: Descriptions are shown in the official language in which they were submitted.
- ~s~
This invention relates to a method and apparatus for
separating blood plasma from whole blood, i.e. blood from a
person or animal, and more particularly to such a method and
apparatus which operates at a relatively low pressure and yet
obtains an improved quantity of separated plasma.
Until relatively recently, the separation of plasma
from whole blood, such as for the purpose of utilizing the
plasma from a donor for transfusion to others or for some sort
of treatment of the blood, has been carried out by extracting
the whole blood and centrifuging it to separate the plasma. Such
procedures are not only time-consuming and cumbersome requiring
large amounts of manual and mechanical handling, but they require a
relatively large amount of expensive equipment.
Recently investigations have been conducted into so-called
on-line membrane plasma separation techniques. In this type of
separation, the blood is passed through the on-line separation
equipment and immediately returned to the donor, the plasma being
separated, and in the case of a donor, collected and stored, or
alternatively in a case of a patient, treated such as by sorption
of a solute which it is desired to remove, and then returned to
the patient. In addition to being much simpler than the
centrifugal techniques of plasma separation in terms of the manual
and mechanical handling of the blood, and lower expense, this
technique when used for the treatment of the plasma has advantages
over the conventional treatment of solute removal which
incorporate treating agents in direct contact with whole blood in
that in many instances the solute which it is desired to remove is
,~
concentrated in the plas~a, making the technique a rapid and simple way to
cleanse the blood. The most suitable treatment material can be chosen and used
for the particular treatment desired without the need to consider the effect of
the treatment material on the blood cells, since blood cell-treating agent
interaction are eliminated, multiple types of treating agents may be employed
and it is easy to filter the treatment material from the plasma before reinfus-
ing it into the patient, thus providing a treatment methodology that is safe
in a wide variety of applications.
Qne method of carrying out such a plasma separation technique and an
apparatus therefor are disclosed in Uhited States Patent No. 3,705,100 to Blatt,
et al. A membrane arrangement is shown in which the pore sizes are 0.1 to 0.8
microns, and the blood is passed over the surface of the membrane at a flow
rate of 2-50 feet per minute while a pressure differential across the membralle
is maintained at from 1 to 15 psi. m is method and apparatus are said to be
effective in separating the plasma from the whole blood.
A similar method is disclosed in X. Ouchi et al, An Efficient,
Specific and Blood Compatible Sorbent System for ~leptic Assist, Vol. XXIV
Transactions American Society Artifical Internal Organs 246, 1978, in which a
cellulose acetate filter was used to separate plasmQ from ~hole blood flowing
through hollow fiber membranes at a rate of 100 ml/min. and at pressure
differentials across the membrane of 60, 100 and 137 mm Hg., the plasma
separation rate at each of these pressures being 37 + 2 ml/min, 34 + 2 ml/min
- 2 -
:
,
and 32 + 2 ml/min respectively.
Recently issued United States Patent No. ~,191,182 to
Popovich et al also discloses a method and apparatus for
continuous separation of plasma by so-called ultra-filtering. As
with the above-described prior art, Popovich et al also operate
at transmembrane pressures in the 50-700 mm Hg. range. While
recognizing that transmembrane pressures which are too high will
cause damage to the cellular components of the blood and that
control of transmembrane pressure is necessary to a~toid clogging
of the filter, Popovich et al nevertheless prefer to operate in
the 100-400 mm Hg. range of transmembrane pressures~
The present invention provides a method of separating
blood plasma from whole blood, i.e. blood from a healthy and/or
diseased person or animal, which method has advantages over the
prior art method, yet which operates at a lower transmembrane
pressure than the prior art methods so as to avoid problems of
damage to cellular components of the plasma and clogging of the
filter.
The invention also provides an apparatus for carrying
out this method.
According to the present invention, it has been found
that, contrary to normal expectations, by operating at a positive
transmembrane pressure differential up to just below 50 mm
I~g., and particularly from about 8.5 mm Hg. up to just below
5Q mm Ha., the filtration rate of the plasma can be increased as
compared with filtration rates when operating above 50 mm Hg. The
advantages of the invention are thus achieved by directing a flow
,
'
o whole blood across one ace of a filtration membrane means
comprising a material suitable for separating plasma from whole
blood and having a pore size from 0.1 to 0.6 microns, said flow
being at a flow velocity of from 5 to 1500 cm/min and being at a
depth sufficient for separating plasma from the flow of blood,
while at the same time generating a positive pressure differential
across said membrane up to just below 50 mm Hg. for forcing
plasma through the membrane, and collecting the plasma separated
by the membrane. Preferably the pressure is in a range of from
about 8.5 mm Hg up to just below 50 mm Hg. More preferably, the
pressure is in a range of from about 20 mm Hg. to about 40 mm Hg.
This is diferent from conventional ultrafiltration, in
which it is generally considered that the filtration rate increases
with an increase in transmembrane pressure. The present invention
demonstrates that the usual considerations do not apply in
filtration of plasma from whole blood, possibly due to the complex
mixture of particles in blood.
It has also been discovered that there is a further
advantage in the plasma separation when it is carried out at such
low transmembrane pressures. Plasma is an extremely complex fluid
containing many solutes the molecules of which have different sizes.
Current developments in the plasma filtering art are judged not
only by the quantity of plasma which can be filtered, but by the
quality or composition of the filtrate/ one measure of which is
the sieving coefficient, namely the relat~ve amounts of desired
components of the plasma present in the filtrate as compared to
~h~ amounts o such components present in the blood rom which the
,:
.
plasma is filtered. The present inventors have found that not
only is the quantity of plasma which can be filtered from whole
blood increased by operating at the low positive transmembrane
pressures, but also the sieving coefEicient for the various
components of the plasma is i.ncreased.
The apparatus according to the invention for carrying
out separation of plasma from whole blood comprises a filtration
membrane means of a material suitable for separating plasma from
whole blood and having a pore size from 0.1 to 0.6 microns; means
for directing a flow o whole blood across one face of said
membrane at a flow velocity of -from 5 to 1500 cm/min and at a
depth sufficient for enabling separation of plasma from the flow
of blood; means for generating a positive pressure differential
across said membrane up to just below 50 mm Hg., for forcing the
plasma through the membrane; and means for collecting the plasma
separated by the membrane. Preferably the positive pressure
differential across said membrane ranges from about 8.5 mm Hg. up
to just below 50 mm Hg. The membrane means can be a film type
membrane or a hollow fiber membrane, for example of cellulose
acetate.
Other and further features of the invention will become
apparent from the following detailed description, taken with the
accompanying drawing, in which:
Figure 1 is a schematic diagram of an apparatus for
separating blood plasma from whole blood, collecting it and then
either treating it, and returning it to the pat'ent after proper
filtering, or forwarding it to storage or further use; and
-- 5 --
Figure 2 is a graph of transmembrane pressure vs. plasma
filtration rate according to the method of the present invention.
Figure 1 shows schematically an apparatus for carrying
out the method of the invention. The apparatus comprises an
inlet blood pump 10 to the inlet of which a line or tube 11 from
a patient or donor is connected and which has a tube 12 extending
from the outlet thereof through a bubble trap 12a to the inlet
to a plasma filter 13. From the downstream end of the plasma
filter 13 a further line 14 extends to a bubble trap 15 and a line
16 extends from the bubble trap back to the patient. From the
filtrate side of the filter 13 a line 17 extends to a plasma
reservoir 18 and a line extending from the outlet of the plasma
reservoir is connected to a plasma pump 19 the outlet of which is
in turn connected to a ~hree-way valve 20. Extending from one
outlet to the valve 20 is a line 23 leading to collection means
or the like for collecting the plasma for further use, or to some
other part of the apparatus for treating the plasma for further
use. The other outlet of the three-way valve is connected to a
treatment means, such as a sorbent cartridge 21, the outlet of
which is in turn connected to a particle filter 22 and through
the particle fllter to:the bubble trap 15.
This arrangement can be modified. For example, the
plasma reservoir 18 can be incorporated into the plasma filter
13. The reservoir need not be vented, in which case the pumping
speed of the plasma pump 19 can be regulated to regulate the
plasma reservoir pressure and therefore also the transmembrane
pressure across the filter element or filter means of the plasma
filter 13.
-- 6 --
The various parts of the apparatus are mostly
conventional, such as the blood pump, the plasma reservoir, the
plasma pump, the sorbent cartridge, the particle filter and the
bubble traps. The plasma filter can be any one of a plurality of
known types of ~ilters. The filter has membranes of a material
which is not affected by whole blood or any of the materials
contained therein and which is thus suitable for filtration of
plasma from blood. A number of materials are available for use
as ~uch membranes, such as hydrophilic materials such as cellulose
~ *
` acetate, cuprophane or cellophane as disclosed in United States
Patent No. 4,031,010 to Nose, or polycarbonate or polypropylene,
but the preferred materials are polycarbonate such as Nuclepore*
040 sold by Nuclepore Corp., and cellulose acetate. The pore size
should be from 0.1 to 0.6 microns. The arrangement of the membranes
in the filter can be any arrangement suitable for producing a
pressure differential across the membrane which causes the plasma
to be filtered out as the whole blood flows across the surface of
the membrane. A number of other such arrangements can be found
in the art. These can be generally divided into parallel film
type membrane arrangements, such as shown in the Nose Patent, and
hollow fiber arrangements. In the parallel plate arrangements, the
space on one side of the parallel plate membranes is connected
to the blood inlet and outlet of the filter and the space on the
other side of the membrane is connected to the filtrate outlet
of the filter. In the hollow fiber arrangements, the fibers are
mounted in the filter so that the space within the fiber is
*Trade mark
j
,, , :
g~8
connected between the blood inlet and outlet of the filter and
the space around the fiber is connected to the filtrate outlet,
or vice versa although the preferred embodiment is with blood
flow through the interior of the Eiber. The hollow fibers which
are partlcularly suitable are cellulose acetate hollow fibers
solcl by Asahi Medical Co., Tokyo, Japan. The advantages of this
type of membrane over the plate type are that the hollow fiber
geometry is inherently strong enouyh so that no dimensional
change occurs at transmembrane pressure neçessary to obtain
required plasma flows, that due to this s-tructural strength, no
additional support structure is necessary, and that because no
support structure is necessary, the overall filter structure is
simpler and less costly. ~his is particularly important in
light oE the strong influence fluid dyanamic conditions play upon
filtration rate and sieving properties.
Where the apparatus is to be used simply to collect
plasma, the three-way valve 20 is turned so that the plasma
from the plasma reservoir is discharged to some conventional
plasma collection means. Where the apparatus is to be used to
treat the separated plasma and return it immediately to the
patient, the three-way valve 20 is turned so that thè plasma from
the reservoir is directed through the treatment, e.g~ absorption
cartridge 21 to the particle filter 22 and bubble trap 15,
whereafter having been filtered to remove any of the treatment
particles, the plasma is recombined with -the whole blood from
llne 14.
. . .
. .
B
.
.
.:
9~
Where the apparatus is to be used for treating the
separated plasma, the sorbent in the cartridge 21 can be any
sorbent wh~ch ~s effective for removing the unwanted material
from the plasma. United States Patent No. 4,013,56~ to
Nose suggests several types o sorbents.
It has been found that with the apparatus as described
above, by operating it under certain conditions of blood flow
and transmembrane pressure, a plasma filtration rate for
separating plasma from normal blood which is unexpectedly high
can be obtained and also sieving coeffients can be increased. The
blood flow rate through the filter should be such -that the flow
velocity of the blood across the one face of the membrane is from
5 to 1500 cm/min. The inlet blood pump 10 and the size of the
filter should be such that, under the downstream pressure
conditions due to directing the blood back to the patient, and
the pressure conditions on the plasma side of the filter
element or filter means is such, i.e. either atmospheric as
in a so-called open system, or a pressure controlled such as
by the pump 19, as to be below the pressure on the blood side
of the filter, the transmembrane pressure is a positive pressure
up to just below 50 mm Hg., and particularly from about 8.5 mm Hg.
to just below 50 mm Hg. Preferably the system is operated so that
the pressure range is from 40 to 20 mm Hg. When this is done,
the plasma filtration rate, i.e., the rate at which plasma is
filtered out of the blood through the membrane, is a maximum. By
positive transmembrane pressure is meant a transmembrane pressure
which is the difference between a higher pressure on the whole
_ g _
,
blood side of the filter and a lower pressure on the plasma
side of the filter.
In order to demonstrate the improved plasma filtration
rate, a series of experiments were carried out on dogs, the
blood of which was sufficiently similar to whole blood with a
substantially normal protein content to provide a useful
indication of how the method and apparatus will operate with
humans~ In each experiment the blood was extracted from the dogs
and passed through the system as shown in Figure 1 under conditions
within the ranges set forth above~ The pressure on the plasma
side of the filter element was atmospheric so that the apparatus
is considered to be a so-called open system.
Three normal dogs were perfused a total of seven times,
three times using an N type plasma filter/ and four times using
an S type filter 13 of Figure 1.
The two types of filters were both hollow fiber
cellulose acetate type filters and corresponded to those available
from Asahi Medical Co., Tokyo, Japan, under the trademark
PLASMAFLO the fibers having an inside diameter of 370 um, a wall
thickness of 190 ~m, a porosity of 84% and a nominal pore size
of 0.2 ,um the N type filter having 2500 fibers with an effective
fiber length ~potting to potting in the fiber structure) of 240
mm, and a surface area of about .7m2, and the S type filter having
3300 fibers with an effective fiber length of 200 mm and a
surface area of about .75m2. The blood tubing used to supply the
blood from the dogs to the filter apparatus and to connect the
parts of the filter apparatus with each other was tubing sold
- 10 -
~.~5~9~
under the trade mark Lifemed by Lifemed Division of Vernitron,
Compton, California. The priming volume of the apparatus was
about 400 ml. Blood access was via the femoral or in-ternal
carotid artery and blood was reinfused via the femoral or
jugular vein through FC-100 cannu]ae sold by Extracorporeal
Medical Co , In~. King of Prussia, Pennsylvania. Systemic
heparinization was used in each perfusion, 2 mg/kg heparin
(A. H. Robins, Richmond, Virginia) being injected prior to
starting perfusion and 0.5 mg/ky/hr for the rest of the perfusion.
10- ~n inlet blood flow of 100 ml/min was maintained by
the pump 10, which was a low amplitude pulsatile flow roller
pump sold by Drake-Willcock Co., Ltd. which was sufficient to
cause a velocity of flow across the membrane of about 25-40 cm/min.
The rate of plasma filtration, the inlet and outlet pressures
of the filter and the sorbent cartridge were determined for
each perfusion. The transmembrane pressures and flow rates were
as shown plotted in Figure 2.
Contrary to the situation normally encountered when
filtering a liquid material through a filter in which the flow
of filtered liquid across the filter falls with a drop in
transmembrane pressure, it will be seen from Figure 2 that the
amount of plasma which is filtered through the membrane actually
increases below pressures heretofore considered a minimum sat-
isfactory transmembrane pressure for filtering plasma, reach a
peak at about 30 mm I~g. of transmembrane pressure before falling
off. From this Figure it can be seen that the most advantageous
transmembrane pressures for achieving the maximum filtration of
. .
.
,' ' ' L
'
,
~5~
plasma from normal whole blood lie in the range of from just
below 50 mm Hg. to about 8.5 mm Hg. with the best pressures in
the range of from about 40 to about 20 mm Hg.
While the data point at the lowest transmembrane
pressure shows a plasma flow rate near the maximum, the
transmembrane pressure of 8.5 mm Hg. for this point is not a
precise pressure for this flow rate. The pressures below 10
mm Hg. cannot be known with any great accuracy because of the
utilization of the low amplitude pulsatile flow roller pump and
the nature and accuracy of interpretation of the instruments
used for the various measurements. The pump does not, as its
name makes clear, operate at a steady pressure. It had an
amplitude of pressure from the lowest pressure to the highest
on the order of 10 mm Hg., which is conventional for plasma
separation from blood, and the transmembrane pressures for the
respective data points were calculated using the mean value of
the pump pressure. Thus the lower pump pressure and thus the
transmembrane pressure is somewhat lower than the mean value,
possibly as low as about 3.5 mm Hg. Moreover, the pressure
gauges used had an accuracy of ~ 2 mm Hg. at best. Further,
the fluid level at the pressure monitoring points was fluctuating,
and the column heights of mercury were varying during the
pressure readings. For the higher transmembrane pressures,
these factors are not very significant, but for those from 10 mm Hg.
down, this is very significant. All of these factors together
indicate that the transmembrane pressure can be a positive
- 12 -
- J
:
,., ~ . .
'
~5~
transmembrane pressure near zero and still produce a very high
plasma flow as compared to what might normally be expected. The
pressures at which the present method is operable is therefore a
positive transmembrane pressure up to just below 50 mm Hg. More-
over, due to these factors, the numerical value of 8.5 mm Hg.
or the transmembrane pressure for the plasma ~low data point at
the lowest transmembrane pressure is only approximate, and in
fact may be considerably lower. For this reason, the numercial
limit on the transmembrane pressure as set forth in the
specification and claims is expressed as "about" 8.5 mm Hg.,
and this expression is intended to include somewhat lower pressures
due to the factors discussed hereinabove.
- 13 -
,
.
