Process/apparatus for the withdrawal/return of body fluids

Process/apparatus for the processing of body fluids, advantageously comprising plasmapheresis technique for the fractionation of whole blood, features (i) means, e.g., a common blood transfusion needle, for withdrawing and returning body fluid from and to a living patient; (ii) a body fluid separating module which comprises an upstream first compartment and a downstram second compartment, and having a semi-permeable membrane body fluid separator disposed therebetween; (iii) first conduit means communicating said withdrawal and return means (i) with the upstream first compartment of said separating module (ii); (iv) means provided along said first conduit (iii) for conveying body fluid in either direction therein; (v) means responsive to said conveying means (iv), adapted to monitor the pressure of body fluid circulating in said first conduit (iii), and provided between said withdrawal and return means (i) and said conveying means (iv); (vi) means for collecting body fluid transported across said semi-permeable membrane and communicating with the downstream second compartment of said separating module (ii); (vii) second conduit means communicating the upstream first compartment of said module (ii) to (viii) means for containing body fluid which has not been transported across said semi-permeable membrane thereof, (ix) third conduit means communicating said container means (viii) to said first conduit means (iii) at a point intermediate said conveying means (iv) and the upstream first compartment of said separating module (ii); (x) means provided along said first conduit (iii) at a point intermediate the upstream first compartment of said separating module (ii) and the juncture of communication between said container means (viii) and the said first conduit means (iii), for conveying body fluid therein in the direction of the said upstream first compartment; and (xi) means for ensuring that the pressure across the said semi-permeable membrane of any body fluid in contact therewith does not exceed predetermined value.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The present invention relates to novel plasmapheresis technique, and, more 
especially, to novel plasmapheresis process/apparatus for the 
withdrawal/return of body fluid from/to a patient and requiring but a 
single needle injection therefor. 
2. Description of the Prior Art 
Plasmapheresis is a known technique entailing separating the whole blood of 
a donor into two fractions, the first fraction constituting the plasma 
phase, while the second fraction constitutes the cellular phase which is 
typically reinjected back into the donor. The plasma phase is a complex 
aqueous solution containing protein in particular, while the cellular 
phase, still containing some of the plasma, comprises the red blood cells 
(or erythrocytes), the white blood cells (or leucocytes) and the blood 
platelets. 
The technique of plasmapheresis has long been used for animal 
experimentation. for example, John J. Abel et al, "Plasma Removal with 
Return of Corpuscles", which appeared in 1914 in J. Pharmacol. Exp. Ther., 
No. 5, pages 625 to 641, in which dog's blood is centrifuged to effect the 
separation. Cf. the article by A. Geiger which appeared in 1931 in J. 
Phys., 71, pages 111-120, entitled "Method of Ultrafiltration in vivo", in 
which there is described a continuous plasmapheresis procedure on a dog, 
the separation apparatus used including a membrane-containing separator, 
the membrane being arranged in a spiral and being selected in such fashion 
as to enable a plasma solution to be obtained which contained the totality 
of the proteins in the treated blood, if so desired. 
Plasmapheresis has also been used in man for a number of years, as 
indicated by the article "La plasmapherese - Technique - Indications" by 
Fr. Oberling et al, J. Med. Strasbourg, pp. 227-279 (March, 1968). 
Plasmapheresis is thus tending to now supercede the total donation of 
blood since the former technique has the advantage of permitting larger 
quantities of plasma to be withdrawn from the patient without drawback or 
disadvantage. Since the elements formed are restored to the donor, the 
withdrawal sessions can follow each other at shorter time intervals than 
when blood in its entirety is donated. 
Thus, plasmapheresis is a technique of long standing and the subsequent 
improvements therein concern either centrifugation-based apparatus or 
membrane-containing apparatus. Among the several improvement patents 
relating to membrane-containing apparatus, compare Amicon's German Pat. 
No. 2,100,209 in which is described a container comprising a membrane 
forming a spiral for the circulation of whole blood withdrawn from a donor 
and in which pressure is exerted on the blood contained in the container, 
either by means of a gas, or by means of a syringe plunger subjected to 
the action of a leaf spring. By comparison with the apparatus of Geiger 
described above, this apparatus has, on account of its design, the 
disadvantage of not permitting continuous operation on the patient. U.S. 
Pat. No. 4,191,182 describes a membrane-containing apparatus and in which 
the blood continuously withdrawn from the donor is separated into plasma 
and a cellular fraction which is continuously returned to the donor, this 
apparatus having as one particular characteristic the ability to allow one 
portion of the cellular fraction to recirculate in an upstream compartment 
of the membrane-containing component and the ability to allow the plasma 
fraction to recirculate in a downstream compartment of the same component. 
In published International Application No. wo 79/01 121, apparatus is also 
described which entails permitting the withdrawal of blood from the donor 
and the reinjection into the donor of the fraction which has not crossed 
the membrane, in continuous fashion. 
However, each apparatus hereinbefore described as allowing continuous 
plasmapheresis, nonetheless has the particular disadvantage of requiring 
insertion of a needle into the patient/donor at two different sites, which 
is obviously rather unpleasant for him. 
SUMMARY OF THE INVENTION 
Accordingly, a major object of the present invention is the provision of 
improved plasmapheresis process/apparatus comprising a membrane-containing 
module which permits, in particular, plasmapheresis procedures to be 
performed on the donor by injecting a needle at but a single site, using a 
conventional blood transfusion needle. 
Another object of the present invention is improved plasmapheresis 
process/apparatus permitting, over the course of one session, the blood to 
be circulated several times from the donor to a blood bag, then from the 
blood bag to the donor, while the blood passes continuously and in the 
same direction of circulation in contact with a membrane-containing 
separatory module. 
Another object of this invention is a specially adapted process/apparatus 
permitting a plasma of very high quality to be obtained under the best 
filtration yield conditions, while ensuring that there is virtually no 
haemolysis of the blood. 
Another object of the invention is process/apparatus permitting the 
pressure of the cellular fraction exiting an upstream compartment of the 
membrane-containing module to be regulated to values generally ranging 
from 0 to 20 mm of mercury in relative pressure, the downstream 
compartment being at atmospheric pressure. 
Another object of the present invention is process/apparatus permitting 
about 600 ml of plasma to be withdrawn from a donor in about 45 minutes 
and even in less time. 
Yet another object of the present invention is process/apparatus for 
withdrawal of plasma in which it is possible to easily adapt the 
operational strategy to the needs of the donor, the wishes of the operator 
and the characteristics of the membrane-containing module utilized. 
Still another object of the present invention is process/apparatus allowing 
a session yield to be obtained which is greater than the intrinsic yield 
of the membrane-containing apparatus. By "session yield" there is intended 
the ratio of the flow rate of liquid which has crossed the membrane (i.e., 
the plasma) to the flow rate of blood withdrawn from or restored to the 
vein of the donor. By "intrinsic yield" of the membrane-containing 
apparatus there is intended the ratio of the flow rate of filtered plasma 
to the flow rate of the blood upon entry into the membrane-containing 
module. 
Another object of this invention is process/apparatus permitting the blood 
to be passed in contact with the membrane at a flow rate which is higher 
than that of the blood withdrawn from the donor. 
Another object of the present invention is process/apparatus in which the 
volumes of blood in circulation outside the body are small. 
And still another object of this invention is process/apparatus equally 
well adapted to plasmapheresis with restoration to the patient, during the 
reinjection (or return) phase, of a replacement liquid corresponding in 
volume to that of the plasma withdrawn. 
Briefly, the present invention features process/apparatus permitting body 
fluid withdrawal from a subject, human or animal, by inserting a needle 
only once, of a liquid which is brought into contact with the membrane(s) 
of a module containing semi-permeable membrane(s) during a phase referred 
to as the withdrawal phase, the said liquid which passes in contact with 
the membrane being separated into a fraction which is transported across 
the membrane and a fraction which is not transported across the membrane; 
and to then cause the fraction of the withdrawn liquid which has not been 
transported across the membrane to be returned to the subject, during the 
phase referred to as the return phase, the liquid in contact with the 
membrane circulating in the same direction over the course of a session 
which may include several phases of withdrawal and return. 
Accordingly, provided hereby is improved plasmapheresis apparatus 
comprising, with reference to the several Figures of Drawing more fully 
described hereinbelow: 
(i) a device 1 for injection into and withdrawal of body liquid from a 
subject; 
(ii) a module 2 containing a semi-permeable membrane separating this liquid 
into a fraction which has been transported across the membrane and a 
fraction which has not been transported across the membrane, said module 
comprising an upstream compartment 3 and a downstream compartment 4 
separated by the membrane 14; 
(iii) a conduit 5 operably connecting the withdrawal device 1 to a tubulure 
6 communicating with the upstream compartment 3 of the membrane-containing 
module 2; 
(iv) a pump 7 situated along the conduit 5, said pump being capable of 
rotating (operating) in both directions; 
(v) a pressure sensor 13 monitoring the liquid circulating in the conduit 
5, said sensor being situated between the withdrawal device 1 and the pump 
7, this sensor influencing the speed of rotation of the pump 7 which is 
controlled thereby; 
(vi) a container 20 for collection of the liquid which has been transported 
across the membrane, this container 20 being in communicating relationship 
with the outlet of the downstream compartment 4 of the membrane-containing 
module 2; 
(vii) a conduit 16 operably connecting a tubulure 15 in the upstream 
compartment 3 of the membrane-containing module 2 to a container 17 for 
collection of the fraction of the liquid which has not been transported 
across the membrane; 
(viii) a conduit 16b operably connecting the container 17 to the conduit 5, 
the junction between the conduit 16b and the conduit 5 being made at a 
point A situated between the pump 7 and the tubulure 6 communicating with 
the upstream compartment 3 of the module 2 containing a semi-permeable 
membrane; 
(ix) a pump 18 situated along the loop defined by the conduit 16, the 
conduit 16b and the part of the conduit 5 included between junction A and 
the tubulure 6 communicating with the upstream compartment 3 of the 
membrane-containing module 2; and 
(x) means 19 for ensuring that the pressure across the membrane of the 
liquid circulating in contact with the membrane 14 does not exceed a 
specified value, said means influencing the speed of rotation of the pump 
18 which is under their control. 
Also featured hereby is improved process utilizing the aforedescribed 
apparatus, notably during a plasmapheresis procedure in which a subject 
donates his plasma.

DETAILED DESCRIPTION OF THE INVENTION 
More particularly according to the present invention, with reference to the 
accompanying non-scale Figures of Drawing, in FIG. 1 there is depicted 
apparatus, especially adapted for donor plasmapheresis, comprising a 
device 1 for withdrawal of blood from the donor, advantageously a blood 
sampling needle. As exemplary, the needle can have an external diameter of 
1.65 mm and an internal diameter of 1.45 mm, such as those indexed in 
blood transfusion centers under the designation 16 G. A module 2 
containing a semi-permeable membrane 14, and comprising an upstream 
compartment 3 and a downstream compartment 4, operably communicates with 
the needle 1 via a conduit 5 extending from said needle 1 to a tubulure 6 
which is in communication with the upstream compartment 3 of the 
membrane-containing module. This conduit 5 typically consists of plastic 
tubing, made, for example, of polyvinyl chloride. Along this conduit or 
line 5 is situated a pump 7 which can rotate or operate in both 
directions, advantageously a peristaltic-type pump. Between the pump 7 and 
the needle 1 is situated a device 8 adapted to transfer an anticoagulant 
into the blood flowing from the donor, for example, a glucose solution 
containing 35.6 g/liter of trisodium citrate, trademark AB 16 of Bieluz 
Co. This device 8 comprises, for example, a reservoir 9 of anticoagulant, 
a conduit 11 joined to the conduit 5 and the reservoir 9, and a pump 10, 
for example a peristaltic pump, situated along the conduit 11. This 
conduit 11 is joined to the conduit 5 as close as possible to the needle 
1. Between the point of junction of the conduits 11 and 5 and the pump 7, 
a bubble detector 12 and a pressure sensor 13 are advantageously situated 
in the conduit 5. The tubulure 15 of the upstream compartment 3 of the 
membrane-containing module 2 is connected by a conduit 16 to a container 
17, or bag, for collection of the blood, said container 17 itself being 
connected via the conduit 16b to the conduit 5, the junction between the 
conduit 5 and the conduit 16b being made at a point A situated between the 
pump 7 and the tubulure 6 of the membrane-containing module 2. For clarity 
in description, this point A will sometimes be referred to as junction A. 
The conduits 16 and 16b can be made from the same material and be of the 
same diameters as the conduit 5, while the container 17 advantageously is 
a bag made from a flexible plastic material. The conduits 16, 16b and the 
length of the conduit 5 situated between junction A and the tubulure 6 of 
the membrane-containing module 2 form or define a loop or circulation path 
for circulation of the fraction of the blood which is not transported 
across the membrane 14 and which is transferred into the upstream 
compartment 3 as well as into the container 17. The downstream compartment 
4 of the membrane-containing module 2 communicates with a container 20 for 
collection of the plasma which has been transported across the membrane 
14, this container 20 being, for example, a plastic bag. 
Along the loop defined above there are, in addition, a pressure sensor 19 
and a pump 18 for recirculation of the blood. 
In the embodiment of FIG. 1, the pump 18 is situated, within the loop 
defined above, in the conduit 16 in close proximity to the tubulure 15 of 
the separation module, while the pressure sensor 19 is situated between 
the said tubulure 15 and the pump 18. 
In the embodiment of FIG. 2, the pump 18 is operably situated, within the 
loop defined above, between the point of junction A and the tubulure 6 of 
the membrane-containing module 2, the pressure sensor 19 being positioned 
between the pump 18 and the said tubulure 6. 
In the embodiment of FIG. 3, the pump 18 is operably situated along the 
conduit 16b while the pressure sensor 19 is in the conduit 5, between the 
point of junction A and the tubulure 6 of the membrane-containing module 
2. 
In the embodiments of FIGS. 1, 2 and 3 described above, the pressure sensor 
19 influences the speed of rotation of the pump 18 which is under its 
control. The arrows placed on the conduits 16b and 16 indicate the 
direction of recirculation of the blood in the loop during a plasma 
donation session. The sensor 19 ensures that the blood does not circulate 
at a pressure greater than a specified selected value, namely, that the 
pressure across the membrane in the membrane-containing module 2 does not 
rise above a selected specified value, for example, in order that the 
blood does not haemolyze. 
The embodiments of FIGS. 1 to 4 additionally include a tourniquet 21, known 
per se, said tourniquet being inflatable and deflatable when desired, by 
means also per se known, for example, by a compressor, a pressure sensor 
arresting the inflation of the tourniquet 21 when a specified pressure is 
attained. The dashed line in FIGS. 1 to 3, between the tourniquet 21 and 
the pump 7, shows that the inflation or deflation of the tourniquet 21 
depends upon the direction of rotation of the pump 7. During the phase of 
withdrawal of blood from the donor, the tourniquet 21 is inflated, while 
during the phase of return of blood to the donor which has not been 
transported across the membrane, the tourniquet 21 is deflated. 
The module 2 above described can comprise a membrane in flat or planar 
form, in spiral form, or in the form of small fine tubes such as hollow 
fibers. When the membrane comprises a plurality of hollow fibers, the 
blood advantageously circulates inside the hollow fibers, the combined 
interior volume of the fibers constituting the upstream compartment 3 of 
the module. When the membrane is in flat or spiral form, the blood 
advantageously circulates between a pair of membranes or series of pairs 
of membranes, which constitute the upstream compartment 3 of the 
membrane-containing module 2. 
The membranes used for plasmapheresis are preferably those which permit the 
collection of a plasma: in which all of the proteins of the original blood 
are found in the same proportions, the protein concentration of which is 
greater than 55.5 g/liter, in which there are no red cells and in which 
the concentration of platelets is less than 15,000 platelets per mm.sup.3. 
The membranes selected are those which also permit no haemolysis of blood 
circulating in contact therewith, while at the same time providing good 
filtration yields. 
These plasmapheresis membranes advantageously have a rejection coefficient 
for latex of less than 75% for latex particles calibrated at 0.27 microns, 
and a rejection coefficient for latex of greater than 15% for latex 
particles calibrated at 0.64 microns. Preferably, the rejection 
coefficient for latex particles calibrated at 0.27 microns is less than 
30%, and the rejection coefficient for latex particles calibrated at 0.64 
microns is greater than 90%. 
To carry out the aforenoted measurement of latex rejection coefficient, the 
following procedure is adopted, when the membranes are flat. 
50 ml of suspension of calibrated polystyrene particles of diameter 
0.27-0.4 or 0.64 microns (marked Rhone-Poulenc under the trademark 
ESTAPOR) diluted to 0.1% with distilled water, with addition of 1% 
surfactant (alkylarylsulphonate, trademark SINOZON HAS 60 of the Sinnova 
Company), are loaded into a cell of type Amicon Model 52. 
The Amicon cell is fitted with a sample of the membrane supported on a 
mesh. An air pressure corresponding to 20 cm of water is established. The 
first six milliliters of filtrate are recovered for determination of the 
concentration (cf) of the calibrated particles. 
The rejection coefficient is defined by the formula: 
##EQU1## 
Membranes having the above characteristics are generally of synthetic 
material, for example, cellulose esters (cellulose nitrate and the like), 
regenerated cellulose, polycarbonate, and the like. These membranes can 
also be based on polyether-urethanes containing heparinized ammonium 
groups, or be of acrylonitrile copolymer. These membranes are 
advantageously reinforced by a mesh when they are in the form of flat 
membranes and advantageously have a thickness of between 50 and 200 
microns. 
FIG. 4 represents an embodiment equivalent to that of FIG. 1, but in which 
are shown the electrical connections of the different components to a 
logic unit 22 for control and monitoring, the electrical leads being 
represented by dashed lines. The unit 22 is connected to a current source 
(not shown). Naturally, all of the elements of the subject apparatus can 
be consolidated on a console or desk having castors, for example, to 
facilitate shifting. The description of the logic unit 22 and also of the 
keyboard 28 and display unit 29, referred to hereinbelow, is not described 
here in great detail, since the creation of the electronic circuits and 
advantageous utilization of microprocessors and memories would be 
trivially apparent to the technician once the problem in question has been 
considered, i.e., after the technician has been requested to arrange that 
the apparatus described should function automatically and reliably. The 
embodiments of FIGS. 2 and 3 are advantageously, and in the same manner, 
connected to a logic unit 22 for control and monitoring (not shown). 
The apparatus of FIGS. 1 to 4 is used as, for example, in the case of a 
donor plasmapheresis procedure. The conduit 11 is first filled with the 
citrate solution, and since the junction between the conduit 11 and the 
conduit 5 is in point of fact very close to the needle 1, the latter may 
be considered to be at least in part filled with this citrate solution. 
The tourniquet 21 having been previously inflated to the desired pressure 
(about 60 mm of mercury) by means of the compressor 23 in conjunction with 
the electromagnetic valve 25 and contact manometer 24, the needle 1 is 
inserted into a vein of the donor after conventional prepraration of the 
insertion site, which is situated between the tourniquet and the extremity 
of the selected limb. At this moment the pump 10 introduces citrate into 
the conduit 5, while the pump 7 rotates in the direction which causes the 
blood to flow towards the tubulure 6 of the membrane-containing module 2 
and into the container 17 through the conduit 16b. The pump 7 is under the 
control of the pressure sensor 13 such that the pressure measured at this 
point in the conduit 5 always remains greater than a certain value, 
generally, close to 0 mm of mercury, designated the threshold pressure, to 
ensure that the pump 7 does not draw the blood directly from the donor's 
vein. If the pressure in this part of the line becomes lower than the 
specified pressure fixed at the sensor 13, the logic unit 22 automatically 
operates and temporarily arrests or slows down the rotation of the pump 7, 
as long as the required pressure has not returned. When the blood in the 
container 17 reaches a minimum volume Vo, the pump 18 is activated and 
causes the blood to circulate in contact with the membrane 14 in the 
upstream compartment 3 of the module 2, the blood following the course 
indicated by the arrows in the loop containing the conduits 16b and 16. 
The pump 18 associated with the pressure sensor 19 is placed in the loop 
16, 16b such as to be upstream of the membrane-containing module 2. The 
sensor 19 indicates the pressure of the blood at entry into the 
membrane-containing module 2. The determination of the volume Vo may be 
made by a tachymetric device functioning in association with the pump 7. 
The pump 18 can for a very short period of time (for example, 15 seconds) 
rotate at the same speed as the pump 7, then its speed of rotation 
subsequently increases such that the speed of circulation of the blood in 
the loop shall be greater than that of the blood in the conduit 5 outside 
of the loop. The speed of circulation of the blood in the loop can be, for 
example, 1.5 to 7 times greater than that of the blood withdrawn from the 
donor. The pressure sensor 19 ensures that the pressure across the 
membrane in the membrane-containing module 2 does not exceed a 
predetermined specified value, in order not to haemolyze the blood. The 
pressure sensor 19 is adjusted such that the blood penetrates into the 
upstream compartment 3 of the membrane-containing module 2 at a pressure 
generally ranging from 40 to 100 mm of mercury in relative terms, and 
preferably from 50 to 90 mm of mercury, when the plasma is at atmospheric 
pressure in the downstream compartment 4 of the membrane-containing module 
2. If this maximal desired value is exceeded, the logic unit 22 
automatically arrests or slows down the pump 18. 
The period during which the blood leaves the vein of the donor is called 
the withdrawal phase. The latter comes to an end, for example, according 
to the predetermined volume of blood desired to be withdrawn from the 
donor (in each withdrawal phase), this volume naturally always being less 
than the volume of the container 17 for collection of the blood 
circulating in the loop. Advantageously, a tachymetric device is operably 
associated with the pump 7 and when the desired volume of blood is 
withdrawn from the donor, the logic unit 22 operates and arrests the pumps 
7 and 10. During this withdrawal phase the blood circulating in the loop 
tends to undergo an increase in its haematocrit; the sensor 19 will 
operate to slow the speed of the pump 18 when the pressure increases. The 
logic unit 22 actuates the electromagnetic valve 25, which becomes set 
such that the tourniquet 21 deflates, and also the pump 7, setting it in 
motion in the opposite direction to that in the preceding phase, referred 
to as the withdrawal phase. Thus begins the phase referred to as the 
return phase, during which the blood contained in the bag 17 returns to 
the donor while circulating in part in the loop (16, 16b) and passing in 
contact with the membrane 14 of the module 2. During this return phase, as 
previously during the withdrawal phase, the blood circulating in the loop 
tends to undergo an increase in its haematocrit, since more plasma passes 
into the container 20. The sensor 19 will operate in this case to slow the 
speed of rotation of the pump 18 when the pressure rises. It is, indeed, 
possible to arrange that, from the beginning of the return phase, the 
speed of rotation of the pump 18 should be slowed slightly, while causing 
it to circulate the blood in the loop at a speed greater than that of the 
blood returning to the donor. During the return phase, during which the 
pump 10 supplying citrate is not operating, the blood passes into the 
bubble detector 12. If any bubbles are detected by the detector 12, the 
logic unit 22 immediately arrests the pump 7 and, if necessary, actuates a 
clamp 26, or similar obstruction device, which closes the conduit 5. 
During the return phase, the pressure sensor 13 acts as a safety device, 
in the sense that it is adjusted in such manner that the pressure of the 
blood does not exceed a certain predetermined value. If this value is 
exceeded, for example, through total or partial obstruction of the needle 
1, the logic unit 22 intervenes immediately to arrest or slow the pump 7. 
During the return phase, the blood can, if necessary, pass through a 
conventional filter provided in the bubble detector, to avoid the 
possibility of returning undesirable particles to the donor. This filter 
can, for example, be moved aside during the withdrawal phase, returning to 
a seating provided in the bubble detector during the return phase. During 
the return phase, the pump 18 rotates, or operates in the same direction 
as during the withdrawal phase, the blood thus circulating in the loop 
(16, 16b) in the direction of the arrows during the phases of withdrawal 
and return. The completion of the return phase is detected, for example, 
by a balance-containing device 27 connected to the logic unit 22, the said 
balance enabling the return phase to be concluded when the volume Vo is 
reached in the container 17. The logic unit 22 then causes the apparatus 
to again operate in the withdrawal phase, i.e., the tourniquet 21 is 
inflated after the compressor 23 has started and the valve 25 has been set 
in the appropriate position; and starts the pump 7 in motion in the 
opposite direction, such that the blood of the donor is conveyed from the 
needle 1 towards the container 17 in the loop, which comprises in 
particular the conduits 16 and 16b and also the upstream compartment 3 of 
the membrane-containing module 2. The pump 10 which distributes the 
anticoagulant is also set in motion from the beginning of the withdrawal 
phase. When, during the last return phase, it is seen that the container 
20 for collection of plasma is sufficiently full, the procedure is stopped 
completely, after having emptied the container 17 and the conduit 5 at 
least as far as the bubble detector 12, during the last return phase. 
The flow rate of the pump 10 is generally adjusted such that, during the 
phase referred to as the withdrawal phase, one volume of citrate is used 
for 8 volumes of blood, or preferably 1 volume of citrate for 16 volumes 
of blood, the ratio being selected by the apparatus operator. This 
dilution ratio is advantageously obtained by placing the speed of rotation 
of the pump 10 under the control of that of the pump 7. 
It will, thus, clearly be seen that the apparatus according to the present 
invention can be made the subject of highly elaborate automation. Thus, as 
is shown more especially in FIG. 4, the logic unit 22 for control and 
monitoring can be connected to a keyboard 28 and a display unit 29. 
Likewise, the logic unit 22 can be connected to a synoptic chart (not 
shown) on which the localization of any anomalous functioning is indicated 
to the operator by a warning light, at the same time that, for example, an 
audible signal is emitted. On the keyboard 28 it is possible to choose the 
maximum volume of blood desired to be circulated during the withdrawal 
phase (300, 350, 400, 450 cm.sup.3 of blood, for example), by pressing the 
corresponding key. It is also possible to choose the volume of plasma 
desired to be withdrawn during the session (400, 500 or 600 cm.sup.3, for 
example), by pressing the corresponding key. Thus, a device 30 is 
advantageously provided on the plasma bag 20 to enable the quantity of 
plasma withdrawal to be known instantaneously as the session progresses, 
this device 30, known per se, being connected to the logic unit 22. On the 
keyboard 28, a key can also be provided for automatic priming of the line 
11 before inserting the needle into the donor. By pressing this key, the 
pump 10 starts and stops automatically when the solution of citrate is 
detected, for example, at the junction 31 of the two lines 11 and 5. On 
the keyboard 28, it is also possible to provide, for example, a key to 
show on the display unit 29 the instantaneous volume of plasma in the bag 
20 at any moment, a key to show on the display unit 29 the flow rate of 
the blood from the pump 7, to show the timing of the session in progress, 
and the like. The apparatus can include, in conjunction with the logic 
unit 22 and the values designated at the keyboard 28 regarding the volume 
of blood desired during the withdrawal phase and the total volume of 
plasma desired, an integration system operating during the last withdrawal 
phase such that the volume of blood withdrawn enables the total desired 
volume of plasma to be obtained upon completion of the last return phase. 
Numerous variations of the apparatus described above will be apparent to 
one skilled in this art. By way of example, the apparatus can include a 
small collapsible balloon in the line 5 between the junction 31 and the 
clamp 26. This small balloon then serves as a double security device with 
the pressure sensor 13, in the sense that it closes when the flow rate at 
the pump 7 is greater than that from the vein, if the sensor has not 
functioned during the withdrawal phase. This small collapsible balloon 
can, if necessary, be substituted for the sensor 13. 
Likewise, the device 8 intended for introducing the anticoagulant can 
optionally be omitted, if the interior of the needle 1, bubble detector 12 
and lines 5, 16 and 16b is coated, for example, with a polymer based on 
polyether-urethanes containing heparinized ammonium groups, such as those 
described in particular in U.S. Pat. No. 4,046,725. If necessary, the 
lines 5 and 16 can comprise a polymer such as those described in the 
aforesaid '725 patent, or a mixture of polyvinyl chloride and 
polyether-urethane containing heparinized ammonium groups, such as the 
mixtures noted in published European Patent Appliation No. 12,701. The 
microporous membrane can also be prepared from a mixture of polymers 
according to said published European Patent Application No. 12,701. 
Likewise, the subject apparatus can include a detector, known per se, in 
the line 11 enabling the absence of anticoagulant in the reservoir 9 to be 
indicated. Likewise, the apparatus too can include an optical detector in 
the line connecting the container 20 to the membrane-containing module 2, 
enabling the presence of haemoglobin in the filtered plasma to be 
indicated. 
The embodiments of FIGS. 2 and 3 comprise the same constituent components 
as those according to FIGS. 1 or 2, however, with the difference that the 
pump 18 and the pressure sensor 19 are positioned in a different manner in 
the loop comprising the conduits 16 and 16b. In the case of the embodiment 
of FIG. 2, the pump 18 is situated in the portion of the conduit 5 between 
the point of junction A and the tubulure 6 of the upstream compartment 3 
of the module 2, the sensor 19 being positioned between the pump 18 and 
the said tubulure 6. In the embodiment of FIG. 3, the pump 18 is situated 
in the conduit 16b, while the sensor 19 is situated close to the tubulure 
6 of the upstream compartment 3 of the module 2, in the portion of the 
conduit 5 between the point of junction A and the tubulure 6. In the 
embodiments of FIGS. 2 and 3, the direction of rotation of the pump 18 is 
such that the latter and the sensor 19 associated with it are situated, as 
in the embodiment of FIG. 1, upstream of the membrane-containing module 2. 
To use the apparatus illustrated in FIG. 2, once the first phase of 
withdrawal from the donor has begun, the pump 18 can be rotated at the 
same speed as the pump 7, as long as the volume Vo is not reached in the 
container 17, and then the speed of rotation of the pump 18 is 
accelerated. During the plasmapheresis session, the blood circulates in 
the direction of the arrows in the loop, i.e., passing from the upstream 
compartment 3 of the module 2 into the conduit 16, then into the container 
17 and the conduit 16b, and returns via the tubulure 6 into the upstream 
compartment 3 of the module 2. 
To use the apparatus illustrated in FIG. 3, once the first phase of 
withdrawal from the donor has begun, it is possible to commence by 
rotating the pump 18 such that it draws into the container 17 one fraction 
of the blood withdrawn, while the other fraction of the blood withdrawn 
passes into the upstream compartment 3 of the membrane-containing module 
2, entering via the tubulure 6, and then into the container 17. When the 
volume Vo is reached in the container 17, the direction of rotation of the 
pump 18 is then reversed, and the pump is set to rotate at a speed which 
allows a greater speed of circulation of the blood in the loop than the 
speed of circulation of the blood withdrawn from the donor. During the 
session, within the loop, the blood circulates following the same 
direction of circulation as that according to the embodiment of FIG. 2, 
i.e., it passes from the upstream compartment 3 of the membrane-containing 
module 2 into the conduit 16, then into the container 17, and into the 
conduit 16b to return via the tubulure 6 of the upstream compartment 3 of 
the membrane-containing module 2. 
With the apparatus such as depicted in FIGS. 1 and 4, and described above, 
plasmapheresis procedures have been performed on a donor using, by way of 
example, a membrane-containing module 2 in which the total membrane area 
is 600 cm.sup.2 and which contains two membranes arranged facing each 
other forming the upstream compartment 3 between which the blood 
circulates. Each membrane is 30 cm long and 10 cm wide and supported on a 
mesh, as described in more detail below. The average thickness of the 
blood film is 500 microns. The withdrawal device 1 is a needle of 1.65 mm 
external diameter and 1.45 mm internal diameter. The conduits 5, 16 and 
16b are made from polyvinyl chloride (PVC) and have an internal diameter 
of 3.5 mm. The conduit 11 is also made of PVC and has an internal diameter 
of 0.9 mm. The pump 10 is a peristaltic pump (reference RP 04, marketed by 
Hospal), said pump comprising a silicone envelope. 
The pumps 7 and 8 are peristaltic pumps (reference RP 01, also marketed by 
Hospal), said pumps also comprising a silicone envelope. The containers 17 
and 18 have a capacity of 1,000 cm.sup.3 and are also made of PVC. 
The membrane used is a membrane supported on a mesh, obtained from a 
solution of polymer in an organic solvent which is permitted to flow onto 
a mesh rotating in contact with a belt having a very smooth surface. This 
solution contains 8% by weight of a copolymer of acrylonitrile/methyl 
methacrylate/sodium methallyl sulfonate, comprising 7.75% by weight of 
methyl methacrylate and 80 mEq/kg of acidic residue, dissolved in a 
mixture of N-methylpyrrolidone/glycerin (70.8/21.2%). This copolymer has a 
specific viscosity of 0.3 at 20.degree. C. in solution at a concentration 
of 2 g/liter in dimethylformamide. 
The mesh used is a monofilament fabric of ethylene glycol 
polyterephthalate, having a mesh size of 75 microns, the thread diameters 
being 55 microns and the open or voids area being 33%. This mesh weighs 55 
g/m.sup.2. 
The microporous membrane which is obtained, supported on the mesh, has a 
thickness of 120 microns and its mass is 10 g of polymer per m.sup.2 of 
dry membrane. 
The microstructure of the polymer phase of the membrane is porous and 
regular. Its porosity is 80%, the porosity being defined as the ratio 
(multiplied by 100) of the volume of the pores to the total volume of the 
membrane (polymer+pores). 
The flow rate for water (with 1% of a surfactant added) of this membrane 
supported on the mesh is 4.5 ml/h cm.sup.2 mm Hg. 
The rejection coefficient for latex of this membrane is: 
(i) 5 to 15% for latex calibrated at 0.27 microns 
(ii) 65 to 80% for latex calibrated at 0.4 microns 
(iii) 98 to 100% for latex calibrated at 0.64 microns 
The sensor 13 is a sensor from National Semiconductor, trademark Lx 1 801 
GB, in which the minimal pressure registered is adjusted to 10 mm of 
mercury during the withdrawal phase and the maximal pressure value is 
adjusted to 80 mm of mercury (in relative value) during the return phase. 
The sensor 19 is a sensor of the same make and same reference as the 
sensor 13. The sensor 19 is adjusted to a maximal relative pressure of 60 
mm of mercury. The containers 17 for collection of the blood and 20 for 
collection of the plasma are at atmospheric pressure and are placed 
without alteration of level in relation to the membrane-containing module 
2. Given that the pressure of the blood upon leaving the upstream 
compartment 3 is 10 mm of mercury, due to the loss of pressure head in the 
line 16b, the average pressure across the membrane is equal to: 
##EQU2## 
During each withdrawal phase, the tourniquet is inflated to 60 mm of 
mercury and the flow rate of citrated blood is 60 ml/mm in the line 5, 
between the needle 1 and the pump 7. The speed of recirculation of the 
blood in the loop (16, 16b) is 170 ml/mm during each withdrawal phase. 
With the apparatus as defined above, fixing the volume of blood at 450 
cm.sup.3 during the withdrawal phase, the total volume of plasma to be 
collected at 600 cm.sup.3, and the ratio of the volume of coagulant 
solution/volume of blood at 1/16, during each withdrawal phase, the 
plasmapheresis procedure was completed in 50 minutes after having 
performed 5 withdrawal phases and 5 return phases. 
The plasma collected is practically acellular. It contains no contamination 
by red cells and only 3,000 platelets per mm.sup.3. The protein 
concentration of the plasma is 57 g/liter. The apparatus according to the 
invention has thus enabled a session yield of 20% to be obtained with a 
membrane-containing module, the intrinsic yield of which is only 11.5%. 
By way of comparison, 87 minutes was needed to collect 600 ml of plasma in 
a plasmapheresis procedure performed under the same conditions of blood 
flow in the line 5, i.e., 60 ml/mm, and pressure across the membrane with 
the same membrane-containing module 2, but without recirculation of the 
blood, i.e., eliminating the line 16b and adding a pressure sensor between 
the pump 7 and the membrane-containing module (in the embodiments shown in 
FIGS. 1 and 4). 
The apparatus as above described can very obviously be used with animals 
(dogs, horses, etc.), in particular for plasmapheresis procedures. 
Generally, the subject apparatus can be used every time it is desired to 
insert a needle into a subject (human or animal) at only one single site, 
using a simple needle (having only one internal channel), and to cause the 
withdrawn liquid (generally blood) to pass in contact with a semipermeable 
membrane at a speed of circulation greater than that of the liquid 
withdrawn, the liquid which has not been transported across the membrane 
returning to the subject by the same conduit which was used for the 
withdrawal. 
Thus, the apparatus described above can be used for applications other than 
donor plasmapheresis. According to the separation characteristics of the 
semipermeable membranes used, it will be possible to deplete the 
circulating blood of only certain of its proteins or certain constituent 
components of the plasma. It is also possible to perform haemofiltration 
sessions by means of, for example, the reinjection of a replacement liquid 
determined by the quantity of filtered liquid collected in the container 
20. 
The subject apparatus can also be used for plasma exchange procedures, 
i.e., reinjecting into the patient, during the return phase, a plasma 
equivalent in quantity to that withdrawn, by means of a pump and conduit 
(not shown) attached, for example, to the conduit 5 between the bubble 
detector 12 and the pump 7. If the patient has an arterio-venous shunt, it 
is not necessary to use the tourniquet 21. 
The apparatus according to this invention can also be used for the 
treatment of the ascites fluid of a patient, there being no need in this 
application for the tourniquet, the device 8 for introduction of the 
anticoagulant, or the bubble detector 12. 
While the invention has been described in terms of various preferred 
embodiments, the skilled artisan will appreciate that various 
modifications, substitutions, omissions, and changes may be made without 
departing from the spirit thereof. Accordingly, it is intended that the 
scope of the present invention be limited solely by the scope of the 
following claims.