Apheresis method and device

A simplified fluid separation method and device usable for various apheresis procedures, including plasmapheresis. At least one pump is utilized to draw a first fluid (e.g. whole blood) into a separation device. The separation device then operates to separate the fluid (e.g. whole blood) into first and second fluid fractions (e.g. a cell concentrate and blood plasma). The first and second fluid fractions are pumped from the separation device to separate first and second fluid fraction containers, both of which are positioned on a single weighing device, such as an electronic load cell. At least one of the fluid fractions is subsequently removed from its fluid fraction container and returned to the human subject or other fluid source. Weights recorded by the single weighing device are then utilized to calculate the actual weights of fluid and/or fluid fractions pumped by at least one pump during the procedure. Such actual weights of fluid and/or fluid fractions are then utilized to calculate new pump flow constants, thereby enabling the calibration of the pump(s) to be corrected, on the basis of such new pump flow constants, prior to subsequent utilization of the pump(s) for pumping the fluid and/or fluid fractions. The single weighing device may also be utilized to monitor the weight change or rate of weight change occurring as the fluid fractions are pumped into and/or out of the fluid fraction containers, thereby providing a means for monitoring and verifying the pressures and flow rates within the system.

FIELD OF THE INVENTION 
The present invention pertains generally to fluid processing equipment and 
more particularly to a method and device for effecting apheresis 
procedures. 
BACKGROUND OF THE INVENTION 
In current practice, there exist numerous situations in which it is 
desirable to efficiently separate fluids such as whole blood into two or 
more specific components (e.g. plasma, red blood cells, leukocytes, 
platelets, etc.). In commercial applications, it is often necessary to 
separate whole blood into two or more constituents in order that a 
specific blood constituent may be harvested and utilized for the 
preparation of medically useful blood derivatives or preparations (e.g. 
packed red blood cells, fresh frozen plasma, specific blood factors, 
etc.). Also, in therapeutic settings it is often desirable to separate 
whole blood into two or more constituents for purposes of treating or 
removing a specific constituent(s) of the blood in accordance with certain 
therapeutic protocols. 
In almost all blood constituent separation procedures, whether commercial 
or therapeutic, quantities of whole blood are withdrawn from a human 
subject, the whole blood is then separated into two or more constituent 
fractions and at least one of the constituent fractions is subsequently 
transfused back into the human subject. The nonreinfused constituent 
fraction(s) may be retained for use in the preparation of various blood 
plasma products (e.g. fresh frozen plasma, albumin, or Factor VIII) or, in 
the therapeutic applications, may be discarded and replaced by plasma from 
a healthy donor or may be subjected to physical pharmacologic or 
radiologic treatment and subsequently returned to the human subject. 
The general term "apheresis" used to describe three-step procedures wherein 
whole blood is a) withdrawn, b) separated into fractions and c) at least 
one of the fractions is retransfused into the human subject. Specific 
types of apheresis procedures include: "plasmapheresis" (for the 
collection of blood plasma), "leukapheresis" (for the collection of 
leukocytes), "thrombocytapheresis" (for the collection of platelets), 
therapeutic plasma exchange (wherein a portion of the subject's blood 
plasma is replaced with other fluids, such as plasma obtained from another 
human), and therapeutic plasma processing wherein a portion of the 
subject's plasma is separated, treated or processed and then returned to 
the subject. 
Prior to the 1970's, when it was desired to separate whole blood into 
specific blood constituent(s), it was generally necessary to draw, on a 
unit by unit basis, quantities of whole blood from a human donor. Each 
unit of whole blood withdrawn was manually centrifuged to effect 
separation of the desired blood constituent or component and, thereafter, 
the remaining portions of the blood were manually reinfused into the 
donor. It was typically necessary to repeat such a procedure, on the same 
donor, several times (i.e. unit after unit) until the maximum allowable 
volume of plasma or other blood constituent had been collected. 
More recently, automated apheresis machines been developed to minimize the 
degree of manual endeavor required when separating and collecting specific 
blood constituents. These automated apheresis machines typically comprise 
a central computer electrically connected to, and programmed to control, a 
system of tubes, vessels, filters and at least one blood separation 
device. The blood separation device is typically a rotating centrifugal 
filter or membrane which operates to separate the desired specific blood 
constituent(s) (e.g. plasma, cells, platelets, etc.). The typical 
automated apheresis machines of the prior art incorporate one or more 
"peristaltic pumps" or "tubing pumps" for moving blood, blood constituents 
and/or reagent solutions through the machine. Such "peristaltic pumps" or 
"tubing pumps" generally consist of a series of rotating rollers or cams 
over which a length of plastic tubing is stretched. Rotation of the cams 
or rollers then serves to dynamically compress regions of the tubing so as 
to move the desired fluids through the tubing at a desired rate. The use 
of such peristaltic pumps is particularly suitable in automated apheresis 
equipment because the mechanical working components of such pumps do not 
come in contact with the blood or other fluids being pumped, thereby 
preventing contamination of such fluids. Moreover, the use of peristaltic 
pumps permits intermittent disposal and replacement of the attendant 
tubing, as is commonly done to maintain sterile and hygienic conditions 
during each blood donation procedure. These peristaltic pumps are, 
however., given to a great deal of uncertainty or "drift" in calibration. 
Such uncertainty or "drift" in the pump calibration occurs because of 
variations in the size and material consistency of the pump tubing, 
variations in the rotational speed of the pump cam or rollers, stretching 
and/or wear of the pump tubing, etc. The resultant variations in the 
throughput of the peristaltic pumps complicates the operation of automated 
apheresis machines because such variations in pump throughout render it 
difficult to accurately control volume of blood or blood constituents 
collected in a particular procedure. Strict control of the volumes of 
blood or blood constituents withdrawn is required by governmental 
regulation intended to prevent inadvertent or purposeful over-withdrawal 
of blood or specific blood constituents from the human subject, as may 
result in injury to the human subject. Furthermore, variations in 
throughput of the pumps is problematic because many steps in automated 
apheresis procedures require precise knowledge of actual fluid flow rates. 
Also, certain system components, such as the separator device 20 require 
pressure and flow control in order to operate safely and efficiently. 
In view of the above-stated shortcomings of the prior art automated 
apheresis machines, there exists a need for new apheresis machines and/or 
methods which minimize the expense and/or complexity of apheresis 
procedures, without any prohibitive diminution in the ability to monitor 
and maintain accurate control of the calibration and throughput of the 
blood and other fluids being extracted from the human subject and 
processed by the apheresis machine. 
SUMMARY OF THE INVENTION 
The present invention comprises a simplified fluid separation method and 
device. 
In accordance with the present invention, there is provided a fluid 
separation or apheresis method wherein at least one pump is utilized to 
draw fluid (e.g. blood) from a source (e.g. a human subject) and to move 
such fluid into a fluid separation device. Thereafter, the separation 
device is utilized to separate the fluid (e.g. blood) into at least a 
first blood fraction (e.g. cell concentrate) and a second blood fraction 
(e.g. plasma). A single weighing device is operatively connected to a 
first fluid fraction container (e.g. a cell bag) and a second fluid 
fraction container (e.g. a plasma vessel) so as to measure the combined 
weight of such first fluid fraction container and second fluid fraction 
container along with the contents thereof. Initially, the weight on the 
weighing device is that of the empty first fluid fraction container and 
the empty second fluid fraction container, and such weight may be recorded 
or stored. After the first and second fluid fractions have been collected 
in the respective containers, a second weight on the weighing device may 
be recorded. Such second weight includes the first and second fluid 
fraction containers as well as the first and second fluid fractions 
contained therein. Thereafter, the first fluid fraction is removed from 
the first fluid fraction container and reinfused into the human subject. 
Following such reinfusion, a third weight on the weighing device (i.e. the 
weight of the empty first blood fraction container and the weight of the 
second blood fraction container plus its contents) may be recorded. The 
weights recorded on the weighing device may then be utilized to calculate 
new flow constants for the pump(s) utilized in drawing and/or reinfusing 
the fluid and/or fluid fraction(s). The calibration of the pump(s) may 
then be adjusted in accordance with the newly calculated flow constants. 
Further in accordance with the invention, weights recorded by the single 
weighing device may be continuously or periodically used to monitor the 
flow of first fluid fraction during reinfusion. The monitored weight, or 
change in weight, is then compared to an "expected" weight based on the 
expected throughput of the pump being utilized to effect such reinfusion. 
If the monitored weight, or change in weight, is found to differ more than 
an allowable amount from the "expected" weight, such is taken to be an 
indicator of either (a) depletion of the first blood fraction from the 
first blood fraction container or (b) a malfunction in the system. At such 
point, the reinfusion pump(s) is stopped. 
Still further in accordance with the invention, there is provided an 
automated fluid processing or apheresis machine having at least one pump, 
a fluid or blood separator and a single weighing device with separate 
fluid fraction collection vessels (e.g. a plasma vessel and a flexible 
cell concentrate bag) positioned thereon. This automated machine may be 
utilized to carry out the method of the present invention as described 
herein. 
Still further in accordance with the invention, an automated apheresis 
machine may comprise a plurality of pumps (e.g. a whole blood pump and a 
cell concentrate pump) which operate, in combination, to effect the 
withdrawal, separation and reinfusion of the blood and/or blood 
components. A single weighing device is utilized to simultaneously weigh 
at least two of the separated blood components, at various points in the 
procedure. The weights recorded by the single weighing device may, 
thereafter, be utilized to calculate actual flow constants for the pumps 
and/or to monitor and verify quantities or dynamics of fluid movement(s) 
within the machine.

DETAILED DESCRIPTION OF THE ILLUSTRATIVE EMBODIMENTS 
i. The System of the Present Invention 
The following detailed description and the accompanying drawings are 
provided for purposes of illustrating certain embodiments of the present 
invention and are not intended to limit the scope of the invention in any 
way. 
The present invention is particularly applicable to automated 
plasmapheresis equipment and, thus, will be described herein with 
particular reference to plasmapheresis procedures. It will be appreciated, 
however, that the invention is equally applicable to other fluid 
processing and apheresis procedures, including but not limited to, 
leukapheresis, thrombocytapheresis, therapeutic plasma exchange, 
therapeutic plasma processing, etc. 
FIGS. 1 through 4 are comparative, schematic illustrations of a prior art 
apheresis method and device (FIGS. 1 and 3) and an embodiment of the 
method and device of the present invention (FIGS. 2 and 4). 
Generally, the apheresis systems of the prior art and those of the present 
invention incorporate certain common components. A venipuncture needle 10, 
10a is percutaneously insertable into a peripheral vein of a human plasma 
donor. A bag or other container of anticoagulant solution 12, 12a is 
fluidly connected, by tube 16, 16a, to a mixing chamber 14, 14a which is 
proximal to needle 10. 
An anticoagulant pump 18, 18a is positioned on tube 16, 16a to draw 
anticoagulant solution from bag 12, 12a through tube 16, 16a, into the 
mixing chamber 14, 14a. Anticoagulant solution entering the mixing chamber 
14, 14a will join with, and will become dispersed in, blood which has been 
extracted proximally through needle 10. 
A blood separation apparatus 20, 20a is fluidly connected to the mixing 
chamber 14, 14a by tube 22, 22a. A bidirectional blood pump 24, 24a, 
preferably a peristaltio pump, is positioned on tube 22, 22a for alternate 
withdrawal of blood and infusion of cell concentrate through needle 10, 
10a. Movement of the blood pump 24, 24a in a clockwise direction will move 
blood in the direction of arrow A (withdraw), while movement of blood pump 
24, 24a in a counter-clockwise direction will move fluids (e.g. cell 
concentrate from line 60) in the direction of arrow B, back to the human 
subject. 
A cell pump 44, 44a is positioned on line 42, 42a to move cell concentrate 
out of the separation device 20, 20a at a controlled rate. Close control 
of the calibration of the cell pump 44, 44a is critical in that there 
exists strict limits on the amount of oxygen transporting red blood cells 
which may be held in the extracorporeal circuit at any point in time. 
Thus, close control of the amount of cell concentrate being pumped by the 
cell pump 44, 44a is necessary to ensure that such limits are not 
exceeded. Also, the calibration and throughput of the cell pump directly 
affects the transmembrane pressure within the separation device 20, 20a. 
If the calibration and throughput of the cell pump 44, 44a is not closely 
controlled, errant pressures within the separation device 20, 20a may 
result in hemolysis of the blood cells, incomplete separation of the blood 
and/or an automatic error signal and shut down of the machine. A plasma 
container 26, 26a is connected to the plasma outlet port of blood 
separator 20, 20a by way of tube 28, 28a. A saline bag or container 30, 
30a is connected to blood line 22, 22a at a point near the inlet port of 
blood separation device 20, 20a. A saline valve 34, 34a is alternately 
positionable in an open position whereby flow through line 32, 32a, is 
permitted and a closed position whereby flow through line 32, 32a is 
prohibited. 
A blood valve 36, 36a is positioned on blood line 22, 22a. Blood valve 36, 
36a is alternately positionable in an open position whereby flow through 
line 22, 22a is permitted, and a closed position whereby flow through line 
22, 22a is blocked. 
A plasma valve 38, 38a is positioned in line 28, 28a. The plasma valve 38, 
38a is alternately positionable in an open position whereby flow through 
line 28, 28a is permitted and a closed position whereby flow through line 
28, 28a is prohibited. 
In the typical apheresis machine of the prior art (FIGS. 1 and 3), a cell 
concentrate reservoir 40 is located remotely from the separate plasma 
vessel 26. Separate, discrete systems are employed to monitor the relative 
weights and/or volumes of a) cell concentrate collected in the cell 
reservoir 40 and b) plasma collected in the plasma vessel 26. As shown, 
the plasma vessel 26 is attached to weighing device 64, such as an 
electronic balance, so as to continuously monitor the weight of the plasma 
container 26 and its contents. The level of cell concentrate in the cell 
reservoir 40 is, on the other hand, often measured by a series of 
electronic sensors or other measuring device(s) located in or adjacent to 
the cell reservoir 40. Thus, the weighing device 64 and the sensors or 
other measuring device(s) associated to the cell reservoir 40, are 
separately connected to, and provide separate signals to a central 
computer 65, 65a. The computer 65, 65a may include an electronic 
microprocessor, timing and logic circuits, program memory, communication 
busses and power supply connections. 
The cell concentrate reservoir of the prior art machine 40 (FIGS. 1, 3) is 
fluidly connected to the cell concentrate output port of the blood 
separation device 20 by way of a flexible tube 42. A cell pump 44, such as 
a peristaltic pump, is positioned on tube 42 so as to pump the cell 
concentrate from the cell concentrate outlet port of the blood separation 
device 20 through line 42 into the cell concentrate reservoir 40. The 
outlet port of cell concentrate reservoir 40 is connected to the lower 
portion of the blood line 22 by way of a flexible tube or line 46. Cell 
concentrate valve 48 is positioned on line 46. The cell concentrate valve 
48 is alternately positionable in an open position whereby flow through 
line 46 is permitted, a closed position whereby flow through line is 
prohibited. 
As shown in the diagrams of FIGS. 2 and 4, the system of the present 
invention differs from the prior art system shown in FIGS. 1 and 3 in that 
the concentrate outlet port of the blood separation device 20a is 
connected to the top inlet port of a blood filter/bubble trap 50 by way of 
a flexible tube or line 52. The cell pump 44a is positioned on line 42a to 
pump cell concentrate from the cell concentrate output port of blood 
separator device 20a into the top port of blood filter/bubble trap 50. 
Another flexible tube or line 56 connects the right side bottom port of 
blood filter/bubble trap 50 to a bottom fill port of cell bag 58. A left 
side bottom port of cell filter/bubble trap 50 is connected to a point on 
line 22a, as shown, by way of a flexible tube or line 60. A cell 
concentrate valve 62 is positioned on line or tube 60. Cell concentrate 
valve 62 is alternately positionable in an open position whereby flow 
through line 60 is permitted, and a closed position whereby flow through 
line 60 is blocked. 
The darkened tubes and components (shown in FIGS. 1 and 2) indicate the 
respective flow paths of fluids within a typical prior art apheresis 
system during collection (FIG. 1) and reinfusion (FIG. 3). 
As specifically illustrated in FIG. 1, the collection of plasma by a prior 
art plasmapheresis machine was generally accomplished with valves 36 and 
38 in their open positions and valves 34 and 48 in their closed positions. 
Anticoagulant pump -8, blood pump 24 and cell pump 44 are concomitantly 
actuated during collection, so as to pump fluids in the directions 
indicated by the arrows of FIG. 1. Specifically, an anticoagulant pump 18 
turns in a clockwise direction to pump dilute anticoagulant solution from 
anticoagulant reservoir 12, through line -6, into the mixing chamber 14 
which is positioned proximal to venipuncture needle 10. Blood pump 24 
rotates in a clockwise direction and operates to withdraw blood through 
needle 10 such that blood will become mixed with anticoagulant solution as 
the blood is drawn through the mixing chamber -4. Whole blood (mixed with 
anticoagulant solution) is then withdrawn by blood pump 24, through line 
22, into the separation device 20. The separation device 20 substantially 
separates blood plasma from a cell concentrate which contains the formed 
elements of the blood (i.e. red cells, white cells and platelets). The 
cell pump 44 operates to withdraw the cell concentrate from the cell 
concentrate outlet port of blood separation device 20, through line 42 and 
deposits the cell concentrate in cell concentrate reservoir 40. Since 
valve 48 is in its "closed" position, the cell concentrate is prevented 
from moving past valve 48 when the device is in the depicted collection 
mode. Air displaced from the interior of the reservoir is vented through a 
hydrophobic filter/vent port 41 formed in the top of the reservoir 40. 
Blood plasma flowing from the plasma outlet port of the blood separation 
device 20 is permitted to drain through line 28 into plasma collection 
vessel 26. 
In the device of the present invention (FIGS. 2 and 4) a single weighing 
device 64a, such as an electronic balance or load cell, is utilized to 
concomitantly weigh a) the plasma container 26a and its contents, and b) 
the cell concentrate bag 58 and its contents. The use of this single 
weighing device 64a for both the plasma container 68a and the cell bag 58 
eliminates the need for a separate system for collecting and measuring the 
cell concentrate at a location remote from the plasma container. Also, the 
use of the single weighing device 64a, in accordance with the method of 
the present invention, provides for highly accurate measurement of the 
throughput, of the blood pump 24, 24a and cell pump 44, 54, thereby 
permitting accurate and frequent recalibrations thereof. Additionally, 
this invention enables continuous, redundant monitoring of the blood/cell 
concentrate flow during withdrawal and reinfusion by providing a continual 
indication of flow rate based on the changes of weight being recorded by 
the single weighing device 64a as the withdrawal or reinfusion occurs. The 
change in weight or rate of change in weight recorded by weighing device 
64a is then continuously or periodically compared to the calculated flow 
rate or actual rotations of pump 44a. If the actual or expected flow 
through pump 44a differs more than a certain amount (e.g. 25%) from the 
flow rate indicated by the change in weight being recorded by the weighing 
device, such will indicate a problem with the system, such as a tubing 
leak, vessel fracture or improperly rigged or malfunctioning pump. Thus, 
this redundant, comparative flow monitoring capability provided by the 
single weighing device 64a, is also an advantage of the present invention. 
Additionally, the invention provides for the use of an inexpensive plastic 
cell concentrate container bag 58 and inexpensive blood filter/bubble trap 
50 as opposed to the more expensive components used in some prior art 
devices, such as the rigid, vented cell reservoir 40 with attendant 
electronic (LED) volume monitoring used in the prior art system shown in 
FIGS. 1 and 3. 
The general method by which the apheresis system of the present invention 
operates is shown in FIGS. 5a-5b. This method is more fully described 
herebelow with specific reference to the schematic diagrams of FIGS. 2 and 
4. 
ii. The Method of the Present Invention 
Initially, the empty plasma reservoir 26a and cell concentrate bag 58 are 
placed on a single weighing device 84a. A "DRY TARE" is then measured by 
the weighing device 64a. The "DRY TARE" value is communicated to the 
computer 65a wherein the "DRY TARE" value is stored. The "DRY TARE" value 
is the combined weight of a) the empty plasma container 26a, and b) the 
empty cell bag 58. This "DRY TARE" step is carried out at the beginning of 
the procedure, prior to the initial priming of the system, as illustrated 
in FIG. 9a. The "DRY TARE" value is the combined weight of the empty 
plasma vessel 26, 26a, 234, 234a and the empty cell bag 58, 237. In 
subsequent cycles after the initial cycle, an "EMPTY CELL BAG TARE" 105 is 
determined and stored instead of the "DRY TARE" determined and stored at 
initiation of the first cycle. The "EMPTY CELL BAG TARE" 105 differs from 
the "DRY TARE" in that it includes the weight of plasma collected in 
previous collection cycles, as illustrated in FIG. 9c. 
Thereafter, a portion of the system (e.g., the blood tube 22a, blood 
separator device 20a, tube 52, blood filter/bubble trap 50, tube 56 and 
blood bag 58) is initially primed with a quantity of anticoagulated whole 
blood withdrawn through venipuncture needle 10a. Such priming of the 
system 110 will typically result in a small amount of whole blood being 
disposed in the bottom of the cell concentrate bag 58. At this point, a 
"PRIMED TARE" is measured 112 by the weighing device 64a. The "PRIMED 
TARE" value is communicated to the computer 65a wherein such "PRIMED TARE" 
value is stored. The "PRIMED TARE" value is the combined weight of the a) 
empty plasma container, and b) cell bag containing the small amount of 
priming blood as illustrated in FIG. 9b. 
After the "PRIMED TARE" has been recorded 112, an initial collection cycle 
is begun 114. During such collection cycle, the blood valve 36a is in its 
"open" position, the infusion valve 62 is in its "closed" position, plasma 
valve 38a is in its "open" position and blood pump 24a and cell pump 44a 
are operated in their respective, clockwise and counter-clockwise 
directions, at specifically controlled rates, as dictated by the program 
of the computer 65a. The set rates of the pumps 24a and 54 are calculated 
by the computer 65a on the basis of the desired pressures to be maintained 
within the attendant tubing 22, 52, 28a and the blood separation device 
20a. The rate of the blood pump 24a is also determine, to some degree, in 
view of the volume and pressure of blood available to be withdrawn from 
the blood vessel of the human subject. 
The total volume of blood to be withdrawn into the extracorporeal circuit 
in any given collection cycle is controlled by presetting the number of 
rotations to be made by the cell pump 44a during the next collection 
cycle. The numbers of rotations that the pumps 24a and 44a will undergo, 
in each given collection cycle, is controlled by computer 65a on the basis 
of a preset "pump flow constant" for each pump (BP and CP). The desired 
number of rotations for any given collection cycle is generally determined 
on the basis of the following equation: 
Equation No. 1 
##EQU1## 
To control the volume to be pumped during the first or start-up collection 
cycle (step 114-116), the desired rotations for the cell pump 44a will be 
preset by the computer 65a on the basis of an "initial" flow constant for 
each pump. Thereafter, for each repetitive collection cycle, an "adjusted" 
flow constant will be determined and stored in the computer 65a. Each such 
"adjusted" flow constant will be based on actual measurements made during 
the previous collection cycle. Such frequent adjustment of the desired 
rotations of the blood pump and cell pump helps to insure that accurate 
fluid volumes are maintained throughout the procedure. 
The collection is accomplished by running the blood pump 24a and cell pump 
54 in their respective "collection" directions or modes. Typically, such 
will require that the blood pump 24a be rotated in a clockwise direction 
while the cell pump 54 be rotated in a counter-clockwise direction. 
Typically, the cell pump 44a is utilized to precisely gage and control the 
amount of red cells withdrawn in a single collection cycle and the blood 
pump 24a continues to run in conjunction with the cell pump 44a until the 
cell pump is stopped (i.e. where it has undergone a present number of 
rotations. Thus, in any collection cycle prior to the final collection 
cycle of a given procedure, the cell pump 54 will undergo a predetermined 
number of rotations as preset in the computer 65a or as selected or 
overridden by the operator. The present number of rotations will achieve a 
precalculated quantity of cell concentrate pumped by cell pump 44a. Such 
precalculated quantity of blood cell concentrate withdrawal is generally 
related to a specific weight of cell concentrate contained within the cell 
bag 58 and is below the maximum allowable extracorporeal red cell volume 
permitted by applicable government regulations. 
In order to insure that the maximum allowable plasma collection is not 
exceeded, it is desirable to continuously or periodically calculate the 
current predicted or calculated plasma wt. (P.sub.pre) and to 
continuously, or at discrete time points during each collection cycle, 
compare such predicted plasma volume to the maximum allowable volume of 
plasma withdrawal (P.sub.max) 116. The P.sub.max, in most instances, is 
determined from generally published data tables or nomograms, based on the 
height and/or weight of a generally healthy blood donor and in accordance 
with governmental regulations. In certain therapeutic instances, however, 
the P.sub.max will be determined and set by the operator or medical 
practitioner taking into account the general health of the patient and/or 
other facts relating to the therapeutic procedure being performed. 
In a preferred embodiment of the present invention, the computer 65a 
continuously monitors the P.sub.pre in comparison to P.sub.max. The 
predicted plasma (P.sub.pre) is determined by the following formula: 
Equation No. 2 
EQU Primed Cell Bag.DELTA.=Primed Tare-Empty Cell 
Bag Tare 
Equation No. 3 
P.sub. =Current Weight-Dry Tare-Primed Cell Bag.DELTA.-Current 
Cell.DELTA.+Coast Bias 
When P.sub.pre is determined to equal P.sub.max, the collection is 
immediately terminated by the computer 65a and the device moves directly 
into the final reinfusion cycle of the procedure, as will be fully 
described hereinafter. 
In a typical prefinal collection cycle (a full collection cycle which 
yields a final volume of plasma collected which is less than P.sub.max) 
prior to the final collection cycle during which the procedure is 
terminated, the end of collection will be marked by a weight of red cell 
concentrate within the cell bag 58 and an attendant weight of separated 
plasma within the plasma container 26a. After the particular collection 
cycle has been ended 118, the weigher 64a will take a "post-collection 
weight" 122, as illustrated in FIG. 11 and will transmit such weight to 
the computer 65a wherein it will be stored. The "post-collection weight" 
122 is the combined weight of a) the plasma container plus all plasma 
contained therein, and b) the cell bag plus all cell concentrate (and any 
priming blood) collected therein plus any priming blood, primed cell 
bag.DELTA., 324, contained therein. 
After the "post-collection weight" has been recorded 122, the blood valve 
36a will move to its "closed" position and reinfusion valve 62 will move 
to its "opened" position. The blood pump 24a will then be operated in its 
counter-clockwise direction to effect reinfusion of the cell concentrate 
(and/or any priming blood) from the cell bag 58, through tube 56, through 
blood filter/bubble trap 50, through tube 60, through mixing chamber 14a, 
and distally through needle 10a, into the blood vessel of the human donor. 
It is desirable that such reinfusion cycle effect complete reinfusion of 
all cell concentrate (and/or priming blood) contained in the cell bag 58a. 
Thus, the computer 65a may be capable of continuously or periodically 
monitoring the flow of fluid through the reinfusion system in order to 
detect when the cell bag 58a has been fully emptied and to automatically 
stop the counter-clockwise movement of the blood pump 24 at such point. 
The actual number of revolutions made by the blood pump 24 during each 
reinfusion of cell concentrate is counted 128 and stored in computer 65a. 
If a subsequent collection cycle is to be completed, (i.e. if the volume 
of plasma collected thus far has not reached P.sub.max), then the weighing 
device 64a will determine and store 134 a "post-reinfusion weight". The 
"post-reinfusion weight" is the combined weight of a) the plasma container 
plus all plasma contained therein, and b) the empty cell bag. 
After the "post-reinfusion weight" has been stored 134 in the computer 65a, 
the computer 65a will proceed to calculate the "weight of cells reinfused" 
136. The "weight of cells reinfused" is determined on the basis of the 
following formula: 
Equation No. 4 
EQU Wt. of Cell Concentrate Reinfused(g)=(Post-Coll.Wt.(g)-Post-Reinf.Wt.(g)) 
Additionally, the computer will calculate the "weight f actual plasma 
collected" 138 as of the end of the just-ended collection cycle. The 
"weight of actual plasma collected" , "wt. of blood pumped during 
collection" and the wt. of cell concentrate pumped during collection" are 
then calculated by the following equations nos. 5, 6, and 7: 
Equation No. 5 
##EQU2## 
Equation No. 6 
##EQU3## 
Equation No. 7 
##EQU4## 
The computer 65a will also calculate new collection flow constants for the 
blood pump 24a and cell pump 44a. Also, the computer 65a will 
automatically, on the basis of such new flow constants, reset the desired 
number of rotations for the blood pump and cell pump for the next 
collection cycle. Such resetting of the desired pump rotations prior to 
each collection cycle serves to ensure that during the next collection 
cycle, there will be accurate control of the volumes of fluids pumped by 
the blood pump 24a and cell pump 44a. 
The calculation of the collection flow constants for the blood pump and 
cell pump are based on the following equations nos. 8 and 9: 
Equation No. 8 
##EQU5## 
Equation No. 9 
##EQU6## 
The weight of cells reinfused will subsequently be utilized in the 
calculation of a revised reinfusion flow constant for the blood pump 24a 
by application of Equation 1 and the newly calculated reinfusion flow 
constant for such pump will be reset in the computer for subsequent 
reinfusion cycles. 
The calculation of the reinfusion flow constant for the blood pump is based 
on the following formula: 
Equation No. 10 
##EQU7## 
After the new flow constants have been calculated and stored in computer 
65a, and, the desired numbers of rotations of the cell pumps 44a has been 
adjusted (steps 140 and 142), a new collection cycle is begun. Steps 
105-142 are repeated until such time as the computer 65a determines, 
during step 116 (i.e. monitoring of P.sub.pre versus P.sub.max) that, the 
P.sub.pre is equal to P.sub.max. When it is determined that P.sub.pre 
equals P.sub.max, the collection is automatically terminated by the 
computer 65a, and the final reinfusion step is carried out. 
After the final reinfusion step has been completed, the actual total amount 
of plasma collected will be determined by the weighing device 65a. Such 
Total Plasma Collected (Actual) will be stored by the computer 65a. The 
Total Plasma Collected (Actual) is determined by the following formula: 
Equation No. 11 
EQU Total Plasma Collected (Actual) (g)=(Post-Reinfusion Wt. (g)-DRY TARE (g)) 
iii. A Specific Plasmapheresis Machine Embodiment of The Present Invention 
In accordance with the general system and method described above, the 
following detailed description of a specific plasmapheresis machine 
embodiment of the present invention is provided. 
A blood line 180, 180a is fluidly connected to a venipuncture needle which 
resides within a peripheral vein of a human donor (not shown). The 
proximal end of the blood line 180, 180a bifurcates into a left venous 
pressure transducer line 182, 182a and a right blood pump tube 184, 184a. 
The left venous pressure transducer line is connected to a venous pressure 
transducer located within the housing 200 so as to provide to the computer 
(not shown) continual or discrete monitoring of the positive or negative 
pressure within the blood line 180, 180a. The blood pump tube 184 is 
operatively positioned within a peristaltic blood pump 186, 186a. The 
opposite end of blood pump line 184a is concomitantly connected, by way of 
a Y connector, to a reinfusion line 188, 188a and a first separator feed 
line 190, 190a bifurcates into a second separator feed line 192, 192a and 
a transmembrane pressure transducer line 194, 194a. The transmembrane 
pressure transducer line 194, 194a is connected to a transmembrane 
pressure transducer (not shown) which, in turn, is connected to the system 
computer (not shown) such that the computer may continuously or discretely 
monitor the junction of the first separator feed line 190, 190a and the 
second separator feed line 192, 192a. 
A presently preferred, automated plasmapheresis machine of the present 
invention is shown in FIGS. 7-7f. FIG. 6 shows a similar machine of the 
prior art, which does not incorporate the method or device of the present 
invention. 
Referring to FIGS. 6 and 7, the prior art machine (FIG. 6) and the machine 
of the present invention (FIG. 7) share certain common components. Both of 
these machines comprise a housing 200, 200a wherein a central computer, 
wiring, electrical connections and other general components of the device 
(all not shown) are mounted. On the frontal surface of the housing 200, 
200a, there is provided a system of tubes, pumps, reservoirs and 
components for effecting the desired a) withdrawal, b) separation, and c) 
reinfusion of blood and/or blood components. Generally, a saline line 202, 
202a leads from an attendant bag or container of physiological 0.9% saline 
solution and an anticoagulant line 204, 204a leads from an attendant bag 
or container of anticoagulant solution. The saline line 202, 202a passes 
through a power actuated clamp 206, 206a and is connected to a Y adaptor 
208, 208a. The opposite side of the Y adaptor 208, 208a is concomitantly 
connected to the inlet port 210, 210a of a blood separation device 212, 
212a. The blood separation device may consist of any type of device 
capable of effectuating the desired separation of blood constituents. In a 
preferred embodiment, separation device 212, 212a comprises a disposable, 
rotational plasma separator having an internal rotatable membrane which is 
driven rotationally by an external magnetic motor drive (not shown). Such 
rotation of the inner membrane causes blood plasma to separate from the 
cell concentrate (a combination of red blood cells, blood white cells, 
platelets and a small amount of plasma). The cell concentrate flows out of 
the separation device 212, 212a through cell concentrate outlet port 214, 
214a. The plasma flows out of the separation device 212, 212a through 
plasma outlet port 216, 216a. 
A concentrated cell line 220, 220a is connected to the cell concentrate 
outlet port 214, 214a of the blood separation device 212, 212a. The 
concentrated cell line 220, 220a is mounted within a peristaltic cell pump 
222, 222a. the peristaltic cell pump 222, 222a may be substantially 
identical to the previously described blood pump 186, 186a, or may 
comprise any other type of pump capable of effecting the desired movement 
of cell concentrate through concentrated cell line 220, 220a. 
In the prior art device (FIG. 6), the concentrated cell line 220 carries 
cell concentrate from the blood separation device 212, through cell pump 
222 and into the inlet port 224 of a rigid cell collection reservoir 226 
having a capacity of approximately 300 milliliters. Such 300 ml capacity 
allows adequate extra space in the cell bag 237 when a usual collection 
amount limit of 180 ml of cell concentrate is observed. A cell concentrate 
outlet 228 is located at the bottom of the cell concentrate reservoir 226. 
The cell concentrate reinfusion line 188 is connected to the cell 
concentrate outlet 228 of the cell concentrate reservoir 226 so as to 
permit reinfusion of the cell concentrate into the human donor when the 
clamp 189 is open, clamp 191 is closed and the blood pump 186 is operated 
in its "reinfusion" direction (counter-clockwise). Also on the device of 
the prior invention (FIG. 6) a plasma line 230 extends downwardly from the 
plasma outlet port 216 of the blood separation device 212, passing through 
plasma clamp 232 and leading directly into the top of plasma collection 
vessel 234. 
In contrast, the device of the present invention (FIG. 7) is configured so 
as to eliminate the need for a rigid cell reservoir and to collect the 
cell concentrate in a low cost flexible cell bag 236 which hangs from the 
same weighing device 235a as the plasma collection vessel 234a. Also, in 
the device of the present invention (FIG. 7) the concentrated cell line 
220a is connected to one of the inlet/outlet ports of a blood 
filter/bubble trap 240. The blood filter/bubble trap 240 contains a screen 
or quantity of fibrous filtration material so as to trap bubbles, foreign 
objects, emboli, etc. (A specific preferred embodiment of the blood 
filter/bubble trap 240 is shown in FIGS. 8a through 8d and will be more 
fully described hereinafter.) 
Also fluidly connected to the blood filter/bubble trap 240, opposite the 
inlet of the concentrated cell line 220a is a lower cell line extension 
242. Such lower cell line extension 242 fluidly connects the blood 
filter/bubble trap 240 to the inlet/outlet port 244 positioned at the 
bottom of the cell collection bag 237. 
A preferred mode of operation of the device shown in FIG. 7 is illustrated 
in FIGS. 7a through 7f. Specifically, FIG. 7a shows a preferred 
plasmapheresis machine of the present invention during the initial priming 
of the system. Such priming of the system is effecting by closing clamp 
191a, opening clamp 189a and operating blood pump 186a in its "collection" 
direction (clockwise) while anticoagulant pump 205a operates relatively 
slowly in its operative direction (clockwise). The combination of such 
will result in withdrawal of whole blood (containing a small amount of 
anticoagulant) through the blood line 180a, blood pump line 184a, opening 
clamp 189a, through blood filter/bubble trap 240, down the lower cell line 
242 and into the very bottom of the cell bag 237. This initial priming 
step is illustrated by the darkened and shaded areas shown in FIG. 7a. 
Generally, it is predetermined, based on the calculated dead space of the 
tubing and components, that approximately 32 ml of whole blood must be 
pumped by the blood pump in order to effect this initial priming step and 
to bring whole blood through to the bottom of the cell bag 237. Thus, the 
computer (not shown) signals the blood pump 186a to rotate in a clockwise 
direction. The blood pump 186a stops after a mass of 12 grams is detected 
on the weighing device 235a, as generally provides for initial priming of 
the lower portion of the system as shown in FIG. 7a. 
After the initial priming step has been completed, the device moves on to a 
secondary priming step known as the "filter prime". The "filter prime" 
step is illustrated by the darkened and shaded areas in FIG. 7b. During 
the filter prime step, the clamp 191a is opened, clamp 189a is allowed to 
remain open, and the blood pump 186a is operated in its "collection" 
direction (clockwise) for a sufficient number of rotations to pass whole 
blood upwardly through line 192a and to generally fill the concentrated 
cell line 220a, and the remainder of blood filter/bubble trap 240. This 
will also result in the flow of some additional whole blood into the lower 
concentrated cell line 242 and the entry of a slight additional amount of 
blood into the bottom of the cell bag 237. Based on the initial, 
empirically determined or otherwise chosen pump flow constants, the blood 
pump 186a and the cell pump 222a are commanded by the computer (not shown) 
to pump sufficient amounts of blood to fill the tubes, blood separator and 
blood filter/bubble trap, as shown in FIG. 7b. The computer (not shown) 
permits the blood pump 186a to undergo a preset number of revolutions 
determined to deliver that desired volume of blood and thereby effecting 
the desired filter prime without aspirating more than the necessary amount 
of blood from the patient. 
After the "filter prime" step has been completed, the "PRIMED TARE" step 
112 as illustrated in FIG. 9d, is carried out. Thereafter, the initial 
collection cycle 114 is begun. 
The collection step, as applied to the presently preferred device, is 
illustrated in FIG. 7c. During collection, the anticoagulant pump 205a, 
blood pump 186a and cell pump 222a are all operative in their "collection" 
directions. Valve 191a is opened and valve 189a is closed. Whole blood, 
along with a small amount of anticoagulant solution, is drawn by blood 
pump 186a, through the attendant tubing, into the blood separation device 
212a. 
Plasma clamp 232a is opened and cell pump 222a operates to withdraw cell 
concentrate 220a from the blood separation device 212a. The cell 
concentrate passes through blood filter/bubble trap 240, down the lower 
cell concentrate line 242 and is collected in the cell bag 237. It will be 
appreciated that, while the collection process is continuing, the computer 
may continually monitor the plasma predicted (P.sub.pre) versus plasma 
maximum (P.sub.max) in accordance with step 116 of the inventive method 
(FIG. 3a). If, at any point, the P.sub.pre becomes equal to P.sub.max, the 
computer will immediately stop the blood pump 186a, anticoagulant pump 
205a, and cell pump 222a, thereby terminating the collection at P.sub.max. 
The device will, upon detection of P.sub.pre equals P.sub.max, move into 
reinfusion mode in accordance with step 124 of the inventive method (FIG. 
3a). However, if P.sub.pre does not become equal to P.sub.max during the 
collection cycle, that collection cycle will be permitted to continue to 
full completion (e.g. collection of 180 milliliters of cell concentrate) 
where the cell pump 222a has undergone its preset number of rotations 
based on the precalculation of necessary rotations to obtain the desired 
amount (e.g. approximately 180 milliliters) of cell concentrate in the 
cell bag 237. When the cell pump 222a has undergone its preset number of 
rotations, the computer will stop the movement of all pumps 184a, 205a, 
222a, thereby ending that collection cycle. Of course, during the 
collection, the computer will continually monitor the instant predicted 
plasma volume (P.sub.pre) and will continuously or periodically compare 
P.sub.pre to the maximum allowable plasma volume, in accordance with step 
118 of the inventive method (FIG. 3a). 
The end of the collection cycle is illustrated in 
FIG. 7d. 
Prior to beginning reinfusion, the weighing device 235a will measure the 
"post-collection weight" and such value will be stored in the computer. 
Thereafter, the device will begin reinfusion of the cell concentrate into 
the donor. 
Reinfusion of the cell concentrate is effected by blood pump 186a in its 
"reinfusion" direction (counter-clockwise) until the entire amount of cell 
concentrate contained in the cell bag 237 has been reinfused into the 
human donor. In a preferred embodiment, the computer will monitor the flow 
of cell concentrate through the device in order to determine when the 
dynamics of reinfusion flow indicate that the entire volume of red cell 
concentrate (approximately 180 ml) has been reinfused. This may be 
achieved by continually monitoring the rate at which the weight on 
weighing device 235a changes with respect to blood pump flow rate and 
determining from the detected change in weight on weighing device 235a, 
when the cell bag 237 has been emptied by applying the function, such as: 
##EQU8## 
wherein: " past weight" is the weight which was on the weighing device at 
the time when the expected ml. of pump flow was 4 ml. less that the 
present expected ml. of pump flow. 
Additionally, during both collection and reinfusion, the computer will 
continually verify the functioning of the pumps by applying a function 
such as the above-set-forth function, and, if at any point, the magnitude 
of difference between current wt. and past wt. exceeds the allowable 
range, the device will shut down and the operator will be signaled to 
check for possible malfunctions (e.g. leaks in the system). Detecting an 
empty cell bag can be distinguished from a system malfunction based upon a 
predicted expected time occurance of the emptying. 
During the reinfusion, the computer will count store the number of 
rotations undergone by blood pump 186a in its "reinfusion" direction. This 
number will be subsequently utilized in recalculating and adjusting the 
reinfusion pump (i.e. reverse direction) flow constant of the blood pump 
186a, in accordance with the method of this invention. 
At the end of reinfusion, the cell bag 237 will be completely empty as 
shown in FIG. 7f. At that point, the weighing device 235a will obtain the 
post-reinfusion weight in accordance with step 134 of the method (FIG. 
3b). 
Thereafter, the computer will calculate the a) weight of cell concentrate 
reinfused (step 136), b) weight of actual plasma collected (step 138), c) 
collection flow constants for the blood pump and cell pump (step 140), and 
d) a reinfusion flow constant for the blood pump (step 142). The desired 
number of cell pump rotations for the next collection cycle will be 
recalculated by the computer on the basis of the newly calculated flow 
constants and, the preset number of cell pump rotations will be 
accordingly reset for the next collection/reinfusion cycle. 
The blood filter/bubble trap 240 of the device may consist of any type of 
outer housing or shell having positioned therein one or more materials 
operative to effect filtration of the blood and/or trapping of bubbles as 
the blood passes through the blood filter/bubble trap 240. 
iii. A Preferred Blood Filter/Bubble Trap Usable in the Device of the 
Present Invention 
One presently preferred type of blood filter/bubble trap is shown 
separately in FIG. 8. This preferred blood filter/bubble trap 300 
comprises an outer plastic shell 302 of generally cylindrical 
configuration. The shell is compressed to a flat, closed configuration at 
its top end 304 and bottom end 306. A filtration bag formed of a material 
approved for use in blood pathway and blood processing, (e.g. certain 
fabrics, filtration media or fine mesh materials, such as a nylon mesh) is 
positioned inside the shell 302. The opening size or mesh size of the mesh 
material or fabric or filtration material is preferably about 220 microns. 
Second 312 and third 314 inlet tubes pass through the closed bottom end 
306 of the shell 302. A stand pipe 316 is fluidly connected to the third 
input tube 314 and extends upwardly therefrom with the confines of the 
shell 302. 
In its preferred embodiment, the filter 300 is approximately 12 centimeters 
in length from the top edge 304 of the shell to the bottom edge 306. The 
stand pipe 316 is approximately 2 centimeters in length. 
In normal operation, the preferred blood filter/bubble trap device shown in 
FIG. 8 is mounted in the device of the present invention (FIG. 7) such 
that the cell concentrate line 220 is connected to the first inlet tube 
308, the reinfusion line 188 is connected to the second inlet tube 312 and 
the lower cell concentrate line is connected to the third inlet tube 314. 
When so mounted in the device of the present invention, the filter bag 310 
will operate to strain or filter cell concentrate flowing into the blood 
filter/bubble trap 300 from the blood separation device 212a. 
Additionally, the presence of the stand pipe 316 within the blood 
filter/bubble trap 300 will insure that a quantity of blood or cell 
concentrate pools in the bottom of the inner chamber of the blood 
filter/bubble trap 300 before such blood or cell concentrate begins to 
flow down the lower cell concentrate line 242. The opening of the second 
inlet tube 312 which is connected to the reinfusion line 188a is generally 
flush with the inner floor or bottom of the interior of the shell 302. 
Thus, the opening into the second inlet tube 312 will routinely be 
maintained below an approximate 2 centimeter head of blood or cell 
concentrate. By this arrangement, cell concentrate flowing through the 
filter bag 310 will fall into the bottom of the chamber and will rise to 
the level of the top of the stand pipe 316 before flowing down the lower 
cell concentrate line 242. This will help to prevent turbulent cell 
concentrate containing aberrant bubbles from entering the lower cell 
concentrate line 242. Such pooling of the cell concentrate in the lower 2 
centimeters of the blood filter/bubble trap 240 will allow the cell 
concentrate an opportunity to degas before beginning to flow down the 
lower cell concentrate line 242. Such will help to prevent the 
introduction of air or bubbles into the cell bag 237. 
The foregoing detailed description has discussed only several illustrative 
embodiments or examples of the present invention. Those skilled in the art 
will recognize that numerous other embodiments, or additions, 
modifications, deletions and variations of the described embodiment, may 
be made without eliminating the novel and unobvious features and 
advantages of the present invention. It is intended that all such other 
embodiments, modifications, deletions and variations be included within 
the scope of the following claims.