Method and apparatus for controlling concentrations in tubing system
FIELD OF THE INVENTION 
     This invention relates to the field of fluid tubing systems and, in particular, relates to monitoring and controlling the flow rate and concentration of one or more constituents in a tubing system. The invention has particular application in controlling flow rates and concentrations of a constituent such as anticoagulant in a blood tubing set used in blood processing such as apheresis procedures and in the donor/patient to which the tubing set is connected. 
     BACKGROUND OF THE INVENTION 
     Various apheresis procedures require the use of anticoagulants such as acid citrate dextrose (&#34;ACD&#34;) or heparin to prevent hemostasis and to permit blood processing. The rate of blood flow and, therefore, the time required to complete a procedure are related to the allowable anticoagulant level in the donor (in the case of a person donating a blood component) or in the patient (in the case of a person whose blood is being treated). If the anticoagulant level in the tubing set is too low, the blood will clot. If the anticoagulant level in the donor/patient is too high, adverse physiological reactions may occur. For example, ACD interferes with clotting by binding with ionized calcium, and excessive ACD levels can result in chills or convulsions. Heparin may cause flushing or hypotension, and its anticoagulant effects (it has a half life of about four hours) can last dangerously long after the procedure is completed. It is therefore desirable to carefully control the anticoagulant level. 
     In the past, anticoagulant levels have been controlled indirectly and imprecisely by controlling the rate of infusion of anticoagulant into the tubing set, without any direct control on the rate of infusion of anticoagulant into the donor/patient. That approach is not exact because it does not account for the anticoagulant that is removed from the tubing set by the procedure itself. The removed anticoagulant never enters the donor/patient. For example, a significant volume of anticoagulant is drawn off in the plasma collect line in plasma collection procedures and in the cell collect line in cell collection procedures. In addition, that approach does not account for anticoagulant added to the tubing set by the donor/patient due to the recirculation of unmetabolized anticoagulant from the donor/patient into the inlet line, nor does it account for anticoagulant added to the tubing set by the replacement fluid. 
     There are many prior art systems for controlling various flow rates in a tubing set, but it is believed that these systems are not applicable to the control of anticoagulant flow rates and concentrations in the manner of the present invention. For example, U.S. Pat. No. 4,582,598 by Bilstad discloses a system in which the collection rate and the replacement fluid rate are continuously monitored and adjusted by a control means that is responsive to measurement signals; U.S. Pat. Nos. 4,447,191 and 4,501,531 by Bilstad include a control circuit for adjusting the anticoagulant pump rate and for discontinuing the anticoagulant pumping in case a failsafe system detects an air bubble or other tripping event. It appears that none of these patents disclose a method for adjusting anticoagulant infusion rates to maintain a desired anticoagulant flow rate or concentration by considering the additive and subtractive effects of the tubing circuit or the recirculation of unmetabolized anticoagulant from the donor/patient. 
     U.S. Pat. No. 4,769,001 by Prince describes a system for calibrating an anticoagulant pump and a blood pump by monitoring the pressure in the line between the two pumps. Neither of these patents teaches a method for maintaining a desired anticoagulant flow rate or concentration by adjusting the anticoagulant infusion rate to account for variations caused by collection, replacement and recirculation. 
     U.S. Pat. No. 4,968,295 by Neumann discloses a blood separation apparatus in which centrifuge speeds are automatically varied in response to blood flow rates so that the volume ratios of the fractions remain constant. The apparatus includes an anticoagulant control wherein the anticoagulant infusion rate is varied as a linear function of the blood flow rate, but without considering collection, replacement or recirculation effects. 
     Other systems in which anticoagulant infusion rates may be directly or indirectly controlled include those described in U.S. Pat. Nos. 4,817,045 by Faeser; 4,923,598 by Schal; 4,655,742 by Vantard; 4,648,866 by Malbrancq; 4,573,961 by King; 4,795,314 by Prybella; 4,657,529 by Prince; and 4,995,268 by Ash. As in the other art described more particularly above, none of these teaches a method for varying the anticoagulant infusion rate to account for collection, replacement and withdrawal effects. 
     Anticoagulant levels can be expressed in several ways, including concentration, volume and flow rate. For purposes of this patent, &#34;concentration&#34; of anticoagulant refers to the volume fraction of anticoagulant in a fluid. &#34;Flow rate&#34; refers to the volume of flowing fluid per unit of time. As explained below, the important anticoagulant levels are typically the concentration of anticoagulant in the donor/patient and the flow rate and concentration of anticoagulant in the inlet line and the return line to the donor/patient. It will be apparent to those skilled in the art that these levels are related to one another and can be expressed in other terms (for example, the flow rate of anticoagulant in the return line can be expressed as the flow rate of fluid in the return line times the anticoagulant concentration in the return line). Unless otherwise specified, the term &#34;level&#34; in the claims will refer to any of, and any combination of, flow rate, concentration and volume. It will also be apparent to those skilled in the art that although it is convenient to express fluid quantities in terms of volume, the invention also includes quantities expressed in terms of weight by making appropriate adjustments to account for the specific gravities of the fluids. 
     SUMMARY OF THE INVENTION 
     The present invention includes an apparatus and method for maintaining a desired anticoagulant level in an apheresis tubing set and, particularly, in the inlet line and return line and in the donor/patient to which the return line is connected. The invention includes a method for determining the anticoagulant removed by various collect lines and the effect of the anticoagulant added by replacement fluid in the return line. By considering these effects, several important procedure-dependent variables can be determined and controlled, including the anticoagulant flow rate. Once the desired variables are determined, the anticoagulant infusion rate into the tubing set can be adjusted accordingly by a suitable controller such as a microprocessor-based controller coupled with a precision peristaltic pump. 
     Another embodiment of the invention considers the effect of unmetabolized anticoagulant recirculating from the donor/patient into the inlet line. The flow rate of unmetabolized anticoagulant in the inlet line can be determined in a process which takes into consideration the anticoagulant flow rate in the return line, the patient blood volume, the anticoagulant half-life, and the time of the procedure. This embodiment lends further precision to the process for determining anticoagulant levels because it accounts for anticoagulant build-up in the system, and it also aids in determining the total anticoagulant volume and concentration in the donor/patient. 
     The invention also has application outside the field of apheresis. It can be used in any other field in which a constituent is added to a flow stream having one or more divertive or additive flow streams, especially if the constituent is a material with a predictable decay rate. 
     In particular, the invention includes a method and apparatus for determining the anticoagulant level in a fluid tubing set used for processing blood from a donor/patient, and the anticoagulant level in the donor/patient, by determining the amount of anticoagulant added to the tubing set, determining the amount of anticoagulant removed from the tubing set, and subtracting the amount removed from the amount added. Further, the invention includes a method and apparatus for processing a body fluid with a tubing set having an inlet on the upstream end in communication with the body, an outlet on the downstream end in communication with the body, a constituent inlet between the tubing set inlet and outlet for adding constituent such as anticoagulant, and a fraction outlet for removing a fluid fraction between the constituent inlet and tubing outlet, by determining the flow rate of constituent in the tubing set between the constituent inlet and the fraction outlet and the flow rate of constituent through the fraction outlet, and determining the flow rate of constituent between the fraction outlet and the tubing set outlet by subtracting the flow rate through the fraction outlet from the flow rate between the constituent inlet and the fraction outlet. The flow rate of constituent into and out of the tubing set can be adjusted accordingly to maintain the constituent at a desired level. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     FIG. 1 shows the flow path for a hypothetical apheresis procedure where the invention is applicable. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The flow paths for a hypothetical blood apheresis procedure is shown in FIG. 1. The flow paths shown in FIG. 1 are not intended to depict any actual apheresis procedure, but instead are intended to present the flow paths for a variety of possible procedures. As explained below, actual procedures will generally not include all of the flow paths shown in FIG. 1. 
     Whole blood is removed from a donor/patient into an inlet line 12. An anticoagulant such as acid citrate dextrose (&#34;ACD&#34;) or heparin is pumped from an anticoagulant reservoir 14 by an anticoagulant pump 16 through an anticoagulant line 18 in fluid communication with the inlet line 12. The whole blood with added anticoagulant is pumped by an inlet pump 24 to a centrifuge 26. The centrifuge 26 may be of the continuous flow type such as the centrifuge used with the SPECTRA brand apheresis system by COBE BCT, Inc. 
     The centrifuge 26 can fraction the whole blood into a variety of blood components such as plasma, platelets, white blood cells and red blood cells. The plasma may be drawn off by a plasma pump 28 to a plasma collect line 30 and into a plasma collect bag 32. Cells may be drawn off by a cell pump 29 to a cell collect line 33 and into a cell collect bag 35. A return line 34 returns to the donor/patient any components that are not collected. In fluid communication with the return line 34 is a replacement fluid line 38. A replacement fluid pump 40 pumps replacement fluid from a replacement fluid reservoir 42 into the replacement fluid line 38. The outlet end of the return line 34 enters the donor/patient. The flow through the various pumps can be monitored and controlled using a microprocessor based controller 80. 
     The flow through the system can be expressed as a generalized equation: 
     
         Q.sub.RP =Q.sub.P+ Q.sub.A +Q.sub.RF -Q.sub.C -Q.sub.PC 
    
     where: 
     Q RP  =plasma flow rate in the return line 
     Q P  =plasma flow rate in the inlet line 
     Q A  =anticoagulant flow rate through the anticoagulant line 
     Q RF  =replacement fluid flow rate 
     Q C  =cell collect flow rate 
     Q PC  =plasma collect flow rate 
     This equation can be expressed in terms of anticoagulant flow rates by multiplying each flow term by its respective anticoagulant concentration variable, with the assumption that the anticoagulant concentration in the anticoagulant line is one. The anticoagulant flow in the cell collect and plasma collect lines is equal to the total flow in those lines multiplied times the anticoagulant concentration in the flow entering the centrifuge (which is the sum of the plasma flow in the inlet line Q P  and the anticoagulant flow Q A ) so that: ##EQU1## where: C RP  =anticoagulant concentration in return line plasma 
     C DP  =anticoagulant concentration in donor/patient plasma 
     C RF  =anticoagulant concentration in replacement fluid 
     This can be converted to blood-based variables so that: 
     
         Q.sub.IN =(Q.sub.AR +A[Q.sub.PC +(1-H.sub.C)Q.sub.C ])/B 
    
     where: 
     Q IN  =total inlet flow rate (combined blood and anticoagulant) 
     Q AR  =specified anticoagulant flow rate through the return line 
     H C  =hematocrit in cell collection line 
     A=[C DB  (R-1)+1]/[R(1-H)+H]-C RF  F 
     B=C DB  (1-1/R)+(1-C RF )/R 
     where: 
     C DB  =anticoagulant concentration in donor/patient blood 
     R=ratio of total inlet flow rate Q IN  to anticoagulant flow rate Q A   
     H=donor/patient hematocrit 
     F=ratio of fluid volume added to fluid volume removed in procedure 
     These values can be calculated in real time to iteratively determine the desired variables whenever the parameters are changed. 
     It is noted that one of the variables in the equations set forth above is the anticoagulant concentration in the donor/patient blood C DB . For procedures that last a short time and involve small volumes of blood there will be very little build-up of unmetabolized anticoagulant in the donor/patient, and this value can be taken as zero. For procedures that last a longer time and involve larger volumes, this value may be determined, preferably on a real-time basis. The rate of change of the volume of anticoagulant in the donor is: ##EQU2## where: V AD  =volume of anticoagulant in donor blood 
     V P  =volume of plasma in donor blood 
     The term K is the anticoagulant metabolic decay constant which is related to the decay half life: 
     
         K=ln2/t.sub.1/2 
    
     where: 
     t 1/2  =anticoagulant half life 
     Substituting the anticoagulant flow equation previously set forth into the above equation for the rate of change of the volume of anticoagulant in the donor/patient: ##EQU3## where: a=(1/V p )[Q A  (1-(Q C  +Q PC )/(Q P  +Q A ))+C RF  Q RF  ] 
     b=(Q P  /V P )[(Q C  +Q PC )/(Q P  +Q A )]+K 
     If this equation expressing the rate of change of the concentration of anticoagulant as a function of time is integrated over time, then: 
     
         C.sub.DB =M.sub.t (1-e.sup.-N.sbsp.t) 
    
     where ##EQU4## N t  =(V BP  /V B )[(V C  +V PC )((1-H)V BP  +V A )]+Kt V C  =volume of cells collected 
     V PC  =volume of plasma collected 
     H=hematocrit of donor/patient 
     V BP  =volume of blood processed 
     V A  =volume of anticoagulant pumped 
     V B  =volume of donor/patient&#39;s blood 
     t=time 
     V RF  =volume of replacement fluid added to the tubing set 
     As mentioned above, this set of equations and the schematic diagram of FIG. 1 which corresponds to the equations do not necessarily portray any real procedure, but are only presented as a generalized hypothetical procedure. In most real procedures, one or more of the variables of the equations will be zero because there will be no flow in one or more of the flow channels shown in the FIGURE. For example, in therapeutic plasma exchange, it can be appreciated that cells are not normally collected. Therefore, the variables for the volume of cells collected V C  and the cell collect flow rate Q C  will be zero. 
     Similarly, in cell collection procedures such as platelet collection, white blood cell collection and red blood cell collection, the collected plasma is returned to the donor/patient. Therefore, the variables for volume of plasma collected V PC  and collected plasma flow rate Q PC  will be zero. Also, for these procedures there may or may not be any replacement fluid added. If no replacement fluid is added, then the volume of replacement fluid V RF  and the replacement fluid flow rate Q RF  become zero. 
     It can be appreciated that other flow configurations may result in other variables becoming zero, thereby simplifying the determinations in other ways. Similarly, other flow configurations may result in the addition of other variables if other collect procedures are used or if other replacement fluids are added. 
     These variables can be monitored and calculated continuously by a microprocessor associated with the controller 80. The controller 80 can then adjust the pump rates to maintain desired parameters. For example, it is typically desired that the anticoagulant level in the centrifuge be kept at a high level to permit large flow rates but not so high that anticoagulant levels in the return line or in the donor/patient become uncomfortably high. These opposing goals can be met by determining and controlling the anticoagulant levels in the return line or in the donor/patient by adjusting the flow rate of anticoagulant from the anticoagulant reservoir and the flow rate of inlet blood. Other parameters can be similarly monitored and controlled to maintain optimum operating efficiency while ensuring the safety of the donor/patient. 
     The description herein contemplates numerical calculations of anticoagulant levels for the purpose of monitoring or adjusting (or both) the anticoagulant levels. It will be apparent that actual numerical calculations may not be necessary to utilize the invention. Instead, for example, the invention may be used to make relative adjustments to various flow rates depending on various other flow rates and parameters so that anticoagulant levels are optimally established even though they are never actually quantified. Such procedures are intended to be within the scope of the claims.