METHOD AND APPARATUS FOR CONTROLLING ANTICOAGULATION DURING EXTRACORPOREAL BLOOD TREATMENT

Abstract

A method and device for controlling anticoagulation during blood treatment. The method includes conveying blood in a first line section, supplying biologically and/or pharmacologically active substances of negative total charge to the blood, separating the blood into corpuscular blood components and blood plasma, conveying the blood plasma in a second line section via an anion exchanger, bringing the blood plasma and corpuscular blood components together in a third line section, determining a first flow rate of blood plasma in the first line section, determining a second flow rate of blood plasma in the second line section, setting a quantity of biologically and/or pharmacologically active substances based on a ratio of the first and second flow rates such that, after the blood plasma and corpuscular blood components are brought together, a concentration of the biologically and/or pharmacologically active substances in the third line section meets a target value.

Claims

1. A method for controlling anticoagulation during extracorporeal blood treatment on an apparatus for extracorporeal blood treatment, said method comprising the steps of: conveying blood in a first line section; supplying at least one biologically and/or pharmacologically active substance of negative total charge to the blood; separating the blood into corpuscular blood components and blood plasma; conveying the blood plasma in a second line section via an anion exchanger for adsorption of lipopolysaccharides; bringing the blood plasma and the corpuscular blood components together in a third line section; determining a first volumetric flow rate of the blood plasma in the first line section before supplying the at least one biologically and/or pharmacologically active substance of negative total charge to the blood; determining a second volumetric flow rate of the blood plasma in the second line section upstream or downstream of the anion exchanger; and setting a quantity of the at least one biologically and/or pharmacologically active substance of negative total charge based on a ratio of the first volumetric flow rate and the second volumetric flow rate, in such a way that, after the blood plasma and the corpuscular blood components are brought together, a concentration of the at least one biologically and/or pharmacologically active substance of negative total charge in the third line section meets a predetermined target value.

2. The method according to claim 1, further comprising the steps of: determining an actual value of the concentration of the at least one biologically and/or pharmacologically active substance of negative total charge in the third line section; and controlling the concentration of the at least one biologically and/or pharmacologically active substance of negative total charge in the third line section based on the actual value, the ratio of the first volumetric flow rate and the second volumetric flow rate, and the quantity of the at least one biologically and/or pharmacologically active substance of negative total charge.

3. The method according to claim 1, further comprising the steps of: determining a hematocrit value of the blood in the first line section; determining a volumetric flow rate of the blood in the first line section; and determining the volumetric flow rate of the blood plasma fraction in the first line section on the basis of the determined volumetric flow rate of the blood in the first line section and the determined hematocrit value.

4. The method according to claim 1, further comprising the step of: setting the second volumetric flow rate of the blood plasma flowing through the anion exchanger.

5. The method according to claim 1, further comprising the step of: additionally supplying medicines and/or blood-inherent substances, which are adsorbed by the anion exchanger, into the third line section.

6. An anticoagulation control device for application during extracorporeal blood treatment, said anticoagulation control device comprising: a blood pump for conveying blood in a first line section; a pump for supplying at least one biologically and/or pharmacologically active substance of negative total charge to the blood in the first line section; a plasma separator for separating blood added with the at least one biologically and/or pharmacologically active substance of negative total charge into corpuscular blood components and blood plasma; a plasma pump, for conveying the blood plasma in a second line section via an anion exchanger for adsorption of lipopolysaccharides; a means for bringing the blood plasma and the corpuscular blood components together in a third line section; a means for determining a first volumetric flow rate of blood plasma in the first line section before the supplying of the at least one biologically and/or pharmacologically active substance of negative total charge; and a means for determining a second volumetric flow rate of blood plasma in the second line section upstream or downstream of the anion exchanger; wherein a control unit which is adapted to control a quantity of the at least one biologically and/or pharmacologically active substance of negative total charge, which is supplied to the blood before the separating, based on a ratio of the first volumetric flow rate and the second volumetric flow rate, in such a way that, after the blood plasma and the corpuscular blood components are brought together, a concentration of the at least one biologically and/or pharmacologically active substance of negative total charge in the third line section meets a predetermined target value.

7. The anticoagulation control device according to claim 6, wherein: a means for determining an actual value of the concentration of the at least one biologically and/or pharmacologically active substance of negative total charge in the third line section; and a means for controlling the concentration of the at least one biologically and/or pharmacologically active substance of negative total charge in the third line section on the basis of the determined actual value, the ratio of the first volumetric flow rate and the second volumetric flow rate, and the supplied quantity of the at least one biologically and/or pharmacologically active substance of negative total charge in the first line section.

8. The anticoagulation control device according to claim 6, further comprising: a means for inputting a hematocrit value of the blood in the first line section; and a means for determining a volumetric flow rate of the blood plasma in the first line section based on a conveying rate of the blood pump and the hematocrit value.

9. The anticoagulation control device according to claim 6, further comprising: a means for determining a hematocrit value of the blood in the first line section; a means for determining a volumetric flow rate of the blood in the first line section; and a means for determining the volumetric flow rate of the blood plasma in the first line section based on the volumetric flow rate of the blood in the first line section and the hematocrit value.

10. The anticoagulation control device according to claim 6, further comprising: a means for setting the second volumetric flow rate of blood plasma.

11. The anticoagulation control device according to claim 6, further comprising: a means for additionally supplying medicines and/or blood-inherent substances, which are adsorbed by the anion exchanger, into the third line section.

12. The anticoagulation control device according to claim 6, wherein the blood pump is arranged in the first line section upstream of the pump and of the plasma separator.

13. The anticoagulation control device according to claim 6, wherein the plasma pump is arranged in the second line section downstream of the plasma separator, but upstream of the anion exchanger.

14. The anticoagulation control device according to claim 6, wherein the anion exchanger has a surface modified with diethylaminoethyl cellulose.

15. The anticoagulation control device according to claim 6, wherein the predetermined target value is constant.

16. The method according to claim 1, wherein the predetermined target value is constant.

Description

BRIEF DESCRIPTION OF THE DRAWING FIGURES

[0038] The present disclosure will be described in more detail in the following by means of a preferred embodiment and under reference to the attached drawings, wherein:

[0039] FIG. 1 shows a representation for the illustration of a system structure according to the present disclosure;

[0040] FIG. 2 shows a diagram for the illustration of the decrease of the heparin concentration in blood during a simulated treatment without the substitution of heparin; and

[0041] FIG. 3 shows a diagram for the illustration of the heparin concentration in the blood during a simulated treatment with a substitution of heparin according to the present disclosure.

DETAILED DESCRIPTION

[0042] In the following there will be described the embodiment of the present disclosure on the basis of the corresponding figures. Identical or functionally equivalent features are provided with the same reference numerals in the individual figures.

[0043] FIG. 1 shows a system structure of an anticoagulation control device 2 for the simulation of a method for an extracorporeal blood treatment. For the adequate implementation of the method, the anticoagulation control device 2 comprises a first line section 4 via which blood which shall be treated, in particular of a patient 22 undergoing the blood treatment, is drawn in by means of a, for example peristaltic, blood pump 6. Downstream of the blood pump 6 heparin will be supplied to the blood located in the first line section 4 by means of a pump 8, in particular a heparin pump 8, in order to guarantee that the blood will not coagulate. The blood added with heparin will finally be conveyed to a plasma separator 10 in which the blood will be separated into its corpuscular components, i.e. cellular components like erythrocytes or leucocytes, on the one hand and into blood plasma on the other hand. Thereby, the blood plasma contains ions and proteins, for example for blood coagulation. While the corpuscular components of the blood together with a fraction of the blood plasma will stay in the plasma separator 10, another fraction of the blood plasma will be sucked in via a vacuum produced by means of a plasma pump 12 into a second line section 14 and will be conveyed therein via an anion exchanger (16).

[0044] By the flowing through the anion exchanger 16, proteins of negative total charge will be bound/adsorbed on the surface of the anion exchanger 16 and will be removed thereby from the blood plasma. Thereby, a coating of the surface of the anion exchanger 16 with DEAE adsorbs above all LPS and heparin quite effectively. Due to the functional principle of the anion exchanger 16, apart from LPS and heparin, however, also medicines and other plasma proteins of negative total charge, as for example coagulation factors, will be removed. After the flowing through the anion exchanger 16, the treated blood plasma is guided into a third line section 18 which is located downstream of the plasma separator 10 and downstream of the anion exchanger 16, wherein in said third line section 18 the treated blood plasma will again be brought together with the corpuscular components which remained in the plasma separator 10 and with the one fraction of the blood plasma which remained untreated, and finally it will be conveyed via the third line section 18 back to the patient 22.

[0045] In order that the blood brought together after the flowing through the anion exchanger 16 will not coagulate due to the adsorption of the heparin and will thereby perhaps cause a stop of the blood treatment, the anticoagulation control device 2 is furthermore provided with a control unit 20 which controls the supplying of heparin in the first line section 4 by means of the heparin pump 8 in such a way that the heparin concentration in the third line section 18, which finally shall flow to the patient 22, obtains a predetermined, preferably constant, value. To this end, the control unit 20 detects a first volumetric flow rate of the blood plasma fraction in the first line section 4 determined at the blood pump 6 and a second volumetric flow rate of the blood plasma in the second line section 14 determined at the plasma pump 12 and brings them into relation. In order to determine the second volumetric flow rate, the anticoagulation control device 2 can for example be provided with sensors which are not shown in FIG. 1, said sensors detecting the volumetric flow rate at the plasma pump 12, or the anticoagulation control device 2 can derive it via the conveying rate of the plasma pump 12. In the same manner, in parallel to heparin also further biologically and/or pharmacologically active substances of negative total charge can be supplied and controlled.

[0046] For the determination of the volumetric flow rate of the blood plasma fraction in the first line section 4, apart from the detection of the volumetric flow rate of the blood at the blood pump 6 also the hematocrit value is required. Despite the fact that the hematocrit value is patient-dependent, it does not vary strongly in the course of the extracorporeal blood treatment of a patient so that, normally, it can be assumed to be constant. As in the case of the plasma pump 12, for the determination of the volumetric flow rate of the blood the anticoagulation control device 2 can comprise sensors or it can derive it by means of the conveying rate of the blood pump 6.

[0047] Furthermore, the anticoagulation control device 2 can comprise a means, for example in the form of a user interface, for inputting the hematocrit value of the blood in the first line section 4.

[0048] Furthermore and in analogy to the state of the art, the anticoagulation control device 2 can also comprise a dialysis unit and/or an ultrafiltration unit which are arranged in the third line section 18.

[0049] FIG. 2 shows a diagram in which the decrease of the heparin concentration in the blood of a patient 22 during a simulated treatment without any substitution of heparin is illustrated. Thereby, the heparin concentration c is represented in so-called International Units per milliliter [IU/ml] as a function of the treatment time tin minutes [min]. Before the treatment, i.e. at the point of time 0, the heparin starting concentration was set to 5 to 11 IU/ml at different conveying rates of the blood pump 6 and of the plasma pump 12, which is why four measurement values per measurement time were recorded. On the basis of FIG. 2 it becomes obvious that the heparin concentration in the blood decreases in an exponential rate with the progressing treatment. This means that the heparin concentration c in the blood sinks starting from the heparin starting concentration G in dependence on the treatment time t and a distance constant k. Said relationship can be represented as follows:

Δc=k**Gf(t))Δt  (1)

[0050] If formula (1) is rearranged to the distance constant k and integrated over the treatment time t, the following relationship is obtained:

[00001]$\begin{array}{cc}\Delta c=k*\left(G-f\left(t\right)\right)\Delta t& \left(2\right)\end{array}$$\frac{\Delta c}{\Delta t}=k*\left(G-f\left(t\right)\right)$$G=0\frac{\Delta c}{\frac{\Delta t}{f\left(t\right)}}=k$$\ln .Math.f\left(t\right).Math.=-k*t+b$$f\left(t\right)-a*a^{-k*t}$$c_{\mathrm{eff}}=c_0*e^{\left(-\mathrm{VSplasma}/\mathrm{GVplasma}\right)*a}$

[0051] wherein c.sub.eff represents the effective heparin concentration at the point of time t, c.sub.0 represents the heparin staring concentration in the blood, VSplasma represents the volumetric flow rate of the blood plasma in the second line section 14 at the plasma pump 12, and GVplasma represents the entire volume of the blood plasma fraction in the first line section 4, in particular at the blood pump 6, before the supplying of heparin by the heparin pump 8. From formula (2) there results in general the relationship that, for a constancy of the heparin concentration in the third line section 18, the heparin quantity to be supplied via the heparin pump 8 has to be increased such that the partial heparin flow via the anion exchanger 16 in the second line section 14 will be compensated for, wherein said partial heparin flow correlates with the plasma flow which can be set via the plasma pump.

[0052] In the clinical practice, however, no heparin concentration will be prescribed, but a heparin infusion with a defined volumetric flow rate. According to the present disclosure, a desired heparin volumetric flow rate HEP2 in the third line section 18, which finally shall flow to the patient 22, can be set before the treatment so that by including said parameter and on the basis of formula (2) the following relationship will be obtained:

HEP2=PF/(BF*(1−HK/100))*HEP1  (3)

[0053] where PF represents the plasma flow in the second line section 14, BF represents the blood flow in the first line section 4, HK represents the predetermined hematocrit value, and HEP1 represents the heparin quantity to be supplied via the heparin pump 8, which heparin quantity will be controlled by means of the control unit 20.

[0054] As already mentioned above, the plasma flow in the second line section 14 PF can be detected by the rate of rotation of the plasma pump 12 or for example by sensors, just as the blood flow in the first line section 4 BF which results from the determined conveying rate of the blood in the first line section 4 at the blood pump 6. Rearranged after HEP 1, for formula (3) the following is obtained:

HEP1=HEP2/(1−(PF/(BF*(1−HK/100)))  (4)

[0055] In order to eventually calculate the heparin quantity to be supplied in the first line section 4 or the conveying rate of the heparin pump 8 by means of formula (4), an operator of the anticoagulation control device 2 inputs for example via the user interface HEP2, PF, BF and the determined HK of the patient 22 beforehand or also during the treatment. By means of the treatment data, the anticoagulation control device 2 can then automatically control the heparin quantity to be supplied in the first line section 4 or the conveying rate of the heparin pump 8.

[0056] In order to keep HEP2 constant even under the influence of possible interfering factors, the control unit 20 of the anticoagulation control device 2 can also be designed as a control unit. The control unit then controls HEP2 on the basis of an actual value determined in the third line section 18, the ratio of the volumetric flow rate of the blood plasma fraction in the first line section 4 before the supplying of the heparin and the volumetric flow rate of the blood plasma in the second line section 14 at the plasma pump 12.

[0057] Thus, one idea of the present disclosure is that, when from the permeate, i.e. the (partial) blood plasma volumetric flow in the second line section 14, which has been withdrawn from the plasma separator 10 by means of the plasma pump 12, the highly toxic LPS can only be extracted in the anion exchanger 16 by a simultaneous co-separation of heparin that likewise has a negative total charge, said loss quantity of heparin has to be substituted in the sense of a constant target concentration as required for example for a sepsis patient 22. Insofar as it can sometimes be a life-essential, detoxifying measure, it can be technically readily accepted that a first fraction of LPS cannot be extracted from the blood plasma without a second fraction of heparin. This also means that the anion exchanger 16 can wear out capacitively much faster as it would be the case in an ideal situation of an available separation matrix being selective specifically for the first fraction of LPS. In other words, the absolute aim of a life-saving detoxification is achieved when it is possible to use an excess of matrix of the anion exchanger 16 in a quasi <<uneconomic >> fashion.

[0058] In a further advantageous manner, the substitution via the heparin quantity supplied in the first line section by means of the heparin pump 8 serves to avoid a coagulation over all three line sections. Also in this point the present disclosure shows a further change of paradigm in that it departs from the teaching of the experts as described in the introduction to preferably not expose or only slightly expose an anion exchanger to heparin.

[0059] In contrast to FIG. 2, FIG. 3 shows a diagram for the illustration of the heparin concentration in the blood of a patient 22 during a simulated treatment with a substitution of heparin according to the present disclosure. Also in FIG. 3 the heparin concentration c is represented in so-called International Units per milliliter [IU/ml] as a function of the treatment time tin minutes [min]. In this case a heparin concentration of 1.4 IU/ml was previously set which finally shall be present in the third line section 18 and shall be supplied to the patient 22. The control unit 20 controls the heparin quantity to be supplied in the first line section 4 or the conveying rate of the heparin pump 8 in FIG. 3 on the basis of formula (4). In this way, HEP2 can be kept constant over the entire treatment duration.

[0060] Thus, the present disclosure enables the use of anion exchangers 16 and the simultaneous use of heparin in the course of an extracorporeal therapy. Thereby the material suited best for the removal of endotoxins from the blood according to Falkenhagen et al. (Int J Artif Organs 2014; 37 (3): 222-232) can be applied in an extracorporeal therapy in humans in case of a sepsis.