SK96897A3 - On-line drug delivery system in extracorporeal therapy - Google Patents

Abstract

A preferred patient blood treatment system and method for the photoactivation of reagents in contact with a patient's blood achieves a well-mixed and accurate drug concentration in extracorporeal therapy. The preferred drug delivery system of the present invention comprises specially designed components and a microprocessor control system including a syringe pump, drug mixer and a reaction chamber, whereby the microprocessor control system monitors patient blood flow and regulates the system components to deliver the desired drug concentration to the reaction chamber maximizing the effectiveness of extracorporeal therapy.

Description

On-line extracorporeal blood processing method and on-line system for extracorporeal delivery of a medicinal solution to the blood

Technical field

The invention relates to a method of on-line momotel processing from fluids, in particular blood, and to an on-line system for extracorporeal delivery of a medicinal solution to the blood. It relates to a process in which medicaments and other biological solutions, such as monoclonal antibody solutions, are to be added at exactly the specified doses, including the addition at doses determined according to further information and / or conditions found during momothelial action. In particular, it relates to the treatment of cells with photoactivatable compounds and radiation, and specifically to clinically useful systems for the extracorporeal treatment of blood cells, especially leukocytes, by UV radiation.

BACKGROUND OF THE INVENTION

It is well known that a number of human disease states can be characterized by overproduction of a certain type of leukocytes, including lymphocytes, as compared to other populations of cells normally present in the blood. Excessive or abnormal lymphocyte populations lead to a number of adverse effects on the patient, including functional damage to body organs, leukocyte autoimmune diseases and leukemic-type diseases, many of which ultimately have fatal consequences.

After achieving the best results in extracorporeal chemotherapy, it is necessary to deliver the drug molecules to the target areas in the blood at the desired concentrations. For example, in conventional extracorporeal chemotherapy (photophoresis), the patient receives orally administered cystalline 8-methoxypsoralene (8-MOP) tablets. Two (2) hours later, when the concentration of 8- MOP in the patient's blood reaches the highest level, peripheral blood is collected from the patient, anticoagulated and pumped into a rotating centrifuge vessel where it is divided into three layers. Plasma, leukocyte concentrate and thickened red blood cells. Plasma and leukocyte concentrate are removed from the vessel. The procedure is described e.g. in U.S. Pat

No. 4,568,328 (King), U.S. Pat. No. 4,573,960 (Goss), and U.S. Pat

4,623,328 (Hartranft).

physiological solution and recirculated by a photoactive chamber (photoceptor), wherein the blood cells in the circulating solution are exposed to UVA radiation in the presence of a photoactivatable substance, molecules 8- MOP. The treated cells are immediately returned to the patient. In this therapy, the concentration of the drug substance is one of the most important parameters.

However, the level of bioavailability of 8- MOP is extremely variable in both patients and from one patient to another, and in certain individuals, such as uremic patients, the bioavailability of 8-MOP is close to zero. Therefore, it is very difficult to provide patients with consistent and optimal therapy.

Several methods are currently used to deliver drugs in liquid form to the extracorporeal circuit, but none of them is satisfactorily achieving its goals.

The most common methods currently used include injecting a pre-calculated dose of the liquid active ingredient into a portion of the extracorporeal blood stream, for example, into a drip chamber or blood bag, and manually mixing. Another common approach is to drip the substance into the drip chamber. These methods are not very accurate and thus complicate the precise control of the active compound concentration during the extracorporeal therapy process.

Another method that is commonly used is to incorporate a solution of the active ingredient into the bloodstream by syringe. In this procedure, the amount of active ingredient can be accurately diluted, but not related to the size of the blood flow. The concentration of the active substance in the blood flow or reaction chamber therefore varies depending on the changes in the blood flow size in the extracorporeal circuit.

Another commonly used peristaltic pump for delivery, for example, a heparin pump, which method is to use the active ingredient as it works depending on the performance of the blood pump for several reasons

This method has limited use from

First of all, the blood flow from the patient's peripheral circulation to the extracorporeal circuit should roughly remain constant during the treatment. However, if blood flow changes, which often happens during treatment due to needle movement or for some other reason, negative extracorporeal pressure may occur, which puts the patient at risk. For this reason, most dialysis patients need to implan the fistula as a blood entry. This method also requires the use of elastic pump tubes, for example silicone and / or PVC, which in many cases leads to adsorption of the active compound molecules.

As mentioned above, no attention is paid to achieving a good mixing of the active ingredient with blood. Stirring is left to the natural course of blood flow. Because in most extracorporeal circuits the flow is laminar, any flow of liquid active substance injected into the blood stream requires a considerable amount of time or flow distance to achieve good mixing.

Known methods for extracorporeal therapy retain the leukocyte concentrate of a portion of the patient's blood throughout the treatment cycle, and therefore do not return a portion of the patient's leukocyte concentrate to the patient until treatment is complete. In order to minimize the time that a patient is free of the leukocyte concentrate used in the treatment, it is desirable to have an extracorporeal treatment system that returns whole blood (including leukocyte concentrate) to the patient at the end of each cycle during the overall treatment.

SUMMARY OF THE INVENTION

The present invention provides an on-line momothelial blood processing system and an on-line system for extracorporeal delivery of a drug solution to the blood. For the above reasons, it is an object of the present invention to overcome the remnants of current systems by providing a system and method for increasing the efficiency of extracorporeal treatment and increasing patient safety, thereby also increasing patient comfort and achieving acceptable standard treatment.

It is a further object of the invention to provide a sufficiently automated system and method that can be monitored and operated by less qualified personnel, thereby reducing treatment costs associated with the recent fiscal policy.

It is a further object of the invention to provide a system and method for the extracorporeal treatment of patients, wherein the concentration of the active agent is regulated and delivered to the reaction chamber used in extracorporeal therapy to increase the efficacy of such therapy.

Yet another object of the invention is to provide a system for extracorporeal therapy that returns each patient with whole blood containing all the components in each treatment cycle.

Yet another object of the invention is to provide a system for extracorporeal treatment in which the active ingredient is mixed and administered uniformly with blood flowing through the extracorporeal circuit.

Yet another object of the invention is to provide an extracorporeal treatment system capable of detecting blood loss in the momothelial circuit.

Yet another object of the invention is to provide a system for extracorporeal treatment capable of detecting the presence of air in the momotel circuit.

Yet another object of the invention is to provide an extracorporeal treatment system that includes a syringe pump and a pressure sensor that prevents the active agent in the syringe pump from being drawn into the bloodstream when it is sucked to a negative pressure.

These and other objects of the invention will be illustrated by the accompanying drawings and the description of the invention.

The present invention relates to a method and apparatus for the extracorporeal treatment of a patient's blood online. The whole blood is first collected from the patient and mixed with the drug solution to form a mixture of whole blood and drug. Processed whole blood is obtained by placing a mixture of the whole blood taken with the active ingredient solution in a centrifuge chamber and exposing the whole blood mixture with the active ingredient to radiation. The processed whole blood is then collected from the centrifuge chamber, stored in a storage medium, and then re-infused with the patient. The process is repeated successively from the initial stage of collection in a given number of cycles, in a preferred embodiment, the processing process is accelerated by the fact that when a single whole blood sample is drawn, the whole blood sample collected in the previous cycle is processed.

According to another object of the rotating blood centrifuge chamber taken from a patient of the present invention, a continuous stream is supplied. When the stream of blood collected by the rotating centrifuge is drawn, the blood that is irradiated in the rotating chamber of the centrifuge chamber and the blood contained in the rotating amount of radiation energy is monitored as a function of the volume of blood contained in the amount of energy used. In the rotating patient being fed into, at that time it is irradiated with radiation. When the centrifuges, the volume changes of the centrifuge chamber and the total for irradiation are dependent on the change in the centrifuge chamber and the total radiation used for irradiation, the time remaining for irradiation is determined.

Based on this determination, it is decided whether the irradiation phase ended by comparing the value of the time remaining for irradiation with a preselected constant. If a comparison of the time remaining for irradiation with a preselected constant shows that the irradiation phase is not yet complete, the new time values remaining for irradiation are gradually determined as long as the comparison of the time remaining for irradiation with the preselected constant is not determined. it is determined that the irradiation phase is complete.

According to a further aspect of the invention there is provided an on-line system and method for the extracorporeal administration of a solution of a medically active agent at a preselected blood concentration of a patient. First, the blood is taken from the patient and placed in a blood reservoir. The collected blood is then pumped from the blood reservoir into the blood tube in the amount given by the first pump performance. The level of blood in the reservoir is scanned by determining the amount of blood collected in the reservoir at any given time to determine the level of the blood reservoir. The first pump power is set depending on the specified blood reservoir level. The medication solution is pumped into the blood tube in an amount given by the second pump performance, which is set depending on the first pump performance. The blood collected in the blood tube is mixed with a solution of the medically active substance in the blood tube and later returned to the patient.

According to a further aspect of the present invention, there is provided an improved syringe pump for use in an on-line system for extracorporeal administration of a predetermined concentration of a medically active agent solution to a patient's blood. The syringe pump includes a mounting block for firmly attaching the syringe pump body, wherein the syringe pump is filled with a medically active agent solution and associated with a bloodstream in an online system. An extrusion block is slidably attached to the mounting block, and the extrusion block has a cutout for attaching the upper portion of the plunger portion of the injection pump to the extrusion block. Drive means connected to the assembly block and to the extrusion block are used to drive the extrusion block towards the assembly block depending on the control signal. The recess for securing the plunger portion of the syringe to the extrusion block is shaped to prevent the on-line system from discharging the medication solution from the syringe when there is a negative pressure in the bloodstream connected to the syringe outlet.

According to yet another aspect of the invention, there is provided a blood loss detector for use in an online system for extracorporeal treatment of a patient's blood, comprising a reaction chamber for processing the patient's blood, wherein the reaction chamber has a drain tube for withdrawing blood from the online system. In the system, a first electrically conductive tube is used which has its first end connected to the drain tube. An insulating block is also provided which includes a first hollow channel into which the second end of the first electrically conductive tube is inserted. The insulating block further comprises a second hollow channel into which the first end of the second electrically conductive tube is inserted. The first and second hollow channels are connected in the insulating block by a second fluidic bridge that conducts fluid from the second end of the first electrically conductive tube to the first end of the second electrically conductive tube. A circuit is used to determine the existence of an electrically conductive connection between the first and second electrically conductive tubes that occurs when the patient's blood flows through a fluid bridge, indicating a loss of blood from the extracorporeal circuit.

According to yet another aspect of the invention, there is provided an air detector for use in an on-line system for extracorporeal processing of patient blood. The first and second oscillators are located on opposite sides of the blood passage tube that guides the patient's blood through the online system. The signal transmitter is coupled to the first oscillator and the signal receiver is coupled to the second oscillator. The microprocessor controller is coupled to a signal transmitter and a signal receiver. The microprocessor controller includes comparing means that periodically compares the signals transmitted by the signal transmitter to the signals received by the signal receiver. The microprocessor controller further comprises means for detecting air, corresponding to comparative means, which indicate the presence of air in the blood conducting tube.

According to yet another aspect of the invention, there is provided an improved method and apparatus for mixing first and second fluids that move in a single laminar flow through a single tube. The combined laminar flows flow into the fluidic mixer through the inlet portion of the fluidic mixer. The combined laminar flows then pass through a mesh located within the fluidic mixer to form a mixture of the first fluid and the second fluid.

Overview of pictures in text

Fig. 1 is a block diagram illustrating on-line extracorporeal blood processing using an active agent operating in accordance with a preferred embodiment of the invention.

Fig. 2 is a flowchart showing the operation of the system of FIG. 1 operating according to a preferred embodiment of the invention.

Fig. 2A is a flow chart illustrating the operation of the system of FIG. 1 operating according to another preferred embodiment of the invention.

Fig. 3 is a flow chart illustrating the operation of a blood and injection pump operating according to a preferred embodiment of the invention.

Fig. 4 and 4A are flow charts illustrating the operation of a blood irradiation time control system contained in a centrifuge chamber operating in accordance with a preferred embodiment of the invention.

Fig. 5 is a block diagram of a system for controlling air detection in the blood circuit of an extracorporeal blood processing system operating according to a preferred embodiment of the invention.

Fig. 6 is a side view of an active ingredient mixer for mixing its solution with a patient's blood in the extracorporeal blood circuit operating in accordance with a preferred embodiment of the invention.

Fig. 7 is a block diagram of a blood loss detection system in the blood circuit of an extracorporeal blood processing system operating according to a preferred embodiment of the invention.

Fig. 8 is a circuit diagram of a radiation lamp monitoring system located in a centifuge chamber according to a preferred embodiment of the invention.

Fig. 9 and 9A are front views of a syringe pump according to a preferred embodiment of the invention.

Examples of the invention

In FIG. 1 is a block diagram illustrating a system 100 for on-line extracorporeal blood processing using an active agent operating in accordance with a preferred embodiment of the invention. The system 100 operates in several modes, which are performed in a repetitive manner as a number of cycles that make up the entire processing. In the collection mode, the system 100 draws the whole blood to the patient 10, adds to the whole blood a specified amount of the drug solution by means of a syringe pump 50 and feeds the mixture of whole blood and the drug solution into the reaction chamber 85 for processing. After the whole blood has been processed in the reaction chamber 85, the system switches to the return mode, during which the whole blood is pumped by the blood pump 80 to the return bag 60. After the contents of the reaction chamber 85 have been pumped into the return bag 60, the system 100 switches to the return infusion mode. wherein the processed whole blood is returned to the patient 10 from the return bag 60 by the force of gravity.

In the first preferred embodiment shown in FIG. 2, the system 100 undergoes 10 consecutive cycles, each of which consists of the aforementioned three modes, during one complete processing ten times in succession. No more than 150 ml of whole blood is drawn in each vial, which is collected, processed and returned (or infused) to the patient. In an alternative embodiment of the system shown in FIG. 2, the operator can vary both the number of repetitions of the blood processing cycles and the amount of blood processed per cycle. As shown in FIG. 2, the system 100 is preferably pre-flushed with brine before beginning the entire treatment.

In a second preferred embodiment (shown in Fig. 2A), the system of the above three modes ten times during one complete processing. Unlike the system shown in FIG. 2, however, this embodiment is accelerated after the first batch of whole blood has been collected, processed, and fed to the return bag 60. In the system of FIG. 2A, after the first dose of whole blood has been taken from the patient, processed and fed to the return bag 60, the second dose of blood is immediately taken from the patient 10, mixed with the medication solution and fed to the reaction chamber 85. at that point it is located in the reaction chamber 85, processed if at the same time the blood that is present in the back bag 60 (and the previous cycle) is simultaneously withdrawn in an infusion back to the patient 10. The treatment of the patient was found to be the time required for can be shortened by the fact that the processing operation and back infusion are done simultaneously. In addition, it has been found that the blood guide tube 12 is less susceptible to clogging if processing and re-infusion are performed simultaneously because this reduces the time the blood guide tube 12 is unused or idle. This was the case with the system of FIG. 2, even in the system of FIG. 2A, only 150 ml of whole blood can be collected, processed and re-infused to a patient 10 per treatment cycle. However, in alternative embodiments, the operator may vary both the number of cycles per complete processing and the volume of whole blood processed per cycle.

As discussed in more detail below, the blood flow through the system 100 is precisely controlled during complete processing by the wet-processor controller 45, which controls both the amount of flow and the direction of blood flow in the extracorporeal circuit. Among other things, the microprocessor controller 45 is connected to the blood pump 80 and the injection pump 50, and further to the selenium-actuated shut-off valves 65, 70, 75. During the removal mode of system 100, blood pump 80 pumps whole blood from pressure cushion 35 to reaction chamber 85. When whole blood leaves the pressure cushion reservoir 35 / injection pump 50 injects a solution of the medically active agent into the blood stream in an amount that is controlled. In the blood collection mode, the microprocessor controller 45 controls the direction of whole blood flow in the extracorporeal circuit by bringing the terminals 65, 70 to the closed state when the terminal 75 is in the open state.

In reverse mode of system 100, the direction of operation of blood pump 80 reverses and blood pump 80 pumps whole blood from reaction chamber 85 to return bag 60. In reverse mode, microprocessor controller 45 controls the direction of processed blood in the extracorporeal circuit by opening terminal 70 while terminals 65 and 70 are kept closed. Finally, in the reverse infusion mode, the processed blood from the return bag 60 is applied by gravity first to the pressure cushion container 35 and then back to the patient. In a preferred embodiment, the same needle is used to draw blood from the patient 10 in the collection mode as for the re-infusion. In the reverse infusion mode, the microprocessor controller 45 controls blood flow in the extracorporeal circuit by opening terminal 65 while terminals 70 and 75 are closed.

After giving an overview of the operation of the system 100 according to the invention, the operation details will be discussed in more detail below. Referring back to FIG. 1, during blood collection mode, whole blood is drawn to the patient 10 by a needle and fed to the system 100 by a detachable blood tube 12. The patient's blood preferably flows by gravitational force into the pressure cushion reservoir 35. Before reaching the pressure cushion reservoir 35 The whole blood in the pressure cushion reservoir 35 is then pumped into the reaction chamber 85 by the blood pump 80 and its flow rate is controlled by the microprocessor controller 45. During the withdrawal mode, the pressure cushion sensor 40 continuously senses the blood level in the patient. a pressure cushion container 35 and sends a level signal to the microprocessor controller 45. If the blood level in the reservoir 35 drops below a predetermined minimum limit, the power of the pump 80 is reduced to zero until the blood level in the reservoir 35 exceeds a predetermined minimum value. The purpose of reducing the performance of the pump 80 when the blood level in the reservoir 35 is low is to ensure that the blood flow coming from the patient 10 is driven solely by gravity and that blood is never pumped from the patient by the blood pump 80. in a number of different ways, such as an electromechanical, optical, ultrasonic or piezoelectric sensor. In addition, in an alternative embodiment, the power of the pump 80 may be reduced gradually as the pressure in the pressure cushion decreases.

When the pump 80 pumps the whole blood from the pressure cushion reservoir 35 of the reaction chamber 85 during the withdrawal mode, the liquid active substance is pumped into the blood circuit by the injection pump 50, the power of which is controlled by the microprocessor controller 45. In calculating the pump power, the microprocessor For example, the injection pump 50 performs the operation of the blood pump 80 such that the injection pump 50 injects the active agent into the blood circuit only when the blood pump 80 is in an active state, moreover, as will be described in more detail below with reference to FIG. 3, the injection pump 50 operates at an increased injection rate during the first cycle of the entire treatment to compensate for the absorption of the substance through the tubes and other material of which the system 100 is made.

After injection of the drug solution into the extracorporeal circuit via the syringe pump 50, the blood flow associated with the delivered liquid drug proceeds to a specially designed drug mixer 55 in which two relatively unmixed streams (i.e., blood stream and drug stream) are interrupted. and mixed to form a mixture of whole blood and drug solution which is pumped by pump 80 into reaction chamber 85

Further details of the embodiment of the active ingredient mixer 55 are given below with reference to FIG. 6.

In a preferred embodiment of the present invention, a photoactivatable agent, such as psoralen, and even more preferably 8- methoxypsoralen, is in liquid form injected into the blood circuit by injection pump 50 during sampling mode of system 100, although other active agent or biological solutions such as for example, monoclonal antibody solutions or other photoactivatable agents. Also, in a preferred embodiment, the reaction chamber 85 is a rotating centrifuge which includes a photoactivation system inside it for irradiating the mixture of whole blood and drug solution with UV radiation while the centrifuge is rotating. A preferred embodiment of the reaction chamber 85, which contains a foroactivation system within, is shown and operates essentially as illustrated and described in US Patent 4,921,473, the subject matter of which is incorporated herein by reference.

Although in a preferred embodiment of the system 100, the whole blood of the patient 10 is collected and delivered to the system to be processed and returned to the patient by infusion, it is clear to the skilled person that the system 100 can also deliver blood from other sources such as not shown). If the blood obtained from the donor center is delivered to the processing system 100, the processed blood may either be directly infused to the patient by the system 100 or collected into a container (not shown) and administered to the patient by infusion at a later time. In addition, although in a preferred embodiment the system 100 is used to process whole blood, it is clear to the skilled person that blood obtained from individual fractions of whole blood can also be processed by the system 100.

In FIG. 3 is a flow chart illustrating the operation of the blood pump system 80 and the injection pump 50 operating in accordance with a preferred embodiment of the invention. When the system 100 is operating in a draw mode, the working power of the blood pump 80 is set so that the power of the pump is less than the amount of blood flow from the patient 10 to the pressure cushion cartridge 35. As a result, in normal operation, the pressure cushion container is still completely filled with patient blood. However, if the blood flow from the patient to the pressure cushion 35 slows down for any reason, the blood volume inside the cushion 35 may eventually decrease, causing collapse of the pressure cushion 35.

This undesirable situation is prevented by the cushion reservoir sensors 40, which determine the blood level in the pressure cushion reservoir 35 and signal its level to the microprocessor controller 45. If the blood level in the pressure cushion container drops, the microprocessor controller 45 will reduce pump performance 50 and 80. This feedback mechanism to patient 10 has been sustained and sustained.

The operation of the feedback mechanism generally described in the previous paragraph is illustrated in more detail as the feedback system 300 in FIG. Referring to this figure, operation of system 300 begins at step 310 by monitoring the pressure sensor 40 in the cushion reservoir that determines the blood pressure in the pressure cushion reservoir 35. The signal indicating the blood level value in the reservoir is then supplied from the pressure sensor 40 to the microprocessor controller 45. In step 320, the microprocessor controller 45 determines in response to a signal coming from the sensor whether the blood level in the pressure cushion container 35 has not fallen below a predetermined value, indicating that the pressure cushion container 35 has collapsed. If it has been determined that the pressure cushion cartridge 35 has collapsed, then system 300 proceeds to step 330 where the microprocessor 45 sends control signals to pumps 50 and 80 to set both pumps to the off state. Alternatively, in step 320, the system determines that the pressure cushion cartridge 35 has not collapsed, and then the system proceeds to step 340, in which the microprocessor controller sends the pump control signal 80 to put the pump 80 on.

Next, in step 350, the microprocessor controller 45 determines whether the system 300 is operating in the first cycle of the entire processing. If the system 100 is in the first cycle of the entire processing, the microprocessor controller sends a control signal to the injection pump 50, which is switched to the active state and sets its power to the first level (R1). Alternatively, if the system 100 is not in the first cycle of the entire processing, the microprocessor controller 45 sends a control signal to the injection pump 50 that is switched to the active state and sets its power to a second level (R2) that is lower than the first level (R1). In a preferred embodiment, the increased power (R1) of the pump in the first cycle is used to compensate for adsorption of the active agent through the tubes and other material constituting the system 100. After adjusting the operating power of the injection pump 50, processing proceeds to step 380, wherein the microprocessor controller 45 determines whether the volume of whole blood to be processed in a given cycle is supplied to the reaction chamber 85 by the blood pump 80. is achieved by repeatedly monitoring the condition and working performance of the blood pump 80 during the collection mode. If the volume required in a given cycle has not been reached, the system 300 returns to step 310 and the process described above is repeated, otherwise the processing goes to step 390. In step 390, the microprocessor controller 45 sends a control signal to the pumps 50 and 80 and makes them stand still.

In FIG. Figures 4 and 4A are flow diagrams illustrating the operation of the irradiation time control system 400 to control the irradiation time of the blood present in the reaction chamber 85 while operating the processing system 100 according to a preferred embodiment of the invention. During the processing mode, the continuous patient 10 mixed with the solution is fed to the reaction chamber 85 with a blood stream obtained from the medication and a pump 80. As mentioned above, in a preferred embodiment of the invention, the reaction chamber 85 is a centrifuge that includes an internal photoactivation system for irradiating the patient's blood with UV radiation. According to the present invention, the system 100 does not wait for UV irradiation treatment until the entire volume of blood used in a given cycle has been collected in the reaction centrifuge chamber (described in connection with step 350 above). Instead, the blood is distributed in a continuous manner as it enters the centrifuge chamber 85 during processing mode, into individual constituents rotating through the central fusion and then irradiated by UV radiation located inside the centrifuge chamber. By separating and irradiating the patient's blood continuously during processing mode the present invention, the time required to treat a patient 10.

The operation of the irradiation time control system, described generally in the just completed paragraph, is described in detail above as the system 400 in FIG. 4. Referring to FIG. System 400 begins its work at the beginning of the treatment mode in step 405 initiating the value of the remaining term irradiation (Ti team that it equated to baseline (T _g).

The value of the remaining periodically increased remaining time (at the time of irradiation is a variable that is or decreased and which represents seconds) during which the blood in the reaction chamber 85 is to be exposed to UV radiation before the blood is returned and re-infused to the patient.

The initial value (T _s ) is set to compensate for the fact that UV radiation from the photoactivation system cannot penetrate whole blood, but that such light can only pass through a concentrate layer of a rotating centrifuge of the constituent, these initial 2 not useful. Therefore, leukocytes. Because the whole blood needs from to

The UV is at the time it has been converted into its single radiation separation applied to the blood for minutes, for the purpose of blood processing in a preferred embodiment of the invention, the initial value is preferably set to a value between 120 to 180 seconds. In the initialization step 405, the time stamp Τρ _Γ βν is set to zero and the volume stamp V p _rev is set to zero. Setting both _{Tp rev} and Vp _rev to zero in the initialization step 405 means that the irradiation step begins at time zero and with the reaction chamber 85 empty.

After the initialization step 405 is performed, in step 410 the determination of the current blood volume (V _curr ) in the chamber 85 is made.

Since blood is continuously pumped into chamber 85 for at least part of the processing mode, the V _curr value varies with time. The microprocessor controller 45 determines the value ⁱⁿ curr by monitoring the status and performance of the pump 80 during the processing cycle. In step 415, the change in blood volume (delta V) is determined by subtracting the values of V _curr and V _prev , and in step 420 Vvrev is replaced by V _curr . In step 425, the time elapsed since the start of the irradiation step (T _curr ). In step 430, the change in elapsed time (delta T) is calculated by subtracting T _prev from T _curr and the ^T curr value ^at step 440 of the UV energy ^uv curr) r that was supplied to the blood in calculating this total at step 435 is T _prev replaced is calculated total value representing total energy, chamber 85 during processing. K UV Energy Value The microprocessor controller 45 monitors the status (on / off)

The UV lamp in the reaction chamber 85 during the treatment cycle. Moreover, the microprocessor controller 45 records the continuous aging (in operating hours) of each bulb in the chamber 85 and adjusts the total UV energy value taking into account the energy emitted by each UV lamp decreases with operating time. of the lamp in question.

Although in FIG. 4, the steps to determine delta V (steps 140, 415 and 420), delta T (steps 425, 430, and 435) and UV _curr (step 440) are shown as parallel, these values can also be determined sequentially. In a preferred embodiment of system 400, the delta V is determined 40 times per second if the delta T and UV _curr is determined 5 times per second. Frequent determination of these values is important to ensure that the transition to zero is detected immediately.

In step 445 which follows the calculation of delta V, delta T, and ^{u in} curr '7 ^{e in} curr L ^dressing ® ^with základnouu ^a value (THRESH)' which is a basic amount of blood that activates the deltaV and deltaT members during the calculation in step 485 (described below). If Vcurr is greater than or equal ^to thresh 'P ° then at step 450, the first (A) and second (B) constants for calculating the radiation time are set equal to one. If ^the curr is not greater than / or equal to V _thresh, then in step 455 it is UVcurr P s ^{dressing with} baseline (UV _thresh). ^{The OT} curr is greater than or equal to UVthresh '. ^At step 460, the first and second constant for calculating the irradiation time are set equal to zero, respectively. otherwise, in step 465, both the first and second constant for calculating the irradiation time are set equal to zero. The preferred amount ^{of UV} thresh ^{equal to} 300. In step 470, system 400 determines (or confirms) whether the UV lamps in chamber 85 is actually turned on. A preferred circuit for determining the state of the UV lamps in the chamber 85 is described below with reference to FIG. 8. if it is determined in step 470 that the UV lamps are in an active state, then the third irradiation time constant (U) is equal to zero in step 475, otherwise the third irradiation time constant (U) is set equal to zero.

To determine the three constants for calculating the irradiation time, the microprocessor controller 45 adjusts the value according to equation (1) below:

T _± = T _± + (A * C * deltaV) - (B * U * deltaT) (1) where C is a constant representing the number of seconds of the irradiation time to be added to the remaining irradiation time T ^, as each milliliter of blood is added to chamber 85. At step 490, Ίύ is compared to a zero baseline. If it is not greater than zero, then this indicates that the irradiation step is complete, otherwise the process shown in FIG. 4 repeats until it reaches zero baseline values or falls below it.

Referring to FIG. 1, a preferred embodiment of the system 100 includes a plurality of air detectors 25, 30 for determining the presence of air in the extracorporeal circuit. In a preferred embodiment, an alarm is issued that immediately informs the operator that air has been detected as soon as air is detected by the system 100. Referring to FIG. 5 is a block diagram of air detectors 25 and 30. The first and second oscillators 505 and 510 are located on opposite sides of the blood passage tube 12 that guides the patient's blood through the online system. The first and second crystal oscillators 505 and 510 are carried by the carrier block of an air detector 515 having outlets adapted to receive the oscillators 505 and 510. The signal transmitter 520 is electrically coupled to the first oscillator 505 and the signal receiver is electrically coupled to the second oscillator 510. The microprocessor controller 45 is coupled to the signal transmitter 520 and the signal receiver 525. The microprocessor controller 45 includes comparing means that periodically compares the signals transmitted by the transmitter 520 to the signals received by the signal receiver 525. Since the signal transmitter 520 periodically transmits the same signal, an unexpected change in the signal received by the receiver 525 indicates the presence of air in the tube 12. The microprocessor controller 45 includes air detection means corresponding to the comparator means to signal the presence of air in the blood conducting tube until the signal received by the receiver 525 is unexpectedly changed.

In a preferred embodiment of the present invention, the operation of each air detector 25, 30 is periodically tested to verify that they are operating properly. In particular, the signal transmitter 520 is turned off at regular intervals and each signal received by the signal receiver 525 is recorded by the microprocessor controller 45. If an unexpected signal is received by the signal receiver 525 during the verification test, this would mean that the air detector is not working properly either because the output of the signal transmitter 520 is blocked, or for some other reason. In a preferred embodiment, if the microprocessor controller 45 detects that the air detector is not operating properly, an acoustic signal will sound to alert the operator system to an incorrect condition.

Although not fig. 1, the air detectors 25 and 30 are shown in a position closer to the anticoagulant pump 15 and the mixer 55, it is clear to the skilled person that the air detectors 25 and 30 can be located anywhere in the system 100. to detect the presence of air in the circuit through which fluid other than blood present in the extracorporeal blood circuit flows.

In FIG. 6 shows an active ingredient for mixing its extracorporeal blood circuit, a side view of a solution mixer 55 with a patient's blood in a working according to a preferred embodiment of the invention

The mixer 55 is formed by a closed hollow chamber 610 with an opening 600 through which the unmixed liquids flow into the mixer and an opener 650 through which the mixed liquids flow out of the mixer. The interior of the chamber 610 is divided into compartments 620 and 630 by a mesh bag 640, which is attached circumferentially to the interior of the hollow chamber 610.

During operation of the fluidic mixer 55, the first and second fluids together flow through the laminar flow through the same fluid conduit which passes into the mixer 55 through the inlet port 600. The combined laminar flows then pass through a mesh bag 640 located within the fluidic mixer to form a mixture of the first fluid and the second fluid. The mesh bag 640 achieves effective mixing of the first fluid and the second fluid by disrupting the combined laminar flow of both. When the mixer 55 is used to mix blood with other solutions, the mesh 640 preferably has a hole size in the range of 100 to 600 microns. One of ordinary skill in the art will recognize that the mixer 55 may be used to mix fluids other than blood and may be used in a manner other than its use in the extracorporeal blood circuit.

In a preferred embodiment of the present invention, system 100 includes means for detecting and losing blood from the extracorporeal circuit. Such blood loss may occur, for example, if an opening or a crack occurs in the blood processing centrifuge chamber, or if the contents overflow inside the centrifuge chamber. If the system 100 detects that blood is being lost from the extracorporeal circuit, a warning signal is given to signal the event to the operator. In FIG. 7 is a block diagram of a preferred embodiment of a blood loss detection system 700 in a system 100 according to a preferred embodiment of the present invention. In a preferred embodiment, the reaction chamber 85 includes an outer shell (not shown) for capturing any overflow or blood leakage from the reaction chamber 85. The lowest portion of the outer wrapper is connected to the drain tube 710 for draining any blood that escapes or splashes into the outer wrapper. In the system 700, a first electrically conductive tube 720 is used having its first end connected to the drain tube 710. Also used is an insulating block 730 that includes a first hollow channel 725 into which the second end of the first electrically conductive tube 710 is inserted. The insulating block is not electrically conductive. The insulating block comprises a second hollow channel 740 into which the first end of the second electrically conductive tube 750 is inserted. The first and second hollow ducts 735 and 740 are connected in the insulating block 730 by a hollow fluid bridge 755 that conducts fluid from the second end of the first electrically conductive tube 720 to the first end of the second electrically conductive tube 750. A comparative circuit is used

760 for determining the existence of an electrically conductive connection between the first and second electrically conductive tubes 720 and 750. Since the electrical conductivity of the blood flowing through the hollow fluid bridge 755 is sufficient to establish a conductive connection between the first and second electrically conductive tubes 720 and 750, the comparator circuit 760 detects the existence of a conductive connection between the first and second electrically conductive tubes 720 and 750, as soon as blood begins to flow through hollow fluid bridge 755, thereby signaling blood loss from the extracorporeal circuit. The output of the comparator circuit 760 is coupled from the clip circuit 770, which causes the blood pump 80 to stop and give an audible warning signal once an electrically conductive connection is established between the first and second electrically conductive tubes 720 and 750.

As mentioned above in the explanation of FIG. 4, in step 470 of system 400, the state (on / off) of the UV irradiation lamps within the reaction chamber 85 is repeatedly monitored in the process of the present invention. In FIG. 8 is now a circuit diagram of a preferred embodiment of a circuit of a radiation monitoring system 800 disposed in a centrifuge chamber according to a preferred embodiment of the present invention. In system 800, the sine wave generator 820 and resistor 830 are connected in series with the radiation lamp 810. If the lamp 810 is in the ON state, then a voltage is generated at the resistor 830 which forms a logic signal 0 at the output of the circuit 840. On the other hand, if the lamp 810 is in the off state, then no voltage is applied to the resistor 830 and a logic signal 1 is generated at the output of circuit 840. In a preferred embodiment of the present invention, three separate irradiation lamps are used within the chamber 85. A separate system 800 is connected so that the state of each lamp is monitored separately during processing.

Finally, in FIG. 9 and 9A are views of a syringe pump 50 according to a preferred embodiment of the present invention. The syringe pump 50 includes a mounting block 900 for firmly attaching a syringe 910 that represents the syringe pump body 50 and

The syringe 910 is preferably glass filled with a solution of medically active substance

The syringe 910 is connected (via its outlet 920) to the extracorporeal blood circuit. The extrusion block 930 is slidably mounted to the mounting block 900 by a pair of metal bars 940 and 950 disposed on opposite sides of the injection molding piston portion 960. A syringe extrusion block 910 is provided in the preferred 930. 930. Notch 970 in the extrusion block

930 for securing the plunger portion 960 of syringe 910 is shaped to prevent the on-line system from discharging the medication solution from syringe 910 when there is a negative pressure in the bloodstream connected to syringe outlet 910. The drive means (not shown but located between blocks 900 and 930 in Figs. 9 and 9A) coupled to the mounting block 900 and to the extrusion block 930 move the extrusion block 930 toward the mounting block 900 in response to the actuator 45 by means, control signal sent by the microprocessor This control signal tells the drive whether the injection pump 50 is to operate with the injection power R1, the injection power R2 or whether the injection pump 50 should remain off. In a preferred embodiment, the drive means used to drive the extrusion block 930 towards the assembly block 900 is constructed as a worm drive mechanism. In a preferred embodiment of the present invention, the injection pump 50 includes a safety closure that prevents the system 100 from operating until the syringe 910 has been placed in the mounting block 910. Fig. 9 shows the safety shutter 980 in the open state as shown in FIG. 9A shows the security closure 980 in a closed state. The control signal prevents the operation of the system of the present invention when the safety shutter 980 is in the open state.

The skilled artisan will appreciate that the syringe pump 50 may be used to deliver precisely determined amounts of fluid other than a solution of the medically active agent, and under conditions other than its use in the extracorporeal blood circuit. In addition, the skilled artisan will appreciate that system 100 can be used to dynamically mix fluids, including instances where drug solutions or other biological solutions, such as monoclonal antibody solutions and instances of other circuits, are added to the blood in the extracorporeal blood circuit. accurate dosing and good mixing prior to feeding the mixture into the processing chamber.

The present invention may be practiced in other ways so as not to depart from the spirit and essential attributes of the invention. Accordingly, when determining the scope of the present invention, reference should be made not to the above description but to the appended claims.

Represented by:

Claims (37)

PATENT CLAIMS 1. Online method of extracorporeal blood processing comprising the following steps: (A) collecting blood from a blood source, (B) mixing said blood with a medicament solution to form a mixture of blood and medicament solution (C) forming a dose of processed blood by feeding said mixture of blood and medicament solution into a processing chamber and exposing said mixture of blood and medicament drug solution to radiation, and (D) draining said dose of processed blood from said processing chamber and storing the dose of processed blood in a returned blood storage container. The method of claim 1, wherein said blood source is a patient and further comprising the following step: (E) returning said infusion-treated dose to said patient. The method of claim 2, further comprising the following step: (F) repeating steps (A) - (E) several times during one treatment of said patient. The method of claim 3, wherein a single needle is used, both for withdrawing said blood to said patient in step (A) and for re-infusing said dose of processed blood back to the patient in step (E). The method of claim 4, wherein said processing chamber is a centrifuge chamber. The method of claim 5, wherein said step of collecting blood for said patient further comprises the following steps: (1) opening a patient clamp located on the blood flow path between said patient and said centrifuge chamber, (2) closing a back clamp located on said blood flow path between said centrifuge chamber and said returning blood storage device, (3) closing the reinfusion a clamp disposed on said path between said returning blood storage container and said patient. Ί. The method of claim 6, wherein said step of draining said portion of processed blood from said centrifuge chamber further comprises the following steps: (1) closing said patient clamp located on a blood flow path between said patient and said centrifuge chamber, (2) opening a back clamp located on said blood flow path between said centrifuge chamber and said returning blood storage means. The method of claim 7, wherein said step of re-infusing said dose of processed blood into said patient further comprises the following steps: (1) closing a clamp located on said blood flow path between said centrifuge chamber and said returning blood retention means, and (3) closing said patient clamp located on the blood flow path between said patient and said centrifuge chamber. The method of claim 3, wherein the dose of processed blood generated during the previous cycle is recovered by said infusion during step (C). The method of claim 1 whole blood. wherein said collected blood is The method of claim 1, wherein said collected blood is a whole blood fraction. 12. On-line extracorporeal method comprising the following steps: (B) irradiating the blood present in said rotating centrifuge chamber by irradiating said patient to said rotating centrifuge chamber when said blood stream enters said (C) during said irradiation step, monitoring the changes in the blood volume present in said rotating centrifuge chamber over a period of time; (E) performing, during said irradiation step, determining the remaining irradiation time depending on said change in blood volume contained in said rotating centrifuge chamber and said total radiation energy value; determining whether said irradiation costume is terminated by comparing said residual irradiation time value with a predetermined constant, (G) if said comparing said residual irradiation time value with said predetermined constant in step (F) determines that said irradiation step is complete; repeating steps (C) - (F) until said comparison of said remaining irradiation time value with said predetermined constant in step (F) determines that said irradiation costume is complete, and (H) returning said blood contained in the centrifuge chamber to said patient in said after said irradiation step. The method of claim 12, further comprising the steps of initializing said remaining irradiation time value and said volume value prior to said irradiation step. The method according to claim 13, wherein the cork (C) consists of the following steps: (1) determining the instantaneous volume of blood contained in said rotating centrifuge chamber at the end of said period of time, (2) determining said change in blood volume by subtracting said instantaneous volume value and said previous volume value, (3) replacing said previous volume value with said instantaneous value volume. The method of claim 14 further comprising, during said irradiation step, a step of monitoring whether the lights in said rotating centrifuge chamber are on. The method of claim 15 (1) comparing said instantaneous volume with a predetermined base value, (2) comparing said total radiation energy value to a predetermined total radiation energy base value, (3) initializing constants indicating the first and second irradiation times to zero (4) if said instantaneous volume is equal to or exceeds said base value, adjusting said first and second irradiation times to one, otherwise, if the total radiation energy value is equal to or greater than a predetermined total radiation energy base value, then adjusting said second irradiation time to one; and (5) adjusting said remaining irradiation time value depending on said blood volume change, said first and second irradiation time constants, and said radiation monitoring in said rotating centrifuge chamber. An online method for extracorporeal administration of a predetermined amount of a solution of a medically active agent to a patient's blood, comprising the following steps: (A) collecting blood from said patient and draining said collected blood into a blood reservoir, (B) pumping said collected blood from said blood reservoir into a blood drain tube using a first performance of a bomb, (C) determining blood level by determining the blood level in said blood (D) adjusting said first pump power according to said determined blood level in said blood reservoir, (E) pumping said medicament active solution into said blood removal tube using a second reservoir; a pump power, (F) adjusting said second pump power according to said first pump power, (G) mixing said collected blood in said blood removal tube with said medically active solution in the blood removal tube, and (H) returning said the blood collected from said patient after said step nia. The method of claim 17 further comprising the step of delivering said collected blood and said medicament active substance stream into the reaction chamber after said mixing step and before said blood is returned to said patient. The method of claim 17 further comprising the step of repeating steps (A) - (H) multiple times and wherein said second pump power is set to a higher value during the first processing cycle to compensate for the adsorption of the active agent caused in the blood conducting tubes. The method of claim 17, wherein said second pump power is adapted to said first pump power. The method of claim 17, wherein said mixing step is accomplished solely by the simultaneous flow of said collected blood and said medicament active substance flow in said blood guide tube. The method of claim 18 wherein said reaction chamber is a photoactivation chamber. The method of claim 22, wherein said medicament active ingredient solution comprises psoralen. The method of claim 17, wherein a syringe pump is used to add said medically active agent solution to said blood guide tube in step (E). An injection pump in an on-line system for extracorporeal administration of a predetermined amount of a drug solution to a patient's blood, comprising: (A) a syringe mounting block, wherein said rigid attachment of the syringe body is filled with said medically effective orzotka (B) an extrusion block slidably attached to said assembly block, wherein said extrusion block has a recess for a syringe plunger for attaching an upper portion of the plunger portion of said syringe to said extrusion block (C) drive means coupled to the assembly block and extrusion block that drive the extrusion block toward the assembly block depending on the control signal, wherein said recess for securing the plunger portion of the syringe prevents the online system from dispensing said solution medically active substance from said syringe at the time when the blood in said negative pressure path. The syringe pump of claim 25, further comprising first and second rods that are disposed on opposite sides of said syringe and allow for sliding attachment of said displacement block to said assembly block. The injection pump of claim 25 further comprising a microprocessor controller for providing said control signals by said drive means. The injection pump of claim 25, wherein said drive means is a worm drive. The syringe pump of claim 25, further comprising a safety closure to prevent operation of said online system when said syringe body is not located on said mounting block. 30. A blood loss detector in an online system for extracorporeal treatment of a patient's blood, said system comprising a reaction chamber for processing said patient's blood, and said reaction chamber comprising a drain tube for withdrawing blood from said online system, and wherein the blood loss detector comprises: (A) a first and a second electrically conductive tube, said first electrically conductive tube having a first end connected to said drain tube, (B) an insulating block comprising a first hollow channel into which the second end of said first electrically conductive tube is inserted the insulating block further comprising a second hollow channel into which the first end of said second electrically conductive tube is inserted, said first and second hollow channels being connected in said insulating block by a hollow fluid bridge that conducts fluid from said second end of said first electrically conductive tube to said (C) detecting means for determining the existence of an electrically conductive connection between said first electrically conductive tube and said second electrically conductive tube when said patient's blood flows through said fluid bridge. 31. The blood loss detector of claim 30, wherein said detecting means comprises a comparator having first and second comparator inputs and said first comparator input electrically connected to said first electrically conductive tube and said second comparator input electrically connected to said second electrically conductive. tube. The blood loss detector of claim 31, wherein said first comparator input is coupled to a positive voltage source and said second comparator input is grounded. An air presence detector in an online system for extracorporeal treatment of a patient's blood, said system comprising blood conduits for guiding the patient's blood in said system and wherein the air presence detector comprises: (A) a first and a second oscillator located on opposite sides of said blood passage tube, (B) a signal transmitter coupled to said first oscillator, (C) a signal receiver coupled to said second oscillator, (D) a microprocessor controller coupled to said signal transmitter and to said signal receiver, said microprocessor controller comprising means for comparing the signals emitted by the signal transmitter to the signals received by the signal receiver, and said microprocessor controller further comprising means for detecting air, indicate the presence of air in the blood conducting tube. The air presence detector of claim 33, wherein said microprocessor controller further comprises verification means that periodically verify said signals transmitted by the signal transmitter and said signals received by the signal receiver by periodically switching off said signal transmitter and monitoring the signals received by the signal receiver. The air presence detector of claim 33, wherein said first oscillator and said second oscillator are crystal oscillators. A method for accommodating first and second fluids that move in a laminar flow through a single said tube, comprising the following steps: (A) supplying said laminar flow to the fluidic mixer via an inlet of said mixer, (B) passing said combined laminar flow through a mesh located within said fluidic mixer thereby producing a mixture of said first and second fluids, and (C) discharging said mixture of said first and a second fluid through the mixer outlet. The method of claim 36, wherein said first fluid is whole blood and said second fluid is a solution of a medically active agent. The method of claim 37, wherein said mesh has a mesh size ranging from 100 to 600 microns.