CZ9900757A3 - On-line method for extracorporeal administration of a predetermined amount of solution of a medicinally active substance into a patient blood treatment of blood and a system for carrying out the same - 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

An online method of extracorporeal administration of a predetermined amount of a solution of a medically active agent to a patient's blood and a system for performing the method

Technical field

The invention relates to an on-line method of extracorporeal administration of a predetermined amount of a solution of a medically active agent to a patient's blood and various systems for carrying out the method.

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 that are 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, autoimmune diseases.

Caused by leukocytes and diseases of the leukemic type, many of which eventually have fatal consequences.

For 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), tablets of crystalline 8-methoxypsoralen (8-MOP) are orally administered to a patient. 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, for example, in US Patent 4,568,328 (King), US Patent 4,573,960 (Goss) and US Patent 4,623,328 (Hartranft).

The collected leukocyte concentrate is mixed with plasma and saline and recirculated by a photoactive chamber (photoceptor) where the blood cells in the circulating solution are exposed to UVA radiation in the presence of a photoactivatable substance, 8-MOP molecules. The treated cells are immediately returned to the patient. In this therapy, the concentration of the active substance is one of the most important parameters.

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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. It is therefore 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 achieve their goals in a satisfactory manner.

The most common methods currently used include injecting a pre-calculated dose of the liquid active ingredient into a portion of the extracorporeal circulation, 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 inject a solution of the active ingredient into the bloodstream via a syringe. In this procedure, the amount of active ingredient can be accurately controlled, but not related to blood flow size. The concentration of the active substance in the blood flow or reaction chamber therefore varies depending on the changes in blood flow size in the extracorporeal circuit.

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Another commonly used method is to use a peristaltic pump to deliver an active agent, such as a heparin pump, which operates depending on the performance of the blood pump. This method has limited use for several reasons. First, the blood flow from the patient's peripheral circulation to the extracorporeal circuit should remain roughly constant during treatment. However, if the blood flow changes, which often happens during treatment due to needle movement or for some other reason, a negative pressure may develop in the extracorporeal circuit, endangering the patient. For this reason, most dialysis patients need to implant the fistula as a blood entry. This method also requires the use of elastic pump tubes, for example silicone 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. The mixing is left to the natural course of blood flow. Since in most extracorporeal circuits the flow is laminar, any flow of liquid active substance injected into the blood stream needs 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 the end of the treatment. In order for the patient to remain free of the medication.

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The leukocyte concentrate used in the treatment was: < tb > ______________________________________ < tb > ______________________________________ < tb > minimized, 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 a method for on-line extracorporeal blood processing and an on-line system for extracorporeal delivery of a medicinal solution to the blood. For the above reasons, it is an object of the invention to overcome these drawbacks of current systems by providing a system and method for increasing the effectiveness of extracorporeal treatment and increasing patient safety, thereby also increasing patient comfort and achieving acceptable standards of treatment.

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

It is another object of the present invention to provide a system and method for the extracorporeal treatment of patients in which the concentration of active ingredient is controlled and administered to a reaction chamber used in extracorporeal therapy to enhance the effectiveness of such therapy.

• · · · · · · · · · · ·

It is yet another object of the invention to provide an extracorporeal therapy system that returns each patient whole blood containing all components in each cycle of overall treatment.

It is yet another object of the present invention to provide a system for extracorporeal treatment in which complete and uniform mixing of the active ingredient administered with blood flowing through the extracorporeal circuit is achieved.

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

Yet another object of the invention is to provide an extracorporeal treatment system capable of detecting the presence of air in the extracorporeal 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 negative pressure occurs.

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

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The present invention relates to a method and apparatus for the extracorporeal treatment of a patient's blood online. 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 removed from the centrifuge chamber, stored in the storage medium, and then reinfused into the patient. The process is repeated from the initial withdrawal stage in a given number of cycles. In a preferred embodiment, the processing process is accelerated by the fact that while a single dose of whole blood is taken from a patient, a dose of whole blood that is collected in a previous cycle is processed.

According to another aspect of the present invention, a continuous flow of blood collected from the patient is supplied to the rotating centrifuge chamber. As the blood stream drawn to the patient is fed into the rotating centrifuge chamber, the blood present in the rotating centrifuge chamber is irradiated with radiation. As blood is irradiated in a rotating centrifuge chamber, changes in blood volume contained in a rotating centrifuge chamber and the total amount of radiation energy used for irradiation are monitored over time. Depending on the change in the volume of blood contained in the rotating centrifuge chamber and the total amount of radiation energy used for irradiation, the amount of time remaining for irradiation is determined.

• · · · · · · · ·

Based on this determination, it is determined 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 indicates that the irradiation phase is not yet complete, the new time values remaining for irradiation are gradually determined until a comparison of the time remaining for irradiation with the preselected constant 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 extracorporeal administration of a solution of a medically active agent at a preselected concentration to a patient's blood. First, blood is collected from the patient and placed in a blood reservoir. The collected blood is then pumped from the blood reservoir into the blood tube in an amount given by the first pump performance. The level of blood in the reservoir is scanned by determining the amount of blood that is present in the reservoir at any given time, thereby determining the level of the 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 power, which is adjusted depending on the first pump power. 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 yet another aspect of the present invention, there is provided an improved syringe pump for use in an on-line system for an on-line system for the use of an on-line syringe pump. Extracorporeal administration of a predetermined concentration of a solution of a medically active substance into the 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 connected to the bloodstream in an online system. An extrusion block is slidably attached to the assembly block, and the extrusion block has a cut-out for attaching the upper portion of the syringe pump piston portion to the extrusion block. Drive means coupled to the assembly block and 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 online system from discharging the medication solution from the syringe when there is 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 on-line system for extracorporeal processing 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 a 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 end is inserted. electrically conductive tubes. The first and second hollow ducts are connected in an insulating block by a hollow fluid 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, which occurs when a patient's blood flows through a fluid bridge, indicating a loss of blood from the mitochemical circuit.

According to yet another aspect of the invention, an air detector for use in an on-line system for extracorporeal processing of a patient's blood is provided. The first and second oscillators are located on opposite sides of the blood passageway 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 comparison means that periodically compare 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 signal 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 common laminar flow through a single tube. Combined laminar • 4 · 4 · · · · · w · w · w · w · w · ·· * · »· ¹¹ ·· * ··« · «··· streams flow into the fluid mixer inlet portion of the fluid 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

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

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

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

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

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

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Giant. 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.

Giant. 6 is a side view of a drug mixer for mixing its solution with patient blood in the extracorporeal blood circuit operating in accordance with a preferred embodiment of the invention.

Giant. 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.

Giant. 8 is a circuit diagram of an irradiation lamp condition monitoring system disposed in a centrifuge chamber according to a preferred embodiment of the invention.

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

DETAILED DESCRIPTION OF THE INVENTION

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. System 100 works · 4 · · · · ·

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9 44 9 44 444 4444 in several modes, which are performed repeatedly as the number of cycles that make up the entire processing. In the withdrawal mode, the system 100 draws whole blood from the patient 10, adds to the whole blood a precisely determined amount of medication solution by means of a syringe pump 50 and feeds the whole blood and medication solution mixture to the reaction chamber 85 for processing. After processing the whole blood in the reaction chamber 85, the system switches to the back-feed mode, during which the processed whole blood is pumped by the blood pump 80 to the return bag 60. After the contents of the reaction chamber 85 are pumped back 60, the system 100 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 consisting of the above three modes, during one complete processing. No more than 150 ml of whole blood is collected per cycle, which is collected, processed and returned (or infused) back to the patient 10. In an alternative embodiment of the system shown in Figure 2, the operator may vary both the number of repetitions of blood processing cycles and the amount of blood processed per cycle. As shown in FIG. 2, the system 100 is preferably pre-flushed with saline prior to commencing the entire treatment.

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In a second preferred embodiment (shown in Fig. 2A), the system of the above three modes ten times during one complete processing. However, unlike the system shown in Fig. 2, 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, it is after the first batch of whole blood has been collected from the patient. The second dose of blood, which is present in the reaction chamber 85, is then processed while the second dose of blood is mixed with the medically active substance solution. at the same time, the blood contained in the return bag 60 (and collected in the previous cycle) is simultaneously infused back to the patient 10. It has been found that the total time needed to treat the patient can be shortened by processing and re-infusions are performed 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, thereby reducing the time the blood guide tube 12 is unused or idle. As with the system of FIG. 2, in the system of FIG. 2A, only 150 ml of whole blood can be collected, processed and re-infused to a patient 10 in each treatment cycle. In alternative embodiments, however, the operator may vary both the number of cycles per complete processing and the volume of whole blood being processed per cycle.

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

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

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 again to Fig. 1, during the 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 gravity into the pressure cushion reservoir 35. Before reaching the pressure cushion reservoir 35 Anticoagulated by an anticoagulant pump 15 which delivers heparin to the patient's blood from the reservoir 20. The whole blood in the pressure 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. 40 of the pressure pad continuously the blood level in the pressure pad 35 and sends a level signal to the microprocessor controller 45. If the blood level in the cartridge 35 falls below a predetermined minimum threshold, the pu power is reduced. mpy 80 to zero until the blood level in the pressure 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 the blood is never pumped out of the patient by the blood pump 80. in a number of different ways as a sensor φ φ φ φ φ φ φ φ φ φ φ φ φ φ

Electromechanical, optical, ultrasonic and / or piezoelectric. In addition, in an alternative embodiment, the power of the pump 80 may be reduced gradually as the pressure in the pressure cushion decreases.

As the pump 80 pumps the whole blood from the pressure reservoir 35 into the reaction chamber 85 during the withdrawal mode, the liquid active substance is pumped into the blood circuit by the injection pump 50, whose power is controlled by the microprocessor controller 45. In calculating the injection pump power adapts the performance of the injection pump 50 to the performance 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. In addition, as 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 absorption of the active agent through the tubes and other material of which the system 100 is formed.

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., whole blood stream and drug stream) are interrupted. and mix, ♦ * · 0 · 0 ·

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1 00 000 »··· 00 00 to form a mixture of whole blood and drug solution that is pumped by pump 80 to reaction chamber 85. Further details regarding the embodiment of the drug mixer 55 are given below in connection with Fig. 6.

In a preferred embodiment of the present invention, a photoactivatable agent, such as psoralen, and even more preferably 8-methoxypsoralen, is injected in liquid form into the blood circuit through a syringe pump 50 during the withdrawal mode of system 100, although other active agents and / or biological solutions may be used. such as monoclonal antibody solutions or other photoactivatable agents. In a preferred embodiment, the reaction chamber 85 is also represented by 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 photoactivation system inside, is shown and operates essentially as shown and described in the US patent

No. 4,921,473, the subject matter of which is incorporated herein by reference.

Although in a preferred embodiment of system 100, whole blood of patient 10 is collected and delivered to the system to be processed and returned to the patient by infusion, it will be appreciated by those skilled in the art that other sources, such as a blood donation center (e.g. not shown). If the blood obtained from the donor center is delivered to the system 100 for processing, the blood is supplied to the system 100 for processing.

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The processed blood may either be directly infused to the patient through the system 100 or collected into a container (not shown) and infused later on to the patient. Moreover, while in a preferred embodiment the system 100 is used to process whole blood, it will be apparent to one skilled in the art that blood obtained from individual fractions of whole blood can also be processed by the system 100.

FIG. 3 is a flow chart illustrating the operation of a blood pump system 300 and a syringe 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 35. Consequently, in normal operation the pressure cushion is still fully filled with patient blood. . However, if blood flow from the patient to the pressure reservoir 35 slows for any reason, the volume of blood inside the pressure reservoir 35 may eventually decrease, causing the pressure reservoir 35 to collapse. This unwanted situation is prevented by the cushion reservoir sensor 40, which determines the blood level. In the pressure cushion reservoir 35 and signals its level to the microprocessor controller 45. If the blood level in the pressure cushion reservoir 35 drops, the microprocessor actuator 45 reduces the performance of pumps 50 and 80. This feedback mechanism helps patient 10 receive uninterrupted and safe care. .

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The operation of the feedback mechanism generally described in the previous paragraph is illustrated in more detail as the feedback system 300 in FIG. 3. Referring to this figure, the operation of the system 300 begins at step 310 by monitoring the pressure sensor 40 in the cushion container. The signal indicating the level of blood 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 received from the sensor whether the blood level in the pressure cushion container 35 has dropped below If the pressure cushion 35 is found to have collapsed, then system 30 proceeds to step 330 where the microprocessor 45 sends control signals to pumps 50 and 80 kt. set both pumps to the off state. Alternatively, in step 320, the system determines that the pressure reservoir 35 has not collapsed, and then the system proceeds to step 340, in which the microprocessor controller sends a control signal to the pump 80 and energizes the pump 80.

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

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0 0 00 · 0000 0000 00 0 0000 0 0 0000 0 0 0 0 0 000 000 «000000 00 '9 9 9 9 9 9 9 0000 active state and sets its power to the first level (R1). Alternatively, if the system 100 is not in the first cycle of all processing, the microprocessor controller 45 sends a control signal to the injection pump 50, which 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 pump power (R1) in the first cycle is used to compensate for adsorption of the active agent through the tubes and other material that creates the system 100. After adjusting the operating power of the injection pump 50, processing proceeds to step 380. The blood processor to be processed in a given cycle is delivered to the reaction chamber 85 by the blood pump 80. The microprocessor controller 45 determines whether the volume required in the cycle has been achieved by repeatedly monitoring the condition and working performance of the blood pump 80 during the collection mode. If the volume required in the 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 pumps 50 and 80 .

FIGS. 4 and 4A are flow diagrams illustrating the operation of the irradiation time control system 400 to control the irradiation time of the blood contained in the reaction chamber 85 while operating the system 100 operating in a processing mode according to a preferred embodiment of the invention. During the processing mode, the continuous blood stream obtained from the patient 10 is mixed with the solution medically

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As mentioned above, in a preferred embodiment of the invention, the reaction chamber 85 is constituted by a centrifuge comprising 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 all the 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 constitutional components rotating through the centrifuge and then irradiated with UV radiation located inside the centrifuge chamber. By separating and irradiating the patient's blood continuously during the processing mode, the present invention minimizes the time required to treat the patient 10.

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The operation of the irradiation time control system, described generally in the just completed paragraph above, is described in detail as system 400 in Fig. 4. Referring to Fig., System 400 commences operation at the start of processing mode at step 405 by initializing the remaining irradiation time (Tj) by placing it equal to the initial value (T _s ). The value of the remaining irradiation time is a variable that is repeatedly increased or decreased and which represents the remaining time (in seconds) for the blood in the reaction chamber 85 to be exposed to UV radiation before the blood is returned and re-infused to the patient. Initial value

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99 (T _s ) is set to compensate for the fact that UV light from the photoactivation system cannot penetrate full blood, but that such light can only penetrate through a layer of leukocyte concentrate. Since whole blood needs about 2-3 minutes from the time it was transferred to a rotating centrifuge to separate it into individual constitutional components, UV radiation applied to blood during these initial 2-3 minutes is useless for blood processing purposes. Therefore, in a preferred embodiment of the invention, the initial value T _{s is} preferably set to a value between 120 to 180 seconds. In the initialization step 405, the time stamp T _{prev is} set to zero and the volume stamp V _pre v is set to zero. Setting both the values T _pr ev and V _prev 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, a determination of the current volume of blood (V _CU rr) in chamber 85 is performed at step 410. Since blood is continuously pumped into chamber 85 during at least part of the processing mode, the V _CU rr value changes with time. The microprocessor controller 45 determines the V _CU value rr by monitoring the condition and power of the pump 80 during the processing cycle. In step 415, the change in blood volume (deltaV) is determined by subtracting the values of the variables V _CU rr and Vprev, and in step 420 the V _pre v is replaced by a V _CU rr · In step 425 the time elapsed In step 430, the elapsed time change (deltaT) is calculated

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Ζ * Τ 00 0 00 00 00 00 by subtracting T _pre v from T _CU rr and in step 435 ie T _pre v replaced by Tcurr- In step 440 ie the total UV energy value (Uv _C urr) is calculated, representing the total energy that was delivered to blood in chamber 85 during processing. To calculate this total energy value of the UV radiation, the microprocessor controller 45 monitors the state (on / off) of the UV lamps in the reaction chamber 85 during the processing cycle. In addition, the microprocessor controller 45 continuously records the age (in hours of operation) of each lamp in the chamber 85 and adjusts the total UV energy value taking into account the fact that the energy emitted by each UV lamp decreases with the lamp's operating time.

Although in Fig. 4 the steps for determining deltaV (steps 410, 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 deltaV is determined 40 times per second, while the deltaT and UV _curr is determined 5 times per second. Frequent determination of these values is important to ensure that the zero-to-zero transition is captured immediately.

In step 445, which follows the calculation of the deltaV, deltaT, and Uvcurr values, Vcurr is compared to a threshold value (Vthresh), which represents the threshold blood volume that activates the deltaV and deltaT members during the calculation of Ti at step 485 (described below). If

Vcurr is greater than or equal to Vthresh, then in step 450 the first (A) and • 4 4 • 4 4444 ··· 44 4 4444

4444 44 4 4444

4,444 4 4 4 4 444 444 ης 444 4444 4 4

4 44 44 44 44 the second (Β) constant for calculating the irradiation time laid equal to one. If V _CU rr is not greater than or equal to Vthresh then in step 455 the UV _{curr is} compared to the threshold (UVthresh). · If UVcurr is greater than or equal to UVthresh, then in step 460 , respectively. otherwise, at step 465, both the first and second constant for calculating the irradiation time are set equal to zero. The preferred UVthresh value is equal to 300. In step 470, the system 400 determines (or confirms) whether the UV lamps in the chamber 85 are actually 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 at step 470 that the UV lamps are in an active state, then the third constant (U) to calculate the radiation time is equal to one. step 475, otherwise, the third irradiation time constant (U) is set equal to zero.

After determining the three radiation time constants, the microprocessor controller 45 adjusts the value of Tj according to Equation (1) below:

Ti = Ti + (A * C * deltaV) - (B * U * deltaT) (1) where C is a constant representing the number of seconds of irradiation time to be added to the remaining irradiation time Tj, as each milliliter of blood is is added to chamber 85. In step 490, T i is compared to a zero threshold. If Tj is not greater than zero, then this indicates that the irradiation step is complete, otherwise it is: · · · * · * krok je jinak je je jinak jinak jinak jinak jinak · · · · ··· ·· t · · · ·

The process illustrated in FIG. 4 is repeated until T1 reaches or falls below the zero threshold.

Referring to Fig. 1, a preferred embodiment of 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 given to immediately inform the operator that air has been detected as soon as air is detected by system 100. Referring to FIG. 5, a block diagram of air detectors 25 and 30 is shown. The first and second oscillators 505 and 510 are located. on opposite sides of a blood passage tube 12 which guides the patient's blood through the online system. The first and second crystal oscillators 505 and 510 are carried by a carrier block of an air detector 515 having outlets adapted to receive 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 driver 45 includes comparing means that periodically compares the signals transmitted by the signal transmitter 520 to the signals received by the signal receiver 525. Since the signal transmitter 520 periodically transmits the same signal, an unexpected change. 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 which signal the presence of air in the tube. · • · * «t ·« · t · »« ·· • · · ·

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4 4 if there is an unexpected change in the signal received by the receiver 525.

In a preferred embodiment of the present invention, the operation of each air detector 25, 30 is periodically tested to verify that they operate in the correct manner. Specifically, signal transmitter 520 is turned off at regular intervals, and each signal received by signal receiver 525 is recorded by microprocessor controller 45. If an unexpected signal is received by signal receiver 525 during the verification test, this would mean that the air detector is not working properly either 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 alarm is sounded to alert the operator to an incorrect condition.

Although in FIG. 1 the air detectors 25 and 30 are shown in a position near the anticoagulant pump 15 and the mixer 55, it will be apparent to those skilled in the art that air detectors 25 and 30 may be located anywhere in the system 100. The air may be used to detect the presence of air in the circuit through which fluid other than blood is present in the extracorporeal blood circuit.

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FIG. 6 shows a side view of the drug mixer 55 for mixing its solution with the patient's blood in the extracorporeal blood circuit operating in accordance with a preferred embodiment of the invention. The mixer 55 is a closed hollow chamber 610 having an opening 600 through which unmixed fluids enter the mixer and an opening 650 through which mixed liquids flow from the mixer. The interior of the chamber 610 is divided into compartments 620 and 630 by a mesh bag 640 which is circumferentially attached to the interior of the hollow chamber 610. During operation of the fluid mixer 55, the first fluid and second fluid flow together through laminar flow through the same fluid conduit. 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 breaking the combined laminar flow of both. When the mixer 55 is used to mix blood with other solutions, the mesh 640 preferably has an aperture size ranging from 100 to 600 microns. It will be appreciated by those skilled in the art 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, the system 100 comprises means for detecting blood loss from the extracorporeal circuit. Such blood loss may occur, for example, if an opening or a crack appears in the blood processing centrifuge chamber, or or this. If the contents overflow inside the centrifuge chamber, the contents will be overflowed. If the system 100 detects that blood is being lost from the extracorporeal circuit, a warning signal is triggered to signal the event to the operator. 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 trapping any overflow or leakage of blood from the reaction chamber 85. The lowest portion of the outer shell is connected to a drain tube 710 to drain any blood that escapes or splashes into the outer shell. In the system 700, a first electrically conductive tube 720 is used having its first end connected to the drain tube 710. An insulating block 730 is also provided that includes a first hollow channel 735 into which the second end of the first electrically conductive tube 710 is inserted. it is not electrically conductive. The insulating block further 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 channels 735 and 740 are connected in the insulating block 730 by a hollow fluid bridge 755. 720 to the first end of the second electrically conductive tube 750. A comparator circuit 760 is used to determine 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 cause a conductive connection between the first and second electrically conductive tubes 720 and 750 in 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 the hollow fluid bridge 755 thereby signaling blood loss from 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 when an electrically conductive connection between the first and second electrically conductive tubes 720 and 750 is detected.

As mentioned above in the explanation of FIG. 4, in step 470 of system 400, the state (on / off) of UV irradiation lamps within the reaction chamber 85 is repeatedly monitored in the process of the present invention. FIG. 8 now shows a circuit diagram of a preferred embodiment a circuit of the radiation monitoring system 800 of a radiation lamp 810 disposed in a centrifuge chamber according to a preferred embodiment of the present invention. In system 800, the sinusoidal voltage 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 that produces a logic signal 0 at the output of circuit 840. the lamp 810 is in the off state, then there is no voltage at 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 and connected to each lamp A separate system 800 so that the status of each lamp is monitored separately during processing.

Finally, FIGS. 9 and 9A are front 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 body of the syringe pump 50. The syringe 910 is preferably a glass syringe and is filled with a medically active agent solution. 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 rods 940, 950 disposed on opposite sides of the syringe 910 piston portion 960. In a preferred embodiment, the extrusion block 930 is provided with a cutout 970 for securing the syringe piston portion 960 to the extrusion block. 930. The notch 970 in the extrusion block 930 for securing the plunger portion 960 of the syringe 910 is shaped to prevent the on-line system from discharging a medically active substance solution from the syringe 910 while in the bloodstream connected to the outlet 920 of the syringe. 910, negative pressure. The drive means (not shown but located between blocks 900 and 930 in Figs. 9 and 9A) coupled to the mounting block 900 and the extrusion block 930 move the extrusion block 930 toward the mounting block 900 in response to the control signal sent by the microprocessor This control signal tells the driving means whether

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The injection pump 50 should operate with an injection rate R1, an injection rate R2 or whether the injection pump 50 should remain in the off state. In a preferred embodiment, the drive means used to drive the extrusion block 930 towards the assembly block 900 is embodied 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 if a syringe 910 has not been placed in the mounting block 910. FIG. 9 shows the safety cap 980 in the open state, while FIG. 9A shows the safety cap 980 in the closed state. The control signal prevents operation of the system of the present invention when the safety shutter 980 is in the open state.

It will be apparent to those skilled in the art 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 other circuits, are added to the blood in the extracorporeal blood circuit. dosing and mixing well before feeding the mixture to the processing chamber.

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The present invention may be practiced in other ways without departing from the spirit and essential attributes of the invention. Accordingly, the scope of the present invention is based not on the above description but on the appended claims.

Claims (10)

PATENT CLAIMS An on-line method for extracorporeal administration of a predetermined amount of a solution of a medically active agent to a patient's blood comprising the steps of: (A) collecting blood from the patient's blood into the blood reservoir, and draining the collected (B) pumping the drawn blood from the blood reservoir into the bloodstream at a first pumping rate, (C) detecting the blood level in the blood reservoir in response to determining a detected blood level in the blood reservoir, (D) adjusting a first pumping rate in response to the detected blood level in the blood reservoir, (E) pumping a medically active substance solution into the bloodstream at a second pumping rate, responses to the first pumping rate, and (G) mixing the collected blood in the blood conduit with a solution of the medically active agent in the blood conduit. 2. The method of claim 1, further comprising, after the mixing step, the step of delivering the collected blood and medically active agent solution to the reaction chamber. • · · · · · · · · · · · 3. The method of claim 1, wherein the second pumping rate is adapted to the first pumping rate. 4. The method of claim 1, wherein the mixing step is achieved solely by simultaneous flow of the collected blood and a solution of the medically active agent in the bloodstream. 5. The process of claim 2 wherein the reaction chamber is a photoactivation chamber. 6. The method of claim 5, wherein the medicament active ingredient solution comprises psoralen. Method according to claim 1, characterized in that a syringe pump is used for pumping a solution of the medically active substance into the blood conduit in step (E). An on-line system for extracorporeal administration of a predetermined amount of a medically active substance solution to a patient's blood by a method according to any one of claims 1 to 7, comprising a blood conduit for transporting the patient's blood through the system and an air detector from (A) the first and second oscillators (505, 510) located on opposite sides of the blood line, (B) a signal transmitter (520) that is connected to the first oscillator (505), • 0 · 000 00 0 0000 000 «· 0 0 0000 0 0 0000 · 0 0 0 0 000 000 000 0000 0 0 00 0 0 9 00 09 00 (C) of the signal receiver (525) connected to the second oscillator (510), (D) a microprocessor controller (45) coupled to the signal transmitter (520) and the signal receiver (525), the microprocessor controller (45) comprising comparing means for comparing the signals transmitted by the signal transmitter (520) to the signals received by the signal receiver (525) and an air detector (25, 30) that is responsive to a comparator for signaling the presence of air in the bloodstream. The system of claim 8, wherein in the air detector (25, 30) the microprocessor controller (45) further comprises an inspection means that periodically inspects the signal transmitter (520) and the signal receiver (525) by periodically switching off the signal transmitter (45). 520) and monitoring signals received by the signal receiver (525). System according to claim 8, characterized in that in the air detector (25, 30) the first oscillator (505) and the second oscillator (510) are crystal oscillators.