Abstract:
A process and device for metering different solutions is provided with which a high rate of repetition of drugs to be metered is possible. To accomplish the object, provisions are made for taking fluid volumes in the range of 50 nL to 50 μL from a fluid source ( 2, 3, 4, 5 ) in rapid succession in time according to the time multiplex method and for introducing them into a collecting channel ( 10 ) without mixing.

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     This application claims the benefit of priority under 35 U.S.C. §119 of German Patent Application 10 2005 045 393.7 filed Sep. 23, 2005, the entire contents of which are incorporated herein by reference. 
     FIELD OF THE INVENTION 
     The present invention pertains to a device and a process for metering solutions in a time multiplex manner. 
     BACKGROUND OF THE INVENTION 
     A device of this type is known from U.S. Pat. No. 4,925,444. The prior-art infusion system offers the possibility of metering different solutions from fluid sources according to the multiplex method into a common collecting channel. A typical metering cycle at a rate of metering of 50 mL per hour lasts about 40 sec. If the cycle time is reduced, a higher flow rate is necessary, which is permissible as a short-term bolus in exceptional cases only. 
     Catecholamines with blood plasma half-lives of less than 2 minutes must be metered either continuously or quasi-continuously at intervals shorter than 15 sec. The smallest metered quantity is about 1 μL. 
     Other drugs are titrated by the physician according to their action; for example, in the case of remifentanil, the rate of metering is changed as a function of the depth of anesthesia. A change in the rate of metering must have reached the patient within a few seconds in the case of these drugs. Such drugs cannot be metered with the prior-art infusion system because of the long rinsing times. Incompatible drugs can also be transported through the same patient line in exceptional cases only with the prior-art infusion system. The desired separation between individual drugs can be achieved with difficulty only. A parabolic flow profile will rather develop in the patient line, which leads to nearly complete mixing on the transport path. 
     SUMMARY OF THE INVENTION 
     The basic object of the present invention is to provide a process for metering different solutions, which makes possible a high rate of repetition. 
     According to the invention, a process is provided for metering liquids from a plurality of fluid sources in a time-multiplex manner according to a fluid release plan into a common patient line. The process includes the selection of a fluid source and removal of the fluid volumes in the range of 50 nL to 50 μL. A fluid stream is formulated from a sequence of the fluid volumes of at least two said different fluid sources. The individual metered volumes for each solution are added up to a total volume. A comparison is made of the total volumes administered for each solution with the fluid release plan in order to minimize deviations. 
     The advantage of the present invention is essentially that the portion size of the drugs being metered is reduced to the extent that the metering of one portion contains markedly less active ingredient than the target quantity of the active ingredient in the blood circulation even in the case of quickly and intensely acting drugs. For example, the minimum target quantity in the blood at a low dosage is approx. 5 μg in the case of the catecholamine norepinephrine. At a usual concentration of 100 μg per mL, the target quantity in the blood will consequently correspond to a drug portion size of approx. 50 μL. If, by contrast, undiluted drug is used, this quantity may be even considerably lower. 
     Helpful is the metering of drug portions of different drugs with predefined volume into a common line, in which the size of the smallest drug portions used is in the range of 50 nL to 50 μL. Especially advantageous is likewise the metering of drug portions of different drugs with predefined size into a common line, in which the enclosed system volume, through which at least two solutions flow from different storage containers, from the point of confluence to the entry into the patient&#39;s bloodstream, is smaller than 0.7 mL. A system volume in the range smaller than 0.3 mL is especially advantageous here. 
     In case of metering drug portions of different drugs with a predefined size into a common line, a mean flow rate of 50 mL per hour will usually become established. A mean velocity of at least 7 cm per second is advantageous. A mean velocity of at least 13 cm per second is advantageous. 
     Immiscible drugs are advantageously separated by a separating medium. A lipid liquid is advantageously used as the separating liquid. Soybean oil is also a suitable separating liquid. It is also possible to use as the separating medium gases, for example, air, oxygen, nitrogen, carbon dioxide or water vapor. It should be borne in mind in case of using gases that the metered gas volume does not exceed the value of 1 mL within 15 minutes. 
     The drugs to be metered can be fed into a common collecting channel in different ways. It is possible in this connection to associate an active pump with each drug line. Suitable pumps are, for example, peristaltic micropumps, with which a stroke volume between 50 nL and 50 μL can be obtained. An alternative possibility of metering is to take a drug portion with a calibrating volume from the fluid source and then feed same into the collecting channel. 
     If actively delivering pumps are arranged in each drug line, high costs may arise, because the element determining the precision must assume both the metering function and the transport function. A total flow pump is therefore advantageously arranged in the connecting channel, and the drug lines are provided with on-off valves, which are briefly opened to release a certain portion of drug into the collecting channel. Fluidic flow resistances in the form of metering capillaries may be associated with the on-off valves. 
     The metering of the drugs is precise if the fluidic resistance is exactly known in each drug line and the vacuum that becomes established is determined in the collecting channel and is also included in the evaluation. 
     Metering capillaries made of glass or silicon, as they are known from laboratory practice, can be used especially advantageously for metering. To minimize the effect of changes in viscosity during temperature changes, all metering capillaries are thermally controlled. As an alternative, the temperature may also be measured and compensated by calculation. 
     It is especially advantageous to use two pumps arranged in series for metering the drug and for transporting same over the patient line and into the patient. The first pump now operates as a precision pump and delivers the drug from a rigid collecting chamber into a soft intermediate chamber, while the second pump takes the drug from the intermediate chamber and delivers same into the patient line. The soft intermediate chamber is used to equalize the pressure between the pump used to meter the drug and the total flow pump, and thus it ensures that the drug metering area is subject to small pressure differences ranging from a few multiples of 10 mbar to a few multiples of 100 mbar only. By contrast, the delivery pressure in the patient line for transporting the drugs to the patient is a few bar. 
     To reduce the dead space volume, the patient line is designed such that its cross-sectional area is in a range between 0.02 mm 2  and 0.2 mm 2  at least in some sections, which corresponds to a diameter between 0.05 mm and 0.5 mm. 
     Metering valves for feeding drugs into the common collecting channel are advantageously arranged directly at the collecting channel. As a result, the drugs can be released directly into the collecting channel, without mixing reactions taking place at the site of feeding in. Dead volumes of &lt;10 μL can thus be obtained. 
     Metering elements for a plurality of drugs and the corresponding collecting channel and, if necessary, also flow- and pressure-measuring systems are advantageously arranged on a common carrier plate in the form of a microfluid metering system. 
     The carrier plate has connections for drug lines as well as two connections for passing through the collecting channel. Due to the use of a common carrier plate, dead space volumes within the metering system can be further reduced. 
     To prevent the velocity of the drug from becoming too low, a small line cross section of the patient line is especially advantageous in case of the metering of drugs with a low flow rate. On the other hand, a small line cross section means a great pressure drop at high flow rates. It is therefore advantageous to select a material for the patient line that increases the cross-sectional area by at least 10% at flow rates between 100 mL per hour and 200 mL per hour compared to the cross-sectional area without flow. This can be achieved by the use of a flexible tube material that stretches in a pressure-dependent manner. 
     Pressure measurement is necessary in the collecting channel for the accurate monitoring of metering. The sterility of the drugs being metered must not be compromised by the pressure measurement. A hydrophobic bacteria filter, which is arranged upstream of the pressure pick-up, is advantageously used for the pressure measurement. The liquid phase in the collecting channel is separated hereby from the gas phase in the area in which the pressure is measured. 
     An exemplary embodiment of the present invention is shown in the drawings and will be explained in greater detail below. The various features of novelty which characterize the invention are pointed out with particularity in the claims annexed to and forming a part of this disclosure. For a better understanding of the invention, its operating advantages and specific objects attained by its uses, reference is made to the accompanying drawings and descriptive matter in which preferred embodiments of the invention are illustrated. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       In the drawings: 
         FIG. 1  is a schematic view of an infusion system according to the present invention; 
         FIG. 2  is a longitudinal sectional view of a peristaltic micropump; 
         FIG. 3  is a schematic view of a drug metering system with a deformable tube section; 
         FIG. 4  is a schematic view of a drug metering system with metering capillaries; 
         FIG. 5   a  is a schematic view showing a drug-metering system with pinch valves in the drug lines and two delivery pumps connected in series; 
         FIG. 5   b  is a schematic view showing a drug-metering system with pinch valves in the drug lines and two delivery pumps connected in series; 
         FIG. 5   c  is a schematic view showing a drug-metering system with pinch valves in the drug lines and two delivery pumps connected in series; 
         FIG. 6  is a schematic view of a drug-metering system in which the pinch valves are arranged in the connection area to the collecting channel; 
         FIG. 7  is the drug metering system according to  FIG. 6  with additional connectors; 
         FIG. 8  is a schematic view showing a micrometering system on a carrier plate; 
         FIG. 9  is a schematic view showing the micrometering system according to  FIG. 8  with additional actuators; 
         FIG. 10   a  is a schematic view showing a drug-metering system with drug metering via a calibrating volume; 
         FIG. 10   b  is a schematic view showing a drug-metering system with drug metering via the calibrating volume; 
         FIG. 11  is a schematic view showing a drug-metering system with sterile pressure measurement; and 
         FIG. 12  is a schematic view showing a drug-metering system according to  FIG. 11  with vacuum generation in the collecting channel. 
     
    
    
     DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     Referring to the drawings in particular,  FIG. 1  schematically illustrates the design of an infusion system  1  for metering drugs from four fluid sources  2 ,  3 ,  4 ,  5 . The fluid sources  2 ,  3 ,  4 ,  5  are connected via metering elements  6 ,  7 ,  8 ,  9  with a collecting channel  10 . A pump  11  connected to the collecting channel  10  delivers carrier liquid  13  from a reservoir  12  into a patient line  14 . The fluid sources  2 ,  3 ,  4 ,  5  contain different drugs, which are introduced into the collecting channel in portions according to a release plan. The drug boli  15 , which are illustrated as an example in the patient line  14 , are separated from one another by the carrier liquid  13 . A control unit  100  is connected to the metering elements  6 ,  7 ,  8 ,  9  and the pump  11  and performs the metering of the drugs according to the multiplex method according to the fluid release plan. The control unit provides means for selecting the fluid source based on the fluid release plan. The total volume of each drug being metered is continuously determined and compared to the preset value in the fluid release plan. If deviations are now detected, the actuating signals for the metering elements  6 ,  7 ,  8 ,  9  are correspondingly adjusted. 
       FIG. 2  shows the longitudinal section of a peristaltic micropump  16  as a metering element as it appears as an example from DE 102 38 600 A1. The micropump  16  comprises a membrane element  17  with three membrane sections  18 ,  19 ,  20 . Each of the membrane sections  18 ,  19 ,  20  is provided with a piezo element  21 ,  22 ,  23  and forms separate piezo membrane transducers together with the membrane sections  18 ,  19 ,  20 . A pump body  24  contains a fluid inlet  25  and a fluid outlet  26 . An inlet valve  27 , a pump chamber  28  and an outlet valve  29  are formed by the membrane sections  18 ,  19 ,  20  in connection with the pump body  24 . 
     With the outlet valve  29  closed and the inlet valve  27  opened, the membrane section  19  of the pump chamber  28  is moved upward, and the drug to be metered is drawn up via the fluid inlet  25 . The inlet valve  27  is then closed, the outlet valve  29  is opened and the drug volume is released via the fluid outlet  26 , and the membrane section  19  is now moved downward. Volume strokes in the range of 0.1 μL, to 010 μL, can be performed with the prior-art micropump  16 . The micropump  16  forms one embodiment of a means for removing fluid volumes. 
       FIG. 3  illustrates an alternative metering element  30  in the form of an elastomer channel  32  deformable by a pump  31 . The alternative metering element  30  forms a means for removing fluid volumes. The drug to be metered is accommodated in a fluid container  33  with low flexural strength. A defined, measured channel section  34  is filled with the drug and is subsequently emptied by the pump  31 . The elastomer channel  32  has an internal cross section in the range of 0.1 mm 2  to 2 mm 2  and a wall thickness greater than 1 mm. The metered fluid volume is fed into the collecting channel  10  that forms a means for forming a fluid stream. 
       FIG. 4  shows a drug metering system  35 , in which drug containers  36 ,  37 ,  38 ,  39  are connected to the collecting channel  10  via temperature-stabilized metering capillaries  40  and corresponding on-off valves  41 ,  42 ,  43 ,  44  that form a means for removing fluid volumes. The collecting channel  10  (means for forming a fluid stream) is connected to the reservoir  12  for the carrier liquid  13  via a throttle  45 . Another on-off valve  46  and a pressure-measuring device  47  are located on the discharge side of the throttle  45 . The pump  11  delivers the fluid stream into the patient line  14 . 
     The metering capillaries  40 , which are schematically illustrated as a block only in  FIG. 4 , consist of glass or silicon with a cross-sectional area smaller than 0.05 mm 2 . The fluidic resistance is more than 50 mbar per 1,000 mm per hour and typically 50 mbar per 20 mL per hour. 
     To meter drug volumes, a defined vacuum is generated with the pump  11 , and this vacuum is measured with the pressure-measuring device  47 . By opening one of the valves  41 ,  42 ,  43 ,  44  for a predetermined time interval, the drug to be metered is drawn in from one of the drug containers  36 ,  37 ,  38 ,  39 . By briefly opening the valve  46  in the collecting channel  10 , carrier liquid can subsequently be delivered before a new drug volume is metered. By temporarily closing the on-off valve  46  in the collecting channel  10 , the rate of delivery of the carrier solution can be reduced if needed. 
       FIGS. 5   a - 5   c  schematically show a drug metering system  50 , in which a total flow pump  52  is arranged downstream of the pump  11  via a flexible intermediate chamber  51 . Two drug lines  53 ,  54  are connected to the collecting channel  10  consisting of solid material via pinch valves  55 ,  56  (means for removing fluid volumes). Another pinch valve  57  is located in the collecting channel  10  on the side on which the flow in the drug lines  53 ,  54  arrives. 
     The pump  11  delivers from the rigid collecting channel  10  into the soft mixing chamber  51  to the inlet of the total flow pump  52 . 
     The soft intermediate chamber  51  is used to equalize the pressure in case of transient differences between the flow rates of the pump  11  and the total flow pump  52  and it thus ensures that the pump  11  is exposed to small pressure differences ranging from a few multiples of 10 mbar to a few multiples of 100 mbar only. The delivery pressure proper for transporting the drugs to the patient is a few bar and is generated by the less precise total flow pump  52 . 
     The course of metering over time is shown in  FIGS. 5   a  through  5   c.    
     In  FIG. 5   a , the pinch valve  57  is opened and the carrier flow in the collecting channel  10  is stagnant. The pinch valve  57  is closed and the pinch valve  56  of the drug line  54  is opened in  FIG. 5   b , so that the pump  11  transports a predefined drug volume  58  into the collecting channel. The rigid collecting channel  10  with a compliance of &lt;100 nL per mbar ensures that exactly as much drug is taken from the drug line  54  as is drawn in by the pump  11 . The pinch valve  57  is opened and the pinch valve  56  is again closed in  FIG. 5   c . The drug volume  58  is transported with the carrier liquid  13  by the pump  11  into the collecting channel  10 . After the metering of the drug, pump  11  opens and carrier liquid is delivered exclusively via the less precise total flow pump  52 . Pressure equalization is achieved as a result in the intermediate chamber  51 . 
     According to an advantageous variant of a drug metering system  60  shown in  FIG. 6 , pinch valves  61 ,  62  (fluid volume removal means) are placed in the connection area between the drug lines  63 ,  64  and the collecting channel  10 . Metering that is controlled over time is thus achieved, and a mixing reaction in the dead space between the solution in the collecting channel  10  and the pinch valves  55 ,  56 ,  FIG. 5 , is avoided. The dead space can be reduced to a value of less than 50 nL with the drug metering system  60  corresponding to  FIG. 6 . The pinch valves  61 ,  62  consist of elastomeric materials, which can be closed by compression. 
     Part of the drug line  63 , the pinch valve  61  and a collecting channel section  101  are made in one piece and integrated into the overall system via contact points  65 ,  66 ,  67  in a variant of the drug metering system  60  according to  FIG. 6 , which is illustrated in  FIG. 7 . 
     The pinch valves  71 ,  72 ,  73 ,  74  (fluid volume removal means) and the collecting channel  10  are arranged on a common carrier plate  75  in the form of a micrometering system in a drug metering system  70  shown in  FIG. 8 . The connection to the peripheral components is performed via so-called Luer Lock connections  76 . 
       FIG. 9  illustrates an alternative drug metering system  80  to the drug metering system  70  according to  FIG. 8 , in which a pump  77 , closing valves  78 ,  79  and a pressure-measuring device  81  are additionally arranged on the carrier plate  75 . Identical components are designated by the same reference numbers as in  FIG. 8 . 
       FIG. 10   a  shows a metering device  82 , in which a drug volume  86  is taken from a drug container  83  by means of a slide  84  that forms the means for removing fluid volumes). The slide  84  has a recess  85  for this in the form of a calibrating volume, which recess is filled with the drug.  FIG. 10   a  illustrates the filling of the recess  85 , and the release of the drug into the collecting channel  10  is illustrated in  FIG. 10   b.    
       FIG. 11  shows as an example a sterile pressure measurement in a drug metering system  90 , which contains the collecting channel  10 , a drug line  91  with a pinch valve  92  and the pump  11 . A volume  93  is divided by a hydrophobic membrane  94 , which is permeable to gas, into two chambers  95 ,  96 . The upper chamber  95  is connected to a pressure pick-up  96  with the measuring membrane  97 . 
     The lower chamber  96  is in flow connection with the collecting channel  10  and is filled with the carrier liquid  13 . 
     When the pump  11  draws in, the volume of gas in the upper chamber  96  increases and the membrane  94  is exposed, so that the hydrostatic pressure of the carrier liquid  13  acts directly on the measuring membrane  97 . This state is illustrated in  FIG. 12 . Sterile separation of the pressure measurement from the delivery of fluid is brought about by the membrane  94 . 
     While specific embodiments of the invention have been shown and described in detail to illustrate the application of the principles of the invention, it will be understood that the invention may be embodied otherwise without departing from such principles.