WO2006132571A1

WO2006132571A1 - Pressure measurements in automatic taking of specimens

Info

Publication number: WO2006132571A1
Application number: PCT/SE2005/000867
Authority: WO
Inventors: Hans Axel Hansson
Original assignee: Dilab I Lund Ab
Priority date: 2005-06-09
Filing date: 2005-06-09
Publication date: 2006-12-14

Abstract

The present invention relates to automatic taking of specimens, wherein a catheter means (10) is connectable to a test object (20) and comprises at least one passageway for a pressure-conducting medium, a pumping means (30) is connectable to said catheter means (10) and configured to control the flow direction and flow rate of said pressure-conducting medium in said passageway, a pressure sensor (40) is arranged at said catheter means (10) and configured to register a pressure value corresponding to the pressure of said pressure-conducting medium in said passageway, and an analyzer (50) is connectable to said pressure sensor (40) and said pumping means (30), and configured to evaluate said registered pressure value, and being configured to control said pumping means (30) in dependence of said evaluation.

Description

PRESSURE MEASUREMENTS IN AUTOMATIC TAKING OF SPECIMENS

Field of the invention The present invention refers to pressure measurements in automatic taking of specimens from a test object, and especially to pressure measurements wherein the taking of specimens is controlled in dependence of the pressure measured in a catheter means connected to the test object.

Background of the invention

There exist today automatic systems for taking of specimens from and for delivering injections to test objects, for example laboratory animals used for experimental purposes such as rats and pigs. Such prior art automatic systems usually includes a computer with accompanying computer program software for controlling the taking of specimens, injecting and communicating with a user as well as computer program software for storing system parameter and log files. The systems further includes actuating devices such as pumps, valves, containers for injections solution, rinsing liquid and specimens, catheter means or tubing system connectable to the test object. Automatic systems for taking of specimens are for example often used in the pharmaceutical industry during the development of new drugs in order to study the biokinetics of an administered drug, i.e. to study the distribution of the drug in a test object over a predefined time period. Specimens are often taken from a living being at several time points separated over time and sometimes the specimens are taken at several time points during several days. During this entire specimen taking period, the catheter means is connected to the test object. Since the test object usually is a freely moving laboratory animal it is important to secure that no imperfections exist in the catheter means. Such imperfections in the catheter means may for example be imperfections in the attachment of the catheter means to a blood vessel of the animal, but it can also be blockage of the passageway of the catheter means or leakage from the catheter means. As understood by the skilled person, imperfections in the catheter means may result in that an improper specimen is taken or in that an expensive injection solution is unnecessarily injected to the test object.

The patent US 5,758,643 to Wong et al. describes a method and a system for monitoring a patient's blood chemistry, and to controlling the drawing of a patient's blood sample to a prescribed position within a blood chemistry sensor assembly. It is ensured that the blood sample reaches all of the sensor assembly's individual analytical sensors and that sufficient additional blood is drawn to minimize the dilution effects of an adjacent infusion fluid. If a patient's blood sample has not been detected by one of the sensors within a predetermined maximum time duration or if the arrival is detected to have occurred before a predetermined minimum time duration, a controller is programmed to actuate an alarm and to switch of the pump. A drawback with the system of US 5,758,643 is that imperfections can only be detected after a time period when withdrawn blood has reached or would have reached the sensor assembly which is configured to analyze the blood. Thus the system of US 5,758,643 does not provide for an early detection of imperfection since either the withdrawn blood has to reach the sensors or a predetermined maximum time has to laps before the system realizes that something is wrong. Another drawback with the system of US 5,758,643 is that the sensor assembly has to be carried by the patient, and preferably is it located close to the sample site, in order to minimize the volume of the blood that is withdrawn from the patient.

The patent US 4,460,355 to Layman describes a method and an apparatus for detecting occlusions in a parenteral administration system of a type that cyclicly pumps a fluid through a feeding tube to a patient, each pumping cycle having a period of reduced fluid flow. The apparatus includes pressure transducer means for measuring the pressure of the fluid being pumped through the tube and for producing a corresponding pressure signal. The apparatus includes further a comparator means for comparing the pressure signal to a prescribed threshold only during the periods of reduced fluid flow in the successive pumping cycles, along with alarm means for producing an alarm whenever the comparator means determines that the pressure signal exceeds the threshold. By comparing the pressure signals to a prescribed threshold only during the period of reduced flow, the undesired effects of the pressure spikes caused by the cycling pumping action are eliminated.

A drawback with the apparatus of US 4,460,355 is that the pressure signal can be compared with a prescribed threshold only during a period of reduced fluid flow, i.e. the comparison can only be done with a pressure signal representing a pressure taken during a short time period in each cyclic pumping action.

The patent US 4,534,756 to Nelson describes an apparatus and a method for use with a parenteral administration system of the type having an infusion device for infusing a parenteral fluid through a fluid tube and needle to a patient's vascular system. The apparatus comprises pressure transducer means for monitoring the pressure of the fluid in the fluid tube and producing a corresponding pressure signal. Fault detection means is further comprised for qualitatively evaluating the pressure signal to determine when the fluid tube is not in proper fluid communication with the patient's vascular system, and for producing a corresponding alarm signal. According to one embodiment of the apparatus of US 4,534,756, the fault detection means detects an infiltration by determining if the pressure signal ever fails to return to its steady state level within a predetermined time duration following each infusion pulse.

According to another embodiment of the apparatus of US 4,534,756, the fault detection means detects infiltration at relatively high infusion rates by determining if the pressure signal ever increases by more than a particular amount during a predetermined time duration.

Neither of the patents US 4,460,355 and US 4,534,756 disclose an apparatus for taking of specimens, wherein pumping means in controlled in dependence of the pressure of the fluid in the fluid tube.

An aim of the present invention is thus to overcome the above mentioned drawbacks with the prior art systems.

Summary of the invention The present invention solves the above-mentioned drawbacks, by a system, an analyzer, a pressure sensor and a computer program product according to the independent claims. Preferred embodiments of the invention are defined in the dependent claims.

Detailed description of the drawings

The invention will now be described in more detail with reference to the accompanying drawings, in which:

FIG. 1 schematically shows an embodiment of a system for automatic taking of specimens from a test object; FIG. 2 schematically shows a normal pressure graph Sl for a correctly arranged catheter means at an artery of a test object;

FIG. 3 schematically shows the normal pressure graph Sl of figure 2 together with an interval of tolerance;

FIG. 4 schematically shows the normal pressure graph Sl of figure 2 together with a pressure graph S2 for a semi-clamped catheter means;

FIG. 5 schematically shows the normal pressure graph Sl of figures 2, 3 and 4, the semi-clamped pressure graph S2 of figure 4 and a pressure graph S3 for a completely clamped catheter means; and

FIG. 6 schematically shows the pressure graphs Sl, S2 and S3 of figure 5 together with five points of pressure measurement indicated at I - V.

Detailed description of the invention

Figure 1 shows schematically a system 1 for automatic taking of specimens according to an embodiment of the present invention. The system 1 comprises a catheter means 10 connectable to a test object 20 and comprising at least one passageway for a pressure-conducting medium. As illustrated in the figure, a part of the catheter means 10 is inserted into the test object 20.

The catheter means 10 can be realized as one or several tubings. The tubings can be connectable to each other by means of one or several valves or the like. Further, a first end of the catheter means is connectable to a specimen taking device, e.g. to a pumping means, and a second end of the catheter means is connectable to the test object. The test object 20 may for example be a living being, such as a freely moving laboratory animal, e.g. a rat or a pig. The pressure-conducting medium may for example be an injection solution, such as a sodium chloride solution or a drug, or a taken specimen, such as a blood sample.

Further, the system 1 comprises a pumping means 30 connectable to said catheter means 10 and configured to control the flow direction and flow rate of said pressure-conducting medium in said passageway of said catheter means 10. The pumping means can be realized as e.g. a piston pump or a roller pump.

A pressure sensor 40 is arranged at said catheter means 10 and configured to register a pressure value corresponding to the pressure of said pressure-conducting medium in the passageway of the catheter means 10. The pressure sensor can be realized as any kind of equipment for pressure measurements, for example based on inductive optical techniques or as another sensor capable of measuring the pressure of a pressure-conducting medium in a passageway of a catheter means.

The pressure sensor 40 is configured to continuously, or at predetermined time points, register a pressure value corresponding to the pressure of said pressure- conducting medium in said passageway at different time points and to communicate the registered pressure value to an analyzer connected to the pressure sensor. Confer for example figure 2 illustrating the pressure variation over time when a catheter means is correctly arranged in an artery of a test object.

The pressure sensor, the analyzer and the pumping means are preferably arranged at a distance from the test object, as illustrated in figure 1, in order not to have an effect on the test object. This is especially important in e.g. biokinetic studies on laboratory animals, when samples are taken at several occasions during several hours or days and when it is important not to disturb the animal or to put them under pressure, since that could negatively affect the result of the study.

According to embodiments of the invention, the pressure-conducting medium in the catheter means 10 at the pressure sensor 40 comprises preferably a sodium chloride solution.

The system 1 comprises further an analyzer 50, which is connectable to the pressure sensor 40 and to the pumping means 30. The analyzer 50 is configured to evaluate the pressure value registered by the pressure sensor and to control the pumping means 30 in dependence of said evaluation.

The analyzer 50 is configured to evaluated said registered pressure value in dependence of predefined limit values. According to an embodiment of the invention, the predefined limit values define an interval of tolerance. If a registered pressure value is within the predefined limit values or within the interval of tolerance, no imperfections in the catheter means is detected. If however a registered pressure value lies without the predefined limit values or without the interval of tolerance, an imperfection in the catheter means is detected. A detected imperfection can for example be an imperfection in the attachment of the catheter means at the test object, but it can also relate to a blockage of the passageway and/or a leakage in the catheter means.

The analyzer 50 is further configured to shut down or alter the operation of the pumping means 30 if a blockage of the passageway or a leakage in the catheter means 10 or an imperfection of the attachment of the catheter means 10 at the test object 20 is detected. The analyzer 50 can also be arranged to provide information regarding the functioning of the system to an operator. The information can for example be communicated as a signal sent by means of wired or wireless techniques.

The specimen taking procedure and the evaluation process of the analyzer 50 will now be described with reference to the figures 2 - 6. The figures 2 - 6 show the pressure as a function of time. In the figures, the pressure is given without unit and the time is given in milliseconds (ms). By means of the reference letters A - C₅ the figures 2 — 5 will be described in more detail and figure 6 will be described by means of the reference numerals I — V. Figure 2 schematically illustrates a normal pressure variation over time when a catheter means is correctly arranged in an artery of a test object. During the time period A, e.g. during the time interval of 0 - 42000 ms as illustrated in figure 2, a specimen is taken from the artery. The specimen is withdrawn from the artery by the pumping means which provide an underpressure in the catheter means. As illustrated in figure 2, the registered pressure in the passageway of the catheter means is reduced during the sample taking period A due to the suction effect from the pumping means. When the specimen has been taken, the pumping means will be stopped and the underpressure in the catheter means will be equalized during the time period B. The equalization of the pressure is due to the normal artery pressure, which is exerted on the pressure-conducting medium since the passageway of the catheter means is open towards the test object.

During the time period C, the pumping means applies an overpressure on the pressure-conducting medium in the passageway, whereby possible residual parts of the specimen and/or pressure-conducting medium is supplied to the test object. In some applications, it is important to supply a volume of a solution that is approximately as large as the volume of the taken specimen. This is especially important when taking blood samples from a laboratory animal having a small blood volume in order not to influence the blood concentration or to avoid e.g. dehydration.

It should be understood that the pressure graph during the time period C as illustrated in the figures, corresponds to the pressure graph achieved during administration of a drug or the like to the test object. It should also be understood that in the case of administration of a drug or like, a drug container will be comprised in the specimen taking system. Further, in application where the drug is administered to the test object prior to the specimen taking procedure, e.g. in biokinetic studies, the pressure peak as illustrated at the time period C in the figures will lie prior to the time period A. Thus, it will be understood that the shown figures only aim to illustrate the inventive principles. As mentioned above, the pressure sensor 40 is configured to continuously, or at predetermined time points, register a pressure value corresponding to the pressure of the pressure-conducting medium in the passageway of the catheter means 10. An analyzer 50 communicatively connected to the pressure sensor 40 is configured to evaluate the registered pressure value in dependence of a predefined limit value. Predefined limit values can for example be stored in a look-up table whereby the analyzer retrieves a lower and an upper pressure limit value corresponding to the same time point as the registered pressure value. If the registered pressure value is within an interval of tolerance defined by the lower and upper limit values, the specimen taking system functions properly and no imperfections in the catheter means is detected. Consequently, no actions have to be taken. However, if the registered pressure value is not within the interval of tolerance, the specimen taking system does not function properly, e.g. an imperfection in the catheter means is detected. A detected imperfection can for example be an imperfection in the attachment of the catheter means at the test object, but it can also relate to a blockage or constriction of the passageway and/or a leakage in the catheter means. Consequently, an action has to be taken.

Figure 3 schematically shows the pressure graph Sl of figure 2 together with an upper or higher tolerance limit indicated as HL and a lower tolerance limit indicates as LL. The higher tolerance limit HL and the lower tolerance limit LL defines the upper and lower limit for pressure graphs that will be accepted according to this example.

Figure 4 shows the normal pressure graph Sl, the upper and lower limit HL and LL, respectively, of figure 2 together with a slightly changed pressure graph S2. In this example, the slightly changed pressure graph S2 lies within the tolerance interval and is thus accepted.

Figure 5 schematically shows the normal pressure graph Sl of figures 2, 3 and 4, the upper and lower limits HL and LL, respectively, the slightly changed pressure graph S2 of figure 4 and a pressure graph S3. The shown pressure graphs, Sl, S2 and S3 correspond to a properly functioning catheter means, a semi-clamped catheter means and a totally clamped catheter means, respectively. As can be seen from a comparison with the tolerance interval defined by HL and LL, the pressure graph S3 lies below the tolerance interval during the time intervals A and B, while it lies above the tolerance interval during a part of the time interval C. Consequently, a specimen taking system resulting in such a pressure graph S3 or registered pressure values that lie on such a pressure graph S3 does not function properly. In the present example, the pressure graph S3 corresponds to a completely clamped catheter means.

Figure 6 schematically illustrates the pressure graphs Sl, S2, S3 and the tolerance graphs HL and LL of figure 5 together with five points of pressure measurement indicated at I - V. As seen from the figure it is possible to detect a totally clamped catheter means early in the sample taking procedure. In the shown example, a measurement at a first measurement point I after approximately 10 seconds would detect a totally clamped catheter means. Cf. figure 6, where a pressure value of pressure graph S3 lies below the tolerance interval at point I.

However, as seen from the figure, a totally clamped catheter means could have been detected after approximately 5 seconds. Thus, the evaluation of the catheter means can be accomplished earlier than what is possible by the existing systems of today, in which it is not possible to evaluate the catheter means unit until after approximately 1 minute or until a point of time when the fluid sample has reached or would have reached an analyzing detector which is configured to analyze the fluid sample.

If a pressure value is measured at the measurement point II of figure 6, i.e. when the pumping means is stopped, it is possible to detect the degree of clamping, e.g. if the catheter means is semi-clamped as in pressure graph S2 or totally clamped as in pressure graph S3. The difference between a measured pressure value and a normal pressure value is a measure of the degree of clamping. The larger the difference is, the larger the clamping is.

When a pressure is measured at the measurement point III it is possible to detect whether the pressure in the passageway is equalized or not. If the pressure is not equalized, it may be desirable to wait a certain time in order to let the pressure equalize. Otherwise, if the pressure is equalized, the pumping means can be controlled to start and an overpressure can be applied to the pressure-conducting medium, whereby a volume of the pressure-conducting medium can be administered to the test object.

At measurement point IV, the maximum pressure value of the administered pressure-conducting medium can be detected. Further at measurement point V, the residual pressure after the pumping means has been stopped, i.e. when a volume of the pressure-conducting medium have been delivered to the test object, is detected. The value of the residual pressure is a measure on how successful the supply of the pressure-conducting medium, e.g. blood, or the injection of a drug to the test object has been.

The present invention thus provides a system for taking of specimen and/or supplying a pressure-conducting medium comprising several advantages compared to the prior art. The invention allows for supervision of the functioning of the system and especially of the functioning of the catheter means thanks to pressure measurements at several time points and to the analysis of the measured pressure. As discussed together with figure 6 the analysis of and the decision making procedure relating to the functioning of the system can be accomplished early. For example, the analysis and the decision making procedure can be accomplished already at a time point when a taken specimen, e.g. a blood sample, is located in a part of the catheter means that is inserted into an artery of the test object. Thus, the analysis and the decision making procedure can be accomplished at time point that is much earlier than the time point for the analysis of a taken specimen.

The present invention also provide diagnosis of the specimen taking system, since it by means of the present invention is possible to detect a component or a part that does not function, i.e. is out of order, or that does not function properly.

Embodiments of the present invention can also comprise automatic flow rate regulation accomplished by means of the pressure means and the analyzer. By taking a first segment of a fluid sample, e.g. 10 micro liter, register a first pressure Pl in the catheter means, waiting a predetermined time period t and register a second pressure P2, and then comparing the first and second pressure values Pl and P2, the operation of the pumping means can be controlled in order to provide a desired relationship between the first and second pressure values Pl and P2. If the second pressure value P2 is equal to the first pressure value Pl, the flow rate is too high, and the first segment of the fluid sample should be reintroduced into the test object. Then the flow rate should be reduced and a new first segment should be taken and new pressures Pl and P2 registered in the same way as described above. If the second pressure value P2 is lower than the first pressure value Pl, then the flow rate is acceptable and a second segment of a fluid sample is taken, a third pressure P3 can be registered and after a time period t' a fourth pressure P4 can be registered, and a comparison between P3 and P4 can then follow and if desired, the flow rate can be changed. As understood, this procedure can be repeated as many times as desired.

Embodiments of the invention can further comprise means for introducing a gas bubble into the catheter means, e.g. a valve. The valve can be arranged at the catheter means and by introducing and moving a gas bubble in the passageway of the catheter means, the quality of the catheter means can be analyzed by means of pressure values taken at different time points during the movement of the gas bubble through the passageway. If an occlusion or constriction exists in the passageway, the registered pressures will be approximately constant as long as the pressure-conducting medium flowing in the passageway passes the constriction, but when the gas bubble passes the constriction the registered pressure will dip, i.e. reduce, and then increase to its constant value when the gas bubble has passed by the constriction. This pressure reduction is due to the fact that the gas bubble passes the constriction easier than the pressure-conduction medium. In this way, the location of a constriction can be determined based on knowledge of the position where the gas bubble was introduced, the velocity by means of which the gas bubble is moved in the passageway of the catheter means, and the point of time when the dip of the pressure value was registered.

Advantageous embodiments of the invention have been described in detail. However, it should be understood that the same inventive principles also applies to a catheter means attached to a vein of a test object and to other systems comprising several catheter means, valves and solutions that are to be administered. The invention may thus be modified in various ways without departing from the scope thereof, as defined by the accompanying claims.

Claims

1. A system (1) for automatic taking of specimens, comprising:

- a catheter means (10) connectable to a test object (20) and comprising at least one passageway for a pressure-conducting medium;

- a pumping means (30) connectable to said catheter means (10) and configured to control the flow direction and flow rate of said pressure-conducting medium in said passageway of said catheter means (10); characterized in

- a pressure sensor (40) arranged at said catheter means (10) and configured to register a pressure value corresponding to the pressure of said pressure- conducting medium in said passageway; and

- an analyzer (50) connectable to said pressure sensor (40) and said pumping means (30), and configured to evaluate said registered pressure value, and being configured to control said pumping means (30) in dependence of said evaluation.

2. A system of claim 1, wherein said pressure sensor (40) is configured to, at a predetermined time point, register a pressure value corresponding to the pressure of said pressure-conducting medium in said passageway at said time point.

3. A system of claim 1, wherein said pressure sensor (40) is configured to continuously register a pressure value corresponding to the pressure of said pressure-conducting medium in said passageway at different time points.

4. A system of any of claim 1 - 3, wherein said analyzer (50) is configured to evaluate said registered pressure value in dependence of predefined limit values.

5. A system of claim 4, wherein said predefined limit values define an interval of tolerance.

6. A system of any of claims 1 - 5, wherein said analyzer (50) is configured to detect imperfections of the attachment of said catheter means (10) at said test object (20).

7. A system of any of claims 1 - 6, wherein said analyzer (50) is configured to detect blockage of said passageway and/or leakage in said catheter means (10).

8. A system of any of claims 1 - 7, wherein said analyzer (50) is configured to shut down or alter the operation of said pumping means (30) if a blockage of said passageway or a leakage in said catheter means (10) or an imperfection of the attachment of said catheter means (10) at said test object (20) is detected.

9. A system of any of claims 1 - 8, wherein said pressure-conducting medium in said catheter means (10) at said pressure sensor (40) comprises a sodium chloride solution.

10. An analyzer for use in a system (1) for automatic taking of specimens according to any of the preceding claims, said analyzer (50) being connectable to a pressure sensor (40) and a pumping means (30), and configured to evaluate a registered pressure value, and being configured to control said pumping means (30) in dependence of said evaluation.

11. An analyzer of claim 10, wherein said analyzer (50) is configured to evaluate said registered pressure value in dependence of predefined limit values.

12. An analyzer of claim 11, wherein said predefined limit values define an interval of tolerance.

13. An analyzer of any of claims 10 - 12, wherein said analyzer (50) is configured to detect imperfections of an attachment of a catheter means (10) at a test object (20).

14. An analyzer of any of claims 10 - 13, wherein said analyzer (50) is configured to detect blockage of a passageway of and/or leakage in a catheter means (10).

15. An analyzer of any of claims 10 - 14, wherein said analyzer (50) is configured to shut down or alter the operation of said pumping means (30) if a blockage of a passageway or a leakage in a catheter means (10) or an imperfection of an attachment of a catheter means (10) at a test object (20) is detected.

16. A pressure sensor (40) configured to measure the pressure in a catheter means (10) of a system (1) for automatic taking of specimens according to any of the preceding claims, wherein said pressure sensor (40) is arranged at said catheter means (10) and configured to register a pressure value corresponding to the pressure in a passageway of said catheter means (10), said pressure sensor (40) further being connectable to an analyzer (50) configured to evaluate said registered pressure value, and being configured to control said pumping means (30) in dependence of said evaluation.

17. A pressure sensor (40) of claim 16, wherein said pressure sensor (40) is configured to, at a predetermined time point, register a pressure value corresponding to the pressure of said pressure-conducting medium in said passageway at said time point.

18. A pressure sensor (40) of claim 16, wherein said pressure sensor (40) is configured to continuously register a pressure value corresponding to the pressure of said pressure-conducting medium in said passageway at different time points.

19. A computer program product for use in a system (1) for automatic taking of specimens, said computer program product comprising code portions configured to perform or realize steps and functions of any of the preceding claims.

20. A system of any of claim 1 - 9, wherein said pumping means is configured to take a first segment of a fluid sample; said pressure sensor (40) is configured to register a first pressure Pl in the catheter means (10), to wait a predetermined time period t and configured to register a second pressure P2; and said analyzer (50) is configured to receive said first and second pressure values from said pressure sensor (40), configured to compare the first and second pressure values Pl and P2, and configured to control the operation of the pumping means (30) in order to provide a desired relationship between the first and second pressure values Pl and P2.

21. A system of claim 20, wherein said analyzer (50) is configured to control the pumping means (30) to reduce the flow rate if the second pressure value P2 is equal to the first pressure value Pl, and to control the pumping means (30) to reintroduce the first segment of the fluid sample into the test object (20), and wherein said analyzer (50) is configured to control the pumping means (30) to withdraw a second segment of a fluid sample if the second pressure value P2 is lower than the first pressure value Pl .

22. A system of claim 1 - 9, or 20 - 21, further comprising means for introducing a gas bubble into the catheter means (10), wherein said pumping means (30) is configured to move the gas bubble in the passageway of the catheter means (10), and said analyzer (50) is configured to detect a constriction in the passageway due to the pressure dip that occurs when the gas bubble passes the constriction.