CN113616204A - Device for monitoring dynamic change of blood ionized calcium in real time on line and applicable to CRRT (continuous room temperature recovery) - Google Patents
Device for monitoring dynamic change of blood ionized calcium in real time on line and applicable to CRRT (continuous room temperature recovery) Download PDFInfo
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- CN113616204A CN113616204A CN202010373420.XA CN202010373420A CN113616204A CN 113616204 A CN113616204 A CN 113616204A CN 202010373420 A CN202010373420 A CN 202010373420A CN 113616204 A CN113616204 A CN 113616204A
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- A—HUMAN NECESSITIES
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- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/14546—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring analytes not otherwise provided for, e.g. ions, cytochromes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/1468—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means
- A61B5/1473—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means invasive, e.g. introduced into the body by a catheter
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- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
- A61M1/3621—Extra-corporeal blood circuits
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- A—HUMAN NECESSITIES
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- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
- A61M1/3621—Extra-corporeal blood circuits
- A61M1/3669—Electrical impedance measurement of body fluids; transducers specially adapted therefor
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M2230/00—Measuring parameters of the user
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Abstract
The invention relates to the field of medical instruments, in particular to a device for monitoring dynamic changes of blood ionized calcium in real time on line, which can be used for CRRT. The invention provides a device for monitoring dynamic changes of blood ionized calcium in real time on line, which can be used for CRRT (CrRT). the device comprises an electrode body, wherein a liquid channel, a working electrode inner cavity, a reference electrode inner cavity and a temperature electrode inner cavity are arranged on the electrode body. The device for monitoring the dynamic change of the ionized calcium in the blood on line and in real time for CRRT can monitor the ionized calcium concentration in the flowing liquid on line, the electrode can stably work in the fluid, has shorter reaction time and higher selectivity on the calcium ions, the measurement result is not influenced by the flow rate and the solution PH value, and compared with the existing clinical common iSTAT blood gas analyzer, the device has smaller bias and can provide on-line real-time monitoring of the ionized calcium in the blood.
Description
Technical Field
The invention relates to the field of medical instruments, in particular to a device for monitoring dynamic changes of blood ionized calcium in real time on line, which can be used for CRRT.
Background
Safe and effective anticoagulation is a key and technical difficulty for blood purification, and is particularly prominent in long-term continuous renal replacement therapy. Regional Citrate Anticoagulation (RCA) has been shown to have an effective in vitro anticoagulation method that avoids prolonged exposure to heparin for continuous renal replacement therapy. RCA can reduce the incidence of bleeding associated with dialysis, increase the service life of the dialyzer, and improve the biocompatibility of the dialyzer. Although RCA has many advantages, there are still many technical limitations and difficulties in clinical practice application, which hinder its popularization. The technical key in RCA implementation is how to identify the appropriate citric acid and calcium infusion rates to maintain the circulating ionized calcium concentration in vivo and in vitro within the appropriate, narrow therapeutic target range. Currently, the most commonly used method for RCA per unit administration is the so-called "trial and error" method, in which the ionized calcium concentration in the patient's in vivo and in vitro circulation is maintained within a target range (around 1.1 and 0.3mM/L, respectively) by frequently monitoring (usually every 0.5-2 hours) the ionized calcium concentration in the patient's in vivo and in vitro circulation and adjusting the calcium supplementation and citric acid infusion rates in time. The method has the advantages that the cost of manpower (at least one experienced nurse and a doctor familiar with the RCA principle is required to be on site for 24 hours) and material resources (at least 2 ionized calcium monitoring times per hour, 80 yuan each time or 2000-3000 yuan each day) is huge, and special monitoring equipment (an iSTAT biochemical instrument, each equipment is 10-15 ten thousand yuan each time) is required, so that the CRRT process is undoubtedly more complicated, the economic burden of a patient and the burden of medical care personnel are increased, and the wide application of RCA-CRRT in clinic is limited.
Ion-selective electrodes are currently the most commonly used laboratory method for the in vitro detection of ionic calcium. The principle of the method is potential analysis, and the potential analysis consists of a working electrode, a reference electrode, a temperature electrode and a signal output device. It can sensitively and specifically respond to the change of the concentration of ionized calcium in the liquid, and the ion concentration is calculated according to the Nernst equation.
Electrodes of conventional construction currently exist: activating for 2-4 days; the zero points are inconsistent, and each electrode needs to be calibrated; the influence of the temperature on the active film is inconsistent, so that the temperature compensation curve is not uniform and the like. In order to realize the monitoring of dynamic plasma calcium without activation, calibration, quick installation, batch production, safety and reliability, the prior art is lack of and cannot realize real-time online monitoring of blood samples, thereby limiting the application of the dynamic plasma calcium in clinic.
Disclosure of Invention
In view of the above-mentioned shortcomings of the prior art, the present invention aims to provide an apparatus for on-line real-time monitoring of plasma calcium dynamics for CRRT, which is used to solve the problems in the prior art.
In order to achieve the above and other related objects, the present invention provides, in one aspect, a device for monitoring dynamic changes of blood ionized calcium in real time on line, which can be used for CRRT, and includes an electrode body, wherein the electrode body is provided with a liquid channel, a working electrode cavity, a reference electrode cavity and a temperature electrode cavity;
the working electrode inner cavity extends to the liquid channel, a membrane electrode is arranged between the working electrode inner cavity and the liquid channel, and working electrode inner liquid and a working electrode are arranged in the working electrode inner cavity;
the reference electrode inner cavity comprises a first electrode inner cavity and a second electrode inner cavity, a first separating membrane is arranged between the first electrode inner cavity and the second electrode inner cavity, the second electrode inner cavity extends to the liquid channel, a second separating membrane is arranged between the second electrode inner cavity and the liquid channel, a reference electrode stationary phase and a reference electrode are arranged in the first electrode inner cavity, liquid in the reference electrode and a microporous fiber rod are arranged in the second electrode inner cavity, and the microporous fiber rod extends to the first electrode inner cavity;
the temperature electrode inner cavity extends to the liquid channel, a heat conduction film is arranged between the temperature electrode inner cavity and the liquid channel, and a temperature monitoring device is further arranged in the temperature electrode inner cavity.
In some embodiments of the present invention, the liquid channel extends linearly, and the diameter of the cross section of the liquid channel is 4.5-5.5 mm.
In some embodiments of the invention, the membrane electrode comprises a first gasket, an active membrane and a second gasket stacked in this order, the first gasket being located on one side of the liquid channel, and the second gasket being located on one side of the working electrode cavity.
In some embodiments of the present invention, the material of the first pad and/or the second pad is a silicone, the active film comprises an active substance, preferably, the active substance is selected from organic phosphorus salts, more preferably, the organic phosphorus salts are selected from calcium bis [4- (1,1,3, 3-tetramethylbutylphenyl) phosphate, the thickness of the first pad is 0.27 to 0.33mm, the thickness of the active film is 0.27 to 0.33mm, and the thickness of the second pad is 0.27 to 0.33 mm.
In some embodiments of the invention, the working electrode internal solution is selected from an aqueous calcium chloride solution and the working electrode is selected from an Ag/AgCl wire.
In some embodiments of the present invention, the volume of the inner cavity of the working electrode is 4.5-5.5 ml, the inner cavity of the working electrode is cylindrical, preferably cylindrical, and the diameter of the cross section of the cavity is 7.2-8.8 mm.
In some embodiments of the present invention, the material of the first separation membrane and/or the second separation membrane is selected from silica gel, and the thickness of the first separation membrane and/or the second separation membrane is 3.6-4.4 mm.
In some embodiments of the invention, the reference electrode stationary phase is selected from potassium chloride gel, the reference electrode internal solution is selected from potassium chloride aqueous solution, the length of the microporous fiber rod is 9.5-10.5 mm, the diameter of the cross section is 0.85-0.95 mm, the pore diameter is 0.28-0.32 mm, and the reference electrode is selected from Ag/AgCl wire.
In some embodiments of the present invention, the volume of the inner cavity of the first electrode is 4.5-5.5 ml, the inner cavity of the first electrode is cylindrical, preferably cylindrical, and the diameter of the cross section of the cavity is 7.2-8.8 mm.
In some embodiments of the present invention, the volume of the inner cavity of the second electrode is 4.5-5.5 ml, the inner cavity of the second electrode is cylindrical, preferably cylindrical, and the diameter of the cross section of the cavity is 7.2-8.8 mm.
In some embodiments of the present invention, the material of the thermally conductive film is selected from thermally conductive silicone.
In some embodiments of the invention, the temperature monitoring device is selected from a thermistor.
In some embodiments of the present invention, the volume of the inner cavity of the temperature electrode is 48-58 mm2The inner cavity of the temperature electrode is cylindrical, preferably cylindrical, and the diameter of the cross section of the cavity is 2.8-3.4 mm.
In some embodiments of the present invention, the apparatus further comprises a connector and a lead, wherein the lead is electrically connected with the working electrode, the reference electrode and the temperature monitoring device respectively, and the connector is positioned at two ends of the liquid channel.
In some embodiments of the present invention, the display device further comprises a signal output device, wherein the signal output device comprises a signal acquisition circuit, an amplification circuit and a display device, which are connected in sequence, and the signal output device is electrically connected to the conducting wire.
The invention provides a CRRT device, which comprises a CRRT device body, wherein the artery end and/or vein end of the CRRT loop of the CRRT device body is connected with the device for monitoring the dynamic change of blood ionized calcium on line and in real time.
Drawings
Fig. 1 is a general schematic diagram of the device for on-line real-time monitoring of dynamic changes of blood ionized calcium, which can be used in CRRT in the present invention.
Fig. 2 is a schematic structural diagram of the device for on-line real-time monitoring of dynamic changes of blood ionized calcium, which can be used in CRRT in the present invention.
Fig. 3 is a schematic diagram of an electrical signal transmission line according to an embodiment of the present invention.
FIG. 4 is a schematic diagram of an in vitro simulation cycle according to an embodiment of the present invention.
FIG. 5 is a diagram of a standard curve for testing a liquid crystal according to an embodiment of the present invention.
FIG. 6 is a schematic diagram showing the reaction time of electrode detection in the embodiment of the present invention.
FIG. 7 is a schematic diagram showing the stability of the electrode in the embodiment of the present invention in long-term operation.
FIG. 8 is a graph showing the effect of flow rate variation on potential readings in an embodiment of the present invention.
FIG. 9 is a graph showing the effect of pH change in a solution on potential readings in an embodiment of the present invention.
FIG. 10 is a graph showing the effect of changes in the concentration of magnesium and potassium ions in a solution on potential readings in accordance with an embodiment of the present invention.
FIG. 11 is a schematic diagram of a blood test standard curve according to an embodiment of the present invention.
FIG. 12 is a graph showing the comparison between the electrode test results and the iSTAT test results in the embodiment of the present invention.
Fig. 13 is a schematic view of a partial structure of the CRRT device of the present invention.
Description of the element reference numerals
1 electrode body
2 liquid channel
3 working electrode cavity
31 film electrode
32 working electrode internal liquid
33 working electrode
4 reference electrode inner cavity
41 first electrode lumen
411 reference electrode stationary phase
412 reference electrode
42 second electrode lumen
421 reference electrode internal liquid
422 micropore fiber rod
43 first separating Membrane
44 second separator film
5 temperature electrode inner cavity
51 temperature monitoring device
52 Heat conduction film
6 conducting wire
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments, and other advantages and effects of the present invention will be apparent to those skilled in the art from the disclosure of the present specification.
The invention provides a device for monitoring dynamic change of blood ionized calcium in real time on line for CRRT, which comprises an electrode body 1, wherein a liquid channel 2, a working electrode inner cavity 3, a reference electrode inner cavity 4 and a temperature electrode inner cavity 5 are arranged on the electrode body 1, as shown in fig. 1 and fig. 2;
the working electrode cavity 3 extends to the liquid channel 2, a membrane electrode 31 is arranged between the working electrode cavity 3 and the liquid channel 2, and working electrode inner liquid 32 and a working electrode 33 are arranged in the working electrode cavity 3;
the reference electrode inner cavity 4 comprises a first electrode inner cavity 41 and a second electrode inner cavity 42, a first separating membrane 43 is arranged between the first electrode inner cavity 41 and the second electrode inner cavity 42, the second electrode inner cavity 42 extends to the liquid channel 2, a second separating membrane 44 is arranged between the second electrode inner cavity 42 and the liquid channel 2, a reference electrode stationary phase 411 and a reference electrode 412 are arranged in the first electrode inner cavity 41, a reference electrode inner liquid 421 and a microporous fiber rod 422 are arranged in the second electrode inner cavity 42, and the microporous fiber rod 422 extends to the first electrode inner cavity 41;
the temperature electrode inner cavity 5 extends to the liquid channel 2, a heat conducting film 52 is arranged between the temperature electrode inner cavity 5 and the liquid channel 2, and a temperature monitoring device 51 is further arranged in the temperature electrode inner cavity 5. The device for monitoring the dynamic change of the blood ionic calcium on line in real time for CRRT can stably work in flowing crystal liquid and blood samples, has shorter reaction time, higher selectivity for calcium ions, and measurement results are not influenced by flow rate and solution PH value.
The device for monitoring the dynamic change of the blood ionized calcium on line in real time, which is provided by the invention and can be used for CRRT, can comprise an electrode body 1, wherein the electrode body 1 can be made of a suitable mould material generally, so that a suitable cavity structure can be formed in the electrode body 1 to accommodate each component in the device for monitoring the dynamic change of the blood ionized calcium on line in real time, which can be used for CRRT. For example, the material of the electrode body 1 may be a 3D printing material or the like, and may specifically be a photosensitive resin or the like.
In the device for monitoring dynamic changes of blood ionized calcium in real time on line for CRRT provided by the invention, the electrode body 1 can be provided with the liquid channel 2, and the liquid channel 2 is usually used for flowing through liquid to be detected. The shape and size of the liquid channel 2 is generally matched to the flow rate of the liquid to be detected flowing through. For example, in the liquid channel 2, the flow rate of the liquid may be 20ml/min to 150ml/min, 20ml/min to 30ml/min, 30ml/min to 40ml/min, 40ml/min to 60ml/min, 60ml/min to 80ml/min, 80ml/min to 100ml/min, 100ml/min to 120ml/min, or 120ml/min to 150 ml/min; for another example, the cross-section of the liquid channel 2 may have a diameter of 4.5 to 5.5mm, 4.5 to 4.8mm, 4.8 to 5.2mm, or 5.2 to 5.5 mm. The direction of extension of the liquid channel 2 in the electrode body 1 can be adjusted by the person skilled in the art, for example, the liquid channel 2 can extend generally straight.
In the device for monitoring dynamic changes of blood ionized calcium in real time on line for CRRT provided by the invention, the electrode body 1 can be provided with a working electrode inner cavity 3, and the working electrode inner cavity 3 is usually used for accommodating each part of a working electrode. The working electrode cavity 3 can extend to the liquid channel 2, and a membrane electrode 31 can be arranged between the working electrode cavity 3 and the liquid channel 2, so that the working electrode can be in proper contact with the liquid to be detected in the liquid channel 2. The shape and size of the working electrode inner cavity 3 can be adjusted for a person skilled in the art, for example, the volume of the working electrode inner cavity 3 can be 4.5-5.5 ml, 4.5-4.8 ml, 4.8-5.2 ml, or 5.2-5.5 ml, the working electrode inner cavity 3 can be cylindrical, preferably cylindrical, and the diameter of the cavity cross section is 7.2-8.8 mm, 7.2-7.5 mm, 7.5-7.8 mm, 7.8-8.2 mm, 8.2-8.5 mm, or 8.5-8.8 mm.
In the working electrode cavity 3, the membrane electrode 31 includes a first gasket, an active membrane, and a second gasket, which are sequentially stacked. The first gasket is positioned on one side of the liquid channel 2, can be contacted with liquid to be detected, and is used for reinforcing the active membrane and reducing the impact force of the fluid on the active membrane. Suitable types and sizes of gasket materials suitable for the working electrode will be known to those skilled in the art, for example, the first gasket material may typically be silicone or the like, and for example, the first gasket may have a thickness of 0.27 to 0.33mm, 0.27 to 0.29mm, 0.29 to 0.31mm, or 0.31 to 0.33 mm. The second gasket is located on one side of the working electrode cavity 3 and can be in contact with the working electrode internal liquid 32 for sealing the electrode cavity. Suitable types and sizes of gasket materials suitable for the working electrode will be known to those skilled in the art, for example, the second gasket material may typically be silicone or the like, and for example, the second gasket may have a thickness of 0.27 to 0.33mm, 0.27 to 0.29mm, 0.29 to 0.31mm, or 0.31 to 0.33 mm. The active membrane is typically located between the first pad and the second pad for sensing the ionized calcium concentration in the fluid, the active membrane is typically selectively responsive to calcium ions, and the relationship between the potential of the active membrane and the calcium ion content should be such that the Nernst equation is satisfied. Suitable active film species will be known to those skilled in the art, for example, the active film may generally include calcium ion actives (e.g., alkyl phenyl calcium phosphate, etc.), may also include plasticizers (e.g., phenyl dioctyl phosphate, etc.), high molecular weight polymers (e.g., PVC, etc.), and the like. The thickness of the active film may be 0.27 to 0.33mm, 0.27 to 0.29mm, 0.29 to 0.31mm, or 0.31 to 0.33 mm. The active substance can generally react specifically with calcium ions. Suitable active materials suitable for use in the active membrane of the working electrode should be known to those skilled in the art, for example, the active material may be an organophosphate or the like, and further for example, the organophosphate may be bis [4- (1,1,3, 3-tetramethylbutylphenyl) calcium phosphate or the like.
In this application, among the working electrode inner chamber 3, can be equipped with working electrode inner liquid 32 and working electrode 33, working electrode 33 main function makes ionic signal change into the signal of telecommunication and transmits to can detect the liquid that awaits measuring in the liquid passage 2. Suitable working electrode internal liquids 32 and working electrodes 33 suitable for working electrodes should be known to those skilled in the art, for example, the working electrode internal liquid 32 may be selected from an aqueous solution of calcium chloride, and the concentration of the solution may be 9.5 to 10.5mmol/L, 9.5 to 9.7mmol/L, 9.7 to 9.9mmol/L, 9.9 to 10.1mmol/L, 10.1 to 10.3mmol/L, or 10.3 to 10.5 mmol/L; for another example, the working electrode 33 may be an Ag/AgCl wire, etc., the Ag/AgCl wire may have a length of 27 to 33mm, 27 to 29mm, 29 to 31mm, or 31 to 33mm, and a diameter of 0.27 to 0.33mm, 0.27 to 0.29mm, 0.29 to 0.31mm, or 0.31 to 0.33 mm. In general, working electrode 33 may be electrically connected to a suitable lead 6 and may extend out of working electrode lumen 3 to deliver a detection signal to a signal output device.
In the device for on-line real-time monitoring of dynamic changes of blood ionized calcium, which is provided by the invention and can be used for CRRT, the electrode body 1 can be provided with a reference electrode inner cavity 4, and the reference electrode inner cavity 4 is generally used for accommodating each part of a reference electrode. The reference electrode lumen 4 can include a first electrode lumen 41 and a second electrode lumen 42, and a first separator 43 can be disposed between the first electrode lumen 41 and the second electrode lumen 42 such that the reference electrode lumen 4 can be separated into the first electrode lumen 41 and the second electrode lumen 42. The second electrode lumen 42 may extend to the fluid channel 2, and a second separator 44 is provided between the second electrode lumen 42 and the fluid channel 2, so that the reference electrode may be brought into proper contact with the fluid to be detected in the fluid channel 2. Suitable materials and dimensions for the separation membrane of the reference electrode should be known to those skilled in the art, for example, the material of the first separation membrane 43 may be selected from silica gel and the like, and the thickness of the first separation membrane 43 may be 3.6 to 4.4mm, 3.6 to 3.9mm, 3.9 to 4.1mm, or 4.1 to 4.4 mm; for another example, the material of the second separating film 44 may be selected from silica gel, etc., and the thickness of the second separating film 44 may be 3.6 to 4.4mm, 3.6 to 3.9mm, 3.9 to 4.1mm, or 4.1 to 4.4 mm; the shape and size of the reference electrode inner cavity 4 should be adjustable for those skilled in the art, for example, the volume of the first electrode inner cavity 41 may be 4.5-5.5 ml, 4.5-4.8 ml, 4.8-5.2 ml, or 5.2-5.5 ml, the first electrode inner cavity 41 may be cylindrical, preferably cylindrical, and the diameter of the cavity cross section is 7.2-8.8 mm, 7.2-7.5 mm, 7.5-7.8 mm, 7.8-8.2 mm, 8.2-8.5 mm, or 8.5-8.8 mm; for another example, the volume of the inner cavity 42 of the second electrode may be 4.5 to 5.5ml, 4.5 to 4.8ml, 4.8 to 5.2ml, or 5.2 to 5.5ml, the inner cavity 42 of the second electrode may be cylindrical, preferably cylindrical, and the diameter of the cross section of the cavity may be 7.2 to 8.8mm, 7.2 to 7.5mm, 7.5 to 7.8mm, 7.8 to 8.2mm, 8.2 to 8.5mm, or 8.5 to 8.8 mm; for another example, the first electrode lumen 41 and the second electrode lumen 42 may extend in the same direction as a whole, so that the reference electrode lumen 4 may be cylindrical as a whole, and preferably, may be cylindrical.
In this application, the first electrode cavity 41 is provided with a reference electrode stationary phase 411 and a reference electrode 412, so that the reference electrode potential is stabilized. Suitable reference electrode internal solutions and reference electrodes should be known to those skilled in the art, for example, the reference electrode stationary phase 411 can be selected from potassium chloride gel and the like, wherein the concentration of potassium chloride can be a saturation concentration; for another example, the reference electrode may be selected from Ag/AgCl wire, etc., and the Ag/AgCl wire may have a length of 27 to 33mm, 27 to 29mm, 29 to 31mm, or 31 to 33mm, and a diameter of 0.27 to 0.33mm, 0.27 to 0.29mm, 0.29 to 0.31mm, or 0.31 to 0.33 mm. In general, the reference electrode may be electrically connected to a suitable lead 6 and may extend out of the first electrode lumen 41 to deliver a detection signal to a signal output device.
In this application, the second electrode inner cavity 42 is provided with a reference electrode inner liquid 421 and a microporous fiber rod 422, and the microporous fiber rod 422 extends to the first electrode cavity 41, so as to form a stable and continuous electronic loop. Suitable reference electrode internal liquids and microporous fiber rods suitable for reference electrodes should be known to those skilled in the art, for example, the reference electrode internal liquid 421 may be selected from potassium chloride aqueous solution and the like, and the concentration of the solution may be 3.5 to 4.0 mmol/L; for another example, the microporous fiber rod may allow the potassium chloride solution to slowly permeate outwards, the length of the microporous fiber rod 422 may be 9.5 to 10.5mm, 9.5 to 9.8mm, 9.8 to 10.2mm, or 10.2 to 10.5mm, the cross-sectional diameter may be 0.85 to 0.95mm, 0.85 to 0.88mm, 0.88 to 0.92mm, or 0.92 to 0.95mm, and the pore diameter may be 0.28 to 0.32mm, 0.28 to 0.29mm, 0.29 to 0.30mm, 0.30 to 0.31mm, or 0.31 to 0.32 mm. Generally, the second electrode chamber 42 is in communication with the first electrode chamber 41 via a microporous fiber rod, allowing for a slow continuous penetration of the potassium chloride solution.
In the device for monitoring dynamic changes of blood ionized calcium in real time on line for CRRT provided by the invention, the electrode body 1 can be provided with a temperature electrode inner cavity 5, and the temperature electrode inner cavity 5 is usually each component for detecting the temperature of liquid to be detected in the liquid channel 2. The temperature electrode cavity 5 can extend to the liquid channel 2, and a heat conducting film 52 is arranged between the temperature electrode cavity 5 and the liquid channel 2, so that the heat conducting film 52 can be in proper contact with the liquid to be detected in the liquid channel 2, and heat can be transferred to the temperature monitoring device 51. The shape and size of the temperature electrode inner cavity 5 can be adjusted by those skilled in the art, for example, the volume of the temperature electrode inner cavity 5 can be 48-58 mm2、48～50mm2、50～52mm2、52～54mm2、54～56mm2Or 56 to 58mm2The inner cavity 5 of the temperature electrode can be cylindrical, preferably cylindrical, and the diameter of the cross section of the cavity can be 2.8-3.4 mm, 2.8-3.0 mm, 3.0-3.2 mm or 3.2-3.4 mm.
Suitable heat conducting film 52 and temperature monitoring device 51 suitable for detecting the temperature of the liquid to be detected in the liquid channel 2 are known to those skilled in the art, for example, the material of the heat conducting film 52 may be selected from heat conducting silica gel and the like, and the thickness of the heat conducting film 52 may be 0.27-0.33 mm, 0.27-0.29 mm, 0.29-0.31 mm, or 0.31-0.33 mm; for another example, the temperature monitoring device 51 may be selected from a thermistor, etc. Generally, the temperature monitoring device 51 may be electrically connected to a suitable lead 6, and the lead 6 may extend into the temperature electrode lumen 5 to transmit a detection signal to a signal output device.
The device for on-line real-time monitoring of dynamic changes of blood ionized calcium, which is provided by the invention and can be used for CRRT, can further comprise a connector, as shown in fig. 13, wherein the connector can be used for installing the device for on-line real-time monitoring of dynamic changes of blood ionized calcium, which can be used for CRRT, at a proper working position. The connectors may be generally located at both ends of the liquid channel 2, the kind of the connectors may be adjusted by those skilled in the art, for example, the connectors may be luer connectors or the like.
The device for monitoring the dynamic change of blood ionized calcium on line in real time for CRRT provided by the invention can also comprise signal output equipment, wherein the signal output equipment usually comprises a signal acquisition circuit, an amplification circuit, display equipment and the like which are sequentially connected, and the signal output equipment usually can be electrically connected with the lead 6, so that data can be collected through the signal acquisition circuit, and signals can be transmitted to the display equipment through the amplification circuit. Suitable signal collectors, amplification circuits, display devices should be known to the person skilled in the art, for example the display device may be a display or the like.
The invention provides a CRRT device, which comprises a CRRT device body, wherein the artery end and/or vein end of a CRRT loop of the CRRT device body is connected with the device for monitoring the dynamic change of blood ionized calcium on line in real time. On the CRRT device, the fluid to be detected is typically a blood sample. After the ionic calcium concentration is measured by the device, the collected signals can be output, and the readings can be displayed by an output device. After the device is used for continuous kidney replacement therapy by adopting RCA anticoagulation, the technical difficulty of RCA implementation can be obviously reduced, and the anticoagulation mode is easier to popularize, thereby bringing clinical benefit to more hemodialysis patients.
The device for monitoring the dynamic change of the ionized calcium in the blood on line and in real time for CRRT can monitor the ionized calcium concentration in the flowing liquid (crystal liquid and blood) on line and in real time, the electrode can work stably in the fluid, has shorter reaction time, has higher selectivity on the calcium ions, the measurement result is not influenced by flow rate and solution PH value, has smaller bias compared with the existing clinical common iSTAT blood gas analyzer, and can provide on-line real-time monitoring of the ionized calcium in the blood. In addition, the device has the characteristics of no activation, no calibration, quick installation, batch production, safety, reliability and the like, and has good industrialization prospect.
The invention of the present application is further illustrated by the following examples, which are not intended to limit the scope of the present application.
Example 1
(1) Calcium ion exchange membrane composition and thermal processing:
calcium ion exchange membrane composition: contains 15mg of bis [4- (1,1,3, 3-tetramethylbutylphenyl) calcium phosphate, 400mg of dioctyl phenylphosphate, and 170mg of PVC. The thickness of the film is 0.3 mm.
Hot processing: the calcium ion exchange membrane is protected and clamped in the middle by a PP thin film material, and is placed in a hot rolling machine, the temperature is kept at 75 ℃,
hot pressing for eight times to make the film thickness uniform and ensure the uniform distribution of the active ingredients in the PVC plastic. (this procedure facilitates the uniformity of the calculated curves and the quantitative production)
(2) A calcium ion sensor:
the electrode mold is made by applying 3D printing technology, the printing material is photosensitive resin, and the printing appearance is as shown in figure 1. The electrode mould includes size 50mm 15mm 45mm cuboid, is equipped with the straight line on the length direction and extends the sample through-hole, and the aperture is on one side of the body of 4.85mm cuboid, is equipped with 1# hole, 2# hole, 3# hole, and the aperture is 8.3mm, 3.2mm respectively, and the interval between each hole is that each hole of 3mm all extends to the through-hole and communicates, and the extending direction all is perpendicular with the extending direction of through-hole.
A working electrode: and sequentially adding a gasket with the thickness of 0.3mm, an active membrane and a gasket with the thickness of 0.3mm into the hole No. 1, extending the three-layer structure to the bottom of the hole No. 1, wherein the diameters of the sections of the gasket and the active membrane are basically the same as the diameter of the hole No. 1, and fixing the film pressing structure by using a screw member with the length of 10mm and M8. Adding 1ml polyurethane solid gel containing 0.01M CaCl2 and 0.1M sodium chloride, 0.3mm silver/silver chloride wire into the cavity, sealing with silica gel pad, adding epoxy resin, encapsulating, and leading out red tetrafluoro wire (in welding and connecting terminal)
Reference electrode: sequentially adding 8.1mm silica gel plugs (with the diameter of 8.1mm and the thickness of 3mm and the center penetrated by a 0.9mm microporous fiber rod), saturated potassium chloride solid gel, 8.1mm silica gel plugs (with the diameter of 8.1mm and the thickness of 3mm and the center penetrated by a 0.9mm microporous fiber rod), saturated potassium chloride gel solution, 0.3mm silver/silver chloride wires, sealing by using a silica gel pad, adding epoxy resin for encapsulation, and leading out yellow tetrafluoro wires (welded in a connecting terminal);
temperature electrode: in the No. 3 hole, NTC type thermistor is placed in 316L medical stainless steel shell and sealed by heat-conducting silica gel, and the tetrafluoro black line is led out (welding and wiring terminal is in)
The luer joint is bonded at the two ends by UV glue to obtain the complete electrode, and the luer joint has good universality with a continuous kidney replacement therapy pipeline. (the above-described sensor configuration facilitates the uniformity and quantitative production of the calculated curves)
(3) And (3) displaying data:
the electrode adopts an external instrument to receive signals and can display potential signals or calcium ion concentration. Meanwhile, the instrument has a simple programming function, and automatic multi-section curve compensation correction can be realized by inputting the slope and intercept of a standard curve and the temperature value. The circuit transmission diagram is shown in fig. 3.
Example 2
Electrode detection
(1) In vitro simulation cycle establishment
A small peristaltic pump, PVC hose, beaker, three-way valve, etc. were used to construct an in vitro simulated closed cycle (see figure 4 for schematic). The beaker is a liquid to be tested, and the liquid to be tested can comprise crystalloid solution, blood and the like. The crystal liquid is calcium chloride solution, and the preparation method comprises the following steps: according to the concentration requirement, adding 10% calcium chloride solutions with different volumes into 0.15mmol/L sodium chloride solution to obtain calcium chloride solutions with different concentrations, wherein the concentration range of calcium ions is 0.01-3.00mmol/L, so as to meet the clinical detection requirement. The blood is whole blood from domestic pigs, common heparin is added in advance for full anticoagulation, the concentration is 5000IU/100ml whole blood, and calcium chloride solution is added according to the experiment requirement to adjust the ionized calcium concentration.
(2) Electrode detection process
The electrode was left standing overnight in 0.1mmol/L calcium chloride solution before electrode detection. After an in vitro simulation closed cycle is constructed, a small peristaltic pump is started to fill the pipeline with liquid, and whether bubbles are generated in the pipeline or not is observed. The electrode is provided with an external display screen which can display potential reading or ion concentration (automatic conversion after inputting slope and intercept). Because the temperature has great influence on the potential, the detection is carried out at room temperature, and the fluctuation of the room temperature is controlled to be less than 0.5 ℃. Data analysis was performed using SPSS 20.0 and medcalc13.5 statistical software. The continuous variable is described by adopting a mean value and a standard deviation, the standard curve is calculated by adopting a linear regression method, and the statistical methods are realized by adopting SPSS software. The Relative Standard Deviation (RSD) is equal to the standard deviation of multiple measurements of the same sample divided by the measurement mean, and is used to describe the accuracy of the electrode measurement.
When the electrode detects the crystal liquid, a standard curve is established by taking the logarithm of the concentration as the abscissa and the reading of the potential as the ordinate according to the known ionic calcium concentration of the solution. The specific result of detecting the electrode in the crystal liquid is shown in FIG. 5, when the calcium ion concentration fluctuates between 0.01 mmol/L and 3.00mmol/L, the potential shown by the electrode and the ionized calcium concentration satisfy Nernst reaction, i.e. the logarithm of the potential and the ionized calcium concentration satisfy a linear relationship (R)20.9970) and a standard curve is established in this way. When the ionic calcium concentration changes, the potential reading of the electrode begins to change after 1-2 seconds, and the reading is stable for about 5-6 seconds, as shown in figure 6 in particular, so that the electrode has short reaction time and can be monitored in real time.
In addition, tests were conducted on the characteristics of the electrodes to examine the effect of the effective working time, reaction time, and liquid flow rate of the electrodes, solution PH, and changes in the concentrations of magnesium and potassium ions on the potential readings.
When the effective working time of the detection electrode is long, taking calcium chloride solutions with lower concentration (0.1mmol/L) and higher concentration (1mmol/L) as liquids to be detected for detection respectively, recording potential readings every 15 minutes, and calculating the relative standard deviation between the recorded values after recording for 6 hours so as to analyze the stability of electrode detection. The results of the measurement of the effective working time of the electrode are shown in FIG. 7 and Table 1, the electrode can stably work in a lower concentration calcium chloride solution (0.1mmol/L) or a higher concentration calcium chloride solution (1.0mmol/L) for at least 6 hours, and the relative standard deviation between records is 0.29% (0.1mmol/L solution) or 0.24% (1.0mmol/L solution).
TABLE 1 differences recorded at different time points
| Calcium chloride solutions of different concentrations | 0.1mmol/L | 1mmol/L |
| Relative standard deviation of each record | 0.29％ | 0.24％ |
When the influence of the flow rate on the potential reading is detected, 0.1mmol/L calcium chloride solution is used as the liquid to be detected, the flow rate is gradually increased to 110ml/min from 50ml/min according to 5ml/min, the reading is recorded, and the experiment is repeated for three times. Effect of flow rate on potential readings the results of the measurements are shown in particular in fig. 8, where the potential readings are hardly affected by the flow rate changes and the measurements are not affected by the flow rate values when the flow rate is gradually increased from 50ml/min to 110 ml/min.
When the influence of the pH value of the solution on potential reading is detected, 0.1mmol/L and 1mmol/L calcium chloride solutions are taken as liquids to be detected, concentrated hydrochloric acid or 1mol/L sodium hydroxide solution is respectively added to adjust the pH value of the solution, and the potential reading when the pH value of the solution fluctuates between 5 and 10 is recorded. The effect of the pH change of the solution on the potential reading is shown in fig. 9, and when the pH value of the solution is in the range of 5-10, the pH change has no obvious effect on the electrode reading, and the measurement result is not affected by the pH value of the solution.
When the influence of the concentration of magnesium ions and potassium ions on potential reading is detected, a pre-prepared 1mol/L magnesium chloride solution and a pre-prepared 3.5mol/L potassium chloride solution are taken as liquid to be detected, added into a 0.1mmol/L calcium chloride solution to adjust the concentration of the magnesium ions and the potassium ions, wherein the concentration range of the magnesium ions is 0-1.25mmol/L, the concentration range of the potassium ions is 0-7mmol/L, and the potential reading is recorded. The effect of the change in the concentration of magnesium ions and potassium ions on the electrode readings is shown in fig. 10, and it can be seen that the addition of magnesium ions or potassium ions to the calcium chloride solution did not significantly affect the potential readings, indicating that the selectivity of the electrode to calcium ions is high.
After testing the characteristics of the electrode, selecting a calcium chloride solution with a known concentration as a liquid to be tested to test in an in vitro simulation cycle, repeatedly testing the solution with the same concentration for 5 times at an interval of 5 minutes every time, comparing the electrode reading with the known concentration, and analyzing the accuracy and precision of the electrode by calculating the ratio of the electrode result to the known concentration and the relative standard difference of the test result. Specific results are shown in table 2. As can be seen from Table 2, when the solution concentration is low, the relative error between different measurements is large, and as the solution concentration increases, the relative error gradually decreases; and the deviation of the measured result from the actual concentration is not more than 5%.
TABLE 2 continuous test results of different concentrations of solution electrodes
In the blood test, the ion calcium concentration in the whole blood was measured using an iSTAT blood gas analyzer (available from yapei corporation), and a standard curve was established based on the logarithm of the ion concentration and the corresponding potential reading, and the result is shown in fig. 11. The electrode potential and the blood ionized calcium concentration also satisfy the linear relation (R)20.9994), the slope was 20.91 ± 0.26 mV. Then, detecting ionized calcium with different concentrations in blood by using an electrode, adjusting the ionized calcium concentration by adding 10% (w/v) calcium chloride solution (0.9mol/L) into the whole blood intermittently, detecting the obtained liquid serving as liquid to be detected in an in-vitro simulation cycle, recording electrode reading, applying MedCalc software, adopting a Bland-altman method and an iSTAT bloodAnd comparing the detection results of the gas analyzer, drawing by taking the iSTAT detection result as an abscissa and taking the percentage of (iSTAT result-electrode result)/iSTAT result as an ordinate, and analyzing the deviation degree of the electrode detection and the iSTAT result. The results are shown in FIG. 12. The linear regression showed that the electrode assay results were significantly linearly related to the iSTAT assay results (R20.999); the bland-altman analysis showed that the mean bias between the electrode results and the iSTAT results was 0.9%, the maximum bias was 4.7%, and the 95% consistency margin was (-3.2%, 5.1%), indicating that the bias between the electrode results and the iSTAT results was less than 10%, which is a clinically acceptable error. Therefore, the electrode can accurately detect the concentration of ionized calcium in flowing blood, and has smaller deviation compared with the currently clinically common method for detecting ionized calcium.
In conclusion, the present invention effectively overcomes various disadvantages of the prior art and has high industrial utilization value.
The foregoing embodiments are merely illustrative of the principles and utilities of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or change the above-mentioned embodiments without departing from the spirit and scope of the present invention. Accordingly, it is intended that all equivalent modifications or changes which can be made by those skilled in the art without departing from the spirit and technical spirit of the present invention be covered by the claims of the present invention.
Claims (10)
1. A device for monitoring dynamic changes of blood ionized calcium in real time on line and capable of being used for CRRT is characterized by comprising an electrode body (1), wherein a liquid channel (2), a working electrode inner cavity (3), a reference electrode inner cavity (4) and a temperature electrode inner cavity (5) are arranged on the electrode body (1);
the working electrode inner cavity (3) extends to the liquid channel (2), a membrane electrode (31) is arranged between the working electrode inner cavity (3) and the liquid channel (2), and working electrode inner liquid (32) and a working electrode (33) are arranged in the working electrode inner cavity (3);
the reference electrode inner cavity (4) comprises a first electrode inner cavity (41) and a second electrode inner cavity (42), a first separating membrane (43) is arranged between the first electrode inner cavity (41) and the second electrode inner cavity (42), the second electrode inner cavity (42) extends to the liquid channel (2), a second separating membrane (44) is arranged between the second electrode inner cavity (42) and the liquid channel (2), a reference electrode stationary phase (411) and a reference electrode (412) are arranged in the first electrode inner cavity (41), reference electrode inner liquid (421) and a microporous fiber rod (422) are arranged in the second electrode inner cavity (42), and the microporous fiber rod (422) extends to the first electrode inner cavity (41);
the temperature electrode inner cavity (5) extends to the liquid channel (2), a heat conducting film (52) is arranged between the temperature electrode inner cavity (5) and the liquid channel (2), and a temperature monitoring device (51) is further arranged in the temperature electrode inner cavity (5).
2. The device for on-line real-time monitoring of blood ionized calcium dynamic change applicable to CRRT according to claim 1, wherein the liquid channel (2) extends straight, and the diameter of the cross section of the liquid channel (2) is 4.5-5.5 mm.
3. The device for on-line real-time monitoring of blood ionic calcium dynamics for CRRT according to claim 1, wherein the membrane electrode (31) comprises a first gasket, an active membrane and a second gasket stacked in sequence, the first gasket being located at one side of the liquid channel (2), and the second gasket being located at one side of the working electrode lumen (3).
4. The device for on-line real-time monitoring of blood ionic calcium dynamics for CRRT according to claim 3, wherein the material of the first pad and/or the second pad is silica gel, the active membrane comprises an active substance, preferably the active substance is selected from organic phosphorus salts, more preferably the organic phosphorus salts are selected from calcium bis [4- (1,1,3, 3-tetramethylbutylphenyl) phosphate, the thickness of the first pad is 0.27-0.33 mm, the thickness of the active membrane is 0.27-0.33 mm, and the thickness of the second pad is 0.27-0.33 mm.
5. The device for on-line real-time monitoring of blood ionic calcium dynamics for CRRT according to claim 1, wherein the working electrode internal fluid (32) is selected from calcium chloride aqueous solution, the working electrode is selected from Ag/AgCl wire;
and/or the volume of the working electrode inner cavity (3) is 4.5-5.5 ml, the working electrode inner cavity (3) is cylindrical, preferably cylindrical, and the diameter of the cross section of the cavity is 7.2-8.8 mm.
6. The device for on-line real-time monitoring of blood ionized calcium dynamic change applicable to CRRT according to claim 1, wherein the material of the first separation membrane (43) and/or the second separation membrane (44) is selected from silica gel, and the thickness of the first separation membrane (43) and/or the second separation membrane (44) is 3.6-4.4 mm;
and/or the reference electrode stationary phase (411) is selected from potassium chloride gel, the reference electrode inner liquid (421) is selected from potassium chloride aqueous solution, the length of the microporous fiber rod is 9.5-10.5 mm, the diameter of the cross section is 0.85-0.95 mm, the pore diameter is 0.28-0.32 mm, and the reference electrode is selected from Ag/AgCl line;
and/or the volume of the first electrode inner cavity (41) is 4.5-5.5 ml, the first electrode inner cavity (41) is cylindrical, preferably cylindrical, and the diameter of the cross section of the cavity is 7.2-8.8 mm;
and/or the volume of the inner cavity (42) of the second electrode is 4.5-5.5 ml, the inner cavity (42) of the second electrode is cylindrical, preferably cylindrical, and the diameter of the cross section of the cavity is 7.2-8.8 mm.
7. The device for on-line real-time monitoring of blood ionic calcium dynamics for CRRT according to claim 1, wherein the material of the heat conducting membrane (52) is selected from heat conducting silica gel;
and/or, the temperature monitoring device (51) is selected from a thermistor;
and/or the volume of the inner cavity (5) of the temperature electrode is 48-58 mm2The inner cavity (5) of the temperature electrode is cylindrical, preferably cylindrical, and the diameter of the cross section of the cavity is 2.8-3.4 mm.
8. The device for on-line real-time monitoring of blood ionized calcium dynamic change applicable to CRRT according to claim 1, further comprising a connector and a lead (6), wherein the lead (6) is electrically connected with the working electrode (33), the reference electrode (412) and the temperature monitoring device (51), respectively, and the connector is positioned at two ends of the liquid channel (2).
9. The device for on-line real-time monitoring of blood ionized calcium dynamic change applicable to CRRT according to claim 8, further comprising a signal output device, wherein the signal output device comprises a signal acquisition circuit, an amplification circuit and a display device which are connected in sequence, and the signal output device is electrically connected with the conducting wire (6).
10. A CRRT device, characterized in that, comprises a CRRT device body, the artery end and/or vein end of the CRRT loop of the CRRT device body is connected with the device for monitoring blood ionized calcium dynamic change on line and in real time of CRRT according to any claim 1 to 9.
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