An online detector for halothane anesthetics in blood and its application

Abstract

An online detector for halothane anesthetics in blood uses ion mobility spectrometry as the basic detection technology and combines it with headspace sampling technology to achieve direct analysis of halothane anesthetic concentrations in whole blood without sample pretreatment. The detector consists of a fully automatic headspace sampler, a three-way connector, a variable-diameter sampling sleeve, and a negative ion mode photoionization ion mobility spectrometer. The fully automatic headspace sampler includes a sample carrier, a heating furnace, an injection needle and control components, a six-way valve quantitative loop, and a sample gas transmission tube; the three-way connector is connected to the sample gas transmission tube, the variable-diameter sampling sleeve, and the air purification tube and air respectively. The detection limit of sevoflurane tested by this device and method can reach a concentration below 1 ng / μl, and the detection and analysis time for a single sample is less than 2 minutes. The method of the present invention is intelligent, fast, efficient, and reliable.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical analysis, and in particular relates to an online detector for halothane anesthetics in whole blood and its application. Background Art

[0002] Sevoflurane is an inhalational anesthetic with a molecular formula of C₄H₃FₐO and a molecular weight of 200.06. Sevoflurane is indicated for the induction and maintenance of general anesthesia in both inpatient and outpatient surgery in adults and pediatric patients. The induction dose must be individualized and adjusted based on the patient's age and clinical condition. At a concentration of 2% to 4% for induction and 3% for maintenance, the blood concentration reaches a steady-state of approximately 360 μmol / L (72 mg / L) 10 to 15 minutes after inhalation; approximately 90 μmol / L (18 mg / L) 5 minutes after discontinuation; and approximately 15 μmol / L (3 mg / L) 60 minutes after discontinuation. Isoflurane, an isomer of enflurane, is an inhalational anesthetic with rapid induction and recovery. It does not stimulate the sympathetic nervous system during anesthesia, but can slightly sensitize the heart to the effects of epinephrine and has a moderate muscle relaxant effect. Due to the properties of inhalational anesthetics, instrumentation for measuring gas states may be subject to interference. The concentration of anesthetics in the blood is often closely related to the depth of anesthesia. Therefore, detecting the concentration of halothane anesthetics in the patient's blood during surgery is of great significance for the anesthesia process. Therefore, the present invention has developed a halothane anesthetic detection device and method.

[0003] A headspace sampling method invented by Fu Qiang et al. (patent number ZL20161095007.5), a fully sealed headspace sampling process for measuring dissolved components in transformer oil, is used to solve the technical problem in the existing technology of large errors caused by the mixing of foreign components and the volatilization of volatile components when injecting oil samples into headspace sampling bottles, as well as the different amounts of oil samples injected each time and changes in the environment.

[0004] Liu Junwei et al. invented a fully automatic headspace sampler (Patent No. ZL201621117139.5), which includes a chassis, bracket, and housing. It also includes a sample area, a sample heating area, a gas pressure control area, a sampling and injection area, a program control area, and a mounting area for the entire device. This utility model is an independent patent describing the fully automatic headspace sampler.

[0005] Li Haiyang et al. invented an online blood sevoflurane detector and its application (Patent No. ZL201510737861.2). This instrument uses ion mobility spectrometry as its basic detection technology, combined with sample thermal desorption and headspace sampling, and achieves continuous online detection of sevoflurane in human surgical waste blood during surgery without the need for blood sample pretreatment. However, the detection sensitivity of the invented method does not fully meet clinical application requirements.

[0006] The current method for detecting halothane inhalation anesthetics is capillary gas chromatography. Blood halothane detection relies on blood as a complex biological sample, requiring sample pretreatment before chromatographic separation. This method is time-consuming and often requires offline analysis, failing to fully meet the clinical needs of intraoperative anesthesia monitoring.

[0007] To address the problems of insufficient sealing of thermal desorption injectors, difficulty in directly separating halothane anesthetics from whole blood, and low halothane anesthetic detection sensitivity, the present invention proposes an online halothane blood detector. This instrument utilizes a fully automatic sealed injection system and a connection interface designed to enhance detection sensitivity, enabling effective separation and efficient ionization of target samples. The device boasts a well-sealed detection device, simple interface installation, and highly reliable detection methods, making it suitable for timely bedside monitoring of halothane anesthetic blood concentrations in clinical settings. Summary of the Invention

[0008] The technical problems to be solved by the present invention are: insufficient sealing of the headspace sampler, difficulty in directly separating halothane anesthetics from whole blood, low sensitivity in halothane anesthetic detection, low ionization efficiency and the like.

[0009] An online detector for halothane anesthetics in blood, comprising a fully automatic headspace sampler (14), a three-way connector, a variable-diameter sampling sleeve, and a negative ion mode photoionization ion mobility spectrometer;

[0010] The sample gas transmission tube (15) of the fully automatic headspace sampler (14) is connected to one interface of the three-way joint, the second interface of the three-way joint is connected to an open end of a variable-diameter sampling sleeve, and the other open end of the variable-diameter sampling sleeve extends into the ionization zone of the ion transfer tube through the ion transfer tube inlet tube of the ion mobility spectrometer; the third interface of the three-way joint is connected to air;

[0011] The variable diameter sampling sleeve is a pipeline with two open ends of different inner diameters. The open end with a larger inner diameter is connected to the second interface of the three-way connector, and the open end with a smaller inner diameter extends into the ionization zone of the ion transfer tube.

[0012] The third interface of the three-way connector is connected to the air through an air purification tube. The air purification tube is a pipeline filled with molecular sieves and activated carbon. It replenishes the sample gas and ensures that the cleanliness and humidity of the air components replenished by the ion mobility spectrometer meet the use requirements, so that the humidity of the replenishing gas entering the ion mobility spectrometer is 0-50ppm.

[0013] The ion transfer tube used includes a photoionization source (such as a VUV light ionization source) and a Faraday disk, which are respectively arranged at the left and right ends, and an ion gate located between the photoionization source and the Faraday disk. The area between the photoionization source and the ion gate is the ionization region, and the area between the ion gate and the Faraday disk is the transfer region.

[0014] Three through holes are sequentially provided on the outer wall of the ion transfer tube from the side of the ionization region close to the photoionization source to the side of the ion gate, which are respectively an ion transfer tube outlet interface (4) for connecting to a vacuum pump, an interface (5) for connecting to a chemical dopant source, and an ion transfer tube sample inlet (6); these three through holes and a drift gas inlet (8) provided on the outer wall of the ion transfer tube from the migration region close to the ion detector together constitute the external interface of the gas circulation system of the ion transfer tube; the ion transfer tube outlet interface (4) is connected to the vacuum pump inlet as the ion transfer tube gas outlet (gas outlet), and the rest are gas inlets (gas inlets);

[0015] A variable diameter sampling sleeve (7) is inserted into the sample inlet (6) of the ion transfer tube, one end of the variable diameter sampling sleeve (7) is located in the ionization zone of the ion transfer tube, and the other end is located outside the ion transfer tube and connected to a three-way connector (9); the variable diameter sampling sleeve (7) is hollow and has a stepped inner diameter structure; the inner diameter of the other end located outside the ion transfer tube is larger than the inner diameter of the end located in the ionization zone;

[0016] The number of steps or steps of the inner diameter stepped variable diameter structure is 2. The variable diameter sampling sleeve (7) is a hollow tube with two open ends formed by sealing and connecting the open end of one of three hollow tubes with different inner diameters with the open ends of the other two. The annular surface formed at the connection between the two hollow tubes in the hollow tube is a stepped table, and the stepped table is perpendicular to the axis of the hollow tube. The hollow tube with a larger inner diameter is located at the other end outside the ion migration tube, and the hollow tube with a smaller inner diameter is located at one end of the ionization zone.

[0017] A variable diameter sampling sleeve (7) is inserted into the sample inlet (6) of the ion migration tube; the variable diameter sampling sleeve is a structure of three sections of tubes with different inner diameters, the section away from the ionization zone (2) is a polytetrafluoroethylene tube φ4 tube, the inner diameter at one end of the ionization zone is 0.5-1.0 mm, and the radial width of the stepped table is 0.25-1.0 mm; the ionization zone and the migration zone are both coaxial cylindrical, and their axial center lines are placed parallel to the horizontal plane;

[0018] The sampling port (6) is a circular through hole, the variable diameter sampling sleeve (7) is a circular tube, and the outer diameter "r1" of the variable diameter sampling sleeve (7) is equal to the inner diameter "r2" of the ion migration tube sample sampling port (6).

[0019] The ion transfer tube is selectively pumped for sampling, and the VUV light ionization source can selectively ionize; the material of the variable diameter sampling sleeve (7) is one or more non-metallic insulating materials such as PG, polytetrafluoroethylene or high temperature resistant (can withstand high temperatures above 120-150°C without physical and chemical property changes) rubber;

[0020] One end of the variable diameter sampling sleeve (7) outside the ion transfer tube is connected to a three-way joint, and the insertion position of the port at the other end in the ionization zone is just located in the area between the cylindrical light path (light irradiation area) emitted by the circular light window of the photoionization source and the side surface of the variable diameter sampling sleeve and the central axis; the radius of the cylindrical light path is equal to the radius of the circular light window of the photoionization source (such as: VUV lamp), and the radius of the cylindrical ionization zone is between 1 and 2 times the radius of the light window;

[0021] The axial distance between the photoionization source lamp window and the ion gate is set to "L", the axial position of the other end port of the variable diameter sampling sleeve (7) in the ionization zone in the ion transfer tube is within the range of 1 / 2-5 / 6L from the photoionization source lamp window, and the radial position is within the range of the central axis of the light path emitted by the lamp window to less than or equal to the radius "R" of the circular lamp window.

[0022] The whole blood separation process for halothane anesthetics is performed using a fully automated headspace sampler (HS-72A / B, Shanghai Star Analytical Instruments Co., Ltd.), which consists of a sample carrier, a heating furnace, an automatic injection needle and control components, a six-way valve quantitative loop, and a sample gas transmission tube. The sample is first sealed in a sample bottle and placed in the multi-position sample carrier hole. An automatically controlled lifting arm moves the sample to the heating furnace incubator. After the headspace above the sealed sample bottle equilibrates, the sample is taken by the automatic injection needle and transferred to the six-way valve quantitative loop. When in the injection state, the six-way valve is rotated to switch the quantitative loop to the carrier gas transmission line. The carrier gas carrying the halothane anesthetic sample gas in the quantitative loop is transmitted through the transmission tube through a three-way connector.

[0023] The end of the transfer tube is connected to one interface of a T-type three-way connector, the second interface of the three-way connector is connected to one end of a variable-diameter sampling sleeve, and the other end of the variable-diameter sampling sleeve is directly inserted into the central ionization region of the ion transfer tube. The target sample molecules can be directly ionized by the photoionization source; the third interface of the three-way connector is the gas supply through-hole of the ion transfer tube; the negative ion mode photoionization ion mobility spectrometry selectively ionizes complex matrix components and then analyzes to obtain detection signals;

[0024] The fully automatic headspace sampler and ion mobility spectrometer combined system can achieve fully automatic operation and continuous analysis; the specific process includes the separation and analytical detection of halothane anesthetics;

[0025] Separation process: Whole blood samples were incubated in a heating furnace at a 30-60°C equilibrium temperature, the six-way valve was set at 100-150°C, the transfer tube was set at 100-150°C, and the needle was set at 100-150°C. The analysis cycle was 0.5-2.00 min, the equilibrium time was 0.10-1.00 min, the pressurization time was 0.10-1.00 min, the injection time was 0.10-1.00 min, the sample filling equilibrium was 0.10-1.00 min, the injection time was 0.10-1.00 min, and the purge time was 0.10-2.00 min. The injection loop was 1-5 ml. The carrier gas regulating valve was set to 10-300 ml / min, and the pressurization valve flow rate was set to 10-100 ml / min.

[0026] Analysis and detection process: The migration tube used is a pump-evacuated sampling method; the float gas is 500-600 ml / min; the dopant gas is 50-100 ml / min; the carrier gas carrying the sample is 100-200 ml / min; the pump-evacuated gas flow rate in the experiment is the sum of the float gas, dopant and carrier gas, and the air flow is 650-900 ml / min; the migration tube in the experiment is a cylindrical structure. If the lamp window radius is set to "R" (usually 0.5-1 cm), the ionization zone radius is (1-3)R, the migration zone radius is greater than the ionization zone radius and less than 5R; the ionization zone axial distance is set to L (usually designed to be 2-3 cm), and the migration zone length is designed to be 3-4L.

[0027] A whole blood sample is added to a sample bottle, and a chemical doping agent, isopropyl alcohol, is added at a volume percentage of 10-50% of the blood sample volume to facilitate separation of gaseous fluorocarbon anesthetics from the blood sample.

[0028] This detector is suitable for one or more of sevoflurane, isoflurane, enflurane, desflurane or methoxyflurane.

[0029] Advantages of the invention

[0030] 1. Compared with traditional chromatographic methods, using ion mobility spectrometry as a means of analyzing halothane anesthetics in blood has the following advantages: blood samples do not require complex pretreatment and are suitable for bedside instant analysis; the added dopant can assist in gas / liquid separation and achieve a new equilibrium system; the dopant can also enhance the ion peak signal of the photoionization ion mobility spectrometry reagent.

[0031] 2. The fully automatic headspace sampler sample transfer tube and ion mobility spectrometer connection interface tube adopt variable diameter technology to concentrate the sample concentration, change the flow field motion mode in the ion mobility tube, and improve the detection sensitivity.

[0032] 3. One end of the variable diameter sampling sleeve is directly introduced into the ionization zone of the negative pressure suction sampling ion transfer tube, so that the sample can be directly and efficiently ionized, thereby improving the sample transmission efficiency. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1-1 A schematic diagram of an online detector device for detecting halothane anesthetics in blood;

[0034] Figure 1-2 Figure C on the left is a schematic diagram of the entertainment dopant cartridge device; Figure 1-2 Figure D on the right shows a schematic diagram of a hollow and sealed sample bottle inside an entertainment dopant cylinder;

[0035] Figure 2 The device of the present invention detects ion mobility spectra of sevoflurane and isoflurane in blood;

[0036] Figure 3 The device of the present invention detects three repeated ion mobility spectra of sevoflurane in blood. DETAILED DESCRIPTION

[0037] Figure 1-1 In the figure, 1 is the VUV light ionization source; 2 is the ion transfer tube ionization region; 3 is the ion transfer tube migration region; 4 is the ion transfer tube outlet interface connected to the vacuum pump; 5 is the interface for connecting the chemical dopant; 6 is the ion transfer tube sample inlet tube; 7 is the reducing sampling sleeve; 8 is the drift gas inlet; 9 is the three-way connector; 10 is the amplifier; 11 is the A / D converter; 12 is the data processing system; 13 is the ion gate; 14 is the fully automatic headspace sampler; 15 is the sample gas transmission tube; 16 is the air purification tube.

[0038] The blood sample is first sealed in a sample bottle and placed in a multi-position sample carrier hole. An automatically controlled lifting arm moves the sample to a heating furnace incubator. After the air above the sealed sample bottle and the headspace is balanced, the sample is taken by an automatic injection needle and transferred to a six-way valve quantitative ring. The halothane anesthetic in the quantitative ring is transferred by a transfer tube through a three-way connector (9) and then sent to an ion migration tube for analysis and detection by a variable diameter sampling sleeve (7).

[0039] Figure 2-3 Several experimental spectra are provided to illustrate the present invention. The experimental conditions for these spectra are as follows: the ionization source is a VUV light ionization source ion mobility spectrometer, in negative ion mode with a high-voltage source; the migration tube temperature is maintained at 100°C, the injector temperature is 60°C, the dopant is acetone, and the door open time is 50 μs; the carrier gas (air), float gas (air), and dopant gas (air) flow rates are 200 mL / min, 600 mL / min, and 50 mL / min, respectively. 1 mL of blood was sampled, and 0.2 mL of isopropyl alcohol was added to each sample.

[0040] Automatic sampler condition parameters: equilibrium temperature is 60℃, six-way valve is 100℃, transfer tube is 100℃, needle is 100℃; analysis cycle is 1.00min, equilibrium time is 0.50min, pressurization time is 0.10min, injection time is 0.05min, sample filling balance is 0.05min, injection time is 0.20min, and purge is 1.00min; carrier gas regulating valve is set to 25ml / min, pressurization valve flow is set to 40ml / min; injection loop is 1ml.

[0041] The ion mobility spectrometry operations involved in the embodiments were all detected using an ion mobility spectrometer device with the structure shown in FIG1 ;

[0042] The ion migration spectrometer in the invention, the ion migration tube detector is VUV lamp (1), ionization zone structure (2), migration zone structure (3) from left to right, and the ion gate (13) is located between the ionization zone (2) and the migration zone (3). The sample is ionized in the ionization zone under the irradiation of the VUV light ionization source, and enters the migration zone through the ion gate in turn. In the migration zone, it is finally received and transmitted by the ion receiver due to different migration speeds. The ion migration tube is a VUV light ionization source, and the circular lamp window cross-sectional radius is 6mm. It includes a coaxial cylindrical ionization zone and a cylindrical migration zone. The ionization zone is 25mm long and the inner tube diameter is 20mm; the migration zone is 90mm long and the inner tube diameter is 25mm. An ion gate 13 is provided between the ionization zone and the migration zone, and a photoionization source 1 is provided on the side of the ionization zone away from the ion gate; an ion migration tube sample inlet 6 is provided on the outer wall of the ion migration tube in the ionization zone;

[0043] A variable diameter sampling sleeve 7 is inserted into the sample inlet 6 of the ion transfer tube. One end of the variable diameter sampling sleeve 7 is located in the ionization zone of the ion transfer tube, and the other end is connected to the sample gas transmission tube 15 through a three-way connector 9.

[0044] The variable diameter sampling sleeve 7 is a hollow structure with a stepped inner diameter; the inner diameter of the other end outside the ion migration tube is larger than the inner diameter of the sample gas transmission tube at one end of the ionization zone. The number of steps or steps of the stepped inner diameter variable structure is 2. It is a hollow tube with two ends open, formed by connecting the open end of one of three hollow tubes with different inner diameters to the open end of the other two, and the annular surface formed at the connection between the two hollow tubes in the hollow tube is the stepped table, which is perpendicular to the axis of the hollow tube; the hollow tube with a large inner diameter is located at the other end outside the ion migration tube, and the hollow tube with a small inner diameter is located at one end of the ionization zone. The variable diameter sampling sleeve 7 is located at one end of the ionization zone.

[0045] The inner diameter of the end is 0.75 mm, and the inner diameter of the other end located outside the ion transfer tube is 3 mm.

[0046] The ion transfer tube includes a photoionization source (e.g., a VUV light ionization source) and a Faraday disk, which are positioned opposite each other at the left and right ends, and an ion gate located between the photoionization source and the Faraday disk. The area between the photoionization source and the ion gate is the ionization region, and the area between the ion gate and the Faraday disk is the transfer region.

[0047] Three through holes are provided on the outer wall of the ion transfer tube in sequence from the ionization region near the photoionization source to the ion gate, namely, an ion transfer tube outlet interface 4 for connecting to a vacuum pump, an interface 5 for connecting to a chemical dopant, and an ion transfer tube sample inlet 6; these three through holes and a drift gas inlet 8 provided on the outer wall of the ion transfer tube in the migration region near the ion detector together constitute the external interface of the gas circulation system of the ion transfer tube; the ion transfer tube outlet interface 4 is connected to the vacuum pump inlet as the ion transfer tube gas outflow port, and the rest are gas inflow ports.

[0048] The material of the variable diameter sampling sleeve 7 is polytetrafluoroethylene and PG tube. One end of the variable diameter sampling sleeve 7 outside the ion transfer tube serves as the port of the sample injection port, and the insertion position of the port at the other end in the ionization zone is just located in the area between the cylindrical light path (light irradiation area) emitted by the circular light window of the photoionization source and the side surface of the variable diameter sampling sleeve and the central axis; the radius of the cylindrical light path is equal to the radius of the circular light window of the photoionization source (such as: VUV lamp), and the radius of the cylindrical ionization zone is 1.5 times the radius of the light window. The axial distance between the photoionization source window and the ion gate is set to "L", and the axial position of the port at the other end of the variable diameter sampling sleeve 7 in the ionization zone in the ion transfer tube is 18 / 25L from the photoionization source window, and the radial position is at the central axis of the light path emitted by the window. In the embodiment, the axial distance "L" between the window and the ion gate is 25mm, and the center point injection position is at the 18mm point.

[0049] The three through-hole tubes near the ionization zone of the VUV lamp in the photoionization ion mobility spectrometer are connected to the ion mobility tube outlet port 4 for the vacuum pump; the chemical dopant port 5 for the dopant; and the ion mobility tube sample inlet port 6. In this embodiment, the ion mobility tube float gas (air) flow rate is 600 mL / min, the vacuum pump flow rate is 850 mL / min, the dopant gas (air as carrier gas) flow rate is 50 mL / min, and the sample carrier gas (air) flow rate is 200 mL / min. The ion mobility tube temperature control is set at 100°C, and the ion gate opening time is set to 50 μs.

[0050] The ion transfer tube is connected to a chemical dopant interface 5 through a pipeline with a dopant cartridge device (such as Figure 1-2 ) is connected, the dopant tube device includes a cylindrical dopant tube (such as Figure 1-2Left, Figure C), the outer wall surface of the upper open end of the dopant cylinder 51 has an external thread, and a cylindrical sealing cover with an internal thread is screwed on the upper open end of the dopant cylinder. The upper open end of the dopant cylinder is sealed by the sealing cover. A lower through hole is provided on the lower side wall surface of the circular dopant cylinder as a dopant gas air source inlet 52 connected to the air source, and an upper through hole is provided on the upper side wall surface of the circular dopant cylinder as a dopant gas outlet 53 connected to the chemical dopant (dopant) interface 5 through a conduit. A hollow and sealed sample bottle (such as Figure 1-2 (Right, Figure D) A sample bottle contains a chemical dopant, acetone 56. A PTFE tube (outer diameter φ4) 54 is inserted into the top of the sample bottle 55. The upper open end of the tube is inside the dopant cartridge, and the lower open end is above the acetone liquid level in the sample bottle. The sample dopant gas (air) purge flow rate is 50 sccm. Acetone vapor evaporates through the PTFE tube hole in the sample bottle's upper cover. Within the dopant cartridge, the acetone vapor is diluted with air and then purged into the ion transfer tube.

[0051] The whole blood used in the experiment was pooled from 10 healthy individuals aged 18-60 years. 10 μl of each sevoflurane and isoflurane drug was dissolved in 1 ml of whole blood and vortexed for 1 minute to prepare the stock solutions. These solutions were then prepared using a serial dilution method to obtain different concentrations of sevoflurane and isoflurane at 1000, 100, 10, and 1 ng / μl.

[0052] Example 1

[0053] A 1ml, 100ng / μl sevoflurane blood sample is sealed in a sample bottle and placed in a multi-position sample tray. The sample is automatically moved to a heating furnace incubator with different incubation temperature settings: 50, 60, 70, and 80°C. After the air above the sealed sample bottle and the headspace are balanced, the sample is sampled by an automatic injection needle and transferred to a 1ml six-way valve quantitative loop. The sample gas is transferred by a transmission tube through a three-way connector (9) and then sent to an ion migration tube for analysis and detection by a variable diameter sampling sleeve (7). The condition parameters of the automatic injection device and the analysis parameters of the detector, except for the equilibrium temperature, are set according to the conditions described in the above specific embodiment. The sample equilibrium temperature affects the concentration of the analyte in the headspace above the sample bottle. When a higher incubation temperature of 70 or 80°C is selected, the blood undergoes a faster coagulation phenomenon during the heating process. At 50°C, the desorption signal of the sevoflurane anesthetic is lower than that at 60°C. Therefore, 60°C is preferred for subsequent experiments.

[0054] Example 2

[0055] A 1ml blood sample containing 1ng / μl of sevoflurane was sealed in a sample vial and placed in a multi-position sample tray. All autosampler parameters, except for the carrier gas control valve and pressurization valve flow rates, and the detector analysis parameters were set according to the conditions described in the above specific embodiment. The carrier gas control valve was set within the range of 5-300ml / min, and the pressurization valve flow rate was set within the range of 10-100ml / min. Ideally, a sufficiently high carrier gas flow rate was set to expel the headspace sample from the sample loop. The pressurization pressure is used to transfer the sample gas phase into the sample loop. Ideally, the pressure should be sufficient to just fill the loop. Excessive pressure will dilute the headspace gas. Based on the 1ml loop structure, a 1ml blood sample, and considering the detectable signal strength of a sevoflurane concentration of 1ng / μl in whole blood, the carrier gas control valve setting was optimized to 25ml / min; the pressurization valve flow rate was set to 40ml / min.

[0056] Example 3

[0057] Initial experiments explored the addition of methanol, ethanol, isopropanol, and carbon tetrachloride to 100 ng / μl of sevoflurane-containing whole blood. A 1ml blood sample was collected, and 0.2ml of each solvent was added to a 20ml sealed vial. The equilibration temperature was 60°C, the six-port valve was set at 100°C, the transfer tubing was set at 100°C, and the needle was set at 100°C. The analysis cycle was 1.00 min, the equilibration time was 0.50 min, the pressurization time was 0.10 min, the injection time was 0.05 min, the sample filling equilibration time was 0.05 min, the injection time was 0.20 min, and the purge time was 1.00 min. The carrier gas regulator was set to 25 ml / min, the pressurization valve flow rate was set to 40 ml / min, and the injection loop was 1 ml.

[0058] Methanol and ethanol are not suitable because they are miscible with blood and contain detectable components in the blood matrix. Adding carbon tetrachloride also results in a lower detection signal than adding isopropyl alcohol, making it unsuitable. Because isopropyl alcohol enhances the photoionization of dopant (acetone) reagent ions and does not interfere with sevoflurane anesthetic detection by components dissolved in blood, isopropyl alcohol was selected in subsequent experiments.

[0059] Example 4

[0060] A 100 ng / μl sample of sevoflurane and isoflurane in 1 ml of blood was added with 0.2 ml of isopropanol solvent, respectively, and the mixture was placed in a 20 ml sealed sample vial. The vial was placed on the autosampler turntable. The autosampler parameters were set as follows: equilibrium temperature of 60°C, six-port valve at 100°C, transfer tube at 100°C, and needle at 100°C; analysis cycle of 1.00 min, equilibrium time of 0.50 min, pressurization time of 0.10 min, injection time of 0.05 min, sample filling equilibration of 0.05 min, injection time of 0.20 min, and purge time of 1.00 min; the carrier gas regulator was set to 25 ml / min, and the pressurization valve flow rate was set to 40 ml / min. The automatic sampler separates the blood gas sample containing sevoflurane. The sample molecules are introduced into the central ionization zone of the ion migration tube by the transfer tube and are directly ionized into positive and negative ions. The hot carrier gas passes through the periodically opened ion gate and enters the drift zone composed of a uniform electric field. The drift zone is separated and detected to obtain the detection signal. The ion migration spectrum obtained by the detection is shown in the figure below. Figure 2 As shown in Figure 2, the migration time of sevoflurane anesthetic is 4.485ms, and the migration time of isoflurane anesthetic is 4.325ms.

[0061] Example 5

[0062] Accurately measure 1 ml of blood sevoflurane samples at concentrations of 10, 100, and 1000 ng / μl, add 0.2 ml of isopropanol solvent, and mix in a 20 ml sealed sample vial. Place the vial on the autosampler turntable. Set the autosampler parameters as follows: equilibrium temperature of 60°C, six-port valve at 100°C, transfer tube at 100°C, and needle at 100°C; analysis cycle of 1.00 min, equilibrium time of 0.50 min, pressurization time of 0.10 min, injection time of 0.05 min, sample equilibration of 0.05 min, injection time of 0.20 min, and purge time of 1.00 min; set the carrier gas regulator to 25 ml / min, and the pressurization valve flow rate to 40 ml / min. The automatic sampler separates the blood gas sample containing sevoflurane. The sample molecules are introduced into the central ionization zone of the ion migration tube by the transfer tube and are directly ionized into positive and negative ions. The hot carrier gas passes through the periodically opened ion gate and enters the drift zone composed of a uniform electric field. The drift zone is separated and detected to obtain the detection signal. The ion migration spectrum obtained by the detection is shown in the figure below. Figure 3 As shown, different concentrations were injected continuously by the autosampler and repeated three times. Figure 3 It can be seen that the analysis process of blood samples with the same concentration of sevoflurane is basically consistent.

Claims

1. An online detector for halothane anesthetics in blood, characterized by: It includes a fully automatic headspace sampler (14), a three-way connector, a variable diameter sampling sleeve, and a negative ion mode photoionization ion mobility spectrometer; The sample gas transmission tube (15) of the fully automatic headspace sampler (14) is connected to one interface of the three-way joint, the second interface of the three-way joint is connected to an open end of a variable diameter sampling sleeve, and the other open end of the variable diameter sampling sleeve extends into the ionization zone of the ion migration tube through the ion migration tube inlet tube of the ion migration spectrometer; the third interface of the three-way joint is connected to air; The variable diameter sampling sleeve is a pipe with two open ends of different inner diameters, the open end with the larger inner diameter is connected to the second interface of the three-way joint, and the open end with the smaller inner diameter extends into the ionization zone of the ion migration tube. The variable diameter sampling sleeve (7) is a hollow, inner diameter stepped diameter reducing structure; the number of steps or steps of the inner diameter stepped diameter reducing structure is 2, and the variable diameter sampling sleeve (7) is a hollow tube with two open ends formed by sealing the open end of one of three hollow tubes with two open ends with different inner diameters and the end faces of the other open ends. The annular surface formed at the connection between the two hollow tubes in the hollow tube is the stepped table, and the stepped table is perpendicular to the axis of the hollow tube.

2. The detector according to claim 1, characterized in that: The third interface of the three-way connector is connected to the air through an air purification tube. The air purification tube is a pipeline filled with molecular sieves and activated carbon. It replenishes the sample gas and ensures that the cleanliness and humidity of the air components replenished by the ion mobility spectrometer meet the use requirements, so that the humidity of the replenishing gas entering the ion mobility spectrometer is 0-50ppm.

3. The detector according to claim 1, characterized in that: The ion transfer tube used includes a photoionization source and a Faraday disk arranged opposite each other at the left and right ends, and an ion gate located between the photoionization source and the Faraday disk. The area between the photoionization source and the ion gate is the ionization region, and the area between the ion gate and the Faraday disk is the transfer region. Three through holes are provided on the outer wall of the ion transfer tube in sequence from the side of the ionization region close to the photoionization source to the side of the ion gate, which are respectively an ion transfer tube outlet interface (4) for connecting to a vacuum pump, an interface (5) for connecting to a chemical dopant source, and an ion transfer tube sample inlet (6); these three through holes and a drift gas inlet (8) provided on the outer wall of the ion transfer tube in the migration region close to the ion detector together constitute the external interface of the gas circulation system of the ion transfer tube; the ion transfer tube outlet interface (4) is connected to the vacuum pump inlet as the ion transfer tube gas outlet, and the rest are gas inlets; A variable diameter sampling sleeve (7) is inserted into the sample inlet (6) of the ion transfer tube, one end of the variable diameter sampling sleeve (7) is located in the ionization zone of the ion transfer tube, and the other end is located outside the ion transfer tube and connected to a three-way connector (9); the inner diameter of the other end located outside the ion transfer tube is larger than the inner diameter of the end located in the ionization zone; The hollow tube with a large inner diameter is located at the other end outside the ion transfer tube, and the hollow tube with a small inner diameter is located at one end of the ionization region.

4. The detector according to claim 3, characterized in that: Insert a variable diameter sampling sleeve (7) into the sample inlet (6) of the ion migration tube; the variable diameter sampling sleeve is a structure of three sections of tubes with different inner diameters, the section away from the ionization zone (2) is a polytetrafluoroethylene tube φ4 tube, the inner diameter at one end of the ionization zone is 0.5-1.0 mm, and the radial width of the stepped table is 0.25-1.0 mm; the ionization zone and the migration zone are both coaxial cylindrical, and their axial center lines are placed parallel to the horizontal plane; The sampling port (6) is a circular through hole, the variable diameter sampling sleeve (7) is a circular tube, and the outer diameter "r1" of the variable diameter sampling sleeve (7) is equal to the inner diameter "r2" of the ion migration tube sample sampling port (6).

5. The detector according to claim 1 or 3, characterized in that: The ion migration tube is selectively pumped for sampling, and the VUV light ionization source can selectively ionize; the material of the variable diameter sampling sleeve (7) is composed of one or more non-metallic insulating materials such as PG, polytetrafluoroethylene or high-temperature resistant rubber, and the high-temperature resistant rubber can withstand high temperatures above 120-150°C without changing its physical and chemical properties; One end of the variable diameter sampling sleeve (7) outside the ion transfer tube is connected to a three-way joint, and the insertion position of the port at the other end in the ionization zone is just located in the area between the cylindrical light path emitted by the circular light window of the photoionization source and the side surface of the variable diameter sampling sleeve and the central axis; the radius of the cylindrical light path is equal to the radius of the circular light window of the photoionization source, and the radius of the cylindrical ionization zone is between 1 and 2 times the radius of the light window; The axial distance between the photoionization source lamp window and the ion gate is set to "L", the axial position of the other end port of the variable diameter sampling sleeve (7) in the ionization zone in the ion transfer tube is within the range of 1 / 2-5 / 6L from the photoionization source lamp window, and the radial position is within the range of the central axis of the light path emitted by the lamp window to less than or equal to the radius "R" of the circular lamp window.

6. Use of the detector according to any one of claims 1 to 5, characterized in that: The whole blood separation process for halothane anesthetics is completed by a fully automatic headspace sampler, which includes a sample carrier, a heating furnace device, an automatic injection needle and control components, a six-way valve quantitative loop, and a sample gas transmission tube. The sample is first sealed in a sample bottle and placed in the multi-position sample carrier hole. An automatically controlled lifting arm moves it to the heating furnace incubation device. After the headspace above the sealed sample bottle is balanced, the automatic injection needle takes the sample and transmits it to the six-way valve quantitative loop. When in the injection state, the six-way valve is rotated to switch the quantitative loop to the carrier gas transmission tube. The carrier gas carrying the halothane anesthetic sample gas in the quantitative loop is transmitted through the transmission tube through a three-way joint. The end of the transfer tube is connected to one interface of a T-type three-way connector, the second interface of the three-way connector is connected to one end of a variable-diameter sampling sleeve, and the other end of the variable-diameter sampling sleeve is directly inserted into the central ionization region of the ion transfer tube. The target sample molecules can be directly ionized by the photoionization source; the third interface of the three-way connector is the gas supply through-hole of the ion transfer tube; the negative ion mode photoionization ion mobility spectrometry selectively ionizes complex matrix components and then analyzes to obtain detection signals; The fully automatic headspace sampler and ion mobility spectrometer combined system can achieve fully automatic operation and continuous analysis; the specific process includes the separation and analytical detection of halothane anesthetics; Separation process: Whole blood samples were incubated in a heating furnace at a 30-60°C equilibrium temperature, the six-way valve was set at 100-150°C, the transfer tube was set at 100-150°C, and the needle was set at 100-150°C. The analysis cycle was 0.5-2.00 min, the equilibrium time was 0.10-1.00 min, the pressurization time was 0.10-1.00 min, the injection time was 0.10-1.00 min, the sample filling equilibrium was 0.10-1.00 min, the injection time was 0.10-1.00 min, and the purge time was 0.10-2.00 min. The injection loop was 1-5 ml. The carrier gas regulating valve was set to 10-300 ml / min, and the pressurization valve flow rate was set to 10-100 ml / min. Analysis and detection process: The migration tube used was pumped for sampling; the float gas flow rate was 500-600 ml / min; the chemical dopant gas flow rate was 50-100 ml / min; and the carrier gas carrying the sample flow rate was 100-200 ml / min. The pumped gas flow rate was the sum of the float gas, chemical dopant, and carrier gas, and the flow rate was 650-900 ml / min. The migration tube used in the experiment was a cylindrical structure, with the lamp window radius set to "R", the ionization zone radius being (1-3)R, and the migration zone radius being larger than the ionization zone radius and less than 5R; the axial distance of the ionization zone was set to L, and the migration zone length was designed to be (3-4)L.

7. The use according to claim 6, characterized in that: A whole blood sample is added to a sample bottle, and a chemical doping agent, isopropyl alcohol, is added at a volume percentage of 10-50% of the blood sample volume to help separate the gas phase halothane anesthetic from the blood sample.

8. The use according to claim 6, characterized in that: This detector is suitable for one or more of sevoflurane, isoflurane, enflurane, desflurane or methoxyflurane.

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