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Online blood electrolyte monitoring with a ChemFET microcell system
471
Sensors and Actuators, BI (1990) 471-480
Online Blood Electrolyte Monitoring with a ChemFET Microcell System W. GUMBRECHT, W. SCHELTER and B. MONTAG Siemens AG, ZFE Fl AMF 32, D-8520 Erlangen (F.R.G.) M. RASINSKI and LJ. PFEIFFER Institut fiir Exp. Chirurgie, Klinik Rechts der Isar, D-8&M Munich (F.R.G.)
Abstract
2. Sample-taking Sensor System
A sample-taking sensor system for online pH and electrolyte monitoring of blood is described. The system consists of a two-lumen catheter with a ChemFET flow-through cell, a syringe pump unit with ChemFET instrumentation and a personal computer. Suitable operation of the pump unit allows the sensor to be calibrated every 2 min before each measurement. The blood sample volume withdrawn from the patient is on the order of 10 ~1. Solvent polymeric membrane ISFETs serve as measurement sensors as well as reference sensors. For this purpose they are spatially separated by a flow-through channel where a liquid junction can be established between the calibration solution and blood. In this way the arrangement saves a conventional reference electrode with the bridge solution. In vivo experiments in pigs show a very good correlation between sensor and analyzer values. There was no blood clotting in the sensor system.
The system comprises a two-lumen catheter with a ChemFET flow-through cell, a syringe pump unit with the ChemFET instrumentation (Fig. 1) and a personal computer. The flowthrough cell is a sandwich arrangement of a chip carrier, a ChemFET chip and a PMMA slide with an engraved flow-through channel. For the measurement of one ion, two ISFETs with the same kind of membrane are located in such a way that the meander flow-through channel separates both ISFETs (Fig. 2). The well-known solvent polymeric membranes [6] are deposited directly onto the S&N., gate insulator by a solvent-casting technique. Figure 2 shows the operation cycle of the sensor system. The flow-through cell is connected to the inner tube of a two-lumen catheter, the outer lumen being longer than the inner one. The outer lumen of the catheter, which is inserted in a blood vessel, is flushed with a calibration solution by pump 2. Due to the shorter inner lumen and a higher flow rate of pump 2 compared with pump 1, a fraction of this solution can be withdrawn to
Keywords: blood pH, blood electrolytes, ChemFET, flow-through cell, ISFET, online monitoring.
1. Introduction
Monitoring of blood pH and electrolytes (K+, Ca*+, Na+, Cl-, HCO; ) is very important in clinical analysis, e.g. during intensive care therapy, cardiac surgery or renal dialysis. The development of the chemically sensitive field-effect transistor (ChemFET) [ 1,2] with its advantages compared to ion-selective electrodes (ISE) was very promising. But the application of ChemFET devices still fails because of problems in packaging, reference electrode and drift. Catheter tip ChemFET sensors are especially prone to problems in fabrication and usage. The disadvantages of catheter tip sensors can be overcome by sample-taking systems which are connected directly to the patient [ 3-51. However, all previous systems suffer from rather complex assemblies. In this paper a simpler arrangement is presented. 09254005/90/$3.50
Fig. 1. Sample-taking sensor system consisting of a two-lumen catheter, flow-through cell and a syringe pump unit with ChemFET instrumentation. 0
Elsevier Sequoia/Printed
in The Netherlands
Fig. 3. Resolution and reproducibility of K+ measurements in Ringer’s solution at room temperature (calibration solution = 4.00 mM K+; measuring solution = 4.20 mM K+).
Cdibmtiaemarls Fig. 2. Operating cycle of the sensor system,
TABLE 1. Typical operation parameters Cycle time: Response time: Sample volume: 24 h blood consumption: Flushing solution: Flushing volume: ISFET membranes:
2 min 30 s 10 pl 7.2 ml Ringer’s + 5 IU/ml Na-Heparin 100 ml/24 h solvent polymeric membranes
calibrate the ISFETs (calibration mode). Interruption of the flushing stream by pump 2 allows blood to enter the cell. After reaching the first ISFET, the difference output gives the measurement signal because the second ISFET acts as a reference sensor with the calibration fluid as the bridge solution (measurement mode). After the measurement, the catheter tip is flushed with calibration solution again to clean the flow-through cell and to establish a new baseline. Typical operation parameters are shown in Table 1.
ion-selective membrane has reached an equilibrium state, and 95 to 98% of the theoretical slope has been achieved. The K+ concentration change from analyte to calibration solution was only 200 pmol/l in the physiological range (Fig. 3), showing the excellent resolution and reproducibility of the sensor system. The time delay between calibration and measurement registration is only about 20 s, eliminating drift problems. In addition, the differential operation of two ISFETs with equal membranes, which are in contact with the same fluids (time averaged), leads to remarkable baseline stability. For a period of 200 h a baseline drift of only 0.05 mV/h has been observed. 3.2. CO, Interference The solvent polymeric membranes are in direct contact with the gate insulator. Penetration of water and CO2 through the membrane may cause a pH change in the Si,N,/membrane interface and would result in CO2 interference, as reported in ref. 7. Therefore the test solution (Ringer’s) was saturated with air and 10% COz in air, respectively. The calibration solution is always air saturated with a content of 3 mmol/l K+. The observed CO2 interference of K+-selective ISFETs is only about 100 PV after 5 days of immersion in Ringer’s solution (Fig. 4).
3. Results 3.1. In Vitro Experiments Experimental data for Ringer’s solution at room temperature, received with K+ selective membranes, are shown in Fig. 3. The ISFET difference signal shows a sinusoidal characteristic during one operation cycle. After baseline and measurement plateau, an inversion of the line shape can be observed. During the cleaning period, the reference ISFET is in contact with blood while the first ISFET is already flushed with calibration solution. It is important to emphasize that on the measurement plateau the response of the
Fig. 4. CO, influence of the sensor signal of a K+-selective FET (PVC membrane/S&N, arrangement) after 5 days of soluimmersion in Ringer’s solution (calibration tion = 3.00 mM KC Ringer’s, air saturated, measuring solution = 3.72 mM K+ in Ringer’s, air- or 10% CO2 saturated).
479
3.3. In Vivo Experiments
The system has been tested experimentally in pigs (n = 9). The microcell was connected to the carotid artery of the anesthetized animal. Samples were taken from the contralateral carotid artery and were analyzed with an electrolyte analyzer (AVL 984) or a blood gas analyzer (IL 1306) respectively. The potassium concentration was controlled by infusing KC1 or glucose/insulin solution into the pig with constant flow rates. Figure 5 shows a very good correlation between sensor and reference values (correlation coefficient 0.998), received with a 4 h experiment. The calcium concentration of the animal was altered by calcium-gluconate or EDTA-infusion over 3 h (Fig. 6).
7.6
I
7.2 1
,
I
I
10
26
36
46 __t
66
66
70 tlmo[mln]
Fig. 7. Monitoring of blood pH.
For monitoring blood pH, the calibration solution was modified in such a way that a 20 mmol/l phosphate buffer (pH 7.2) was introduced leaving Ca and Mg ions out. The ionic strength was kept at 160 mmol/l. The blood pH of the animal was altered by variation of the expiratory volume (Fig. 7). The correlation is quite good, but has to be improved by suitable calibration solutions. 4. Discussion
I
I
21 1
2
-
J
4 tlm* [houn]
3
Fig. 5. Monitoring of blood potassium concentration. b+
I
+ Immol/ll
1.6
I
I
1
I
I
No problems with respect to blood clotting in the sensor system were observed during the tests, although the blood samples were not heparinized. The double-lumen catheter in combination with a syringe pump unit acts as a three-way valve with minimum size and dead volume. Therefore the sample volume can be reduced to 10 ~1. The baseline calibration before each measurement eliminates drift problems. Because the calibration solution acts as a bridge solution during measurement, an excellent reproduction of the liquid junction potential can be observed. No contamination of a porous plug can occur. Furthermore, the double-lumen catheter acts as a heat-exchanger, warming up the calibration solution and cooling down the blood sample to a mean temperature of about 30 “C. A continuous flow of calibration solution and blood through the cell guarantees a constant temperature during operation. 5. Cooclusions
1.1 / 1
2
3 -
time[hwnl
Fig. 6. Monitoring of blood calcium concentration.
In vivo experiments with a sample-taking ChemFET sensor show the feasiblity of online blood electrolyte monitoring. Problems of blood
480
clotting, reference electrode and calibration have been solved with a simple arrangement. 4
References J. Janata, Chemically sensitive field effect transistors, in J. Janata and R. J. Huber (eds.), Solid State Chemical Sensors, Academic Press, Orlando, FL, 1985. P. Bergveld and A. Sibbald (eds.), Analytical and biomedical applications of ion-sel&tive field-effect transistors, in Comorehensiue Analvtical Chemistrv. _ Vol. XXIII. Elsevier. Amsterdam, 1988. . A. Sibbald, A. K. Covington and R. F. Carter, Online patient-monitoring system for the simultaneous analysis of
5 6
7
blood K+, Ca2+, Na+ and pH using a quadrupole-function ChemFET integrated circuit sensor, Med. Biol. Eng. Cornput., 23 1985) 329-338. S. Shoji, M. Esashi and T. Matsuo, Blood pH monitoring micro cell using micro valves, Proc. %d Int. Meet. Chemical Sensors, Bordeaux, July 7-10, 1986, pp. 550553. T. Tamura, T. Togawa, K. Suematsu and K. Sato, Continuous blood pH monitoring by use of the null method, Sensors and Actuators, 16 (1989) 273-285. D. Ammann, W. E. .Morf, P.’ Anker, P. C. Meier, E. Pretsch and W. Simon, Neutral carrier based ion-selective electrodes. Ion-Selective Electrode Rev., 5 (1983) 3-92. H. van den Vlekkert, C. Francis, A.. Ghsel and N. de Rooij, Solvent polymeric membranes combined with chemical solid-state sensors, Analyst, 113 (1988) 1029-1033.
Sensors and Actuators, BI (1990) 471-480
Online Blood Electrolyte Monitoring with a ChemFET Microcell System W. GUMBRECHT, W. SCHELTER and B. MONTAG Siemens AG, ZFE Fl AMF 32, D-8520 Erlangen (F.R.G.) M. RASINSKI and LJ. PFEIFFER Institut fiir Exp. Chirurgie, Klinik Rechts der Isar, D-8&M Munich (F.R.G.)
Abstract
2. Sample-taking Sensor System
A sample-taking sensor system for online pH and electrolyte monitoring of blood is described. The system consists of a two-lumen catheter with a ChemFET flow-through cell, a syringe pump unit with ChemFET instrumentation and a personal computer. Suitable operation of the pump unit allows the sensor to be calibrated every 2 min before each measurement. The blood sample volume withdrawn from the patient is on the order of 10 ~1. Solvent polymeric membrane ISFETs serve as measurement sensors as well as reference sensors. For this purpose they are spatially separated by a flow-through channel where a liquid junction can be established between the calibration solution and blood. In this way the arrangement saves a conventional reference electrode with the bridge solution. In vivo experiments in pigs show a very good correlation between sensor and analyzer values. There was no blood clotting in the sensor system.
The system comprises a two-lumen catheter with a ChemFET flow-through cell, a syringe pump unit with the ChemFET instrumentation (Fig. 1) and a personal computer. The flowthrough cell is a sandwich arrangement of a chip carrier, a ChemFET chip and a PMMA slide with an engraved flow-through channel. For the measurement of one ion, two ISFETs with the same kind of membrane are located in such a way that the meander flow-through channel separates both ISFETs (Fig. 2). The well-known solvent polymeric membranes [6] are deposited directly onto the S&N., gate insulator by a solvent-casting technique. Figure 2 shows the operation cycle of the sensor system. The flow-through cell is connected to the inner tube of a two-lumen catheter, the outer lumen being longer than the inner one. The outer lumen of the catheter, which is inserted in a blood vessel, is flushed with a calibration solution by pump 2. Due to the shorter inner lumen and a higher flow rate of pump 2 compared with pump 1, a fraction of this solution can be withdrawn to
Keywords: blood pH, blood electrolytes, ChemFET, flow-through cell, ISFET, online monitoring.
1. Introduction
Monitoring of blood pH and electrolytes (K+, Ca*+, Na+, Cl-, HCO; ) is very important in clinical analysis, e.g. during intensive care therapy, cardiac surgery or renal dialysis. The development of the chemically sensitive field-effect transistor (ChemFET) [ 1,2] with its advantages compared to ion-selective electrodes (ISE) was very promising. But the application of ChemFET devices still fails because of problems in packaging, reference electrode and drift. Catheter tip ChemFET sensors are especially prone to problems in fabrication and usage. The disadvantages of catheter tip sensors can be overcome by sample-taking systems which are connected directly to the patient [ 3-51. However, all previous systems suffer from rather complex assemblies. In this paper a simpler arrangement is presented. 09254005/90/$3.50
Fig. 1. Sample-taking sensor system consisting of a two-lumen catheter, flow-through cell and a syringe pump unit with ChemFET instrumentation. 0
Elsevier Sequoia/Printed
in The Netherlands
Fig. 3. Resolution and reproducibility of K+ measurements in Ringer’s solution at room temperature (calibration solution = 4.00 mM K+; measuring solution = 4.20 mM K+).
Cdibmtiaemarls Fig. 2. Operating cycle of the sensor system,
TABLE 1. Typical operation parameters Cycle time: Response time: Sample volume: 24 h blood consumption: Flushing solution: Flushing volume: ISFET membranes:
2 min 30 s 10 pl 7.2 ml Ringer’s + 5 IU/ml Na-Heparin 100 ml/24 h solvent polymeric membranes
calibrate the ISFETs (calibration mode). Interruption of the flushing stream by pump 2 allows blood to enter the cell. After reaching the first ISFET, the difference output gives the measurement signal because the second ISFET acts as a reference sensor with the calibration fluid as the bridge solution (measurement mode). After the measurement, the catheter tip is flushed with calibration solution again to clean the flow-through cell and to establish a new baseline. Typical operation parameters are shown in Table 1.
ion-selective membrane has reached an equilibrium state, and 95 to 98% of the theoretical slope has been achieved. The K+ concentration change from analyte to calibration solution was only 200 pmol/l in the physiological range (Fig. 3), showing the excellent resolution and reproducibility of the sensor system. The time delay between calibration and measurement registration is only about 20 s, eliminating drift problems. In addition, the differential operation of two ISFETs with equal membranes, which are in contact with the same fluids (time averaged), leads to remarkable baseline stability. For a period of 200 h a baseline drift of only 0.05 mV/h has been observed. 3.2. CO, Interference The solvent polymeric membranes are in direct contact with the gate insulator. Penetration of water and CO2 through the membrane may cause a pH change in the Si,N,/membrane interface and would result in CO2 interference, as reported in ref. 7. Therefore the test solution (Ringer’s) was saturated with air and 10% COz in air, respectively. The calibration solution is always air saturated with a content of 3 mmol/l K+. The observed CO2 interference of K+-selective ISFETs is only about 100 PV after 5 days of immersion in Ringer’s solution (Fig. 4).
3. Results 3.1. In Vitro Experiments Experimental data for Ringer’s solution at room temperature, received with K+ selective membranes, are shown in Fig. 3. The ISFET difference signal shows a sinusoidal characteristic during one operation cycle. After baseline and measurement plateau, an inversion of the line shape can be observed. During the cleaning period, the reference ISFET is in contact with blood while the first ISFET is already flushed with calibration solution. It is important to emphasize that on the measurement plateau the response of the
Fig. 4. CO, influence of the sensor signal of a K+-selective FET (PVC membrane/S&N, arrangement) after 5 days of soluimmersion in Ringer’s solution (calibration tion = 3.00 mM KC Ringer’s, air saturated, measuring solution = 3.72 mM K+ in Ringer’s, air- or 10% CO2 saturated).
479
3.3. In Vivo Experiments
The system has been tested experimentally in pigs (n = 9). The microcell was connected to the carotid artery of the anesthetized animal. Samples were taken from the contralateral carotid artery and were analyzed with an electrolyte analyzer (AVL 984) or a blood gas analyzer (IL 1306) respectively. The potassium concentration was controlled by infusing KC1 or glucose/insulin solution into the pig with constant flow rates. Figure 5 shows a very good correlation between sensor and reference values (correlation coefficient 0.998), received with a 4 h experiment. The calcium concentration of the animal was altered by calcium-gluconate or EDTA-infusion over 3 h (Fig. 6).
7.6
I
7.2 1
,
I
I
10
26
36
46 __t
66
66
70 tlmo[mln]
Fig. 7. Monitoring of blood pH.
For monitoring blood pH, the calibration solution was modified in such a way that a 20 mmol/l phosphate buffer (pH 7.2) was introduced leaving Ca and Mg ions out. The ionic strength was kept at 160 mmol/l. The blood pH of the animal was altered by variation of the expiratory volume (Fig. 7). The correlation is quite good, but has to be improved by suitable calibration solutions. 4. Discussion
I
I
21 1
2
-
J
4 tlm* [houn]
3
Fig. 5. Monitoring of blood potassium concentration. b+
I
+ Immol/ll
1.6
I
I
1
I
I
No problems with respect to blood clotting in the sensor system were observed during the tests, although the blood samples were not heparinized. The double-lumen catheter in combination with a syringe pump unit acts as a three-way valve with minimum size and dead volume. Therefore the sample volume can be reduced to 10 ~1. The baseline calibration before each measurement eliminates drift problems. Because the calibration solution acts as a bridge solution during measurement, an excellent reproduction of the liquid junction potential can be observed. No contamination of a porous plug can occur. Furthermore, the double-lumen catheter acts as a heat-exchanger, warming up the calibration solution and cooling down the blood sample to a mean temperature of about 30 “C. A continuous flow of calibration solution and blood through the cell guarantees a constant temperature during operation. 5. Cooclusions
1.1 / 1
2
3 -
time[hwnl
Fig. 6. Monitoring of blood calcium concentration.
In vivo experiments with a sample-taking ChemFET sensor show the feasiblity of online blood electrolyte monitoring. Problems of blood
480
clotting, reference electrode and calibration have been solved with a simple arrangement. 4
References J. Janata, Chemically sensitive field effect transistors, in J. Janata and R. J. Huber (eds.), Solid State Chemical Sensors, Academic Press, Orlando, FL, 1985. P. Bergveld and A. Sibbald (eds.), Analytical and biomedical applications of ion-sel&tive field-effect transistors, in Comorehensiue Analvtical Chemistrv. _ Vol. XXIII. Elsevier. Amsterdam, 1988. . A. Sibbald, A. K. Covington and R. F. Carter, Online patient-monitoring system for the simultaneous analysis of
5 6
7
blood K+, Ca2+, Na+ and pH using a quadrupole-function ChemFET integrated circuit sensor, Med. Biol. Eng. Cornput., 23 1985) 329-338. S. Shoji, M. Esashi and T. Matsuo, Blood pH monitoring micro cell using micro valves, Proc. %d Int. Meet. Chemical Sensors, Bordeaux, July 7-10, 1986, pp. 550553. T. Tamura, T. Togawa, K. Suematsu and K. Sato, Continuous blood pH monitoring by use of the null method, Sensors and Actuators, 16 (1989) 273-285. D. Ammann, W. E. .Morf, P.’ Anker, P. C. Meier, E. Pretsch and W. Simon, Neutral carrier based ion-selective electrodes. Ion-Selective Electrode Rev., 5 (1983) 3-92. H. van den Vlekkert, C. Francis, A.. Ghsel and N. de Rooij, Solvent polymeric membranes combined with chemical solid-state sensors, Analyst, 113 (1988) 1029-1033.