Evolution of Blood Chemistry Analyzers Based on Ion Selective

Waters Symposium: Ion Selective Electrodes

waters symposium: ion selective electrodes

Evolution of Blood Chemistry Analyzers Based on Ion Selective Electrodes C. C. Young Nova Biomedical, 200 Prospect Street, Waltham, MA 02254 Ion selective electrodes and some electrochemical sensors, owing to their unique ability to directly sense analytes, are well suited for whole blood, plasma, and serum critical analyte testing. These critical analytes are major electrolytes, blood gases, and some metabolites. Analyzers based on ion selective electrodes (ISE) can provide fast turnaround time (TAT) for critical care testing. Following their historical development, these instruments can be conveniently divided into the following products: arterial blood gas (ABG) analyzers; electrolyte analyzers; integrated blood gas/electrolyte analyzers; and integrated blood gas/electrolyte/metabolite analyzers. This presentation will trace the development of these analyzers. The single-use disposable cartridge will not be included. Critical Care Profile Table 1 shows the analytes that are measurable with ISE and electrochemical sensors. These analytes provide important diagnostic information to physicians for the care of critically ill patients. The condition of these patients changes constantly; therefore, fast TAT is critical for treatment and intervention in these patients. ABG Analyzers The arterial blood gases CO2 and O2 are in equilibrium with pH and other blood components. Any dilution of blood would alter these parameters. ISE is the logical method of choice for their measurement. Throughout the years many physicians and chemists have investigated and theorized about the blood’s acid–base balance. The pH glass electrode, which was discovered in the early 1900s (1, 2) and later became the standard method for pH measurement, was used to investigate blood acid–base balance. In 1954, Poul Astrup and Bjorn Ibsen discovered that blood pH could provide vital diagnostic information in the treatment of polio patients in

Table 1. Critical Care Profile Critical Function

Analyte

Conduction

K+, Ca2+

Contraction

Ca2+, Mg2+

Energy level

Glucose, Po2, Lac, Hct

Ventilation

Po2, Pco2

Perfusion

Lactate, SO2%, Hct

Acid–base

pH, Pco2, HCO3– (calculated)

Osmolality

Na+, Glucose

Electrolyte Balance

Na+, K+, Ca2+, Mg2+

Renal Function

BUN, Creatinine

respiratory distress. Radiometer, in 1954, introduced the first pH meter, the E50101, for blood measurement. It soon was widely used to help assess respiratory and metabolic acidosis or alkalosis. pH provides only part of the information needed for completely assessing acid–base balance. The other necessary parameter is PCO2 (partial pressure of carbon dioxide). Before 1958, measurement of CO2 was based on a manometric method. In 1932, Donald D. Van Slyke introduced a gasometric apparatus for measuring CO2. This was the first technique to make clinical measurement of CO2 practical in hospitals worldwide. Although tedious and cumbersome, it was used for the next 20 years. In 1958, John W. Severinghaus and A. Freeman Bradley (3) developed an electrode for direct measurement of blood PCO2. This electrode was a modification of that of Stow et al. from 1957 (4). The Severinghaus electrode combines a pH glass electrode and a silver–silver chloride (Ag/AgCl) reference electrode. These two electrodes are separated from the blood sample by a carbon dioxide gas–permeable membrane. A thin film of bicarbonate solution is trapped between the membrane and the electrodes. The pH of this bicarbonate film is proportional to P CO2 of the sample when CO2 reaches equilibrium across the membrane. This electrode development led to the introduction of the first pH and PCO2 analyzers by Radiometer (the AME1) and by Instrumentation Laboratory (the IL 100) in 1959. The combination of pH and PCO 2 makes it possible to differentiate metabolic acidosis and alkalosis from respiratory acidosis and alkalosis, and provides the information for alveolar ventilation. The partial pressure of oxygen (PO2) is indicative of ventilation and oxygenation in the lung. Efficient oxygen exchange in the lung provides the necessary oxygen for tissue consumption. A practical means of measuring PO2 was first presented in 1956. At the FASEB meeting in Atlantic City, Leland Clark (5) disclosed his polarographic electrode for measuring PO2. Clark’s electrode placed both the platinum cathode and the Ag/AgCl reference electrode behind an O2-permeable membrane, thus completely preventing contact with the blood sample and eliminating the protein build-up that would poison the platinum electrode. The dissolved O2 in the internal filling solution is reduced and the current produced is proportional to the PO2 in the blood sample. It was two and one-half years later, at the pH and Blood Gas Symposium sponsored by the Ciba Foundation, that the Yellow Springs Instrument Company (YSI) and Clark presented the first commercial version of Clark’s PO2 electrode. To complete the assessment of a patient’s acid– base status and respiratory condition, manufacturers of blood gas analyzers soon added the measurement of PO2 using this polarographic electrode. During the 1960s, there was a flurry of introduc-

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tions of “blood gas” analyzers as Radiometer, Instrumentation Laboratory, and Corning Medical modified and introduced various combinations of pH, PCO2, and PO2 electrodes. In 1970, Corning Medical introduced the Corning 165, the first ABG analyzer, which measured all three parameters using a single sample. These parameters became and still remain the most important profile in critical care testing. Over the years, test methodologies have changed little, although analyzers have become more compact and automated through computerization, and throughput has been improved. Electrolyte Analyzers With the commercialization of blood gas analyzers, physicians and researchers could more easily study the blood’s acid–base status and the conditions that affected it. Major cations are important in maintaining electrolyte balance, hydration, contraction, and conduction required for proper cardiovascular function. The measurement of Na, K, Ca, and Mg is important for routine monitoring of patients and for assessment of critical care patients. Unlike the analysis of pH, PCO2, and PO2, which requires arterial whole blood samples, the methodologies used to measure electrolytes can use serum and plasma.

Replacing Flame Photometry For many years, sodium (Na+), potassium (K+ ), chloride (Cl{), total calcium (T Ca), total magnesium (T Mg), and total CO2 (T CO2) were the key electrolytes used by a physician to assess a patient’s electrolyte balance. After 1950, sodium and potassium were exclusively determined using flame photometry (6). Chloride was measured either colorimetrically or with coulometric titration; T Ca, TMg, and T CO2 were determined spectrophotometrically. All these methods require a diluted serum or plasma sample. Even though flame photometry provided a good method for measuring sodium and potassium ions in serum samples, there was great interest in replacing it owing to the dangers surrounding the handling of propane fuels used in the analysis. The Na/K ISE fulfilled this need and offered additional benefits. The response of the glass membranes to ions such as sodium had been observed as early as 1924. However, not until 1957 did George Eisenman (7) develop a working sodium-sensitive glass electrode. The best sodium glass is NAS11-18, which has a composition of 71 mol % SiO2, 11 mol % Na2O, and 18 mol % Al2O3. The selectivity over other major monovalent cations, with the exception of the hydrogen ion, is on the order of 300 (8). In the normal physiological pH range this glass electrode exhibits negligible interferences from H+, K+, Li+ , and divalent ions such as Ca2+ and Mg2+. However, the effort to develop a potassium-sensitive glass electrode was not as successful. The glass potassium electrode developed by Eisenman lacked sufficient selectivity over ions commonly existing in blood samples, especially sodium (8). Since Na+ and K+ were most frequently measured together, there was no clinical application for the sodium glass electrode until the early 1970s when more selective liquid potassium membrane electrodes became available. In 1967, Ross (9) reported the discovery of a calcium ISE based on calcium didecylphosphate in di-n-octylphenyl phosphonate. This opened a new approach to the development of liquid ISEs. Around the same time, Wilhelm Simon (10) developed the first neutral carrier– based liquid membrane ISE for potassium. It had good selectivity against all other common cations in physi-

178

Figure 1. Orion SS-30.

Figure 2. NOVA 1.

ological fluids.

PVC Revolutionizes Liquid ISEs Then in 1970 Thomas and Moody introduced the new concept of using plasticized polyvinyl chloride (PVC) as a solid support for incorporating ionophores or ion exchangers (11). This revolutionized the manufacturing of liquid membrane ISEs and made them much more suit-

Journal of Chemical Education • Vol. 74 No. 2 February 1997


Table 2. Effect of Elevated Triglyceride Level on Na/K Determinationa Before Ultracentrifugation NOVA (mM)

Flame (mM)

After Ultracentrifugation

Triglycerides (mg/dL)

Patient

Na

K

Na

K

1

139.1

4.63

126

4.2

2

137.9

7.39

126

3

135.6

4.96

110

NOVA (mM)

Flame (mM)

Triglycerides (mg/dL)

Na

K

Na

K

7010

138.4

4.56

136

4.5

QNS

6.7

6230

137.7

7.4

135

7.2

1230

4.2

16000

137.2

5.11

141

5.3

1340

a

Ladenson, J.; Koch, D. Pseudohyponatremia in multiple myeloma; Clin. Chem. 1981, 27, 1094.

able for miniaturization and clinical application.

Whole Blood Measurement Replaces Dilute Serum With both Na + and K+ ISEs available, Technicon in 1971 incorporated them into the SMAC continuous-flow chemistry analyzer for measuring Na and K in diluted serum. This was followed by Stat-Ion, Photovolt’s PVA4, and Beckman’s Astra 4. In 1976, Orion took the next major step for the critical care testing that exists today and introduced the SS30 analyzer for the direct measurement of Na and K in whole blood (Fig. 1). This was soon followed by Nova Biomedical’s Na/K analyzer NOVA 1 (Fig. 2). Because of its low operating cost, user friendliness, and reliability, the NOVA 1 soon became the leading whole blood Na/K analyzer. The ability to analyze whole blood or plasma directly significantly reduced the TAT for obtaining test results. Hence, it soon became the method of choice for Na+ and K+ testing in operating rooms and intensive care units. Before the direct ISE measurement of Na/K, an observation called “pseudo-hyponatremia” was well recognized in laboratories. When a flame photometer is used to measure Na/K in a highly lipemic sample, large differences are observed for both Na and K before and after removal of lipids from the sample. The difference is very significant for sodium (Table 2). The results for lipemic samples by flame photometry were erroneously low because of the presence of volume-occupying insoluble lipid. If this is not recognized, therapy based on such an artificially low sodium result could seriously injure the patient. This is due to the dilution step and not to the flame photometry per se; the diluted ISE used on SMAC will have the same problem. However, if a direct method is used, the results will be correct and will be the same before and after the removal of lipid. It soon became clear that there were some differences between direct (undiluted) Na/K and indirect (diluted) Na/K serum/plasma measurement even for samples having normal lipid and protein concentrations. The difference in these samples is typically 3–4%, direct measurement giving the higher results. The issue was what theoretical difference existed between direct and indirect methodologies. Several studies were published during the early 1980s. In 1983, a symposium was organized by the National Bureau of Standards to discuss the issues of activity coefficients, liquid junction potentials, protein, and bicarbonate binding of Na/K (12). The discrepancy between direct and indirect Na/K results can be accounted for by the protein water displacement effect, and by protein and bicarbonate binding of Na/K. Another electrolyte of interest was chloride (Cl{), the major anion in extracellular body fluids, which was typically measured colorimetrically on automated analyzers. While the usefulness of a stat chloride result is contro-

versial, many physicians have been trained to use “anion gap” as a means of flagging the presence of metabolic disorders that alter a patient’s electrolyte balance. Anion gap is the difference between the sum of the measured cations (Na+ and K+) and the sum of the measured anions (Cl{ and HCO 3{). The solid state AgCl/Ag2S ISE, when used for direct measurement of chloride, encounters major interferences due to proteins that contain sulfhydryl groups. The quaternary amine–based chloride ISE (13) was more suited to blood/plasma chloride measurement. A lot of effort has been devoted to reducing the interference of salicylate with chloride. In 1980, Nova Biomedical introduced the first ISE-based 4-channel electrolyte analyzer (Na+, K +, Cl{, and total CO2), which measures T CO2 in an acidified sample using a PCO2 electrode. The medical community by mid-1980 had pretty much accepted direct and indirect ISE measurement methodologies. Technicon (SMAC, Stat-ION, RA 1000, RA 2000), Beckman Instrument (E4A, E2A), Hitachi (702), and Photovolt introduced indirect Na/K analyzers. Abbott, AMDEV, Corning, DuPont, IL, Nova Biomedical, AVL, Horiba, Jokoo, Olympus, Radiometer, and TOA all introduced direct Na/K analyzers. The College of American Pathologists Survey also confirmed the trend of replacing flame photometry by ISE for electrolyte measurement (Table 3). As shown in this table, in 1980, only 18% of the laboratories surveyed reported the Na result by ISE, whereas in 1985, almost 80% of laboratories reported the Na result by ISE.

Lithium by Flame Replaced by ISE Even with the acceptance of direct Na and K measurements, laboratories still needed a flame photometer to measure lithium, a common drug for control of manic depression. Lithium ISEs with good selectivity toward Na+ and K + began to appear in the early 1980s. Simon (14) continued his theoretical work and reported a neutral carrier lithium ISE. Ishibashi (15) and Kitazawa et al. (16) reported a crown ether–based lithium ISE. In 1986, lithium analyzers were introduced by Nova Biomedical, AVL, and AMDEV. The calcium ISE developed by Ross was first used for blood ionized calcium measurement in 1975 on the Orion SS-20 analyzer. This was followed by a commercially more successful analyzer introduced by Nova Biomedical in 1978. The neutral carrier calcium ISE was discovered by Simon (17) in the late 1970s. This ionophore has great selectivity toward major cations and was soon adopted by most manufacturers for ionized calcium measurement. Calcium and magnesium in human plasma exist mainly in three fractions: free or ionized, protein-bound, and ligand-bound. Figure 3 shows the relative amounts of these species. In 1934, McLean and Hasting (18) dem-


179


Figure 3. Bound and ionized fractions of magnesium and calcium.

A recent clinical study reported that magnesium was the most frequently abnormal analyte observed in pediatric patients admitted to intensive care units (19). Clinical studies also show significant magnesium derangements in other hospitalized patients. Magnesium is a known antagonist for calcium and is also linked with a large number of enzymes. Ionized magnesium (iMg) could be an important diagnostic tool for patient care. The development of an iMg sensor proved to be more difficult than development of the calcium sensor. Thomas (20) in 1980 reported an electrode based on an organophosphate compound. Suzuki (21) in 1989 reported one based on the antibiotic A12187. Neither of these compounds had good selectivity. Suzuki (22) in 1990 reported a magnesium electrode based on β-diketone, which had good selectivity over calcium. However, hydrogen ion interference was serious. Between 1990 and 1993, Simon (23, 24) reported use of diamide and triamide for iMg sensing, achieving good selectivities. In 1994, Nova Biomedical introduced the first iMg analyzer, the NOVA CRT 8. This analyzer finally permits measurement of all important cations by ISEs and helps clinicians greatly in studying many physiological effects of ionized magnesium. Investigators have already discovered that low iMg levels are seen in hypertension, coronary spasm, stroke, seizures, and eclampsia, to name a few conditions (25). With these studies comes the possibility of new ways to diagnose and treat many illnesses. Integrated ABG and Electrolyte Analyzers

Figure 4. Calcium monitoring of a liver transplant patient. Note that total calcium can increase while ionized calcium decreases.

Table 3. CAP Survey Participants/Sodium 1980 C-B 1982 C-B 1983 C-B 1984 C-C 1985 C-B A ll I S E

1038

2272

3115

3627

4312

All flame

4823

4123

2862

2063

1877

onstrated that ionized calcium (iCa) is the physiologically active fraction. The direct ISE is the only practical way of measuring iCa in blood/plasma samples. The ability to measure iCa provides a distinct advantage over the traditional colorimetric determination of TCa in critical procedures such as open-heart surgeries and organ transplants, where physicians need to instantly assess a patient’s status. During these operations the patient receives large volumes of citrated blood. Citrate binds calcium, so even if TCa is within normal range, the ionized fraction can be much lower than normal and the patient may experience renal, cardiac, or pulmonary failure. Figure 4 shows the inadequacy of measuring T Ca. By the mid-1980s iCa analyzers were also available from AVL, Corning Medical, and Radiometer.

Ionized Magnesium Sensor Introduced by Nova Biomedical

180

During the late 1970s and early 1980s it became apparent to us and other manufacturers that in critical care testing, whole blood electrolyte analyzers were often used side by side with blood gas analyzers. Blood gas, sodium, potassium, and ionized calcium analyses were requested routinely by physicians for critically ill patients. Sensing the need of combining these tests into one analyzer to improve TAT, reduce sample volume, reduce cost, and simplify data collection, Nova Biomedical in 1985 introduced the first integrated blood gas/electrolyte analyzer. NOVA Stat Profile 1 (Fig. 5) measures pH, PCO2, PO2, Hct (hematocrit), Na, K, and iCa with a single sample. This integrated analyzer reduces the sample volume, further improves the TAT, and permits faster diagnoses and treatment of a patient, thereby helping to reduce hospital stays and associated costs (Fig. 6). In 1987, Mallinkrodt Sensor Systems introduced the first cartridge-based ISE blood gas/electrolyte analyzer. By 1992 major blood gas manufacturers, such as Ciba Corning, Instrumentation Laboratory, Radiometer, and AVL, also entered the integrated blood gas/electrolyte analyzer market. Integrated Blood Gas/Electrolyte/Metabolite Analyzers After the integrated ABG/electrolyte analyzers became commonly used in critical care testing, clinicians were waiting for other metabolites to be included in the integrated blood analyzers. These metabolites were glucose, lactate, BUN, and creatinine. Patients often become hypoglycemic or hyperglycemic due to stress, trauma, starvation, end stage shock, or surgery. It is important to monitor glucose and if necessary to manage the glucose level in the critical care setting. Lactate is a leading indicator for tissue hypoxia and inadequate perfusion. When combined with PO2, lac-



Figure 5. Stat Profile 1.

tate provides a good picture of oxygenation and tissue perfusion. Studies have shown not only lactate’s importance in characterizing tissue oxygenation but also its role as the best single indicator of the presence and severity of shock. Critically ill patients are at a higher risk of inadequate kidney function. The timely measurement of urea/creatinine is very important during surgery and recovery to assess organ function. The best way for direct measurement of blood metabolites is through biosensors based on the use of enzymes and ISE or amperometric sensors. Updike and Hicks (26) in 1971 reported the first glucose sensor based on glucose oxidase and the oxygen electrode. In 1974, YSI introduced the first glucose analyzer using an enzyme electrode. This was followed in 1976 by their model 23A. A platinum electrode was covered by an enzymatic glucose oxidase membrane. The end product of the enzymatic reaction is hydrogen peroxide, which is oxidizable on the platinum electrode. The current produced is proportional to glucose concentration. This analyzer can be used to measure glucose only by dilution of samples. The oxygen is a cofactor in the enzymatic reaction and a limiting factor in achieving the range for blood glucose measurement. The higher range

is obtained by effectively reducing the glucose concentration through dilution with air-saturated reagent. To integrate this sensor into a blood gas/electrolyte analyzer is cumbersome and inaccurate, owing to the presence of red blood cells. Vadgama (27) in 1986 used a silanized polycarbonate membrane to limit glucose diffusion. This glucose sensor could measure blood glucose directly. In 1988, Nova Biomedical introduced Stat Profile 5, which measures glucose, blood gases, Na, K, Cl, iCa, and Hct on a 200-µL whole blood sample. The limiting oxygen problem was resolved by a multiple-layered membrane. Lactate is one of the earliest and best indicators of impending shock. Whether used as a triage tool in the emergency department, a monitor of resuscitative efforts in surgery, or a quantitative assessment of shock, lactate is a vital part of the comprehensive testing panel for critically ill patients (28). Mascini (29) in 1984 reported measurement of lactate using lactate oxidase. YSI in 1986 introduced a lactate analyzer. The sample is diluted as in the case of their 23A Glucose Analyzer. In 1991 Nova Biomedical introduced Stat Profile 9, which added direct whole blood lactate to the repertoire of the Stat Profile 5 analyzer. The convenient real-time measurement of whole blood lactate in conjunction with PO2 and Hct gives the clinician a comprehensive picture of a patient’s oxygenation status. In 1995, Ciba Corning, Instrumentation Laboratory, and AVL started to market integrated blood gas/electrolyte/metabolite analyzers. Guilbault (30) first reported a urea sensor. The urea is hydrolyzed to ammonium and bicarbonate when a urease enzyme is used. Ammonium was measured with a glass ammonium electrode. However, potassium interferes with the ammonium determination. Nonactin (31) has better selectivity for the ammonium ion. By combining an ammonium ISE and the urease enzyme membrane, Nova Biomedical introduced the first direct BUN (blood urea nitrogen) electrode in the late 1980s. The BUN was soon incorporated into the Stat Profile 10 analyzer, which measures pH, PCO2, PO2, Hct, Na, K, Cl, glucose, lactate, and BUN. With a single sample, renal function can be monitored along with acid–base balance, electrolyte balance, and oxygenation. Renal function can be monitored by either urea or creatinine, or both. BUN is diet-dependent, whereas creatinine is not. It is best to have both results for diagnosis. In the routine chemistry profile, the traditional Figure 6. Time, labor, and patient blood loss advantages for each stat request.


181


“Chem 7” (Na, K, Cl, T CO2, glucose, urea, creatinine) tests constitute up to 70% of a laboratory’s testing volume. The consolidation of hospitals and laboratory testing has led to a growth of small satellite testing facilities to cover these basic, high-volume tests and facilitate faster patient treatment. Chem 7 is traditionally performed on diluted serum. The methods typically combine ISEs and colorimetry (e.g., the Beckman CX3). A whole blood equivalent analyzer would further improve TAT in emergency departments and on medical floors. The creatinine sensor can use three enzymes to convert creatinine to hydrogen peroxide (32). This sensor eliminates the use of picric acid, which is widely used for creatinine assay (Jaffe). Nova Biomedical introduced a whole blood Chem 7 analyzer based on ISEs early in 1996. The Future of ISEs in Blood Chemistry Analyzers To date, advances in ion selective electrode technology have led to key stat analytes being assayed in whole blood. The commercialization of whole blood ISE analyzers has allowed traditional laboratory testing to move closer to the patient for improved patient care in the emergency, surgical, and critical care settings. The future of ISEs will continue to be driven by the needs of the clinical market. With reliability, sample size, throughput, cost effectiveness, serviceability, and ease of use topping the list of “wants” from this market, you can expect to see ISEs become smaller and maintenance-free. The disposable electrodes from iStat, Diametrics, and AVL are easy to use and maintenance-free, and require small sample volumes. They unfortunately are not cost-effective, and they encounter resistance in this new era of cost containment. I believe the electrode of the future will be reusable, providing continuous cost reduction. The ideal analyzer would then be small, userfriendly, and maintenance-free, and could be used at the point of care or for in-home testing. And the ultimate goal is to have ex vivo and finally in vivo cost-effective and stable sensors for the real-time continuous monitoring of critically ill patients. Literature Cited 1. Cremer, M. Z. Biol. 1906, 47, 562. 2. Haber, F.; Klemensiewicz, Z. Z. Physik. Chem. 1909, 67, 385–431.

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3. Severinghaus, J. W.; Bradley, A. F. J. Appl. Physiol. 1958, 13, 515– 522. 4. Stow, R. W.; Baer, R. F.; Randall, B. F. Arch. Phys. Med. Rehab. 1957, 38, 646–650. 5. Clark, L. J.; Wolf, R.; Granger, D.; Taylor, Z. J. Appl. Physiol. 1953, 6, 189–193. 6. Henry, R. J.; Cannon, D. C.; Winkelman, J. W. Clinical Chemisty Principles and Techniques, 2nd ed.; Harper: New York, 1974; pp 639–754. 7. Eisenman, G.; Rudin, D. P.; Casby, J. U. Science 1957, 126, 831– 833. 8. Eisenman, G. In Glass Microelectrodes; Lavallée, M.; Schanne, O. F.; Hebert, N. C., Eds.; Wiley: New York, 1969; Chapter 3, pp 32– 61. 9. Ross, J. W. Science 1967, 156, 1378–1379. 10. Pioda, L. A. R.; Stankova, V.; Simon, W. Anal. Lett. 1969, 2, 665– 674. 11. Moody, G. J.; Oke, R. B.; Thomas, J. D. R. Analyst 1970, 95(1136), 910–918. 12. Proceedings of the Workshop on Direct Potentiometric Measurements in Blood; Koch, W. F., Ed.; U. S. Department of Commerce, National Bureau of Standards, 1983. 13. Coetzee, C. J.; Freiser, H. Anal. Chem. 1968, 40, 2071. 14. Zhukov, A. F.; Erne, D.; Ammann, D.; Guggi, M.; Pretsch, E.; Simon, W. Anal. Chim. Acta 1981, 131, 117–122. 15. Imato, T.; Katahira, M.; Ishibashi, N. Anal. Chim. Acta 1984, 165, 285–289. 16. Kitazawa, S.; Kimura, K.; Yano, H.; Shono, H. Analyst 1985, 110, 295–299. 17. Amman, D.; Guggi, M.; Pretsch, E.; Simon, W. Anal. Lett. 1975, 8, 709–720. 18. McLean, F. C.; Hasting, A. B. Biol. Chem. 1934, 107, 337–350. 19. Broner, C. W.; Stidham, G. L.; Westenkirchner, D. F.; Tolley, E. A. Crit. Care Med. 1990, 18, 921–928. 20. Hassan, S. K. A. G.; Moody, G. J.; Thomas, J. D. R. Analyst 1980, 105(1247), 147–153. 21. Suzuki, K.; Tohda, K.; Tanda, Y.; Ohzora, H.; Nishiyama, S.; Inoue, H.; Shirai, T. Anal. Chem. 1989, 61, 382–384. 22. Nagashima, H.; Tohda, K.; Matsunari, U.; Tsunekawa, Y.; Watanabe, K.; Inoue, H.; Suzuki, K. Anal. Lett. 1990, 23, 1993– 2004. 23. Spichiger, U. E.; Eugster, R.; Hasse, E.; Rumpf, G.; Gehrig, P.; Schmid, A.; Rusterholz, B.; Simon, W. Fresenius J. Anal. Chem. 1991, 341, 727–731. 24. Eugster, R.; Spichiger, U. E.; Simon, W. Anal. Chem. 1993, 65, 689– 695. 25. Altura, B. T.; Altura, B. M.; Tranbaugh, R. F.; Ziebrod, Z.; Burack, J.; Barbour, R. L. Magnesium Trace Elem. 1990, 9, 311–325. 26. Updike, S. J.; Hicks, G. P. Nature 1971, 214, 986–988. 27. Mullen, W. H.; Keady, F. H.; Churchouse, S. J.; Vadgama, P. H. Anal. Chim. Acta 1986, 183, 59–66. 28. Rackow, E. C.; Weil, M. H. Clin. Chem. 1990, 36, 1544–1546. 29. Mascini, M.; Moscone, D.; Palleschi, G. Anal. Chem. Acta 1984, 157, 45–51. 30. Montalvo, J. G., Jr.; Guilbault, G. G. Anal. Chem. 1969, 41, 1647– 1969. 31. Scholer, R. P.; Simon, W. Chimia 1970, 24, 372–374. 32. Tsuchida, T.; Yoda, K. Clin. Chem. 1983, 29, 51–55.


Evolution of Blood Chemistry Analyzers Based on Ion Selective

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