Contributions of Analytical M Chemistry
Kristen J. Skogerboe Departmentof Laboratory Medicine S E I 0 University of Washington School of
MBdlCine Seattie. WA 98195 Clinical chemistry is built on the strong foundation of analytical chemistry, and fundamental knowledge of analytical chemistry, medicine, and physiology is essential to the success of the clinical chemist. Because of the applied nature of clinical chemistry, technological developments in many areas of science are eventually used in a clinical setting. The close relationship between analytical and clinical chemistry provides an interesting example of the impact of analytical chemistry on other scientific disciplines. Most analytical research focuses on development of state-of-the-art instrumentation and establishment of methods that provide accurate and precise measurements. The amount of time it takes to transfer technology from the academic research laboratory through industrial development to routine use is determined by the intent of the clinical laboratory to provide the most clinically useful lab tests quickly and inexpensively and to provide patients with the best possible care. Whether or not an analytical technique will ever he used in the clinical laboratory depends on whether it provides valuable clinical information, is cost effective for the health care system, 0003-2700/88lA360-127 1/$0 1.5010 @ I988 American Chemical Society
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* minimizes assay time, is accurate over the entire pbysiologic range, offers acceptable precision levels, and is simple and reliable in routine implementation. If a method is to have clinical utility, quantitative data obtained for a chemical species must correlate well with some physiologic condition. A test will not be useful to the clinician unless it provides diagnostic or prognostic information. Clinical testing must also be coat effective. If an assay costs too much, physicians and insurance companies may judge that the information gained by doing the test does not justify the coat. Turnaround time is another
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important consideration in clinical chemistry; a rapid assay may be critical in an emergency. The accuracy of clinical assays plays an important role in implementing new technologies. A physician does not want to make a clinical decision based on an assay that may not reflect the actual concentra.tion of the measured analyte. The required degree of precision varies, depending on the analyte being measured. Finally, reliable instrumentation is a prerequisite in the clinical lab. A malfunctioning piece of equipment that yields an erroneous laboratory value can complicate the clinical assessment
of a patient. All of these criteria are reviewed carefully before a new technology or method is implemented in the clinical laboratory. These criteria are second nature to individuals whose careers center around laboratory medicine, hut they may not be obvious to analytical chemists who believe that a technique may have clinical potential. Because both economics and quality health care assume important roles in clinical chemistry, much of the research and development is performed by companies that manufacture clinical instrumentation and laboratory reagents. State-of-the-art instrumentation in clinical labs now includes automated spectrophotometers, and 40?6 of the tests performed in large centralized laboratories are based on ion-selective electrodes. These methods have met the requirements for commercialization. Which new technologies will emerge as valuable contributors to the clinical laboratory? Will lasers, optical fibers, diode arrays, and microbore chromatography become commonplace in lab medicine? This REPORT will highlight several analytical techniques that are being used in state-of-the-art clinical labs and will illustrate how other advances in instrumentation may contribute to clinical chemistry in the future.
Biosensosfor transcutaneous and on-llne monHorlng The development of sensors for clinical use has been an active area of analyti: cal research and the focus of several reviews ( I , 2). Biosensors present excit-
ANALYTiCAL CHEMISTRY, VOL. 60. NO. 22, NOVEMBER 15, 1988
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ing possibilities because of their relative simplicity, small size, and ease of operation. The commercial viability of some of these sensors has been questioned, however, raising issues of biocompatibility, clinical accuracy and precision, and sensor lifetime. One positive new use of sensor technology is the application of biosensors to on-line monitoring in the newborn (neonatal) intensive care unit. Biosens o r ~are particularly valuable for neonatal monitoring because these tiny patients may have a total of only 120 mL of blood, and obtaining an adequate blood sample can be difficult and dangerous to the patient. (The average 75kg adult has a blood volume of 5 L.) Both electrodes and optical probes are used to transcutaneously (across the skin) monitor the oxygenation of blood in a premature infant. These noninvasive methods are used a t the bedside to ensure that an infant is receiving the correct amount of oxygen via a respirator. Premature infants can die from too little oxygen and suffer lung and brain damage from too much. Because these fragile neonates require intensive care, it is desirable to monitor oxygenation continually, thus enabling early intervention in a life-threatening respiratory crisis. Transcutaneous monitoring of the partial pressures of oxygen and carbon dioxide is accomplished by using ionselective electrodes (ISEs) attached to the skin surface. The electrode is enclosed in a heated adhesive “patch” that is placed on the infant’s skin. The heat of the patch (-44 “C) warms the skin, inducing blood flow to the area under the patch. The oxygen and carbon dioxide in the blood diffuse across the skin, through semipermeable membranes, and are detected by the electrode. The signal obtained by this transcutaneous method correlates well with oxygen levels measured in arterial blood samples (3). Biosensors based on optical fibers are also used to assess oxygen status. One such instrument, called a pulse oximeter, determines the percentage of oxyhemoglobin saturation of functional hemoglobin by measuring the absorption of red and near-IR light as it passes through tissue. A pulsatile arterial bed (such as the patient’s toe) is sandwiched between a pair of lightemitting diodes (-660 and 925 nm) and a photodetector. Light a t each wavelength passes through the toe, is collected by an optical fiber, and is sent to the photodetector. The intensity of light reaching the detector is determined by the pigmentation and thickness of the skin and the absorption of venous and arterial blood in the tissue. The absorbance of skin and venous blood is constant; that of arterial blood changes because of pulsatile blood
flow. With synchronous detection, the constant background can be subtracted from the arterial signal, and the corrected hichromatic absorbance of light can be used to calculate the amount of oxygenated and nonoxygenated hemoglobin. The success of these electrochemical and optical sensors reflects the potential for other probes in patient monitoring. One new direction for optical probe research may be the use of nearIR analysis, which has been clinically demonstrated by the pulse oximeter. The advantage of the near-IR spectral region, compared with visible radiation, is the substantial throughput of near-IR radiation through tissue, which implies that transcutaneous monitoring of other clinical analytes may be possible in the near-IR region. The measurement of cytochrome-c oxidase using near-IR has been reported (4). Although transcutaneous applications have not yet been demonstrated, near-IR has been used for the quantitation of serum lipids (5) and fats in human samples (6). Given the success of pulse oximetry, it is possible that this technology can be used to monitor lipids, fats, and other analytes. Although transcutaneous sensors are advantageous because no blood needs to he drawn, it is certainly not possible to measure all analytes across the skin. Therefore biosenson that can be inserted into the body would be clinically useful. One interesting example of a sensor that could be used for invasive monitoring is an optical sensor that measures penicillin (7). The experimental configuration of this probe is shown in Figure 1.Penicillin present in a sample solution is converted to penicilloic acid. The reaction is enzymatically catalyzed by penicillinase that has been immobilized on the end of a fiber-optic probe, and the amount of penicilloic acid formed is proportional to the fluorescence measured by the same fiber. The specificity provided by the enzyme system coupled with the optical fiber indicates the potential utility of probes of this type in clinical analysis.
Polarization spectroscopy Although automated absorbance spectrophotometers are still the mainstay of most clinical analyses, instrumentation based on other spectroscopic principles is emerging. For example, fluorescence polarization spectroscopy (FPS)is becoming a common laboratory technique. FPS measures the anisotropy, or rotation, of a fluorophore between the time it absorbs light and emits that light as fluorescence. FPS was once used only in research labs to determine molecular size and other properties of a molecule in solution. Now, however, commercially available
1272A * ANALYTICAL CHEMISTRY, VOL. 60, NO. 22. NOVEMBER 15, 1988
Flgurr 1. Configuration of fiber-optic
biosensor for measurement of penicil-
lin. FPS instruments are used in the clinical laboratory in several different ways. One unique application of FPS is in the area of assessing fetal lung maturity. Lack of lung surfactants, which enable the air sacs to expand and stay open, makes a premature infant susceptible to respiratory distress syndrome (RDS) and decreases the chance of survival. Physicians want to avoid delivering an infant before the lungs begin to produce adequate surfactant. Analysis of the amniotic fluid, which bathes the fetal lung and contains some of the lipophilic surfactant, is used to determine fetal lung maturity. For years, the standard method for such analyses has been a time-consuming thin-layer chromatographic procedure that measures the ratio of lecithin to sphingomylin in the amniotic fluid. A faster FPS method, however, is now often used. In this analysis, a fluorescent tag is added to the sample and attaches to the surfactant material. Because the frictional resistance of the sample decreases as more lung surfactant is present, the microviscosity of a sample coming from a fetus with mature lungs is lower than that of a sample originating from an immature fetus. Decreasing FPS values correlate well with decreased probability that an infant will develop RDS (8).Thus the FPS result can be used to evaluate the lung maturity of a fetus carried by a woman in premature labor. If the results indicate that the lungs are immature, the physician may put off elective delivery or decide to deliver early if the mother is at risk. A second application of FPS is in the area of therapeutic drug monitoring,
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Figure 2.
Fluorescence polarization immunoassay and a characteristic response curve.
where FPS is coupled with immunoassay to quantitate a drug contained in a blood or urine sample (Figure 2). The sample is added to a cuvette containing antibodies specific for the analyte being monitored and a tracer, consisting of the drug with a fluorescent tag. Because any analyte present in the sample will compete with the tracer to bind with the antibody, there is a direct correlation between the amount of analyte in the sample and the quantity of free tracer in solution. The free tracer rotates more easily in solution and has a lower degree of fluorescence polarization than tracer bound to antibody. Therefore, as the analyte concentration increases, the polarization decreases, yielding a characteristic response curve. FPS-based immunoassays have been developed for a number of analytes, including anticonvulsant drugs and sedatives. Because FPS only works well for small molecules with relatively large Brownian motion, it cannot be used to assay large analytes. Optical rotary dispersion (ORD) and circular dichroism (CD) also have potential clinical laboratory use, because many molecules of clinical interest display optical activity (OA). OA has been exploited for the quantitation of cannabinoids by CD (9)and in laser-based ORD detection following liquid chromatography (LC) for determination of cholesterol and amino acids (10, 11). Because OA measurements provide considerable selectivity, complex samples may not need extraction to isolate the analyte from interfering compounds or matrix constituents. Assays based on OA detection are not routinely performed in the clinical lab because the instrumentation is complex and the available commercial instrumentation is limited in sensitivity. Eventually, however, the capability for selective assay of physiologic analytes and drugs where enantiomericmonitoring is crit cal may encourage the development c sensitive OA detection in clinical instrumentation. 1274A
ANALYTICAL
Other spectroscopicteclmk#tes Techniques such as chemiluminescence, laser and time-resolved fluorescence, and photothermal deflection are among the spectroscopic methods that have recognized clinical potential. Although they are based on different principles, each provides either improved sensitivity or selectivity and uses technology that is not found in every laboratory. Several of these methods are the basis for commercially available clinical instrumentation; others have only demonstrated feasibility. Chemiluminescence. This technique is routinely used in the laboratory, and the use of chemiluminescent labels in inmunoaway has been particularly successful.As in FPS immunoassays, this spectroscopic label bypasses the use of radiolabels. But unlike FPS techniques, chemiluminescence is not limited to lower molecular weight analytes, and concentrations as low as m o m can be measured. Thus
chemiluminescence has the potential for greater sensitivity than either radiochemical or fluorescence-based immunoassays. An m a y of thii type might he basad on the creation of an antibody-antigen complex with a chemiluminescent label. When this complex is combined with a reagent that initiates a chemiluminescentreaction, the amount of light emitted is related to the quantity of antigen pressnt in the sample. A number of labels have been investigated, including luminol (12) and acridinium esters ( 1 3 , and commercial producta based on this general technology have been introduced for a number of analytss such as thyroid and pituitary hormones. Gas-phase chemiluminescence is also being implemented for the measurement of analytes of clinical interest, and it is the basis of an assay of urinary nitrogen for which a commercial instrument is available (Figure 3). An injected urine sample is carried by oxygen into a combustion furnace
Figure 3. Experimental arrangement for total nitrogen determination by -phase
chamliuminescence.
CHEMISTRY. VOL. 80, NO. 22. NOVEMBER 15, 1988
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where all nitrogen in the sample is converted to nitric oxide. Water vapor is removed via a dryer, and the nitric oxide is mixed with ozone, creating an excited nitrogen dioxide molecule that relaxes and emits light.
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The emission of red and near-IR radiation from this molecule correlates well with the amount of total nitrogen present in the sample. Because the amount of nitrogen in the urine correlates with the breakdown of protein by the body, total nitrogen levels provide the physician with a way to assess the nutritional status of a patient. If a patient is using stored protein to meet metabolic needs, the nitrogen level in the urine exceeds the amount of nitrogen taken in from food. For years, the standard clinical method for determining total nitrogen has been the Kjeldah1 method, a time-consuming test that uses caustic reagents. The chemiluminescent total nitrogen method not only correlates with the Kjeldahl method (14) but also is rapid and requires no reagents. Thus the convenience and time-saving factors justify this application of chemiluminescence in the clinical lab. Fluorescence. This technique is beginning to come of age in the clinical lab. Traditionally, the application of fluorescence to the analysis of clinical specimens has often been difficult because of quenching and background fluorescence of native fluorophores. Spectral interferences can be minimized by careful instrumental filter design and further reduced with signalprocessing techniques. Time-resolved emission techniques reduce the signal contribution caused by background emission, thus improving fluorescence applications (15).The commercial application of time-resolved fluorescence to the area of fluorometric immunoassays is now underway. A representative fluorometric immunoassay involves formation of an antibody-antigen complex in which the antigen may be a drug or hormone of clinical interest present in blood or urine. A second fluorescent-labeled antibody is then attached to the antigen. This sandwich-type complex is extracted from solution and subjected to fluorometric analysis. If the fluorometric label is conventional so that normal fluorescence is measured, this technique may not be more sensitive than conventional methods based on isotope-labeled immunoassay. However, if the assay is based on the more advanced time-resolved fluorescence, improvements are obtained. Assays that use lanthanide chelates as fluorescent labels have demonstrated this potential for improvement. 1276A
These labels work well because the fluorescence lifetime of lanthanide metal chelates is -1 ms, compared with decay lifetimes of only a few nanoseconds for native fluorophores. In an assay for thyroid-stimulating hormone with a europium label, the detection limit achieved by time-resolved fluorescence is 10 times better than that obtained with classical techniques (16). Further improvements in fluorescence detectability have been sought by using laser light as an excitation source. A commercial nitrogen laser-based, time-resolved fluorometer has been applied to the lanthanide-labeled assay of hormones (171, where gated detection decreases the background signal and increased laser power increases sensitivity. These two features combined yield improved detection limits. In addition to its application to immunoassay, laser-excited fluorescence may have other uses in the clinical lab (18).Some research has focused on the use of laser fluorometry for the assay of enzymes in biological samples. Argonion laser radiation has been used for the measurement of enzyme activity (191, where the laser system improved the detection limit of the enzyme substrate by !&fold relative to using a conventional light source. A He-Cd laser has also been used in enzyme assay systems (201, where 1 X mol of the enzymatic reaction product, NADP, was detected. In applications such as these, where detectability and selectivity are critical considerations, the cost and unfamiliarity of lasers may be overridden by clinical need. Photothermal deflection. Another unique laser-based technology that may become important in the clinical lab is photothermal deflection spectrophotometry (PTDS), one of a class of ultrasensitive spectroscopies that determine the heat produced by the absorption of light. Photothermal methods require absorption of radiation from a focused laser beam. In one configuration, the heat produced as the excited molecule undergoes radiationless decay causes a laser beam aligned parallel to the sample surface to be deflected. An aperture placed in front of a photodetector limits the amount of light reaching the detector when absorption occurs. Determining the deflection caused by the absorption, rather than measuring simple absorbance, can improve detection limits by several orders of magnitude. PTDS has been used for detection in thin-layer chromatography and electrophoresis (21). For both of these techniques it is easy to identify situations in which ultrasensitive PTDS detection would provide an advantage in clinical analysis. For example, in the assessment of urinary protein by electrophoresis, protein concentrations are
ANALYTICAL CHEMISTRY, VOL. 60, NO. 22, NOVEMBER 15, 1988
on the order of 1 mg/dL and are difficult to quantitate without sample preconcentration. In certain disorders, quantitation of trace levels of proteins may aid in diagnosis or treatment, and physicians are beginning to be interested in how small changes in the level of urinary albumin may correlate with clinical outcome in diabetes (22). Recently a PTDS densitometer was used in the assay of proteins separated by polyacrylamide gel electrophoresis, extending the detection limit to 1 ng of protein (21). Instrumentation based on the PTDS principle is not yet commercially available, but the diagnostic utility that has been demonstrated may justify commercial development. Chromatography in clinical analysis Gas and liquid chromatography are integral parts of the clinical lab. Even with the widespread use of immunoassays, chromatography is still used for analyses when antibodies either cannot be developed or are not specific enough. Chromatography is also useful for monitoring concentration rather than activity and for determining metabolites that might be physiologically active. One area of research is the development of microbore LC. The trend toward smaller columns, and detectors designed to accommodate this type of chromatography, should eventually be appreciated by clinical chemists. Microbore systems are advantageous for applications in which the amount of sample is limited, such as pediatric drug monitoring. Because youngsters have smaller blood volumes, sample size is often limited. The benefit of microbore chromatography has been demonstrated in the analysis of chloramphenicol, a drug given to young children to fight infection (23). In this study, the amount of blood serum required for the assay was reduced to only 10 WL. Microbore columns also reduce solvent consumption. In the assay of cyclosporine, a drug given to organ transplant recipients, solvent consumption was reduced by 80% (24) by using microbore rather than conventional LC. In the cost-conscious clinical lab, this advantage may encourage the switch to microbore columns. Another emerging trend in clinical chromatography is the use of sophisticated detectors that provide qualitative as well as quantitative information. The use of photodiode array (PDA) detectors has been reported; PDA detection is particularly useful in determining drugs when co-eluting, interfering compounds jeopardize accuracy. PDA detection has also been used in the diagnosis of genetically inherited metabolic defects such as maple syrup disease ( 2 5 ) . Here, spectra from the
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PDA. obtained with ion-exchange chromatography help indentify abnormal organic acids in urine. TheMure The diverse methodologies discussed here indicate that the research and development efforts in analytical chemistry are being applied in the clinical laboratory. Techniques based on bimen801s. chemiluminescence, and timeresolved fluorescence have met the criteria for clinical implementation and are routinely used. Further developments in spectroscopy. chromatography, and electrochemistry will continue to contribute to the clinical laboratory. ROtUWUXS (1) Czaban. J.C. AMI. 345 A-356 A.
Chem. 1985, 57.
(2)Spitz. W.R. Anal. Chem. 1984. 56.
Hnn,S. M.; Pudie, N. AMI. Chem. 1985,57.2068-71. (10) Ye E. S.; Steenhook, L. E.; Woodruff, s%; Kuo, J. C. AMI. Chem. 1980, 52,1399-1402. (11) Reitsma, B. H.;Yeung. E. S. Anal. Chem. 1987,59,1059-61. (9)
1986,32,1407-9.
(25) Allen, K.R.;
Khan, R.; Watson, D. Clin. Chem. 1985.31,561-63.
(12) Kohen, F.; Kim,J. B.; Lindner, H.R.;
Barnard, C. In Bioluminescence and Chemiluminescence, Basic Chemistry and Analytical Applications; DeLuca, M.; McElroy. W. D.. a s . ; Academic: New York. 1981;pp. 351-56. (13) Sturgess. M. L.; Weeks, 1.; Mpoko, C. N.; Laing. I.; Woodhead, J.S. Clin. Chem. 1986,32.532-35. (14) Skogerboe, K. J.; Rettmer, R. L.; Sundquist. J.; Gargett, A; Labbe, R. F.. submitted for publication in Clm. Chem. (15) Lytle, F. E.; Kelsey. M. S. Anal. Chem. 1974,46,855-60. (16) Lawson. N.;Mike, N.; Wilson.R.;Pandov, H. Clin. Chem. 1986,32.684-86.
Dechaud. H.;Bador, R.; Claustrat, F.; Desuzinges. C. Clin. Chem. 1986, 32,
(17)
Kristen J. Skogerboe is a senior fellow in the Department of Laboratory
Medicine a t the University of Washington in Seattle. After graduating in (18) Sepaniak, M. J. Clin. Chem. 1985.31, 1982 from Colorado State Uniuersity fi7lL7R in Fort Collins, she worked as a sum(19) Egan. B.2.;Lee, N. E.; Burtis, C. A,; mer analytical research participant at Kao, J. Y.; Holland, J. M. Clin Chem. the F’rocter and Gamble Company in 1983.29,161€-19. (20) Imasaka, T.; 7.are. R N. Anal. Chem. Cincinnati, OH. She received her 1979,51,2082-85. Ph.D. in analytical chemistry in I987 (21) Peck, K.; Morris, M.D. AMI. Chem. from the Ames Laboratory a t Iowa 1986,56,2879-83. State Uniuersity under the direction (22) Mogensen. C.E. Kidney International 1987,31.67349. of E. S. Yeung. Her research interests (23) Won , S H Y ; Cudny, B.; Aziz. 0.; include applications of laser spectrosMarzouf. N.; Sheeran, R Clin. Chem. copy and fiber optics to chromatogra1987.33,1021. phy and unique uses of spectroscopy (24) Annesley, T.;Ma?, K.; Bplogh. L.; Clayton, L.; Ciacherio, D. Clin. Chem. in clinical research. 1323-27.
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