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Lithium determination in outpatient clinics by an ion-selective electrode in venous and capillary whole blood
71
Psychiatry Research, 44~71-77 Elsevier
Lithium Determination in Outpatient Clinics by an lonSelective Electrode in Venous and Capillary Whole Blood Waldemar Received
Greil and Birgit Steller
October 23, 1991; revised version received March 11, 1992; accepted April 9. 1992.
Abstract. The use of an ion-selective electrode (ISE) to determine lithium (Li) in routine clinical application was evaluated by repeatedly analyzing reference specimens (precision evaluation) and by comparing blood concentrations in Litreated patients assessed by ISE and flame emission spectrometry (FES) (correlation and agreement). Precision evaluation was sufficiently high. Li values determined by ISE in venous and capillary whole blood showed high correlations with FES plasma values (correlation coefficients between 0.86 and 0.99). Within the therapeutic range (0.3-1.0 mmole/l Li), agreement was sufficient for venous and less satisfactory for capillary blood (mean differences, FES minus ISE: -0.03 and -0.11 mmole/l Li). Above the therapeutic range, ISE values markedly exceeded FES results. Key Words. Membrane potential, flame emission spectrometry, plasma, maintenance treatment, methodology.
During lithium (Li) therapy, routine tests of Li plasma levels are necessary to achieve therapeutically effective Li concentrations and to avoid intoxications. Furthermore, regular determinations of Li levels are generally helpful in increasing patients’ compliance and especially important for patients receiving additional medication that could influence the Li plasma concentrations (e.g., diuretics, nonsteroid antiphlogistics, and possibly calcium antagonists; Jefferson et al., 1983). Until now, Li concentrations in blood of Li-treated patients have usually been measured by flame emission spectrometry (FES) or atomic absorption spectrometry (AAS), respectively (Coombs et al., 1975; Xie and Christian, 1987). Both techniques are based on the analysis of light wavelengths set free by the movement of electrodes to different energy orbits in the atom: When heated, the atoms are transformed into an excited state (the electrons move to higher energy orbits), absorbing light at different wavelengths (AAS). The analysis of the emission of light by atoms returning to the ground state again is the basis for FES (see Xie and Christian, 1987).
Waldemar Greil, Priv.Doz. Dr. med., Psychiatrist and Neurologist, is Lecturer of Psychiatry, and Birgit Steller, Dr.phil., is Research Psychologist, Psychiatric Hospital, University of Munich, Munich, Germany. (Reprint requests to PD Dr. W. Greil, Psychiatric Hospital, University of Munich, Nussbaumstr. 7, D-8000 Munich 2, Germany.) 0165-1781/92/$05.00
@ 1992 Elsevier Scientific
Publishers
Ireland
Ltd.
72 In 1987, Li determination by means of special ion-selective electrodes (first generation ISEs) became available for clinical practice (Bertholf et al., 1988; Gross et al., 1988; Phillips et al., 1989; Okorodudu et al., 1990; Birch, 1991). In the ISE technique, Li is determined by measuring the membrane potential produced through the contact between an appropriate electrode membrane and the Li solution. The potential is proportional to the logarithm of the lithium concentration in the blood sample (Xie and Christian, 1987). ISE technology allows quick “on the spot” determination of Li without any pretreatment or dilution of the samples. If the procedures recommended by the ISE producers (implementation of a preventive maintenance schedule, quality control, and calibration) are regularly adhered to, the ISE analyzer is easy to handle. By a button press (Robinson et al., 1989), the results for sodium, potassium, and Li are given simultaneously within seconds on the display and as a printout. Given these advantages, the measurement can be directly executed in outpatient clinics or in doctors’ practices. Furthermore, patients’ blood samples need not be centrifuged, as analysis by ISE of Li plasma level can also be performed in whole blood. In this study, a second generation Li/ISE analyzer was applied that required only a minimal amount of blood (40 ~1). Hence, capillary blood from the fingertip or from the earlobe can be used instead of venous blood. For venous and capillary whole blood of Li-treated patients, we compared the Li values obtained by a Lii ISE analyzer to those determined by FES in plasma, as FES is considered an appropriate method for Li determination in routine application (Coombs et al., 1975; Xie and Christian, 1987). To our knowledge, this is the first time that such a comparison between FES and ISE has been performed with whole blood samples, as previous studies on ISE Li measurement used (mostly pooled) plasma specimens (Okorodudu et al., 1990). Moreover, there are no reports on Li determination in capillary blood assessed by means of ISE.1 Our major aim, however, was to assess the ISE’s usefulness in clinical settings.
Methods Precision data for ISE were obtained by repeatedly analyzing special reference specimens with different Li concentrations: three lots of specimens of CIBA-CORNING (Certain Lyte, level I low-lot 62950, which should contain 0.65 mmole/l Li, level 2 mid-lot 62960: 1.17 mmole/l Li, and level 3 high-lot 62970: 1.88 mmole/ 1 Li) and two additional reference specimens usually used for control purposes in laboratories from the lower (Labtrol E, BAXTER & DATE: 0.38 mmole/l Li) and upper (Qualitrol H, MERCK: 0.96 mmole/l Li) therapeutically relevant range. To judge the ISE’s diagnostic value (validity), we compared the results of ISE Li level assessments for venous and capillary blood with the results of the respective FES determinations. Blood was drawn both from Li-treated inpatients and outpatients of the psychiatric hospital of the University of Munich (within regular routine control of Li level). The abnormally high Li data were obtained by repeatedly measuring Li concentrations in the blood of Li-treated patients who were taking part in a pharmacokinetic study and of one patient with a Li intoxication. 1. A curve of Li levels determined by ISE in venous intoxication is given in Greil et al. (1992).
and capillary
whole blood from a patient
with Li
73 For venous blood, we used Monovetten (SARSTEDT; with NH,-heparin as anticoagulant). Capillary blood was taken from the fingertip with 50-~1 capillary tubes (with Na/ Ca-heparin as an anticoagulant according to the specifications of the ISE producer). The ISE determination by means of an Na/K/Li-Analyzer No. 654 (CIBA-CORNING2) was performed in the outpatient Li clinic of the hospital by student assistants who received a brief introduction into the run of ISE analyzers. The FES determination (FCM 6341, EPPENDORF) was executed by professional medical laboratory technicians in the Neurochemical Department of the hospital, which takes part in regular quality-control evaluations. For the ISE/ FES comparison, first the correlations between the Li blood levels assessed by the two techniques were examined. We then calculated the linear regression equation (Westgard et al., 1978) and also analyzed the differences between the two methods (Bland and Altman, 1986).
Results Day-to-Day Precision (Reliability). We repeatedly analyzed the reference specimens over a 12-week period. The observed deviations from the five reference values were very small. Table 1 lists the corresponding statistical measures. Table 1. Means, ranges, standard deviations (SDS), coefficients of variation (CVs), and number of observations (n) for the repeated testing of 5 reference specimens Reference specimens1 Mean
Range
Measured ISE values’ Mean
Range
SD
CV
n
0.38
0.32-0.44
0.36
0.23-0.44
0.04
0.111
37
0.65
0.55-0.75
0.63
0.54-0.68
0.02
0.032
129
0.96
0.84-1.08
0.97
0.87-1.13
0.04
0.041
46
1.17
1.07-1.27
1.16
1.11-1.25
0.02
0.017
90
1.88
1.78-1.98
1.90
1.81-1.99
0.03
0.016
99
Note.ISE = ion-selective electrode.
1.mmolell
lithium.
Correlation and Agreement (Validity). Figs. 1 and 2 illustrate
the relationships between the ISE determinations for venous and capillary whole blood and the respective FES measures. For these data, various correlation coefficients were estimated: coefficients for all observations, coefficients for those observations that fell within the therapeutically relevant range (from 0.3 to 1.O mmole/ 1 Li, according to the ISE determination results), and coefficients for those observations that were therapeutically relevant according to the FES determination results. For all correlation coefficients (0.86-0.99) the level of significance was below 0.001. According to Bland and Altman (1986; Altman and Bland, 1983) and Westgard et al. (1978), however, correlation coefficients are not an adequate indicator of the amount of agreement between two methods measuring the same dependent variable 2. ISE analyzers are also available from AVL (Nr. 985), BECKMAN (Lablyt 830), NOVA (No. DU PONT (Na/ K/ Li; for sale in the USA).
I I) and
74
Fig. 1. Relationship between lithium values obtained by flame emission spectrometry (FES) in plasma and values measured by ion-selective electrode (ISE) in venous whole blood (r= 0.994; 1:l line included)
0
1
2 KS
3
(Plasma)
The linear regression is y = 1.165x - 0.041 (x = FES, y = ISE; SE for slope: 0.01,
t = 110.6).
(the Li level in our case). Westgard et al. (1978) identified major limitations of using correlation coefficients: They are sensitive to random analytical error, as well as to constant and proportional errors, and they are very sample-dependent. Whereas Westgard et al. (1978) used regression analyses to control for these kinds of errors (calibration approach), Altman and Bland (1983; Bland and Altman, 1986), who do not consider one method predictive of the other, prefer the analysis of the differences between two measurement methods (reference value for differences is the average of the compared methods). For the ISE assessments of whole blood specimens within the therapeutically relevant range, we thus calculated the differences between the FES determination results and the respective ISE results. Fig. 3 illustrates the scattering of differences (FES minus ISE) for venous blood. The mean difference is -0.03 (SD: 0.05 mmole/l). Only 1.72% (two cases) of the 116 observations deviate more than + 2 SD from the mean. Fig. 4 shows the scattering of differences for capillary blood within the therapeutically relevant range according to the ISE determination results. For this comparison, the mean difference is -0.11 (SD: 0.07 mmole/l); 6.56 % (four cases) of the 61 observations exceed the level of acceptance.
75
Fig. 2. Relationship between lithium values obtained by flame emission spectrometry (FES) in plasma and values measured by ion-selective electrode (ISE) in capillary whole blood (r= 0.974; 1:l line included) ISE(Capillary. Whole Blood) 4
.
0
J
2
1
3
FES (Plasma)
The linear regression is y = 1.336~ - 0.001 (x = FES, y = ISE; SE for slope: 0.03, t = 40.6).
Fig. 3. Scattering of differences of lithium values obtained by flame emission spectrometry (FES) and ion-selective electrode (ISE) in venous whole blood (FES minus ISE) from lithium-treated patients (n = 116, r= 0.951)
. 0,05 .
. 0
.
’
-0,t
-
‘_
. .
.. ..
.
’
’
’
0.4
0.45
.
. ..
. ..
..* **
.
. . *
*
.
.
.
. .
.
.
.
. .
’
’
0.6 0.65 0.7 0.75 0.8 0.85 and ISE values [mmol/l U]
0.9
0.95
. ..
..
.
’
. . . . ..
.
.
---.~--.. 0.35
.
.
. .
#
~-~--* . .
-0.20.3
. .
. .
.
. .. .. . . . - ----- . : . , . ‘:. . . . . . . . . .
.
-
-0.25
.
.
..
. -0.05
.
’
’
0.5
0.55
Meanof FES
’
’
’
’
’
’
1
Fig. 4. Scattering of differences of lithium values obtained by flame emission spectrometry (FES) and ion-selective electrode (ISE) in capillary whole blood (FES minus ISE) from lithium-treated patients (n = 61, r= 0.865) Dlff*renc*l 0.05 . 0 -0,05
. .
. .
:
*
-
0.3
_’
0.35
0.4
0.45 0.5 0.55 0.6 Mean of FES and
0.65 0.7 ISE wIu#s
0.75 0.8 [mmol/l
0.85 LI]
0.9
0.95
1
Discussion According to the results of this ISE/ FES comparative study, the determination of Li levels in venous whole blood by means of the ISE is a sufficiently precise method that possesses diagnostic power. The results obtained for capillary blood, however, show less agreement with FES plasma values. Furthermore, the ISE Li values above the therapeutic range are generally higher than the determinations achieved by means of the FES, confirming previous observations (Okorodudu et al., 1990). The correlation coefficients between the ISE and FES methods were very high and statistically significant @ < 0.001). However, for determining the amount of agreement between the two analytical techniques, the calculation of correlation coefficients is not quite sufficient (Westgard et al., 1978; Altman and Bland, 1983; Bland and Altman, 1986). In fact, for ISE capillary blood values, the scattering of differences revealed considerable deviations between the ISE results and the FES plasma data. These findings may indicate that a diagnostically valuable Li determination by ISE in capillary blood is not possible. However, in pharmacokinetic studies, the ISE data for venous as well as for capillary blood were equally well suited to register the peaks of the Li levels. Furthermore, the patterns of the curves were very similar, the only difference being that generally higher values were obtained for capillary blood in comparison with venous blood (data not shown, manuscript in preparation). Thus, it appears that capillary values measured by means of the ISE technique do possess some diagnostically relevant information, although they are not in agreement with the respective ISE and FES measures in venous blood. On the basis of the data obtained, we cannot provide an answer for the generally higher Li values found for capillary blood by means of the ISE compared with the ISE and FES data in venous blood. This finding may be attributable to several (still speculative) factors: the different coating of the tubes used for capillary blood
77 (Na/ Ca-heparin instead of NH,-heparin as specified by the producer), the possibility of some lithium being contained in the coating, a higher amount of intracellular electrolytes in capillary blood as compared with venous blood resulting from the blood-taking technique (pressing blood from the fingertip), a contamination of the capillary blood solution by substances on the surface of the skin, and a different proportion of tissue water in capillary as compared with venous blood. Future studies should shed light on this issue.
Conclusion The results of this study suggest that the use of ISE techniques to determine Li levels offers an attractive alternative to the FES in clinical practice. Within the therapeutically relevant range, ISE measurements in venous whole blood or plasma lead to precise and diagnostically valuable “on the spot” determinations of patients’ Li levels, whereas measurements in capillary blood appear to be less useful.
References Altman, D.G., and Bland, J.M. Measurement in medicine: The analysis of method comparison studies. The Statistician, 32:307-317, 1983. Bertholf, R.L.; Savory, M.G.; Winborne, K.H.; Hundley, J.C.; Plummer, G.M.; and Savory, J. Lithium determined in serum with an ion-selective electrode. Clinical Chemistry, 7:1500-1502, 1988. Birch, N.J. Lithium in the cellular environment. In: Birch, N.J., ed. Lirhium and the Cell: Pharmacology and Biochemistry. London: Academic Press, 1991. pp. 159-I 74. Bland, J.M., and Altman, D.G. Statistical methods for assessing agreement between two methods of clinical measurement. Lancer, 1:307-310, 1986. Coombs, H.I.; Coombs, R.R.H.; and Mee, U.G. Methods of serum lithium estimation. In: Johnson, F.N., ed. Lithium Research and Therapy. London: Academic Press, 1975. pp. 165-177. Greil, W.; Runge, H.; and Steller, B. Sofort-Bestimmung von Lithium im Blut mittels ionenselektiver Elektrode: Eine neue Lithium-Bestimmungsmethode zur Verbesserung der Lithiumtherapie. Der Nervenarrr, 63:184-186, 1992. Gross, S.F.; Shibata, G.; Shwu-jian, L.; Chen, K.; and Khayam-Basi, H. Lithium measurements by ion-selective electrode on the Automated Beckman Lablyte 830 (abstract). Clinical Chemistry, 6:1261-1262, 1988. Jefferson, J.W.; Greist, J.H.; and Ackerman, D.L. Lithium Encyclopedia for Clinical Practice. Washington, DC: American Psychiatric Press, 1983. Okorodudu, A.O.; Burnett, R.W.; McComb, R.B.; and Bowers, G.N. Evaluation of three first-generation ion-selective electrode analyzers for lithium: Systematic errors, frequency of random interferences, and recommendations based on comparison with flame atomic emission spectrometry. Clinical Chemistry, 36: 104-l 10, 1990. Phillips, J.D.; King, J.R.; Myers, D.H.; and Birch, N.J. Lithium monitoring close to the patient. Lancer, 11:1461, 1989. Robinson, J.L.; Browning, D.M.; Clark, S.E.; Crafter, V.A.; Gray, B.C.; Hurrell, A.E.; Kilshaw, D.; Morris, K.; and White, J.M. Clinical chemistry outside laboratories: Report of a second survey. Medical Laboratory Sciences, 46: 16-22, 1989. Westgard, J.O.; de Vos, D.J.; Hunt, M.R.; Quam, E.F.; Garber, C.C.; and Carey, R.N. Concepts and practices in the evaluation of clinical chemistry methods: III. Statistics. American Journal of Medical Technology, 441552-571, 1978. Xie, R.Y., and Christian, G.D. Measurement of serum lithium levels. In: Johnson, F.N., ed. Depression and Mania: Modern Lithium i%erapy. Oxford: IRL Press, 1987.
Psychiatry Research, 44~71-77 Elsevier
Lithium Determination in Outpatient Clinics by an lonSelective Electrode in Venous and Capillary Whole Blood Waldemar Received
Greil and Birgit Steller
October 23, 1991; revised version received March 11, 1992; accepted April 9. 1992.
Abstract. The use of an ion-selective electrode (ISE) to determine lithium (Li) in routine clinical application was evaluated by repeatedly analyzing reference specimens (precision evaluation) and by comparing blood concentrations in Litreated patients assessed by ISE and flame emission spectrometry (FES) (correlation and agreement). Precision evaluation was sufficiently high. Li values determined by ISE in venous and capillary whole blood showed high correlations with FES plasma values (correlation coefficients between 0.86 and 0.99). Within the therapeutic range (0.3-1.0 mmole/l Li), agreement was sufficient for venous and less satisfactory for capillary blood (mean differences, FES minus ISE: -0.03 and -0.11 mmole/l Li). Above the therapeutic range, ISE values markedly exceeded FES results. Key Words. Membrane potential, flame emission spectrometry, plasma, maintenance treatment, methodology.
During lithium (Li) therapy, routine tests of Li plasma levels are necessary to achieve therapeutically effective Li concentrations and to avoid intoxications. Furthermore, regular determinations of Li levels are generally helpful in increasing patients’ compliance and especially important for patients receiving additional medication that could influence the Li plasma concentrations (e.g., diuretics, nonsteroid antiphlogistics, and possibly calcium antagonists; Jefferson et al., 1983). Until now, Li concentrations in blood of Li-treated patients have usually been measured by flame emission spectrometry (FES) or atomic absorption spectrometry (AAS), respectively (Coombs et al., 1975; Xie and Christian, 1987). Both techniques are based on the analysis of light wavelengths set free by the movement of electrodes to different energy orbits in the atom: When heated, the atoms are transformed into an excited state (the electrons move to higher energy orbits), absorbing light at different wavelengths (AAS). The analysis of the emission of light by atoms returning to the ground state again is the basis for FES (see Xie and Christian, 1987).
Waldemar Greil, Priv.Doz. Dr. med., Psychiatrist and Neurologist, is Lecturer of Psychiatry, and Birgit Steller, Dr.phil., is Research Psychologist, Psychiatric Hospital, University of Munich, Munich, Germany. (Reprint requests to PD Dr. W. Greil, Psychiatric Hospital, University of Munich, Nussbaumstr. 7, D-8000 Munich 2, Germany.) 0165-1781/92/$05.00
@ 1992 Elsevier Scientific
Publishers
Ireland
Ltd.
72 In 1987, Li determination by means of special ion-selective electrodes (first generation ISEs) became available for clinical practice (Bertholf et al., 1988; Gross et al., 1988; Phillips et al., 1989; Okorodudu et al., 1990; Birch, 1991). In the ISE technique, Li is determined by measuring the membrane potential produced through the contact between an appropriate electrode membrane and the Li solution. The potential is proportional to the logarithm of the lithium concentration in the blood sample (Xie and Christian, 1987). ISE technology allows quick “on the spot” determination of Li without any pretreatment or dilution of the samples. If the procedures recommended by the ISE producers (implementation of a preventive maintenance schedule, quality control, and calibration) are regularly adhered to, the ISE analyzer is easy to handle. By a button press (Robinson et al., 1989), the results for sodium, potassium, and Li are given simultaneously within seconds on the display and as a printout. Given these advantages, the measurement can be directly executed in outpatient clinics or in doctors’ practices. Furthermore, patients’ blood samples need not be centrifuged, as analysis by ISE of Li plasma level can also be performed in whole blood. In this study, a second generation Li/ISE analyzer was applied that required only a minimal amount of blood (40 ~1). Hence, capillary blood from the fingertip or from the earlobe can be used instead of venous blood. For venous and capillary whole blood of Li-treated patients, we compared the Li values obtained by a Lii ISE analyzer to those determined by FES in plasma, as FES is considered an appropriate method for Li determination in routine application (Coombs et al., 1975; Xie and Christian, 1987). To our knowledge, this is the first time that such a comparison between FES and ISE has been performed with whole blood samples, as previous studies on ISE Li measurement used (mostly pooled) plasma specimens (Okorodudu et al., 1990). Moreover, there are no reports on Li determination in capillary blood assessed by means of ISE.1 Our major aim, however, was to assess the ISE’s usefulness in clinical settings.
Methods Precision data for ISE were obtained by repeatedly analyzing special reference specimens with different Li concentrations: three lots of specimens of CIBA-CORNING (Certain Lyte, level I low-lot 62950, which should contain 0.65 mmole/l Li, level 2 mid-lot 62960: 1.17 mmole/l Li, and level 3 high-lot 62970: 1.88 mmole/ 1 Li) and two additional reference specimens usually used for control purposes in laboratories from the lower (Labtrol E, BAXTER & DATE: 0.38 mmole/l Li) and upper (Qualitrol H, MERCK: 0.96 mmole/l Li) therapeutically relevant range. To judge the ISE’s diagnostic value (validity), we compared the results of ISE Li level assessments for venous and capillary blood with the results of the respective FES determinations. Blood was drawn both from Li-treated inpatients and outpatients of the psychiatric hospital of the University of Munich (within regular routine control of Li level). The abnormally high Li data were obtained by repeatedly measuring Li concentrations in the blood of Li-treated patients who were taking part in a pharmacokinetic study and of one patient with a Li intoxication. 1. A curve of Li levels determined by ISE in venous intoxication is given in Greil et al. (1992).
and capillary
whole blood from a patient
with Li
73 For venous blood, we used Monovetten (SARSTEDT; with NH,-heparin as anticoagulant). Capillary blood was taken from the fingertip with 50-~1 capillary tubes (with Na/ Ca-heparin as an anticoagulant according to the specifications of the ISE producer). The ISE determination by means of an Na/K/Li-Analyzer No. 654 (CIBA-CORNING2) was performed in the outpatient Li clinic of the hospital by student assistants who received a brief introduction into the run of ISE analyzers. The FES determination (FCM 6341, EPPENDORF) was executed by professional medical laboratory technicians in the Neurochemical Department of the hospital, which takes part in regular quality-control evaluations. For the ISE/ FES comparison, first the correlations between the Li blood levels assessed by the two techniques were examined. We then calculated the linear regression equation (Westgard et al., 1978) and also analyzed the differences between the two methods (Bland and Altman, 1986).
Results Day-to-Day Precision (Reliability). We repeatedly analyzed the reference specimens over a 12-week period. The observed deviations from the five reference values were very small. Table 1 lists the corresponding statistical measures. Table 1. Means, ranges, standard deviations (SDS), coefficients of variation (CVs), and number of observations (n) for the repeated testing of 5 reference specimens Reference specimens1 Mean
Range
Measured ISE values’ Mean
Range
SD
CV
n
0.38
0.32-0.44
0.36
0.23-0.44
0.04
0.111
37
0.65
0.55-0.75
0.63
0.54-0.68
0.02
0.032
129
0.96
0.84-1.08
0.97
0.87-1.13
0.04
0.041
46
1.17
1.07-1.27
1.16
1.11-1.25
0.02
0.017
90
1.88
1.78-1.98
1.90
1.81-1.99
0.03
0.016
99
Note.ISE = ion-selective electrode.
1.mmolell
lithium.
Correlation and Agreement (Validity). Figs. 1 and 2 illustrate
the relationships between the ISE determinations for venous and capillary whole blood and the respective FES measures. For these data, various correlation coefficients were estimated: coefficients for all observations, coefficients for those observations that fell within the therapeutically relevant range (from 0.3 to 1.O mmole/ 1 Li, according to the ISE determination results), and coefficients for those observations that were therapeutically relevant according to the FES determination results. For all correlation coefficients (0.86-0.99) the level of significance was below 0.001. According to Bland and Altman (1986; Altman and Bland, 1983) and Westgard et al. (1978), however, correlation coefficients are not an adequate indicator of the amount of agreement between two methods measuring the same dependent variable 2. ISE analyzers are also available from AVL (Nr. 985), BECKMAN (Lablyt 830), NOVA (No. DU PONT (Na/ K/ Li; for sale in the USA).
I I) and
74
Fig. 1. Relationship between lithium values obtained by flame emission spectrometry (FES) in plasma and values measured by ion-selective electrode (ISE) in venous whole blood (r= 0.994; 1:l line included)
0
1
2 KS
3
(Plasma)
The linear regression is y = 1.165x - 0.041 (x = FES, y = ISE; SE for slope: 0.01,
t = 110.6).
(the Li level in our case). Westgard et al. (1978) identified major limitations of using correlation coefficients: They are sensitive to random analytical error, as well as to constant and proportional errors, and they are very sample-dependent. Whereas Westgard et al. (1978) used regression analyses to control for these kinds of errors (calibration approach), Altman and Bland (1983; Bland and Altman, 1986), who do not consider one method predictive of the other, prefer the analysis of the differences between two measurement methods (reference value for differences is the average of the compared methods). For the ISE assessments of whole blood specimens within the therapeutically relevant range, we thus calculated the differences between the FES determination results and the respective ISE results. Fig. 3 illustrates the scattering of differences (FES minus ISE) for venous blood. The mean difference is -0.03 (SD: 0.05 mmole/l). Only 1.72% (two cases) of the 116 observations deviate more than + 2 SD from the mean. Fig. 4 shows the scattering of differences for capillary blood within the therapeutically relevant range according to the ISE determination results. For this comparison, the mean difference is -0.11 (SD: 0.07 mmole/l); 6.56 % (four cases) of the 61 observations exceed the level of acceptance.
75
Fig. 2. Relationship between lithium values obtained by flame emission spectrometry (FES) in plasma and values measured by ion-selective electrode (ISE) in capillary whole blood (r= 0.974; 1:l line included) ISE(Capillary. Whole Blood) 4
.
0
J
2
1
3
FES (Plasma)
The linear regression is y = 1.336~ - 0.001 (x = FES, y = ISE; SE for slope: 0.03, t = 40.6).
Fig. 3. Scattering of differences of lithium values obtained by flame emission spectrometry (FES) and ion-selective electrode (ISE) in venous whole blood (FES minus ISE) from lithium-treated patients (n = 116, r= 0.951)
. 0,05 .
. 0
.
’
-0,t
-
‘_
. .
.. ..
.
’
’
’
0.4
0.45
.
. ..
. ..
..* **
.
. . *
*
.
.
.
. .
.
.
.
. .
’
’
0.6 0.65 0.7 0.75 0.8 0.85 and ISE values [mmol/l U]
0.9
0.95
. ..
..
.
’
. . . . ..
.
.
---.~--.. 0.35
.
.
. .
#
~-~--* . .
-0.20.3
. .
. .
.
. .. .. . . . - ----- . : . , . ‘:. . . . . . . . . .
.
-
-0.25
.
.
..
. -0.05
.
’
’
0.5
0.55
Meanof FES
’
’
’
’
’
’
1
Fig. 4. Scattering of differences of lithium values obtained by flame emission spectrometry (FES) and ion-selective electrode (ISE) in capillary whole blood (FES minus ISE) from lithium-treated patients (n = 61, r= 0.865) Dlff*renc*l 0.05 . 0 -0,05
. .
. .
:
*
-
0.3
_’
0.35
0.4
0.45 0.5 0.55 0.6 Mean of FES and
0.65 0.7 ISE wIu#s
0.75 0.8 [mmol/l
0.85 LI]
0.9
0.95
1
Discussion According to the results of this ISE/ FES comparative study, the determination of Li levels in venous whole blood by means of the ISE is a sufficiently precise method that possesses diagnostic power. The results obtained for capillary blood, however, show less agreement with FES plasma values. Furthermore, the ISE Li values above the therapeutic range are generally higher than the determinations achieved by means of the FES, confirming previous observations (Okorodudu et al., 1990). The correlation coefficients between the ISE and FES methods were very high and statistically significant @ < 0.001). However, for determining the amount of agreement between the two analytical techniques, the calculation of correlation coefficients is not quite sufficient (Westgard et al., 1978; Altman and Bland, 1983; Bland and Altman, 1986). In fact, for ISE capillary blood values, the scattering of differences revealed considerable deviations between the ISE results and the FES plasma data. These findings may indicate that a diagnostically valuable Li determination by ISE in capillary blood is not possible. However, in pharmacokinetic studies, the ISE data for venous as well as for capillary blood were equally well suited to register the peaks of the Li levels. Furthermore, the patterns of the curves were very similar, the only difference being that generally higher values were obtained for capillary blood in comparison with venous blood (data not shown, manuscript in preparation). Thus, it appears that capillary values measured by means of the ISE technique do possess some diagnostically relevant information, although they are not in agreement with the respective ISE and FES measures in venous blood. On the basis of the data obtained, we cannot provide an answer for the generally higher Li values found for capillary blood by means of the ISE compared with the ISE and FES data in venous blood. This finding may be attributable to several (still speculative) factors: the different coating of the tubes used for capillary blood
77 (Na/ Ca-heparin instead of NH,-heparin as specified by the producer), the possibility of some lithium being contained in the coating, a higher amount of intracellular electrolytes in capillary blood as compared with venous blood resulting from the blood-taking technique (pressing blood from the fingertip), a contamination of the capillary blood solution by substances on the surface of the skin, and a different proportion of tissue water in capillary as compared with venous blood. Future studies should shed light on this issue.
Conclusion The results of this study suggest that the use of ISE techniques to determine Li levels offers an attractive alternative to the FES in clinical practice. Within the therapeutically relevant range, ISE measurements in venous whole blood or plasma lead to precise and diagnostically valuable “on the spot” determinations of patients’ Li levels, whereas measurements in capillary blood appear to be less useful.
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