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Falsely elevated chloride during treatment with sodium thiosulfate
Clinica Chimica Acta 433 (2014) 264–265
Contents lists available at ScienceDirect
Clinica Chimica Acta journal homepage: www.elsevier.com/locate/clinchim
Letter to the Editor Falsely elevated chloride during treatment with sodium thiosulfate
Dear Editor: A recent Case Report by Wendroth et al. [1] describes interference by sodium thiosulfate (STS) with measurement of plasma chloride. STS is used to treat calciphylaxis and cyanide poisoning but can result in severe anion gap acidosis. Interference by STS with chloride measurement can make an elevated anion gap appear normal, potentially delaying recognition and treatment of acidosis. In the Case Report, interference with measurement of chloride from STS up to a concentration of 20 mmol/l was tested on 9 different analyzers. Level of interference varied widely, from no interference or slightly negative interference to significant positive interference, exceeding CLIA allowable error of 5% for measurement of chloride. Electrochemical sensors of 2 varieties are used for measurement of plasma chloride: potentiometric Ag/AgCl electrodes or potentiometric sensors based on dissociated anion exchangers. The former is rarely used in instruments measuring plasma chloride due to many limitations and, in the case of the reported STS interference, a system utilizing this type of sensor showed the largest interference by STS on measurement of chloride. Dissociated anion exchanger-based sensors are more commonly used and are the only practical choice for chloride sensors in systems measuring electrolytes in undiluted blood. In the Case Report, 5 of the 9 tested analyzers were blood gas/electrolyte analyzers and showed large variability in the STS interference. Most likely, these 5 analyzers all use dissociated anion exchanger-type chloride sensors, known to be susceptible to interference from anions more lipophilic than chloride. Specific sensor formulations are not known but may be modified slightly to reduce relative interference from anions more lipophilic than chloride [2]. Except for the RAPIDPoint 500, the blood gas analyzers evaluated are older models, FDA cleared in 2003 and earlier, and may not present an up-to-date picture of types of interferences observed with measurement of chloride in newer analyzers, especially those designed for point-of-care measurement of blood gases, electrolytes and related analytes. We evaluated 3 latest generation blood gas/electrolyte analyzers for interference from STS with measurement of plasma chloride; GEM Premier 4000 (Instrumentation Laboratory, FDA cleared 2006), ABL 90 (Radiometer, FDA cleared 2010) and RAPIDPoint 500 (Siemens, FDA cleared 2011). The test protocol was similar to that in the Case Report. Heparinized plasma from a healthy volunteer was spiked to STS concentration equal to 20 mmol/l. Spiked sample was mixed volumetrically with unspiked sample to obtain 6 intermediate concentrations of STS. Since magnitude of interference is expected to increase at lower concentrations of primary ion, interference from STS was measured at 2 chloride concentrations; one within the reference range (100– 108 mmol/l) and one below the reference range (approximately 90 mmol/l). The lower chloride concentration was obtained by adding
http://dx.doi.org/10.1016/j.cca.2014.04.001 0009-8981/© 2014 Elsevier B.V. All rights reserved.
140 mmol/l sodium acetate to a plasma sample from a healthy donor, to keep plasma ionic strength constant, until the target chloride concentration was reached. Acetate is less lipophilic than chloride and known not to interfere with measurement of plasma chloride by ion-selective electrodes. Fig. 1A shows interference with chloride measurement on the 3 analyzers for chloride concentration within the reference range (mean value of reported result = 107 mmol/l). Data are shown as difference in measured chloride vs. unspiked sample as the STS concentration is increased. The RAPIDPoint and the ABL showed a small, but statistically significant negative interference while the GEM showed no interference (slope not statistically significantly different from zero). Data from none of the analyzers exceeded the CLIA allowable error limit for chloride (±5 mmol/l) at the highest STS concentration tested (dashed lines in Fig. 1A). The negative interference for the RAPIDPoint is similar to that presented in the Case Report. Negative interference for ion-selective electrodes is not common and may be caused by factors reducing activity of the primary ion, including: complexation, ion pairing, coextraction of counter-ion along with primary ion, or a large increase in sample ionic strength. Sodium thiosulfate is a 2:1 electrolyte and addition of 20 mmol/l STS will produce an ionic strength increase equal to 60 mmol/l. The data of Fig. 1A were corrected for chloride activity differences from increasing ionic strength as STS concentration increases, assuming a normal plasma ionic strength equal to 160 mmol/l and an estimated chloride ion activity coefficient equal to 0.744 [3]. Reduction in ion activity from increased ionic strength accounts for approximately 2.3 mmol/l at the highest STS concentration and does not fully explain the negative interference for two of the analyzers. Fig. 1B shows chloride interference from added STS at a lower chloride concentration target of 90 mmol/l (mean value of the unspiked plasma across the 3 analyzers = 86 mmol/l). In this case, all tested analyzers show slopes statistically significantly different from zero, with RAPIDPoint and ABL again with negative interference and the GEM with positive interference. Interference from STS is more pronounced at the lower chloride concentration but again interferences are within the CLIA allowable error of ±5% (dashed lines in Fig. 1B). Correction of the data for ionic strength will increase the measured chloride concentration by approximately 1.8 mmol/l at the highest STS concentration and will nearly completely account for negative interference for 2 of the analyzers. Correction for ionic strength will likewise increase the reported chloride concentration for the GEM by 1.8 mmol/l; however, the result is still within the CLIA allowable error of ±5%. Of the 3 analyzers tested, none showed interference from thiosulfate on measurement of chloride exceeding the CLIA allowable error limit of ± 5%. Thiosulfate was tested up to a concentration of 20 mmol/l, exceeding the peak plasma concentration expected during patient treatment (16.7 mmol/l) [1]. Thiosulfate anion is more lipophilic than
Letter to the Editor
Change in Cl-vs. unspiked sample
A 6.0 4.0 2.0
GEM 4000
0.0
RapidPoint
-2.0
ABL 90
chloride and would be predicted to produce interference with measurement of chloride using ion-selective electrodes based on dissociated ion-exchange. Modifications to membrane chemistry, including hindering ion accessibility to the sensing membrane based on size (MW chloride = 35, MW thiosulfate = 112) is one method used to improve sensor selectivity in the latest generation blood gas/electrolyte analyzers. In summary, the reported clinically significant interference by sodium thiosulfate on measurement of plasma chloride has been solved in the latest generation blood gas/electrolyte analyzers. References
-4.0 -6.0
0
5
10
15
[1] Wendroth SM, Heady TN, Haverstick DM, et al. Falsely increased chloride and missed anion gap elevation during treatment with sodium thiosulfate. Clin Chim Acta 2014;431:77–9. [2] D'Orazio P, Meyerhoff ME. Electrochemistry and chemical sensors. In: Burtis CA, Ashwood ER, Bruns DE, editors. Tietz textbook of clinical chemistry and molecular diagnostics. St. Louis: Saunders/Elsevier; 2012. p. 259. [3] Covington K, Ferra MIA. Calculation of single-ion activities in solutions simulating blood plasma. Scand J Clin Lab Invest 1989;49:667–75.
20
Plasma STS, mmol/L
B Change in Cl-vs. unspiked sample
265
6.0 4.0 GEM 4000
2.0
RapidPoint
0.0 -2.0
ABL 90
-4.0 -6.0
0
5
10 15 Plasma STS, mmol/L
20
Fig. 1. Effects of sodium thiosulfate on measured chloride from 3 blood gas/electrolyte analyzers for chloride concentration (A) within the reference range and (B) below the reference range (target = 90 mmol/l).
Paul D'Orazio Instrumentation Laboratory, 180 Hartwell Ave., Bedford, MA, United States Tel./fax: +1 781 861 4240. 20 March 2014 Available online 12 April 2014
Contents lists available at ScienceDirect
Clinica Chimica Acta journal homepage: www.elsevier.com/locate/clinchim
Letter to the Editor Falsely elevated chloride during treatment with sodium thiosulfate
Dear Editor: A recent Case Report by Wendroth et al. [1] describes interference by sodium thiosulfate (STS) with measurement of plasma chloride. STS is used to treat calciphylaxis and cyanide poisoning but can result in severe anion gap acidosis. Interference by STS with chloride measurement can make an elevated anion gap appear normal, potentially delaying recognition and treatment of acidosis. In the Case Report, interference with measurement of chloride from STS up to a concentration of 20 mmol/l was tested on 9 different analyzers. Level of interference varied widely, from no interference or slightly negative interference to significant positive interference, exceeding CLIA allowable error of 5% for measurement of chloride. Electrochemical sensors of 2 varieties are used for measurement of plasma chloride: potentiometric Ag/AgCl electrodes or potentiometric sensors based on dissociated anion exchangers. The former is rarely used in instruments measuring plasma chloride due to many limitations and, in the case of the reported STS interference, a system utilizing this type of sensor showed the largest interference by STS on measurement of chloride. Dissociated anion exchanger-based sensors are more commonly used and are the only practical choice for chloride sensors in systems measuring electrolytes in undiluted blood. In the Case Report, 5 of the 9 tested analyzers were blood gas/electrolyte analyzers and showed large variability in the STS interference. Most likely, these 5 analyzers all use dissociated anion exchanger-type chloride sensors, known to be susceptible to interference from anions more lipophilic than chloride. Specific sensor formulations are not known but may be modified slightly to reduce relative interference from anions more lipophilic than chloride [2]. Except for the RAPIDPoint 500, the blood gas analyzers evaluated are older models, FDA cleared in 2003 and earlier, and may not present an up-to-date picture of types of interferences observed with measurement of chloride in newer analyzers, especially those designed for point-of-care measurement of blood gases, electrolytes and related analytes. We evaluated 3 latest generation blood gas/electrolyte analyzers for interference from STS with measurement of plasma chloride; GEM Premier 4000 (Instrumentation Laboratory, FDA cleared 2006), ABL 90 (Radiometer, FDA cleared 2010) and RAPIDPoint 500 (Siemens, FDA cleared 2011). The test protocol was similar to that in the Case Report. Heparinized plasma from a healthy volunteer was spiked to STS concentration equal to 20 mmol/l. Spiked sample was mixed volumetrically with unspiked sample to obtain 6 intermediate concentrations of STS. Since magnitude of interference is expected to increase at lower concentrations of primary ion, interference from STS was measured at 2 chloride concentrations; one within the reference range (100– 108 mmol/l) and one below the reference range (approximately 90 mmol/l). The lower chloride concentration was obtained by adding
http://dx.doi.org/10.1016/j.cca.2014.04.001 0009-8981/© 2014 Elsevier B.V. All rights reserved.
140 mmol/l sodium acetate to a plasma sample from a healthy donor, to keep plasma ionic strength constant, until the target chloride concentration was reached. Acetate is less lipophilic than chloride and known not to interfere with measurement of plasma chloride by ion-selective electrodes. Fig. 1A shows interference with chloride measurement on the 3 analyzers for chloride concentration within the reference range (mean value of reported result = 107 mmol/l). Data are shown as difference in measured chloride vs. unspiked sample as the STS concentration is increased. The RAPIDPoint and the ABL showed a small, but statistically significant negative interference while the GEM showed no interference (slope not statistically significantly different from zero). Data from none of the analyzers exceeded the CLIA allowable error limit for chloride (±5 mmol/l) at the highest STS concentration tested (dashed lines in Fig. 1A). The negative interference for the RAPIDPoint is similar to that presented in the Case Report. Negative interference for ion-selective electrodes is not common and may be caused by factors reducing activity of the primary ion, including: complexation, ion pairing, coextraction of counter-ion along with primary ion, or a large increase in sample ionic strength. Sodium thiosulfate is a 2:1 electrolyte and addition of 20 mmol/l STS will produce an ionic strength increase equal to 60 mmol/l. The data of Fig. 1A were corrected for chloride activity differences from increasing ionic strength as STS concentration increases, assuming a normal plasma ionic strength equal to 160 mmol/l and an estimated chloride ion activity coefficient equal to 0.744 [3]. Reduction in ion activity from increased ionic strength accounts for approximately 2.3 mmol/l at the highest STS concentration and does not fully explain the negative interference for two of the analyzers. Fig. 1B shows chloride interference from added STS at a lower chloride concentration target of 90 mmol/l (mean value of the unspiked plasma across the 3 analyzers = 86 mmol/l). In this case, all tested analyzers show slopes statistically significantly different from zero, with RAPIDPoint and ABL again with negative interference and the GEM with positive interference. Interference from STS is more pronounced at the lower chloride concentration but again interferences are within the CLIA allowable error of ±5% (dashed lines in Fig. 1B). Correction of the data for ionic strength will increase the measured chloride concentration by approximately 1.8 mmol/l at the highest STS concentration and will nearly completely account for negative interference for 2 of the analyzers. Correction for ionic strength will likewise increase the reported chloride concentration for the GEM by 1.8 mmol/l; however, the result is still within the CLIA allowable error of ±5%. Of the 3 analyzers tested, none showed interference from thiosulfate on measurement of chloride exceeding the CLIA allowable error limit of ± 5%. Thiosulfate was tested up to a concentration of 20 mmol/l, exceeding the peak plasma concentration expected during patient treatment (16.7 mmol/l) [1]. Thiosulfate anion is more lipophilic than
Letter to the Editor
Change in Cl-vs. unspiked sample
A 6.0 4.0 2.0
GEM 4000
0.0
RapidPoint
-2.0
ABL 90
chloride and would be predicted to produce interference with measurement of chloride using ion-selective electrodes based on dissociated ion-exchange. Modifications to membrane chemistry, including hindering ion accessibility to the sensing membrane based on size (MW chloride = 35, MW thiosulfate = 112) is one method used to improve sensor selectivity in the latest generation blood gas/electrolyte analyzers. In summary, the reported clinically significant interference by sodium thiosulfate on measurement of plasma chloride has been solved in the latest generation blood gas/electrolyte analyzers. References
-4.0 -6.0
0
5
10
15
[1] Wendroth SM, Heady TN, Haverstick DM, et al. Falsely increased chloride and missed anion gap elevation during treatment with sodium thiosulfate. Clin Chim Acta 2014;431:77–9. [2] D'Orazio P, Meyerhoff ME. Electrochemistry and chemical sensors. In: Burtis CA, Ashwood ER, Bruns DE, editors. Tietz textbook of clinical chemistry and molecular diagnostics. St. Louis: Saunders/Elsevier; 2012. p. 259. [3] Covington K, Ferra MIA. Calculation of single-ion activities in solutions simulating blood plasma. Scand J Clin Lab Invest 1989;49:667–75.
20
Plasma STS, mmol/L
B Change in Cl-vs. unspiked sample
265
6.0 4.0 GEM 4000
2.0
RapidPoint
0.0 -2.0
ABL 90
-4.0 -6.0
0
5
10 15 Plasma STS, mmol/L
20
Fig. 1. Effects of sodium thiosulfate on measured chloride from 3 blood gas/electrolyte analyzers for chloride concentration (A) within the reference range and (B) below the reference range (target = 90 mmol/l).
Paul D'Orazio Instrumentation Laboratory, 180 Hartwell Ave., Bedford, MA, United States Tel./fax: +1 781 861 4240. 20 March 2014 Available online 12 April 2014