Falsely increased chloride and missed anion gap elevation during treatment with sodium thiosulfate

doi:10.1016/j.cca.2014.01.020

Clinica Chimica Acta

Volume 431, 20 April 2014, Pages 77-79

https://doi.org/10.1016/j.cca.2014.01.020 Get rights and content

Highlights

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Sodium thiosulfate (STS) treatment can cause a severe anion-gap acidosis.
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An unexplained hyperchloremia was discovered in a patient taking STS.
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STS interfered with chloride measurement on most (8 of 9) analyzers tested.
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STS interference masked the presence of an increased anion gap in the patient.
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In patients on STS, measured anion gaps are often unreliable.

Abstract

Background

Sodium thiosulfate (STS) is used to treat calciphylaxis and cyanide poisoning, but can lead to a serious anion-gap acidosis. We suspected that the calculated anion gap in a patient treated with STS for calciphylaxis was decreased to normal by a falsely increased chloride, and we hypothesized that STS directly interfered with chloride measurements.

Methods

Plasma pools were prepared with 12 concentrations of STS from 0 to 20 mmol/l. Chloride was measured in each sample on 9 analyzers: Architect 16200, StatProfile pHOx Plus, RapidLab 1265®, Vitros 350®, Advia 1800, Roche Modular, iSTAT1, RAPIDpoint 500, and Radiometer ABL735.

Results

Statistically significant, dose-dependent increases in reported chloride concentrations were seen with all analyzers except the RAPIDpoint 500 and Vitros. The increases ranged from 5 to 75 mmol/l at the peak thiosulfate concentrations (33 mmol/l) expected in treated patients. The CLIA-allowable error of 5% was exceeded by 4 analyzers (Architect 16200, iSTAT1, StatProfile pHOx Plus, and Radiometer ABL735). The RAPIDpoint 500 showed a 3-mmol/l decrease in measured chloride over the tested range. The Vitros analyzer showed no interference.

Conclusions

Interference of STS in chloride measurement in several common analyzers may lead to erroneous anion-gap calculations and confound the diagnosis of STS-induced anion-gap acidosis.

Introduction

Calciphylaxis, also known as calcific uremic arteriolopathy, is a rare disease characterized by painful cutaneous ulcers formed secondary to dystrophic calcium deposition in the vasculature of the skin. The disease occurs most often in patients with end-stage renal disease on hemodialysis or those with chronic inflammatory conditions even without renal failure [1]. Although the disease has historically portended a poor prognosis, patients have been successfully treated in the last decade with sodium thiosulfate (STS), a drug previously used to treat cyanide poisoning [1], [2].

While the drug commonly causes mild gastrointestinal symptoms, the most serious side effect is that of severe anion gap acidosis. To monitor patients for this effect, plasma electrolytes are measured after each dose [3], [4]. We recently encountered an unexplained increase of the plasma chloride concentration in a patient receiving STS, and sought an explanation for this finding.

Section snippets

Case report

A 33-y-old woman with systemic lupus erythematosus and associated vasculitis and nephritis presented to the clinic for continuing treatment of bilateral lower extremity ulcers. The ulcers had been present for 18 months, and had a biopsy-proven diagnosis of calciphylaxis. Despite treatment of her lupus with immunosuppression, the wounds continued to worsen. Eight months before the current clinic visit she was started on 25-g intravenous infusions of sodium thiosulfate (STS) thrice weekly to treat

Methods

To examine the effect of STS on chloride measurements by clinical analyzers, we prepared samples of pooled plasma with 12 concentrations of STS. The concentration of chloride in each of these samples was measured by 9 different analyzers. The maximum concentration of STS was chosen to represent the highest concentration likely to be seen in plasma after infusion of a 12.5-g dose of STS. Assuming that the 12.5-g dose of STS pentahydrate is distributed in a typical blood volume of 5 l with a

Results

The dose–response curve illustrating the relationship of STS concentration and the chloride results from the various analyzers is shown in Fig. 1. Using SAS software (SAS Institute INC) an analysis of covariance was performed on the data and showed significant non-homogeneity (P < 0.0001) of the slopes of the thiosulfate dose–response curves among the analyzers. Regression analysis of these dose–response curves resulted in slopes that were statistically significantly different from zero for all

Discussion

These studies demonstrate that STS produces a positive interference in chloride measurements on most of the representative analytical platforms studied. The levels of interference can be grouped into 3 categories based on expected clinical significance: (i) analyzers that showed large interference beyond the CLIA acceptable limit of 5% variation (Architect 16200, iSTAT1, StatProfile pHOx Plus, and Radiometer ABL735); (ii) those that showed statistically significant interference without

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Data on the clinical, analytical, and laboratory factors associated with negative anion gaps at an academic medical center
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Certain pathologic states, drugs, and laboratory abnormalities have been associated with low anion gap measurements [1,6,8,13]. These include hypoalbuminemia [8,14-16], chronic respiratory acidosis with compensatory metabolic alkalosis [17], hypercalcemia [18], hypermagnesemia [19], marked hyperkalemia [9], polyclonal gammopathy [20], presence of paraproteins (e.g., multiple myeloma) [21,22], pseudohyponatremia (due to factors such as hypertriglyceridemia, severe hypercholesterolemia, or hyperproteinemia) [23], pseudohyperbicarbonemia (such as due to ketoacidosis or monoclonal proteins) [9], bromism (intoxication with bromides) [24], iodine administration [10], lithium toxicity [19,25], thiosulfate [26], salicylate poisoning [9,12], and administration of the antimicrobial polymyxin B [27]. Previous studies have also identified pre-analytical specimen issues (e.g., contaminated specimens), analytical errors, and post-analytical errors (e.g., data entry mistake into the medical record) as a relatively frequent cause of low anion gaps [1,6,28].
The anion gap is a calculated parameter derived from the difference between the major plasma cations and anions in serum/plasma or whole blood, with a widely used simple equation utilizing concentrations of sodium, chloride, and bicarbonate. While there is extensive literature on the clinical significance and causes of elevated anion gaps, there is comparatively less data on low anion gaps. Occasionally, anion gap calculations result in a negative number (-1 or less). From the published literature, causes of these 'negative anion gaps' include laboratory error, specimen contamination or interference, hypoalbuminemia, extreme hyperkalemia, bromism, and paraproteins from multiple myeloma or similar pathologic processes. The data in this article present results from retrospective review of clinical chemistry and blood gas analysis testing at an academic medical center. The data include electrolyte concentrations and anion gap values derived from a total of 2,948,574 specimens (2,841,863 serum/plasma specimens analyzed on Roche Diagnostics clinical chemistry analyzers, 93,987 whole blood specimens analyzed on Radiometer blood gas analyzers, and 12,724 whole blood specimens on point-of-care chemistry devices) from 371,925 unique patients, clinical area where testing was ordered (for serum/plasma samples), sex, and age. For serum/plasma specimens with a negative anion gap, the data additionally include information from detailed chart review of possible factors and disease conditions contributing to the negative anion gap, pattern of electrolyte abnormalities, presence or absence of hypoalbuminemia, and corrected anion gap (if hypoalbuminemia is present).
Approach to the Patient with a Negative Anion Gap
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Citation Excerpt :
Of note, a similar artifact was recently reported in patients receiving sodium thiosulfate, which has been used to treat calciphylaxis and cyanide poisoning.56 As with salicylism, the artifact is due to the effect of thiosulfate on the electrode and is very electrode specific.57 Box 1 lists causes of low and negative anion gaps and categorizes them by mechanism.
When anion gap calculation generates a very small or negative number, an explanation must be sought. Sporadic (nonreproducible) measurement errors and systematic (reproducible) laboratory errors must be considered. If an error is ruled out, 2 general possibilities exist. A true anion gap reduction can be generated by either reduced concentrations of unmeasured anions such as albumin or increased concentrations of unmeasured cations such as magnesium, calcium, or lithium. This teaching case describes a patient with aspirin (salicylate) poisoning whose anion gap was markedly reduced (−47 mEq/L). The discussion systematically reviews the possibilities and provides the explanation for this unusual laboratory result.
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Case reportFalsely increased chloride and missed anion gap elevation during treatment with sodium thiosulfate

Highlights

Abstract

Background

Methods

Results

Conclusions

Introduction

Section snippets

Case report

Methods

Results

Discussion

Kidney Int

Am J Kidney Dis

Emerg Med Clin North Am

J Am Acad Dermatol

Calciphylaxis, diagnosis and clinical features

Clin Exp Nephrol

Evolution of treatment strategies for calciphylaxis

Am J Nephrol

Severe anion gap acidosis associated with intravenous sodium thiosulfate administration

J Med Toxicol

Unexpectedly severe metabolic acidosis associated with sodium thiosulfate therapy in a patient with calcific uremic arteriolopathy

Semin Dial

Bromide interference: is less really better?

Clin Chem

Sodium thiosulfate pharmacokinetics in hemodialysis patients and healthy volunteers

Clin J Am Soc Nephrol

Case report
Falsely increased chloride and missed anion gap elevation during treatment with sodium thiosulfate