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Equimolar ammonia interference in potassium measurement on the Osmetech OPTI CCA: a reply.

To the Editor:

We agree that the Osmetech OPTI Critical Care Analyzer (OPTI) measurement of potassium ion shows a bias with samples containing extremely high plasma ammonia concentrations, as reported by Carayanopoulos et al. (1). As a result of this report we have notified all OPTI customers of this interference at these rare high ammonia concentrations.

Hyperammonemia has an estimated incidence in newborns of 1 per 25 000-53 000 live births (2, 3). Urea cycle disorders are the usual cause (4), occasionally leading to ammonia concentrations >400 [micro]mol/L, which would increase the potassium reported on OPTI by 0.5 mmol/L. Such a bias is greater than allowed under the US Healthcare Financing Administration/CLIA proficiency testing criteria for acceptable performance (5). In rare cases, newborns may also suffer hyperammonemia attributable to other pathologies (6), such as organic acidemias, fatty acid oxidation disorders, congenital lactic acidosis, lysinuric protein intolerance, hepatic or renal dysfunction, Reye syndrome, certain drugs (valproate, asparaginase, fluorouracil), transient hyperammonemia in newborn, and perinatal asphyxia.

In a 10-year retrospective study of 9958 plasma ammonia measurements at a tertiary referral children's hospital (7), 4.0% of the values were >200 [micro]mol/L and ~1.4% were >400 [micro]mol/L ("almost all" associated with inborn errors of metabolism). Similarly, one peer reviewer provided data from his/her tertiary care pediatric setting showing a consistent frequency of 3% of ammonia results >200 [micro]mol/L. Both estimates are from tertiary care institutions. Lower frequencies may be seen in institutions caring for children with less severe illness. In a 1997 review of inborn errors of metabolism (8), the collective incidence of the most commonly encountered organic acidurias was estimated at 0.007%, and the collective incidence of all urea cycle defects was estimated at 0.003%. Assuming a distribution of increased ammonia concentrations consistent with that cited in Chow et al. (7), fewer than half of these acidurias and defects will lead to ammonia concentrations >400 [micro]mol/L, and the frequency of potassium bias >0.5 mmol/L on the OPTI would thus be <1 per 20 000 (0.005%) pediatric samples submitted in a typical (non-tertiary) institution.

In adults, hyperammonemia is similarly rare but typically far less severe. In 3 studies of liver failure patients, involving 129 acute and chronic cases (9,10), mean plasma ammonia concentrations were 49 to 172 [micro]mol/L. Valproate-induced encephalopathy has led to ammonia concentrations up to 140 [micro]mol/L (11). In 2004, in 4 unusual cases of emergency room--treated adult hyperammonemia, maximum ammonia concentrations were 103, 133, 300, and 500 [micro]mol/L, the last in a patient under high-dose fluorouracil chemotherapy (12). Hence we expect the occurrence of OPTI potassium bias >0.5 mmol/L to be extremely rare in adult samples.

The Clinical and Laboratory Standards Institute (CLSI) Guidelines for interference testing (13) suggest a high ammonia test point of 80 [micro]mol/L, which was measured on the OPTI during its development and revealed no offset in reported potassium. Because no significant bias was seen in potassium at ammonia concentrations <300 [micro]mol/L, we (the developers /manufacturers) considered this method to be interference free. The OPTI has been marketed globally for 8 years, and we have received no previous complaint, query, or observation concerning ammonia interference with potassium measurement.

As part of our risk assessment, we included the possibility of incorrect clinical action based on an erroneous high potassium reported by the OPTI. We consulted an independently contracted expert (Professor Alan Plummer, Emory University School of Medicine) who believes it is possible, but extremely unlikely, that harm could come to a patient if the ammonia interference problem with the OPTI were not known by the clinicians treating the patient. In his opinion, ammonia concentrations >500 [micro]mol/L are very rare, and if they do occur, he doubts any clinical remedy to normalize the potassium would occur before the measurement was repeated, most likely on a different analyzer. If the institution had only the OPTI analyzer, then a repeat falsely increased potassium concentration would be found, and if no other tests were obtained (e.g., electrocardiogram), it is possible the patient could receive potassium-lowering medications (e.g., insulin), which could lower potassium to clinically dangerous concentrations. Professor Plummer said he considers this scenario to be extremely unlikely because virtually all such patients would be in intensive care units and monitored very closely.

In short, we acknowledge that plasma ammonia concentrations can exceed 400 [micro]mol/L. We thank the authors for their study, and regardless of the rarity of the extremely high ammonia concentrations that produce potassium interference, we have since included a warning statement within our Operator's Manual and will modify our protocols to include medical opinions concerning pathological test ranges of potential interferents, above and beyond those recommended by the CLSI Guidelines.

References

(1.) Carayannopoulos MO, Whilhite TR, Reddy L, Landt M, Smith CH, Dietzen DJ. Equimolar ammonia interference in potassium measurement on the Osmetech OPTI Critical Care Analyzer. Clin Chem 2006;52:1603-04.

(2.) Applegarth DA, Toone JR, Lowry RB. Incidence of inborn errors of metabolism in British Columbia, 1969-1996. Pediatrics 2000;105:e10-e15.

(3.) Summar M, Tuchman M. Proceedings of a consensus conference for the management of patients with urea cycle disorders. J Pediatr 2001;138:S6-S10.

(4.) Leonard JV, Morris AAM. Urea cycle disorders. Semin Neonatol 2002;7:27-35.

(5.) Burtis CA, Ashwood ER, Bruns, DE, ed. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics, 4th ed. St. Louis, MO: Elsevier Saunders, P517, Table 19-8.

(6.) Batshaw ML. Hyperammonemia. Curr Probl Pediatr 1984;14:1-69.

(7.) Chow SL, Gandhi V, Krywawych S, Clayton PT, Leonard JV, Morris AAM. The significance of a high plasma ammonia value. Arch Dis Child 2004;89:585-6.

(8.) Seymour CA, Thomason MJ, Chalmers RA, Addison GM, Bain MD, Cockburn F et. al. Newborn screening for inborn errors of metabolism: a systematic review. Health Technol Assess 1997;1:1-95.

(9.) Bhatia V, Singh R, Acharya SK. Predictive value of arterial ammonia for complications and outcome in acute liver failure. Gut 2006;55:98-104.

(10.) Kundra A, Jain A, Banga A, Bajaj G, Kar P. Evaluation of plasma ammonia levels in patients with acute liver failure and chronic liver disease and its correlation with the severity of hepatic encephalopathy and clinical features of raised intracranial tension. Clin Biochem 2005;38:696-9.

(11.) Laterza OF, Gerhardt G, Sokoll U. Measurement of plasma ammonia is affected in patients receiving asparaginase therapy. Clin Chem 2003;49:1710-1.

(12.) Weng TI, Shih FF, Chen WJ. Unusual causes of hyperammonemia in the ED. Am J Emerg Med 2004;22:105-7.

(13.) Clinical Laboratory Standards Institute (CLSI; formerly NCCLS). Interference testing in clinical chemistry; Approved Guideline, 2nd ed. CLSI Pub.EP07-A2. Wayne, PA: CLSI, 2005.

Chao Lin*

James K. Tusa

Osmetech Inc.

Roswell, GA

* Address correspondence to this author at: Osmetech Inc, 235 Hembree Park Drive, Roswell, GA 30076. Fax 770-510-4444; e-mail chao.lin@osmetech.com.

DOI: 10.1373/clinchem.2006.072033
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Title Annotation:Letters
Author:Lin, Chao; Tusa, James K.
Publication:Clinical Chemistry
Article Type:Letter to the editor
Date:Nov 1, 2006
Words:1170
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