Abstract Hyperkalemia in specimens from patients with chronic lymphocytic leukemia (CLL) may be due to tumor lysis syndrome (TLS) or specimen processing. This report describes a 55-year-old Caucasian woman with CLL who presented to an outside hospital with hyperkalemia and was transferred to a second hospital. Initial evaluation on the core laboratory chemistry analyzer (the VITROS 5600) and the ABL90 FLEX blood gas analyzer showed markedly elevated levels of potassium (K+). TLS was subsequently diagnosed, and dialysis was initiated. However, follow-up K+ measurements in whole blood (WB) yielded low levels that were unexpected after a single dialysis treatment. We then discovered that the initially elevated K+ level was from centrifuged plasma specimens and concluded that it indicated pseudohyperkalemia, likely from centrifugation. This case demonstrates that medical teams need be alert to potentially false K+ results in patients with elevated white blood cell counts. WB specimens are preferable, and steps to minimize trauma to the specimen and immediate analysis using blood gas instruments are recommended. chronic lymphocytic leukemia, tumor lysis syndrome, pseudohyperkalemia, sample type, centrifugation, in vitro hyperkalemia Clinical History A 55-year-old Caucasian woman with a 6-year history of chronic lymphocytic leukemia (CLL) presented to an outside hospital (OSH) with enlarging neck lymph nodes; she reported having experienced fatigue and weakness for the past month. Three weeks before admission, the patient had been restarted on chemotherapy consisting of pentastatin, cyclophosphamide, and rituxan, due to her lymphadenopathy. On examination, her neck lymph nodes were 3 to 4 cm in diameter, a left axillary node was 5 cm in diameter, and smaller nodes were felt in her inguinal area. After admission to the OSH, the patient had a peripheral blood smear performed; the results showed marked lymphocytosis and atypical prolymphocytoid cells (25% to 30% of cells). Flow cytometry results were consistent with CLL. Bone marrow biopsy results showed hypercellularity of approximately 90%. During her hospital stay, her white blood cell (WBC) count ranged between 200 and 300 × 109 per L (reference interval: 4.0 to 11.0 × 109/L) and her plasma uric acid level was elevated, at greater than 8 mg per dL (2.5 to 7.5 mg/dL). Also, the patient had fluctuating hyperkalemia, with whole blood (WB) potassium (K+) levels between 5 and 7 mmol per L (reference range, 3.4 to 5.3 mmol/L). Due to the hyperkalemia and hyperuricemia, tumor lysis syndrome (TLS) was suspected, and the patient was treated with rasburicase to lower her serum uric acid levels. She received sodium polystyrene sulfonate, and her WB K+ level decreased to 3.7 mmol per L on the day of transfer to a new institution (University of Minnesota Health). The patient was transferred to University of Minnesota Health due to her high risk of complications from suspected TLS. On the day of her admission to the new facility, the patient had a WBC count of 277.6 × 109 per L; plasma K+ levels of 9.9 mmol per L, as measured on the VITROS 5600 immunoanalyzer (Ortho Clinical Diagnostics); a confirmatory K+ level of 9.3 mmol per L, as measured on the ABL90 FLEX blood gas analyzer (Radiometer America); lactate dehydrogenase (LDH) level of 2579 U per L (reference interval [RI], 325–750 U/L); phosphorus level of 1.1 mg per dL (RI, 2.5 to 4.5 mg/dL); magnesium level of 1.4 mg per dL (RI, 1.6 to 2.3 mg/dL); and uric acid levels in the normal range (4.4 mg/dL). Electrocardiogram (ECG) readings demonstrated normal PR intervals with no ST or T wave changes. The patient reported no major symptoms. Because the markedly elevated potassium levels were concordant on the ABL90 FLEX blood gas analyzer and the VITROS 5600, and there was no evidence of hemolysis, the assessment from the medical team was that the patient had severe hyperkalemia, likely secondary to TLS, with concern for accelerated CLL transformation (particularly prolymphocyte leukemia). The patient was given calcium gluconate, insulin, dextrose, high-dose albuterol, intravenous fluids, and furosemide. The team planned to repeat K+ testing in 1 hour and requested a nephrology consultation to assess for the potential need for emergency dialysis. Discussion Hyperkalemia can occur due to a variety of causes. Those causes include including renal failure, adrenal insufficiency, disorders associated with massive tissue breakdown (eg, trauma, rhabdomyolysis, marked hemolysis, or TLS), and pseudohyperkalemia. TLS refers to a group of metabolic complications caused by the breakdown products of dying cancer cells. These complications include hyperkalemia, hyperphosphatemia, hypocalcemia, hyperuricemia, and hyperuricosuria, with the subsequent consequence of acute uric acid nephropathy and acute renal failure. Hyperkalemia can alter cardiac excitability with significant changes in the ECG reading, including the induction of cardiac arrhythmias, which requires an aggressive therapeutic approach. Increased potassium levels are associated with a higher probability of ECG changes, and potassium levels higher than 8 mmol per L are almost invariably associated with ECG changes.1 There has been an occasional report2 of patients with extremely elevated potassium levels but unremarkable ECG findings, generally in patients with renal failure. The term pseudohyperkalemia refers to an increased in vitro blood potassium level in the absence of in vivo hyperkalemia. The causes of pseudohyperkalemia include variables in blood specimen collection, such as fist clenching, mechanical trauma during or after phlebotomy, contamination from ethanol containing antiseptics, K+ carryover from K+–ethylenediaminetetraacetic acid (EDTA) or oxalate/fluoride tubes, refrigeration before centrifugation, delay in centrifugation, decreased transport or storage temperature, pneumatic tube transport, hemolysis, and clotting. Also, clinical conditions of leukocytosis, including CLL or infectious mononucleosis; thrombocytosis associated with myeloproliferative disorders; and erythrocyte disorders, such as in familial pseudohyperkalemia, renal disease, and rheumatoid arthritis may also present along with pseudohyperkalemia. In CLL with extreme leukocytosis, cell lysis with release of intracellular K+ can result in pseudohyperkalemia. Clotting in serum collection was originally believed to contribute to the in vitro cell lysis; this theory is supported by a number of case reports on patients with CLL in whom hyperkalemia was noted in serum but not in plasma or in WB analyzed with a blood gas analyzer.3 However, conflicting observations were also reported4 in a patient with leukemia who had pseudohyperkalemia in plasma but not in serum or WB. A few studies tried to address the discrepancy in K+ levels in different blood specimen types based on the cell sources of K+. Sevastos et al5 studied 435 patients with thrombocytosis, erythrocytosis, leukocytosis, or mixed-type disorders and reported that different cell-type disorders contributed variably to the elevation of K+ levels. Patients with platelet, erythrocyte, or mixed-type disorders showed more increased levels of K+ in serum compared with plasma, whereas a subgroup of 20 patients with CLL or AML showed comparable increase in levels of K+ in serum and plasma. In another study of 37 paired specimens from patients with cancer,6 K+ levels in serum were significantly greater than those in plasma, on average. Platelet counts were significantly associated with K+ levels in serum but not in plasma. In this case, the laboratory measured K+ levels on the main chemistry analyzer (VITROS 5600) and the ABL90 FLEX blood gas instrument using heparin plasma. Both results demonstrated significant hyperkalemia which, in conjunction with the previous findings of hyperuricemia at the OSH, led to the diagnosis of TLS, despite that the null finding on ECG did not fully support the diagnosis of in vivo hyperkalemia. Role of the Laboratory in Diagnosis The patient was transferred to the medical intensive care unit (MICU). Intermittent hemodialysis (IHD) was performed for 2 hours, followed by left internal jugular catheter placement and overnight continuous renal replacement therapy (CRRT). The team started the patient on prednisone and planned to decide the next step once her K+ level became stabilized. Two hours after initiating intermittent hemodialysis, the plasma K+ level had dropped significantly to 5.6 mmol per L—such a decline would exceed the expected speed of K+ removal via hemodialysis (typically, 25 to 50 mmol of K+/hour). The potassium level, as measured the next morning after 6 hours of overnight CRRT, was 7.1 mmol/L, a value higher than the previous result. This finding did not make sense to us because the patient had undergone several hours of additional dialysis between measurements. Given the unexpectedly large decrease in potassium after IHD and the increase in potassium level after CRRT, the health care providers suspected pseudohyperkalemia. It was noted that ionized calcium had been measured in WB at the same time as the 2 K+ measurements, so the laboratory measured a K+ level on both remnant WB specimens using the ABL90 FLEX blood gas analyzer. The WB K+ levels were 2.4 mmol per L and 2.5 mmol per L—these values were significantly discordant from the simultaneous plasma K+ measurements of 5.6 and 7.1 mmol per L (Table 1), and consistent with pseudohyperkalemia. After additional investigation within the laboratory, it was discovered that the initial confirmatory K+ test on the ABL90 FLEX blood gas instrument was run on a plasma specimen, rather than an uncentrifuged WB specimen. Therefore, given the discrepancy in K+ values between uncentrifuged WB and centrifuged plasma, it was concluded that centrifugation likely caused disruption of the CLL cells leading to pseudohyperkalemia. Table 1. Measurements of K+ in the Patient, a 55-Year-Old Woman Time Test Specimen Type Analyzer Result Reference Range Day 1 WBC WB XE-2100a 277.6/L 4–11 × 10^9/L K+ plasma VITROS 5600b 9.9 mmol/L 3.4–5.3 mmol/L K+ plasma ABL90 FLEXc 9.3 mmol/L 3.4–5.3 mmol/L Day 2 (After Dialysis) K+ plasma VITROS 5600 5.6 mmol/L 3.4–5.3 mmol/L K+ WB ABL90 FLEX 2.4 mmol/L 3.4–5.3 mmol/L Day 3 K+ plasma VITROS 5600 7.1 mmol/L 3.4–5.3 mmol/L K+ WB ABL90 FLEX 2.5 mmol/L 3.4–5.3 mmol/L Time Test Specimen Type Analyzer Result Reference Range Day 1 WBC WB XE-2100a 277.6/L 4–11 × 10^9/L K+ plasma VITROS 5600b 9.9 mmol/L 3.4–5.3 mmol/L K+ plasma ABL90 FLEXc 9.3 mmol/L 3.4–5.3 mmol/L Day 2 (After Dialysis) K+ plasma VITROS 5600 5.6 mmol/L 3.4–5.3 mmol/L K+ WB ABL90 FLEX 2.4 mmol/L 3.4–5.3 mmol/L Day 3 K+ plasma VITROS 5600 7.1 mmol/L 3.4–5.3 mmol/L K+ WB ABL90 FLEX 2.5 mmol/L 3.4–5.3 mmol/L K+, potassium; WBC, white blood cells; WB, whole blood. aManufactured by Sysmex Corporation. bManufactured by Ortho Clinical Diagnostics. cManufactured by Radiometer America. View Large Table 1. Measurements of K+ in the Patient, a 55-Year-Old Woman Time Test Specimen Type Analyzer Result Reference Range Day 1 WBC WB XE-2100a 277.6/L 4–11 × 10^9/L K+ plasma VITROS 5600b 9.9 mmol/L 3.4–5.3 mmol/L K+ plasma ABL90 FLEXc 9.3 mmol/L 3.4–5.3 mmol/L Day 2 (After Dialysis) K+ plasma VITROS 5600 5.6 mmol/L 3.4–5.3 mmol/L K+ WB ABL90 FLEX 2.4 mmol/L 3.4–5.3 mmol/L Day 3 K+ plasma VITROS 5600 7.1 mmol/L 3.4–5.3 mmol/L K+ WB ABL90 FLEX 2.5 mmol/L 3.4–5.3 mmol/L Time Test Specimen Type Analyzer Result Reference Range Day 1 WBC WB XE-2100a 277.6/L 4–11 × 10^9/L K+ plasma VITROS 5600b 9.9 mmol/L 3.4–5.3 mmol/L K+ plasma ABL90 FLEXc 9.3 mmol/L 3.4–5.3 mmol/L Day 2 (After Dialysis) K+ plasma VITROS 5600 5.6 mmol/L 3.4–5.3 mmol/L K+ WB ABL90 FLEX 2.4 mmol/L 3.4–5.3 mmol/L Day 3 K+ plasma VITROS 5600 7.1 mmol/L 3.4–5.3 mmol/L K+ WB ABL90 FLEX 2.5 mmol/L 3.4–5.3 mmol/L K+, potassium; WBC, white blood cells; WB, whole blood. aManufactured by Sysmex Corporation. bManufactured by Ortho Clinical Diagnostics. cManufactured by Radiometer America. View Large Patient Follow-Up Although the patient underwent unnecessary dialysis with catheter placement, she did not experience any significant harm from this misdiagnosis. Given the documented susceptibility of patient specimens to centrifugation, the clinical team and laboratory put a plan in place to measure all future K+ levels in WB on the ABL90 FLEX blood gas analyzer to avoid breakage of cells via centrifugation. Also, according to this plan, all future specimens will be hand-delivered to the laboratory to avoid any potential for disruption of cells in the pneumatic tube system, although there was no evidence that disruption of cells was a contributing factor in this case. The patient was subsequently started on chemotherapy for CLL and died 3 months later. The patient had no significant ECG findings despite that her K+ levels were higher than 9 mmol per L; in retrospect, this information could have been a clue that pseudohyperkalemia was the etiology. However, the similar results on the main chemistry analyzer (VITROS 5600) and ABL90 FLEX blood gas analyzer at presentation led the clinical team to discount the possibility of pseudohyperkalemia because the results were concordantly high. This finding highlights the important need for close communication between the laboratory and clinical care team—earlier discovery that both specimens were plasma could have avoided the unnecessary dialysis procedures. This case serves as a strong reminder that in patients with extremely elevated WBC counts or other cell counts, pseudohyperkalemia should be seriously considered as a potential cause for elevated K+ levels and actively ruled out to prevent unneeded K+-lowering therapies. Abbreviations CLL chronic lymphocytic leukemia OSH outside hospital WBC white blood cell TLS tumor lysis syndrome LDH lactate dehydrogenase RI reference interval ECG electrocardiogram EDTA ethylenediaminetetraacetic acid MICU medical intensive care unit IHD intermittent hemodialysis CRRT continuous renal replacement therapy WB whole blood References 1. Montague BT , Ouellette JR , Buller GK . Retrospective review of the frequency of ECG changes in hyperkalemia . Clin J Am Soc Nephrol . 2008 ; 3 ( 2 ): 324 – 330 . 2. Martinez-Vea A , Bardají A , Garcia C , Oliver JA . Severe hyperkalemia with minimal electrocardiographic manifestations: a report of seven cases . J Electrocardiol . 1999 ; 32 ( 1 ): 45 – 49 . 3. Lee HK , Brough TJ , Curtis MB , Polito FA , Yeo KT . Pseudohyperkalemia–is serum or whole blood a better specimen type than plasma ? Clin Chim Acta . 2008 ; 396 ( 1-2 ): 95 – 96 . 4. Abraham B , Fakhar I , Tikaria A , et al. Reverse pseudohyperkalemia in a leukemic patient . Clin Chem . 2008 ; 54 ( 2 ): 449 – 451 . 5. Sevastos N , Theodossiades G , Efstathiou S , Papatheodoridis GV , Manesis E , Archimandritis AJ . Pseudohyperkalemia in serum: the phenomenon and its clinical magnitude . J Lab Clin Med . 2006 ; 147 ( 3 ): 139 – 144 . 6. Handy BC , Shen Y . Evaluation of potassium values in a cancer patient population . Lab Med . 2005 ; 36 : 95 – 97 . © American Society for Clinical Pathology 2018. All rights reserved. For permissions, please e-mail: email@example.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
Laboratory Medicine – Oxford University Press
Published: Mar 28, 2018
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