ISSN: 1040-8363 (print), 1549-781X (electronic) Crit Rev Clin Lab Sci, Early Online: 1–11 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/10408363.2014.966898


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Pseudohyperkalemia: A new twist on an old phenomenon Qing H. Meng and Elizabeth A. Wagar Department of Laboratory Medicine, MD Anderson Cancer Center, The University of Texas, Houston, TX, USA



Severe hyperkalemia is a potentially life-threatening condition requiring immediate medical intervention. Pseudohyperkalemia can be misleading and result in incorrect interpretation and inappropriate patient management. Immediate recognition and appropriate interpretation of pseudohyperkalemia, on the other hand, prevents misdiagnosis and unnecessary intervention. Pseudohyperkalemia is induced by hemolysis and excessive leakage of potassium from cells during or after blood collection. It has been increasingly seen in many hematological disorders such as leukocytosis and thrombocytosis. Reverse pseudohyperkalemia has recently been reported in leukemic patients in whom the plasma potassium levels are greater than the serum potassium levels because of heparin-induced cell membrane damage. Although pseudohyperkalemia has long been recognized and understood, it continues to be misinterpreted. To improve patient care, an algorithm for investigation of pseudohyperkalemia and preventive measures should be established and implemented in the clinical laboratory.

Hyperkalemia, potassium, pseudohyperkalemia, reverse pseudohyperkalemia History Received 6 August 2014 Revised 10 September 2014 Accepted 15 September 2014 Published online 15 October 2014

Abbreviations: ECG: electrocardiogram; ISE: ion-selective electrode; K2-EDTA or K-EDTA: potassium ethylenediaminetetraacetic acid; LDH: lactate dehydrogenase; POCT: point-of-care testing; RBC: red blood cells; WBC: white blood cells

Introduction Severe hyperkalemia is a dangerous and life-threatening condition requiring immediate medical intervention. Pseudohyperkalemia, the most common pre-analytical error1, is defined as a rise in the potassium concentration in serum that occurs in vitro because of excessive leakage of potassium from cells while blood is drawn, or afterward, in the absence of clinical evidence of electrolyte imbalance2–5. It can be misinterpreted as hyperkalemia and result in inappropriate patient management. Pseudohyperkalemia has been extensively reported and discussed in the literature2–4,6–9. It is usually induced by excessive tourniquet time or fist clenching during phlebotomy, by hemolysis due to mechanical stress during venipuncture, or during transportation10. It has been increasingly seen in hematological disorders such as leukocytosis and thrombocytosis. Reverse pseudohyperkalemia has recently Referees Dr. Michael P Cornes, Department of Clinical Chemistry, New Cross Hospital, Wolverhampton, West Midlands, UK; Dr. Hong Kee Lee, Assistant Director, Clinical Chemistry, Dartmouth-Hitchcock Medical Center, Lebanon, NH USA; Mr. Trefor Higgins, Director of Clinical Chemistry, DynaLIFEDx, Edmonton, AB, Canada Address for correspondence: Dr. Qing H. Meng, Department of Laboratory Medicine, MD Anderson Cancer Center, The University of Texas, 1515 Holcombe Blvd, Houston, TX 77030-4009, USA. E-mail: [email protected]

been reported in leukemic patients in whom the plasma potassium level is greater than the serum potassium level because of heparin-induced cell membrane damage9. It has been shown that individuals with ‘‘leakier’’ cell membranes can have pseudohyperkalemia, and their blood must be separated immediately to avoid this11. Immediate recognition and appropriate interpretation of pseudohyperkalemia prevents misdiagnosis and unnecessary intervention. Although the phenomenon of pseudohyperkalemia has long been recognized and understood, it continues to be misinterpreted and improperly managed in the clinic. We hope to bring this very common problem to the attention of clinicians and clinical laboratory professionals to raise awareness and promote prevention. In this review, we take an in-depth look at this very practical and everyday but persistent problem. We begin with a brief review of true hyperkalemia and then focus on the common and uncommon causes of pseudohyperkalemia. The recently described ‘‘reverse pseudohyperkalemia’’ is discussed in detail. Finally, an algorithm for approaching pseudohyperkalemia, and a policy on differential diagnosis, prevention and investigation of pseudohyperkalemia, are provided.

Potassium metabolism and hyperkalemia The total body potassium concentration in an adult male is approximately 50 mmol/kg of body weight. Under

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physiological conditions, approximately 98% of the total body potassium is present in the intracellular fluid and only 2% is in the extracellular fluid. This translates to an intracellular potassium concentration of 150–160 mmol/L and an extracellular potassium concentration of 3.5–5.0 mmol/L. Most of the intracellular potassium is distributed in muscle; other sites are bone, liver and red blood cells (RBC). In tissue cells, the average potassium concentration is about 150 mmol/L12,13. In RBC, the potassium concentration is about 105 mmol/L, which is about 25 times its plasma concentration. The potassium concentration in white blood cells (WBC) is about 120 mmol/L and in platelets, 100 mmol/L. The high intracellular potassium concentration is maintained by the Na+–K+ ATPase pump with slow diffusion of potassium outward via the cell membrane. The plasma potassium concentration is a reliable indicator of total potassium stores and homeostasis. The potassium gradient is critically important for many physiological processes, including maintenance of cellular membrane potential, homeostasis of cell volume and transmission of action potentials in nerve cells. The concentrations of potassium in the various fluid compartments are influenced by a number of factors, including potassium transportation and redistribution regulated by hormones and acid–base status. Potassium is obtained mainly through dietary intake. The kidney excretes approximately 95% of the daily intake to maintain body potassium homeostasis. Abnormally high or low plasma potassium concentrations can be critical and potentially lifethreatening, requiring immediate medical action and intervention. Hyperkalemia develops in clinical conditions associated with excessive intake, tissue breakdown, excessive release from cells or ineffective elimination of potassium12. A full list of clinical conditions known to cause hyperkalemia is presented in Table 1. Ineffective elimination can be due to reduced glomerular filtration and renal tubular excretion or hormone deficiency (e.g. aldosterone). In extensive muscle injury, tumor lysis syndrome, cell damage, massive hemolysis or acidosis, intracellular potassium may be released and shifted into extracellular fluid. Medical therapy can cause iatrogenic hyperkalemia through redistribution of potassium14,15. In rare cases, hyperkalemia is caused by increased intake or medical infusion in patients with pre-existing renal insufficiency16. A rare type of true hyperkalemia induced by heparin in patients undergoing long-term hemodialysis has been reported17. That study found that patients who received unfractionated heparin had higher plasma potassium levels than patients who received low-molecular-weight heparin during dialysis. The investigators speculated that this was attributable to lower aldosterone levels caused by unfractionated heparin. As administration of low-molecular-weight heparin has become the standard of practice, this cause of hyperkalemia has become extremely rare. In some cases, the actual in vivo blood potassium may be normal, but the measured serum/plasma potassium is elevated because of hemolysis or leakage of potassium from blood cells. This is called pseudohyperkalemia. The causes and investigation of pseudohyperkalemia are discussed later in this review.

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Table 1. Causes of hyperkalemia. Decreased elimination  Renal insufficiency: Decreased glomerular or renal tubular function, sickle cell disease, systemic lupus erythematosis.  Medication that interferes with urinary excretion: ACE inhibitors and angiotensin receptor blockers, potassium-sparing diuretics (amiloride, spironolactone, and triamterene), penicillin, cyclosporin A, tacrolimus.  Mineralocorticoid deficiency or resistance: Addison disease, aldosterone deficiency, congenital adrenal hyperplasia, type IV renal tubular acidosis (resistance to aldosterone).  Gordon syndrome: a type of pseudohypoaldosteronism with hypertension and hyperkalemia. Excessive release and redistribution  Rhabdomyolysis, burns, and tissue necrosis, including tumor lysis syndrome, massive blood transfusion or hemolysis, massive tissue hypoxia.  Shifts out of cells caused by acidosis, dehydration, insulin deficiency, beta-blocker therapy, digoxin overdose, the paralyzing agent succinylchlorine, epsilon-aminocaproic acid, hyperglycemia. Excessive intake  Excess intake via salt substitutes, potassium-containing dietary supplements or potassium chloride (KCl) infusion. Hyperkalemia by potassium intake would be seen only with large infusions of KCl or oral doses of several hundred mmol of KCl.

Diagnosis of hyperkalemia Hyperkalemia is defined as a plasma potassium level greater than 5.0 mmol/L. A plasma potassium level between 5.0 and 6.0 mmol/L is considered mild hyperkalemia, whereas potassium levels between 6.1 and 7.0 mmol/L or greater than 7.0 mmol/L are considered moderate hyperkalemia and severe hyperkalemia, respectively. Severe hyperkalemia is lifethreatening and requires immediate medical action. The clinical symptoms of hyperkalemia include mental confusion, weakness, tingling, flaccid paralysis of the extremities and weakness of the respiratory muscles18. However, clinical symptoms are not reliable and helpful for making the diagnosis of hyperkalemia. The plasma potassium level and typical changes on an electrocardiogram (ECG) are the most important diagnostic criteria. Typical ECG changes in hyperkalemia include bradycardia, reduced size of P wave, peaked T wave, prolonged PR interval and in severe cases, widening of the QRS complex18.

Causes of pseudohyperkalemia Pseudohyperkalemia is a laboratory artifact rather than a biological abnormality5. It is the most prominent factitious occurrence in the pre-analytical phase. This phenomenon was first reported by Hartmann and Mellinkoff in 195519. Traditionally, pseudohyperkalemia is defined as and characterized by marked elevation of serum potassium levels (40.4 mmol/L) as compared to the normal plasma potassium concentration in the absence of clinical evidence of electrolyte imbalance. The elevation of potassium is due to the release of potassium from cells and platelets during the processes of specimen collection and clot formation. Pseudohyperkalemia can be caused by a number of factors and variables during and after blood collection and by medical conditions (Table 2). These factors include, but are not limited to, collection technique, such as excessive tourniquet time or fist clenching during phlebotomy;


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Table 2. Factors resulting in spuriously high potassium levels. Hemolysis Leaving tourniquet on for extended time Excessive fist clenching Povidone-iodine contamination EDTA contamination via inappropriate order of draw Drawing above intravenous infusion site Benzalkonium heparin contamination (used to coat catheters) Vigorous mixing of tube contents Inappropriate collection technique (traumatic venipuncture, small-gauge needle) Chilling the specimen Re-centrifugation Transport through pneumatic tube system Delayed separation of blood cells from serum/plasma Myeloproliferative disorders and thrombocytosis Familial pseudohyperkalemia

contamination by a potassium-containing substance (e.g. potassium ethylenediaminetetraacetic acid [K2-EDTA]); mechanical trauma during venipuncture (e.g. excessive vacuum during the blood draw and use of a fine-gauge needle) and specimen transport10,13,20–24. The time delay between specimen collection and centrifugation can also give rise to high potassium results for patients with marked leukocytosis25–28. Clinical conditions such as leukocytosis and thrombocytosis are often associated with false elevation of potassium level. Hemolysis and pseudohyperkalemia Hemolysis is defined as the release of cellular components of RBCs and other blood cells into the extracellular space of the blood29. Since the intracellular potassium concentration in blood cells, especially RBC, is much higher than that in extracellular fluid (more than 20-fold), hemolysis can readily lead to release of potassium from RBCs and cause significant elevation of the potassium concentration in serum/plasma. Indeed, hemolysis during or after phlebotomy is the commonest cause of pseudohyperkalemia30. The increase in potassium value is correlated with the degree of hemolysis in adults and neonates30. Several studies have shown that hemolyzed serum or plasma containing 1 g/L of hemoglobin will cause an increase of 0.27–0.33 mmol/L potassium31–34. Mansour et al.35 showed that plasma hemoglobin concentration is correlated with increments in potassium concentration. We also observed that increased hemolysis (which increases hemoglobin concentration) increases plasma potassium level36. It is generally known that the potassium concentration in serum is slightly higher than that in plasma because of the release of potassium from platelets during clotting. The mean difference between serum and plasma potassium levels is 0.36 ± 0.18 mmol/L. There is a significant correlation between platelet count and the difference between serum and plasma potassium values4. Dimeski et al.37 found that increased plasma potassium concentration is correlated not only with the hemolytic index of RBC but also with leukocyte count and leukocyte lysis. There is evidence that capillary blood samples have higher potassium concentrations than venous samples; this could be due to greater leakage of potassium from erythrocytes in capillary samples. These


results are especially important considering the increasing use of whole blood point-of-care testing (POCT) analyzers, where the hemolysis index is often not determined38. A number of factors have been implicated in the etiology of hemolysis39. Factors such as collection techniques, devices and errors in specimen handling can cause hemolysis and thus pseudohyperkalemia. Some of these are discussed in the following sections. Fist clenching Don et al. demonstrated that fist clenching for 1 min during phlebotomy increased potassium levels by as much as 1.0 mmol/L. Handgrip exercise raised the plasma potassium concentration to an even greater degree (by 1.4 mmol/L)10. Nevertheless, there was no change in plasma potassium concentration in the samples obtained from the contralateral arm. The elevation in potassium concentration that results from fist clenching is due to the local release of potassium during contraction of forearm muscles. Repeated fist clenching induced elevation in potassium concentration, while cessation of fist clenching reduced the falsely elevated serum potassium level40. Baer et al. reported a study in which volunteers had a tourniquet placed on both their right and left arms. The right hand was relaxed while at the same time the left hand pumped by opening and closing the hand for 15 s, continuing as blood was drawn from both arms. Analysis of heparinized plasma from these peripheral blood samples showed that the potassium concentration in the left (pumping) arm was 1.04 mmol/L higher than in the right arm34. Fist clenching during phlebotomy leads to a temporary increase in the local potassium concentration that could mislead clinicians about the true potassium concentration in their patients. Application of tourniquet Although Don et al.10 did not observe a significant change of plasma potassium concentration after application of a tourniquet for 3 min, another study by Saleem et al.41 showed that application of a tourniquet for more than 1 min caused 20% of the samples to become hemolyzed, while application of the tourniquet for less than 1 min was associated with a hemolysis rate of only 1.3%. In another study, a significant increase of plasma potassium concentration, varying from 0.05 to 0.5 mmol/L, was observed with application of a tourniquet42. A combination of prolonged and excessively tight tourniquet use and repeated fist clenching during venipuncture may increase the frequency of pseudohyperkalemia43. Prolonged tourniquet time of more than 1 min is associated with a significantly increased risk of hemolysis. Tourniquet time is critical in inducing hemolysis and should be minimized to avoid this effect. Specimen contamination Specimens may be contaminated by introduction of potassium through drawing specimens from an i.v. line, by contamination from a previous draw that used a K-EDTA tube, or by introduction of other substances that interfere with the ionselective-electrode (ISE) measurement of the potassium ion. In vitro K-EDTA contamination is a common but often

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unrecognized cause of spurious hyperkalemia. Several studies have reported this occurrence44–47, although other studies found that incorrect order of draw did not have a significant impact on potassium values48,49. Our laboratory found a plasma potassium level of 9.4 mmol/L in a 10-year-old boy whose condition was stable with no remarkable symptoms. Interestingly, his total calcium concentration was 1.36 mmol/ L (5.44 mg/dL) and ionized calcium 0.13 mmol/L (0.52 mg/ dL). A second specimen had a potassium concentration of 4.5 mmol/L, total calcium 2.30 mmol/L (9.2 mg/dL) and ionized calcium 1.18 mmol/L (4.72 mg/dL). After learning that the first specimen had been collected after a draw into a K2-EDTA tube, we ordered a second collection without a prior draw into a K2-EDTA tube, and the potassium was normal. Thus, this was a case of factitious hyperkalemia caused by K-EDTA contamination due to inappropriate order of draw50. K-EDTA is an anticoagulant widely used for specimen collection for laboratory analysis. In vitro K-EDTA contamination may occur through backflow when blood is collected into K-EDTA tubes before other sample tubes, syringe needle contamination when blood is delivered into a K-EDTA tube before other tubes or direct transfer of blood from a K-EDTA tube to other tubes. This is not an uncommon occurrence in our practice. If a blood sample shows unexpected marked hyperkalemia and hypocalcemia, K-EDTA contamination should be strongly suspected and investigated. EDTA contamination can be differentiated by measurements of analytes affected by EDTA, such as calcium, magnesium, iron and alkaline phosphatase, or by direct measurement of EDTA44,45,51,52. The recommended order for collecting peripheral blood specimens is as follows: blood cultures, sodium citrate tubes, serum tubes, SST with gel, heparin tubes, heparin gel tubes, EDTA tubes and finally sodium fluoride–potassium oxalate tubes53. If the recommended order of draw during phlebotomy is not followed, carryover and back flow of K-EDTA or potassium oxalate can cause false elevation of the measured potassium concentration. Continuing education and following standard operating procedures and the recommended order of draw should minimize K-EDTA contamination and thus errors in potassium values. Drawing blood above an intravenous infusion site Drawing blood above an intravenous infusion site can directly contaminate the blood specimen and can increase the potassium level if the infusion solution contains a substantial concentration of potassium. To prevent contamination by the infusion solution, blood should be drawn from the other arm. Blood may be drawn below an intravenous infusion site, but it is not recommended. Potassium-containing infusion fluids are common contaminants. Povidone-iodine Povidone-iodine (Betadine), a broad-spectrum antiseptic for topical application (scrubs, spray, swabs, pads, etc.), can occasionally cause an erroneous increase in plasma potassium concentration. Van Steirteghem et al.54 reported a 1 mmol/L increase in potassium in a specimen drawn by skin-puncture

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of skin treated with povidone-iodine. The mechanism of this effect is unknown. To avoid distorting results, povidoneiodine should be completely removed from the skin using 70% alcohol prior to venipuncture, or the first few milliliters of blood should be discarded. Hand disinfectants have been shown to significantly elevate the potassium concentration, especially in whole blood specimens on POCT analyzers with a direct ISE technique55. Substance interference Benzalkonium heparin-bonded catheters are commonly used as intravascular-access devices in critical care areas. Blood sampling through a benzalkonium heparin-coated catheter and measurement with certain ISEs was recently shown to raise serum sodium and potassium levels. Studies have shown that benzalkonium heparin falsely increases potassium measurements when instruments with indirect ISEs are used to measure potassium concentration in diluted serum56,57. The false elevation of potassium concentration is due to benzalkonium heparin interference with the ISE measurement. After the catheter is washed with 10 mL of blood, there is no interference with indirect ISE potassium assay. If the laboratory uses an ISE system that measures potassium from undiluted plasma or whole blood, there is no interference. Another case of spurious hyperkalemia was reported to be caused by infusion of epsilon-aminocaproic acid during coronary bypass in a dialysis patient, though the cause was not clear58. We found that high doses of vitamin C could interfere with potassium measurement by ISE on a Beckman Coulter analyzer, causing false elevation of potassium concentration59,60. Mechanical factors Traumatic venipuncture or probing; inappropriate needle diameter; excessive force with syringe draws during either aspiration or transfer; or increased turbulence due to diameter mismatch of catheter, tube adapter device, or needle can all result in hemolysis and pseudohyperkalemia1,34. Inverting the tube too vigorously to mix the blood with anticoagulant also causes turbulence. Mechanical force during specimen collection and processing, such as vigorous mixing, excessive centrifugal force, prolonged fixed angle centrifugation or re-centrifugation of gel separator tubes, should also be considered as causes of spurious hyperkalemia1,34. Using a syringe with excessive suction rather than an evacuated tube for drawing blood is the most common cause of hemolysis34. Nineteen percent of syringe-collected specimens were hemolyzed in one study, as compared to 3% of specimens that were collected in evacuated tubes1. Forcibly squirting the blood from a syringe into an evacuated tube causes shear forces on the RBC membrane, resulting in rupture of the cells39; evacuated tubes should be allowed to fill slowly from the vacuum in the tube, without pressing on the syringe plunger. Drawing the blood through a small needle or catheter also ruptures RBCs as they pass through. The hemolysis rate is inversely proportional to the diameter of the needle or catheter61,62. Hemolysis of blood samples was significantly more common in samples obtained via an


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intravenous catheter than in samples obtained through venipuncture with evacuated tubes, because the greater force needed for an intravenous catheter draw can rupture RBCs. However, drawing blood into Becton Dickinson vacuum tubes can still cause pseudohyperkalemia for patients with leukemia63.

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Delayed separation of serum/plasma from blood cells A minimum of 30 min is needed to form a blood clot for serum preparation64. The maximum recommended time between collection and separation of clot and serum is 2 h53. Allowing the serum to sit on the clot for too long can significantly alter potassium values. Pseudohyperkalemia (7.3 mmol/L) in a 35-year-old man was reported to be due to delayed specimen processing65. A repeat measurement gave a potassium concentration of 7.8 mmol/L. The patient was asymptomatic with normal blood cell counts and ECG. A third measurement, this time a venous blood sample in a lithium heparin tube analyzed on a blood gas machine immediately after collection, gave a potassium value of 3.1 mmol/L. However, the potassium level rose steadily when the sample was left at room temperature for a few hours65. Serum potassium concentration remains stable for 3 h, and thus it is recommended that the serum should be separated from the clot within 3 h for potassium measurement64,65. The Clinical Laboratory Standards Institute recommends that serum or plasma be physically separated from contact with cells as soon as possible and that the maximum contact time is 2 h53. Our observations are in line with this recommendation, as we observed significant change of potassium levels after 2 h at room temperature without separation. Delayed processing for any reason can result in factitious elevation of potassium concentration in serum or plasma. Storage and temperature A very early study showed that if a whole blood specimen is stored at 25  C, serum potassium concentration increases 0.2 mmol/L in 1.5 h64,66. This increase is even greater (by 2 mmol/L) after 5 h stored at 4  C67. This is mainly due to inhibition of glycolysis of RBCs and the Na+–K+ ATPase pump by cold temperatures, resulting in leakage of potassium from cells and inhibition of the potassium shift into cells. Smellie reported that a 72-year-old man had an initial plasma potassium concentration of 7.2 mmol/L on a blood sample that was stored at 3  C during transportation. A repeat measurement was 4.8 mmol/L68. Storage at refrigerated temperatures causes efflux of potassium out of the cells and thus high extracellular potassium concentrations. Therefore, specimens for potassium analysis should be stored at ambient temperatures prior to centrifugation and separation. At elevated temperatures (32  C), the change is bidirectional, with a decrease of potassium concentration due to glycolysis, followed by an increase due to potassium diffusion out of cells64,69,70. The latter phenomenon is probably related to increased usage and exhaustion of glucose that generates ATP for the Na+–K+ ATPase pump. Maintaining blood sample temperature a few degrees above 20  C will minimize the risk of spurious serum potassium concentration measurements71.


The recommended temperature for specimen storage prior to testing is 15–25  C1. Elevations in potassium concentration are observed more frequently in samples from doctors’ offices than in those collected in inpatient or laboratory settings; this difference is attributed to the temperature changes during transport in winter, a phenomenon called ‘‘seasonal pseudohyperkalemia’’72,73. Maintaining proper blood sample temperature during transport in extremely hot or cold weather can be problematic. All clinical laboratories should be aware of the impact of temperature on potassium concentration results and the potential for errors. Improper centrifugation and re-centrifugation Hira et al.74 reported several cases of hyperkalemia as an initial finding. As part of their investigation, they collected blood samples into gel-separator tubes and subjected them to centrifugation, but the serum was not removed. The specimens were transported to the laboratory, where they were stored and subjected to centrifugation again. The longer the samples were stored, the higher were the potassium values measured after re-centrifugation. The investigators concluded that re-centrifugation of blood specimens in gel-separator tubes was the cause of the pseudohyperkalemia. They determined that after centrifugation for 5 min at 3000 rpm there were no cells in the serum layer. As time passed, a new serum layer that was rich in potassium developed in the blood-cell layer. When the sample was subjected to centrifugation again, this potassium-rich serum moved to the original serum layer, thus raising the potassium concentration. This observation was confirmed in their subsequent study75. Re-centrifugation causes potassium-rich RBCs to release potassium into serum or plasma. As a result, the specimen will likely render an elevated potassium result75. They concluded that blood samples stored in serum gel-separator tubes can prevent potassium leakage from the cell layer to the serum layer. Re-centrifugation should be avoided for specimens to be tested for potassium75. Pneumatic tube systems Specimen transport through pneumatic tube systems is a common practice of laboratories. Improper specimen handling can disrupt specimen integrity and cause leakage of intracellular components into plasma. Kellerman et al.21 described pseudohyperkalemia caused by mechanical disruption of WBCs from a leukemic patient during pneumatic tube transport. Similarly, Dickinson et al.76 observed pseudohyperkalemia associated with leukemic cell lysis during pneumatic tube transport of blood samples. This false elevation was not caused by hemolysis but was likely related to lysis of the fragile leukemic WBCs during transport, which was exacerbated by traumatic turbulence, vibration and physical shear force22,76,77. The effects of pneumatic tube transport on potassium concentrations can vary by sample type. A recent study showed a higher frequency of potassium concentration elevation in samples collected in PST tubes than in SST tubes. They concluded that the spurious potassium concentration elevations in PST samples resulted from potassium


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leakage from the cells or separator gel during the transport process78. Laboratories should be particularly cautious in handling samples from leukemia patients due to the high potential for pseudohyperkalemia.

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Myeloproliferative disorders and thrombocytosis We have seen that, as the intracellular potassium concentration is much higher than the serum/plasma potassium concentration, any leakage or release of potassium from cells during specimen collection, handling or processing prior to analysis can lead to potassium concentration elevation. Pseudohyperkalemia is a common finding in myeloproliferative disorders79. This elevation is proportional to the WBC or platelet count. Pseudohyperkalemia was initially observed in patients with thrombocytosis80. Elevation of blood platelet count by 1000  109/L caused an increase of about 0.2 mmol/L in plasma potassium concentration and 0.7 mmol/L in serum potassium4,81. Pseudohyperkalemia was caused by reactive thrombocytosis in an infant with a yolk sac tumor82. This phenomenon can be worsened by co-existing cancer or tumor lysis syndrome83. Pseudohyperkalemia was also observed in patients with Kawasaki disease with a markedly high platelet count. Graber et al.84 found that the incidence of pseudohyperkalemia was 34% in patients with a platelet count over 500  109/L and only 9% if the platelet count was less than 250  109/L, indicating that the serum potassium concentration was directly proportional to the platelet count. Markedly elevated platelet or leukocyte counts have been associated with pseudohyperkalemia in other studies2,26,80,85–91. Severe thrombocytosis and leukocytosis can result in significantly rise of high potassium levels4,85,92. Pseudohyperkalemia has been increasingly seen in many hematological disorders such as leukocytosis and thrombocytosis26,85,93–95. Ho et al.96 reported a patient with marked thrombocytosis and leukocytosis associated with myelofibrosis who was found to have spurious hyperkalemia caused by in vitro cell lysis. Rifkin97 reported two patients with chronic lymphocytic leukemia and extreme leukocytosis with pseudohyperkalemia in both serum and plasma. Chan et al.98 presented a case of pseudohyperkalemia in a patient with chronic lymphocytic leukemia that was the result of WBC lysis during phlebotomy. Similarly, pseudohyperkalemia has also been seen in patients with erythrocytosis99,100. Pseudohyperkalemia was identified in a myelofibrosis patient exhibiting giant platelets and nucleated RBCs101. A common explanation for pseudohyperkalemia in these conditions is the in vitro release of potassium from leukocytes undergoing lysis during the clotting process, but this explains only the high serum potassium levels. Since pseudohyperkalemia is seen quite often in plasma as well, it has been postulated that severe leukocytosis causes higher consumption of metabolic fuels that may lead to impaired Na+–K+ ATPase pump activity, resulting in release of potassium from the high number of WBCs93,102. As already described, the leukocytes in leukemia are abnormally fragile, leading to potassium release when they are exposed to mechanical stress.

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Familial pseudohyperkalemia Familial pseudohyperkalemia, also called the ‘‘leaky red cell syndrome’’, is an inherited condition in which RBCs show a temperature-dependent potassium leakage through the RBC membrane when stored at room temperature. A significant increase in plasma potassium concentration is seen after 2 h at room temperature, with a maximum increase at 4 h. Affected subjects are not anemic and are otherwise asymptomatic. The circulating plasma potassium concentration is normal. The incidence of this condition is unknown, but it is rare11,103. It is an autosomal dominant disorder, a hereditary stomatocytosis. Increased RBC membrane permeability associated with a genetic defect is seen in dehydrated hereditary stomatocytosis and overhydrated hereditary stomatocytosis104. A recent study showed that deficiency of GLUT1 (glucose transporter 1) can cause a RBC membrane defect, and thus induce leaky membranes and pseudohyperkalemia105. Another novel gene mutation has been identified as responsible for familial pseudohyperkalemia106. Miscellaneous causes Using plasma reference ranges to interpret serum values can result in pseudohyperkalemia, as plasma potassium levels are slightly lower than serum potassium levels. Mislabeling of patient samples should be excluded. Crying-associated hyperventilation causing acute respiratory alkalosis can result in a significant hyperkalemic response mediated by enhanced alpha-adrenergic activity. Though the exact cellular mechanism for this phenomenon is not known, animal models suggest a role for alpha receptor-mediated activation of hepatic calcium-dependent potassium channels107. Splenectomy can cause pseudohyperkalemia, as the spleen is a major reservoir for platelets108,109. Splenectomy may worsen pseudohyperkalemia in patients with chronic idiopathic myelofibrosis or thrombocytosis110. In patients with chronic renal failure, pseudohyperkalemia can occur in the presence of a myeloproliferative neoplasm3,100.

Reverse pseudohyperkalemia Traditionally, pseudohyperkalemia has been defined as a rise in serum potassium concentration attributed to the release of potassium from cells and platelets during the processes of specimen collection and clot formation with concurrently normal plasma potassium concentration28,111. A number of cases of reverse pseudohyperkalemia have recently been reported in leukemic patients with leukocytosis in whom the plasma potassium level was greater than the serum potassium level because of heparin-induced cell membrane damage in the setting of hematological malignancy6,7,9,112,113. Reverse pseudohyperkalemia is now defined as a plasma potassium concentration that is falsely high while the serum potassium concentration is normal7–9,114. This phenomenon has been reported in patients with leukemia or lymphoma. We recently encountered a case in which the potassium concentration was highly elevated. Further investigation revealed discrepant potassium concentration results in heparinized plasma and serum9. The patient, an 86-year-old woman with end-stage chronic lymphocytic leukemia, was transferred


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DOI: 10.3109/10408363.2014.966898

from the oncology service to cardiology and then to the intensive care unit for investigation of severe hyperkalemia with arrhythmia. She was given an insulin–glucose infusion to correct the hyperkalemia. The patient’s plasma potassium value was 7.5 mmol/L, and repeat measurement was 7.4 mmol/L. Surprisingly, the potassium in whole blood collected at the same time and measured on blood gas analyzer was 2.8 mmol/L. Contrary to typical ECG changes in hyperkalemia, her ECG revealed prolonged QT, indicating hypokalemia. Due to the inconsistent findings and the presence of leukocytosis, the high potassium concentration was considered to be spurious and eventually a diagnosis of pseudohyperkalemia was made. Instead of treating to lower the potassium level, this patient was given potassium to correct her hypokalemia9. To further investigate the cause of the pseudohyperkalemia in this patient, specimens were collected into different tubes and analyzed. The plasma potassium concentration of a sample collected in a lithium heparin tube was greater than 10.0 mmol/L, higher than the simultaneously measured serum potassium concentration9. The degree of increase in potassium level was directly related to the amount of heparin in the collection tube. Potassium measured from a sample collected by a balanced heparin-coated syringe, which contains about one-third the amount of heparin as a tube, did not cause an increase in the plasma potassium concentration. There was no evidence of hemolysis, suggesting that the source of the potassium was not RBCs. Potassium levels measured on a blood gas analyzer from venous blood collected in a balanced heparin syringe were comparable to serum potassium levels measured on an automated chemistry analyzer9. It is postulated that heparin-induced cell membrane damage and potassium leakage in the setting of hematological malignancy are the main reasons for reverse pseudohyperkalemia6,7,9. High values of potassium and lactate dehydrogenase (LDH) in the absence of hemolysis might indicate in vitro lysis of WBCs. Recently we had another case of reverse pseudohyperkalemia in an 84-year-old woman with chronic lymphocytic leukemia with leukocytosis. Her plasma potassium levels were persistently elevated (410.0 mmol/L). Repeat measurements of potassium on a Vitros Fusion 5.1 showed potassium 410.0 mmol/L in plasma from lithium heparin tubes both with and without gel, whereas serum potassium level was only 3.6 mmol/L. A sample collected into a balanced lithium heparin syringe showed a potassium level of 3.6 mmol/L on blood gas analyzer, while the potassium level was reported to be 11.1 mmol/L in venous blood collected in a lithium heparin tube at the same time. The patient’s potassium level was 3.5 mmol/L as determined by POCT (Chen M, Meng QH, ASCP Case report, Recurrent hyperkalemia in a patient with chronic lymphocytic leukemia). We found good agreement in potassium levels from whole venous blood collected in a lithium heparin balanced syringe and run on a blood gas analyzer, serum run on a chemistry analyzer and capillary blood by POCT. A blood gas analyzer or POCT are preferred for cases in which pseudohyperkalemia is suspected. Both offer advantages such as rapidity, no delay in processing, no centrifugation and minimal mechanical trauma over automated analysis of serum or plasma samples


Table 3. Differential diagnosis of high potassium level. Differential diagnosis Hyperkalemia Pseudohyperkalemia

Serum potassium

Plasma potassium

Elevated Elevated Elevated Normal (falsely) Reverse Normal Elevated pseudohyperkalemia (falsely) Tumor lysis syndrome Elevated Elevated

Other changes ECG change ECG normal ECG normal ECG change Elevated uric acid Elevated phosphorus Decreased calcium

Differential diagnosis of hyperkalemia Hyperkalemia is a common clinical and laboratory phenomenon. On the one hand, many clinical disorders can cause hyperkalemia, which requires immediate medical attention and intervention. On the other hand, pseudohyperkalemia is one of the most common pre-analytical and analytical errors, often leading to misdiagnosis and errors in patient management. Thus, the correct diagnosis must be made in a timely fashion. The characteristic biochemical changes and ECG changes pertinent to the differential diagnosis of high potassium levels are summarized in Table 3. Both hyperkalemia and tissue damage such as that seen in tumor lysis are associated with high potassium levels in both serum and plasma specimens; such levels are often accompanied by abnormal ECG changes. The earliest changes on ECG are peaking and narrowing of T waves, followed by shortening of the QT intervals. As the condition progresses, the ECG shows the absence of P waves and PR prolongation. In severe situations with a potassium concentration greater than 7.0 mmol/L, a junctional escape rhythm, a sine wave pattern with widening of the QRS complex merging with P waves, ventricular fibrillation or asystole may appear. In pseudohyperkalemia, serum potassium levels are high while plasma potassium levels may be normal or relatively low compared to serum potassium levels. The typical ECG changes of hyperkalemia are not present. In reverse pseudohyperkalemia, as it is defined, plasma potassium levels are highly elevated while serum potassium levels may be normal or relatively low. Again, the typical ECG changes of hyperkalemia are not present.

Laboratory investigation of pseudohyperkalemia Pseudohyperkalemia is frequently seen in laboratory and clinical practice. When faced with an elevated potassium level, clinicians have to judge relatively quickly whether this result is an artifact. Immediate recognition and appropriate interpretation of pseudohyperkalemia/reverse pseudohyperkalemia prevents misdiagnosis and unnecessary intervention. Communication between clinicians and laboratory professionals is critical when laboratory results are discrepant or discordant with the clinical presentation115. The clinician needs to make the appropriate interpretation of the potassium results in conjunction with the patient’s clinical findings and ECG changes, so that the condition can be managed appropriately and in a timely fashion.


Q. H. Meng & E. A. Wagar

Crit Rev Clin Lab Sci, Early Online: 1–11

Potassium > 6.5 mmol/L (Adult) > 6.0 mmol/L (Pediatric) (assuming QC & calibration OK)

Hemolysis Yes

Follow recollection procedure and add comment


Does result match patient history? Does patient have a known clinical disease (↑urea/creatinine, medication)? Critical Reviews in Clinical Laboratory Sciences Downloaded from by Nyu Medical Center on 10/18/14 For personal use only.

Look for another acceptable specimen from same draw or add comment to report if slightly hemolyzed and no other sample


Release result and critical value reporting


Collection/transportation • >4 h contact with cells • Drawn from a line (IV fluid) • Incorrect anticoagulant

Investigation on cause of pseudohyperkalemia. Follow “Criteria and Procedure for Rejection of Specimens”

Leukocytosis: WBC>150 x 109/L Thrombocytosis: Platelet >800 x 109/L Pseudohyperkalemia?

Notify the MD/RN that results are questionable Collect venous blood in balanced heparin syringe and run on blood gas analyzer, or run serum potassium

Figure 1. Algorithm for investigation of hyperkalemia.

We have developed a policy and an algorithm for the investigation of hyperkalemia (Figure 1). A step-by-step investigation should be adopted in the laboratory. Furthermore, laboratory procedures should be followed to minimize hemolysis by avoiding practices such as fist clenching, prolonged application of the tourniquet and stress force during venipuncture. Other practices that can avoid or minimize hemolysis include careful transport of specimens, prompt centrifugation and analysis within 30 min, if possible. Pseudohyperkalemia should be suspected in any patient with marked leukocytosis or thrombocytosis and a high potassium level. Serum and plasma potassium levels should be measured simultaneously for comparison. If reverse pseudohyperkalemia is suspected for a heparinized plasma specimen from a patient with leukocytosis or thrombocytosis, a whole blood venous specimen collected in a balanced heparin syringe should be analyzed on the blood gas analyzer, and analysis of serum potassium is also recommended. Potassium measurement by POCT also may be helpful in such cases as it avoids delay in processing and lysis of cells. An ECG can be helpful in differentiating pseudohyperkalemia/reverse pseudohyperkalemia from true hyperkalemia. The absence of typical ECG changes is usually helpful in identifying pseudohyperkalemia. High plasma LDH levels may indicate hemolysis or rupture of fragile WBCs. Ideally, specimens for patients with hematological malignancies should be delivered in person to minimize hemolysis.

While the importance of pseudohyperkalemia must be recognized, pseudonormokalemia may also be easily ignored in clinical and laboratory practice. In cases of hypokalemia, the same factors that cause pseudohyperkalemia can mask hypokalemia as ‘‘normal-kalemia’’ by falsely raising potassium levels to the reference interval. This is even more dangerous than hyperkalemia as it can be easily ignored and interpreted as normal. Such cases should receive the same degree of awareness and investigation as pseudohyperkalemia. If a potassium level from a whole blood sample analyzed by a blood gas analyzer is high (or sometimes pseudonormal), pseudohyperkalemia due to hemolysis needs be ruled out, as the hemolysis index is usually not determined. Similarly, capillary blood can yield higher potassium levels on POCT analyzers, where the hemolysis index is often not determined. These cases are often very difficult to recognize and can be easily ignored.

Summary and conclusions A number of factors, either alone or in combination, can cause a spurious elevation of measured potassium or mask hypokalemia so it appears as pseudonormokalemia. Efforts must be made to minimize these factors as potassium is predominantly intracellular and small shifts can cause large changes in the measured values. Clinicians should have a high degree of suspicion for pseudohyperkalemia when two


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consecutive potassium results are discordant or when the clinical picture does not suggest true hyperkalemia. If pseudohyperkalemia is suspected, the laboratory should be consulted so that appropriate samples can be submitted and an investigation conducted. In the laboratory setting, the following measures should be taken to investigate and prevent pseudohyperkalemia: (1) rule out specimen hemolysis by visual inspection or the use of indices on all samples; (2) minimize excessive trauma to the sample to avoid hemolysis; (3) carry out the centrifugation and assay promptly; (4) if the potassium concentration in serum samples is high, repeat the measurement of the potassium level in both plasma and serum specimens for comparison; (5) consider pseudohyperkalemia in any patient with marked leukocytosis or thrombocytosis; (6) in the presence of pseudohyperkalemia in a heparinized plasma specimen from a patient with leukocytosis, determine the potassium level in a whole blood specimen collected in a balanced heparin syringe on a blood gas analyzer; and (7) deliver the specimen in person if possible to minimize hemolysis induced by pneumatic tube transport. Finally, while recognizing the importance of pseudohyperkalemia, maintain an awareness of pseudonormokalemia, which is easily ignored in clinical and laboratory practice. Such cases should receive the same degree of investigation as those with suspected pseudohyperkalemia. In the case of reverse pseudohyperkalemia, analysis of samples by blood gas analyzer or POCT is recommended, but caution must be paid to potential hemolysis, as the hemolysis index is not detected on these instruments.

12. 13. 14. 15. 16. 17.


19. 20. 21. 22.

23. 24.

Declaration of interest Authors have no declarations of interest to report.

25. 26.

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Pseudohyperkalemia: A new twist on an old phenomenon.

Severe hyperkalemia is a potentially life-threatening condition requiring immediate medical intervention. Pseudohyperkalemia can be misleading and res...
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