Clinical and electrophysiological consequences of hyperkalemia
Hyperkalemia is a common electrolyte disorder, especially among patients with chronic kidney disease (CKD), diabetes mellitus, or heart failure.1–3 Hyperkalemia represents one of the most important acute electrolyte abnormalities, due to its potential for causing life-threatening arrhythmias. Whereas hyperkalemia occurs relatively infrequently in individuals with normal kidney function, hyperkalemia can be much more common in patients who have predisposing conditions. As discussed by Kovesdy,4 patients with CKD are the most severely affected group by virtue of their diminished ability to excrete potassium.
Read more articles from the hyperkalemia series
- Hyperkalemia as a barrier to treatment: Heart failure with reduced ejection fraction
- Arrhythmias and sudden cardiac death in hemodialysis patients
- Potassium homeostasis in chronic kidney disease
The problem is further aggravated by the superimposed additional predisposing conditions that often cluster within patients with CKD. These include comorbidities (eg, congestive heart failure, diabetes mellitus) and a wide array of medications and herbal over-the-counter formulations.
Hyperkalemia is associated with increased risk for all-cause mortality and for malignant arrhythmias such as ventricular fibrillation. The increased risk for adverse outcomes is observed even in serum potassium ranges that are usually not considered targets for therapeutic interventions. The heightened risk of mortality associated with hyperkalemia is present in all patient populations, even in those in whom hyperkalemia occurs otherwise rarely, such as individuals with normal kidney function.
In the following sections, we focus on two topics: 1) the clinical evaluation of the patient with hyperkalemia, and 2) electrocardiographic manifestations of hyperkalemia.
Potassium, a metallic inorganic ion with atomic weight of 39, is the most abundant cation in the body. The vast majority of potassium resides in the intracellular compartment, with only a small amount in the extracellular space. The “normal” range for serum potassium is often defined as from 3.5 to 5.5 mEq/L; however, plasma potassium is 0.5 mEq/L lower. It is interesting to note that while total body potassium is lower in females and in older patients, serum potassium concentration is independent of sex and age.
Technique for measuring serum potassium
Serum potassium is measured by the use of a flame photometer or ion-selective electrode. Although the procedure is rapid, simple, and reproducible, caution is in order. In interpreting serum potassium, the clinician should be aware that because the intracellular potassium concentration is approximately 40-fold greater than the extracellular concentration, any maneuver that would result in the release of a small amount of intracellular potassium into the sample will erroneously raise serum potassium.
As detailed in Table 1, these include: a) tight tourniquet, b) vigorous exercise of the extremity during blood drawing, c) hemolysis due to vigorous shaking of the test tube, d) thrombocytosis (platelet count > 600,000), and/or (e) leukocytosis (white blood-cell count > 200,000). In the latter two situations, the longer the blood stands, the greater the rise in serum potassium will be.
Clinical significance of minor deviations from the narrow normal range
The normal range for serum potassium is narrow (3.5–5.5 mEq/L), and a minor departure from this range (by less than 1.0 mEq/L) is associated with significant morbidity and mortality. Although a 1.0 mEq change in concentration is small in absolute terms, it profoundly changes the ratio of intracellular to extracellular potassium, sometimes by as much as 25%. Therefore, rapid evaluation and—when indicated—treatment of both hypo- and hyperkalemia are critical. In the following sections we summarize the clinical consequence of hyperkalemia. These symptoms, signs, and laboratory findings should alert the clinician to the possible existence of a significant derangement in serum potassium.
Hyperkalemia is generally attributable to either intracellular shifts of potassium or impaired renal potassium excretion. Cell shifts account for transient increases in serum potassium levels, whereas sustained hyperkalemia is generally caused by diminished renal potassium excretion. Impaired renal potassium excretion can be caused by a primary decrease in distal sodium delivery, a primary decrease in mineralocorticoid level or activity, or abnormal cortical collecting duct function. Excessive potassium intake is an infrequent cause of hyperkalemia when renal function is intact, but the increased potassium intake can worsen the severity of hyperkalemia in the context of impaired renal excretion.
Before concluding that a cell shift or renal defect in potassium excretion is present, the physician must exclude pseudohyperkalemia (see Table 2).5 Pseudohyperkalemia is an in vitro phenomenon caused by the mechanical release of potassium from cells during the phlebotomy procedure or specimen processing. This diagnosis is made when the serum potassium concentration exceeds the plasma potassium concentration by 0.5 mEq/L (0.5 mmol/L). As summarized in Table 1, common causes include fist-clenching during the phlebotomy procedure, application of tourniquets, and use of small-bore needles.
Pathologic causes of hyperkalemia are primarily encountered in the setting of hematologic disorders, such as thrombocytosis (platelets 500,000/cm3) and pronounced leukocytosis (leukocytes 70,000/cm3). Contamination with potassium ethylenediaminetetraacetic acid (EDTA) in certain sampling tubes can cause a spurious increase in plasma potassium concentration accompanied by a very low plasma calcium concentration.
The clinical evaluation of the patient with hyperkalemia
Evaluation of the physical examination
Patients with hyperkalemia are often asymptomatic. When present, the symptoms of hyperkalemia are nonspecific and predominantly related to muscular or cardiac function. The most common complaints are weakness and fatigue. Occasionally, a patient may complain of frank muscle paralysis or shortness of breath. Patients also may complain of palpitations or chest pain, or may report nausea, vomiting, and paresthesias. The patient’s history is most valuable in identifying conditions that may predispose to the development of hyperkalemia.
The next step in the evaluation of the hyperkalemic patient is to obtain a thorough medical and dietary history. Is there evidence of excess dietary potassium intake? In the presence of normal renal and adrenal function, it is difficult to ingest sufficient potassium to overwhelm the normal renal excretory process and become hyperkalemic. In the setting of impaired kidney function, however, dietary intake usually is a contributor to hyperkalemia.
Dietary sources that are particularly enriched with potassium include melons, citrus juice, and salt substitutes. Other hidden sources of potassium reported to cause life-threatening hyperkalemia include raw coconut juice (potassium concentration, 44.3 mEq/L [44.3 mmol/L]) and noni juice (potassium, 56 mEq/L [56 mmol/L]).
For excessive potassium intake, patients should be queried about the following:
Eating disorders: Very unusual diets consisting almost exclusively of high-potassium foods, such as fruits (eg, bananas, oranges, melons), dried fruits, raisins, fruit juices, nuts, and vegetables with little to no sodium.
“Heart-healthy diets”: Ironically, these may be incriminated. The very low-sodium and high-potassium diets recommended for patients with cardiac disease, hypertension, and diabetes mellitus may predispose patients to an increased risk of hyperkalemia.
Use of potassium supplements: In over-the-counter herbal supplements, sports drinks, dietary supplements such as noni (Morinda citrifolia) juice, salt substitutes, or prescribed pharmacologic agents
Laxative use: Another interesting, surreptitious source of potassium is Movicol (Norgine BV, the Netherlands), a brand-name laxative that includes polyethylene glycol (macrogol) 3350. Macrogol 3350 is a widely used iso-osmotic laxative (also called MiraLAX Powder [Bayer AG, Leverkusen, Germany], or glycolax). Each packet of Movicol contains macrogol 3350, with the addition of sodium bicarbonate, sodium chloride, and potassium chloride. It is important to note that each 13.8 g sachet of Movicol contains 46.6 mg of potassium chloride (approximately 5.4 mmol/L). Electrolytes are included to help mitigate the possibility of electrolyte imbalance and dehydration. The contents of the sachets are mixed with water to make a drink. Hyperkalemia is the most common reported electrolyte imbalance as a result of treatment with macrogol laxative. In value terms, Movicol is currently the largest-selling laxative in the world. The point to be emphasized is that other macrogol powders may be “fortified” by additional potassium chloride.
When evaluating hospitalized patients, the physician should review the medication list for potassium supplements or high-dose penicillin G potassium, and review the chart to determine whether the patient has received transfusions. With patients who have undergone cardiac surgery, the possibility of residual effects of cardioplegic solutions should be considered.
When evaluating decreased potassium excretion, the physician should query patients regarding a history of renal insufficiency or renal failure. In addition, any history of diabetes mellitus or sickle-cell disease or trait, or symptoms of lower urinary tract obstruction, should be elicited. These conditions predispose patients to type IV renal tubular acidosis, also called hyperkalemic renal tubular acidosis.6–8 Type IV renal tubular acidosis also may accompany other tubulointerstitial disorders, polycystic kidney disease, or amyloidosis.
Often, patients with type IV renal tubular acidosis also have hyporeninemic hypoaldosteronism.6,8–11 Patients with ureteral diversion into the ileum can develop hyperkalemia due to reabsorption of secreted potassium.
The next step in the diagnostic evaluation: Consider whether the hyperkalemia is the result of a cellular shift
Cellular redistribution is a more important cause of hyperkalemia than of hypokalemia. Clinicians should realize that as little as a 2% shift in intracellular potassium to the extracellular fluid may result in a serum potassium level as high as 8 mEq/L (8 mmol/L) (see Table 2). The major physiologic regulators of potassium shift into cells are insulin and catecholamines.
Additional etiologies of hyperkalemia
Metabolic acidosis and hyperkalemia
It has been generally assumed that acidosis produces hyperkalemia because of shifts of potassium from the intracellular to the extracellular compartment. There is ample clinical and experimental evidence, however, to support the conclusion that uncomplicated organic acidemias do not produce hyperkalemia.
Metabolic acidosis promotes potassium exit from cells depending on the type of acid present. Mineral acidosis (NH4Cl or HCl), by virtue of the relative impermeability of the chloride anion, results in the greatest efflux of potassium from cells; whereas organic acidosis (ie, lactic, hydroxybutyric, or methylmalonic acid) results in no significant efflux of potassium.
Patients with diabetic ketoacidosis frequently are depleted of total-body potassium because of renal potassium losses resulting from increased distal sodium delivery (the osmotic diuretic effect of glucose and excretion of sodium-ketoacid salts) occurring in the setting of high aldosterone levels, which are stimulated by volume depletion.
Does the patient have a disturbance in renal potassium excretion?
Although redistribution of potassium can result in hyperkalemia, the increase in potassium levels is generally mild and not sustained. Hyperkalemia that is prolonged and severe implies the presence of impaired renal potassium excretion. Usually, the clinical setting will enable the clinician to determine whether there is a disturbance in renal potassium excretion.
Drug-induced hyperkalemia is an important but often overlooked problem that is encountered commonly in clinical practice, in the ambulatory as well as the impatient setting. Every evaluation of a hyperkalemic patient should include a careful review of medications to determine if a drug capable of causing or aggravating hyperkalemia is present. As detailed in Table 1, medications generally produce hyperkalemia either by causing redistribution of potassium (β2-adrenergic blockers, succinylcholine, digitalis overdose, hypertonic mannitol) or by impairing renal potassium excretion. Drugs cause impaired renal potassium excretion by 1) interfering with the production and/or secretion of aldosterone (nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, angiotensin-II receptor antagonists, heparin, cyclosporine, and FK 506); or 2) blocking the kaliuretic effects of aldosterone (potassium-sparing diuretics, trimethoprim, pentamidine, and nafamostat mesilate).
A careful search for “hidden” potassium loads and for causes of impaired tubular secretion of potassium (including drugs) is necessary. Finally, it is important to recognize that the causes of hyperkalemia may be additive. Patients may have more than one cause of hyperkalemia at the same time. Therefore, all potential causes of hyperkalemia, including drugs and surreptitious sources of potassium, should always be systematically evaluated in every hyperkalemic patient.14,15
Interpretation of urinary electrolytes
Chronic disorders in potassium homeostasis are associated with a defect in the cation’s handling by the kidney.5 The interpretation of urinary electrolyte values is helpful. First, it must be emphasized that there are no normal values for urinary potassium excretion. Rather, what is important is whether the laboratory values are appropriate for the clinical setting. Normal subjects who are potassium-deprived may excrete as little as 10 to
15 mmol/day. In contrast, potassium excretion can attain levels of 200 mmol/day in response to a substantive increase in dietary potassium intake.12 Nevertheless, determination of the transtubular potassium gradient (TTKG) is a popular tool among some clinicians to assess renal potassium handling. The TTKG is most helpful in the evaluation of hyperkalemia when the physician is attempting to discriminate between low aldosterone levels and aldosterone resistance.13
Because potassium is vital for regulating the normal electrical activity of the heart, it is readily apparent that hyperkalemia can produce changes in the electrocardiogram (EKG). Increased extracellular potassium reduces myocardial excitability, with depression of both pacemaking and conducting tissues. With progressive worsening, hyperkalemia leads to suppression of impulse generation by the sinoatrial node and reduced conduction by the atrioventricular (AV) node and His-Purkinje system, thereby resulting in bradycardia and conduction blocks and, ultimately, cardiac arrest.16,17
Table 3 summarizes the sequential stages of EKG changes induced by hyperkalemia, and Table 4 shows the different cell types susceptible to potassium-induced effects on myocardial conduction and contractility. The latter list explains well the differential observations that can be made from an electrophysiological point of view. The numerical limits for potassium concentrations given in Table 3 with regard to EKG alterations are, of course, estimates and not absolute values. As an example, potassium levels of around 8 mEq/L could already lead to cardiac arrest in the presence of co-medications and factors causing QT prolongation, additional electrolyte disorders (calcium, magnesium), or generally increased susceptibility of myocardial target cells or structures.18–26
Indirect evidence on how clinically and adversely meaningful hyperkalemia can be in dialysis patients came from the End-Stage Renal Disease Clinical Performance Measures Project demonstrating increased mortality, especially including cardiac arrest and dysrhythmia events toward the end of the long dialysis interval.27 Although no laboratory proof could be provided (due to the nature of this analysis), one key feature of this post-dialysis phase is the presence of the highest probability for moderate to severe hyperkalemia. Elsewhere in this supplement, Epstein and Roy-Chaudhury review the pivotal role of electrolytes, especially hyperkalemia, in the pathogenesis of arrhythmias and sudden cardiac death on the patient being treated with dialysis.28
The earliest electrocardiographic manifestation associated with “mild” hyperkalemia (serum potassium = 5.5–6.5 mEq/L) may include tall, peaked, narrow-based T waves in precordial (V2–V4) leads and fascicular blocks (left anterior and left posterior fascicular blocks).29 Moderate hyperkalemia (serum potassium between 6.5 and
7.5 mEq/L) may be associated with first-degree AV block, decreased P-wave amplitude followed by disappearance of the P waves, and sinus arrest. ST segment depression and sometimes ST segment elevation simulating an acute myocardial infarction have also been described. Severe hyperkalemia (serum potassium >7.5 mEq/L) is manifested by atypical bundle branch block, intraventricular conduction delay, ventricular tachycardia, ventricular fibrillation, idioventricular rhythm, the “sine wave,” and asystole.
Several other electrocardiographic alterations may occur, including AV arrhythmias, pacemaker dysfunction, rate-dependent bundle branch block, AV block with junctional rhythm, and pseudonormalization of inverted T waves.
The concomitant use of other medications may also be of importance. Mild hyperkalemia, for instance, has been associated with junctional bradycardia in patients on verapamil.30 Although typical EKG manifestations of hyperkalemia are more likely in the presence of severe hyperkalemia, it is important to note that the characteristic EKG changes described are not always present, even in patients with severe hyperkalemia.22–24 Conversely, other factors, in addition to serum potassium levels, modify the EKG manifestations of hyperkalemia (see Table 5).
It is imperative when treating hyperkalemia that the whole clinical picture is taken into account, rather than just the numerical potassium values. Further, EKG changes have low sensitivity in identifying individuals with hyperkalemia or predicting severity.31,32 Among patients with end-stage renal disease, a population at particularly high risk for hyperkalemia, differences in calcium levels may contribute to the predictive value of the EKG in detecting hyperkalemia.22,24 Older age and the presence of diabetes have also been associated with a lower likelihood of hyperkalemia-induced peaked T waves.
Hyperkalemia is a common electrolyte disorder, especially among patients with CKD, diabetes mellitus, or heart failure. Hyperkalemia represents one of the most important acute electrolyte abnormalities, due to its potential for causing life-threatening arrhythmias. In this article we have reviewed two aspects of hyperkalemia: 1) a suggested approach to the clinical evaluation of the patient with hyperkalemia, and 2) electrocardiographic manifestations of hyperkalemia. We have reviewed an approach to the clinical evaluation of the patient with hyperkalemia. We have also emphasized that drug-induced hyperkalemia is an important but often overlooked problem encountered commonly in clinical practice, and have provided examples of surreptitious sources of potassium that may promote hyperkalemia. -by Murray Epstein, MD, FACP, FASN; Markus Ketteler, MD, FERA
- Kovesdy CP. Management of hyperkalaemia in chronic kidney disease. Nat Rev Nephrol. 2014; 10: 653–662.
- Elliott MJ, Ronksley PE, Clase CM, et al. Management of patients with acute hyperkalemia. CMAJ. 2010; 182: 1631–1635.
- Weisberg LS. Management of severe hyperkalemia. Crit Care Med. 2008; 36: 3246–3251.
- Kovesdy CP. Patterns, causes, and effects of hyperkalemia. In: Current concepts and emerging therapeutic options. supplement, Nephrol News Issues. 2016; 30: 4-7.
- Epstein M. The Kidney: A Handbook. 1992.
- Perez GO, Pelleya R, Oster JR. Renal tubular hyperkalemia. Am J Nephrol. 1982; 2: 109–114.
- Aronson PS, Giebisch G. Effects of pH on potassium: new explanations for old observations. J Am Soc Nephrol. 2011; 22: 1981–1989.
- Pelleya R, Oster JR, Perez GO. Hyporeninemic hypoaldosteronism, sodium wasting and mineralocorticoid-resistant hyperkalemia in two patients with obstructive uropathy. Am J Nephrol. 1983; 3: 223–227.
- Schambelan M, Sebastian A, Biglieri EG. Prevalence, pathogenesis, and functional significance of aldosterone deficiency in hyperkalemic patients with chronic renal insufficiency. Kidney Int. 1980; 17: 89–101.
- Karet FE. Mechanisms in hyperkalemic renal tubular acidosis. J Am Soc Nephrol. 2009; 20: 251–254.
- Haas CS, Pohlenz I, Lindner U, Muck PM, et al. Renal tubular acidosis type IV in hyperkalaemic patients—a fairy tale or reality? Clin Endocrinol (Oxf). 2013; 78: 706–711.
- Huth EJ, Squires RD, Elkinton JR. Experimental potassium depletion in normal human subjects. II. Renal and hormonal factors in the development of extracellular alkalosis during depletion. J Clin Invest. 1959; 38: 1149–1165.
- Choi MJ, Ziyadeh FN. The utility of the transtubular potassium gradient in the evaluation of hyperkalemia. J Am Soc Nephrol. 2008; 19: 424–426.
- Ray K, Dorman S, Watson R. Severe hyperkalaemia due to the concomitant use of salt substitutes and ACE inhibitors in hypertension: a potentially life threatening interaction. J Hum Hypertens. 1999; 13: 717–720.
- Doorenbos CJ, Vermeig CG. Danger of salt substitutes that contain potassium in patients with renal failure. BMJ. 2003; 326:35–36.
- Wagner, GS. Strauss, D.G. Marriott’s Practical Electrocardiography 12th edition. Philadelphia: Lippincott Williams & Wilkins. 2013.
- Surawicz B, Childers R, Deal BJ, et al. AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram. Circulation. 2009; 119: e235–240.
- Diercks DB, Shumaik GM, Harrigan RA, et al. Electrocardiographic manifestations: electrolyte abnormalities. J Emerg Med. 2004; 27: 153–160.
- Slovis C, Jenkins R. ABC of clinical electrocardiography: conditions not primarily affecting the heart. BMJ. 2002; 324: 1320–1323.
- Yu AS. Atypical electrocardiographic changes in severe hyperkalemia. Am J Cardiol. 1996; 77: 906–908.
- El-Sherif N, Turitto G. Electrolyte disorders and arrhythmogenesis. Cardiol J. 2011; 18: 233–245.
- Szerlip HM, Weiss J, Singer I. Profound hyperkalemia without electrocardiographic manifestations. Am J Kidney Dis. 1986; 7: 461–465.
- Montague BT, Ouellette JR, Buller GK. Retrospective review of the frequency of ECG changes in hyperkalemia. Clin J Am Soc Nephrol. 2008; 3: 324–330.
- Aslam S, Friedman EA, Ifudu O. Electrocardiography is unreliable in detecting potentially lethal hyperkalaemia in haemodialysis patients. Nephrol Dial Transplant. 2002; 17: 1639–1642.
- Green D, Green HD, New DI, et al. The clinical significance of hyperkalaemia-associated repolarization abnormalities in end-stage renal disease. Nephrol Dial Transplant. 2013; 28: 99–105.
- Manohar N, Young ML. Rate dependent bundle branch block induced by hyperkalemia. Pacing Clin Electrophysiol. 2003; 26: 1909–1910.
- Foley RN, Gilbertson DT, Murray T, et al. Long interdialytic interval and mortality among patients receiving hemodialysis. N Engl J Med. 2011; 365: 1099–1107.
- Epstein M, Roy-Chaudhury P. Arrhythmias and sudden cardiac death in hemodialysis patients: Temporal profile, electrolyte abnormalities, and potential targeted therapies. In: Current concepts and emerging therapeutic options. supplement, Nephrol News Issues. 2016; 30: 23–26.
- Campese VM, Adenuga G. Electrophysiological and clinical consequences of hyperkalemia. Kidney Int Suppl. 2016; 6: 6–19.
- Hegazi MO, Aldabie G, Al-Mutairi S et al. Junctional bradycardia with verapamil in renal failure—care required even with mild hyperkalaemia. J Clinical Pharm Ther. 2012; 37: 726–728.
- Acker CG, Johnson JP, Palevsky PM et al. Hyperkalemia in hospitalized patients: causes, adequacy of treatment, and results of an attempt to improve physician compliance with published therapy guidelines. Arch Intern Med. 1998; 158: 917–924.
- Wrenn KD, Slovis CM, Slovis BS. The ability of physicians to predict hyperkalemia from the ECG. Ann Emerg Med. 1991; 20: 1229–1232.