BRIEF REVIEW www.jasn.org How Dangerous Is Hyperkalemia? † ‡ John R. Montford* and Stuart Linas* *Division of Renal Disease and Hypertension, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado; †Renal Section, Medicine Service, Veterans Affairs Eastern Colorado Health System, Denver, Colorado; and ‡Division of Nephrology, Department of Medicine, Denver Health and Hospitals, Denver, Colorado ABSTRACT Hyperkalemia is a potentially life-threatening electrolyte disorder appreciated with lower the resting cardiac membrane po- greater frequency in patients with renal disease, heart failure, and with use of certain tential. This decreases the threshold for medications such as renin angiotensin aldosterone inhibitors. The traditional views rapid phase-0 Na+-dependent depolar- that hyperkalemia can be reliably diagnosed by electrocardiogram and that partic- ization resulting in an increase in cardiac ular levels of hyperkalemia confer cardiotoxic risk have been challenged by several conduction velocity.7 By electrocardio- reports of patients with atypic presentations. Epidemiologic data demonstrate gram (ECG), these changes are manifes- strong associations of morbidity and mortality in patients with hyperkalemia but ted by “peaked” or “tented” Twaves these associations appear disconnected in certain patient populations and in differ- most prominent in the precordial (V2– ing clinical presentations. Physiologic adaptation, structural cardiac disease, medi- V4) leads. With larger acute rises in ex- cation use, and degree of concurrent illness might predispose certain patients tracellular potassium concentration, presenting with hyperkalemia to a lower or higher threshold for toxicity. These conduction delay becomes prominent factors are often overlooked; yet data suggest that the clinical context in which in the atrioventricular node and His– hyperkalemia develops is at least as important as the degree of hyperkalemia is in Purkinje system due to action potential determining patient outcome. This review summarizes the clinical data linking shortening and prolongation of phase-4 hyperkalemia with poor outcomes and discusses how the efficacy of certain treat- diastolic depolarization.7,8 Indeed, pro- ments might depend on the clinical presentation. longation of the PR interval, P-wave am- plitude, and increased QRS complex J Am Soc Nephrol 28: 3155–3165, 2017. doi: https://doi.org/10.1681/ASN.2016121344 width are ominous findings in patients with advanced hyperkalemia that can precede a classically described “sine-wave” INTEGRATED DISCUSSION processes. Blunted potassium redistribu- pattern on ECG.9 Thus, hyperkalemia tion typically occurs through insulin predisposes to both cardiac hyperexcit- Introduction deficiency, decreases in aldosterone bio- ability (ventricular tachycardia, ventricular Hyperkalemia is an electrolyte distur- synthesis or action, diminished adrener- fibrillation) and depression (bradycardia, bance occurring with increased fre- gic signaling, and osmolar disturbances atrioventricular block, interventricular quency among patients with CKD, including hyperglycemia. Renal failure, conduction delay, and asystole), both of diabetes, heart failure, and use of certain and/or failure to augment distal tubular which can be fatal. medicationssuchasreninangiotensin potassium secretion, is largely respon- Despite a wealth of animal data dem- aldosterone system (RAAS) inhibitors sible for the maintenance of hyperkale- onstrating cardiotoxicity from acute and nonsteroidal anti-inflammatory mia. Many studies reproducibly identify hyperkalemia, these presentations are drugs.1–4 Extracellular potassium con- common clinical risk factors that are as- centration is usually kept within a narrow sociated with the development of hyper- physiologic range by redundant and kalemia regardless of the clinical setting Published online ahead of print. Publication date highly efficient homeostatic mechanisms (Table 1). available at www.jasn.org. that simultaneously control internal po- The fatal consequences of rapid in- Correspondence: Dr. John R. Montford, Division of tassium redistribution while regulating creases in extracellular potassium con- Renal Disease and Hypertension, University of Colorado Anschutz Medical Campus, Research 2, net potassium excretion. Hyperkalemia centration have been demonstrated in Box C281, 12700 E. 19th Avenue, Aurora, CO 80045. occurs when rises in extracellular potas- the setting of acute intravenous potas- Email: [email protected] 5,6 sium concentration are accompanied by sium loading in animals. Early rises Copyright © 2017 by the American Society of one, or additive, defects in these two in extracellular potassium concentration Nephrology J Am Soc Nephrol 28: 3155–3165, 2017 ISSN : 1046-6673/2811-3155 3155 BRIEF REVIEW www.jasn.org Table 1. Risk factors for the degrees of hyperkalemia and only ap- to 7.32). Furthermore, as compared development of hyperkalemia proached minimal predictive power with survivors with hyperkalemia, Clinical Risk Factor Medication Exposure with potassium levels of 7.2–9.4 meq/ nonsurvivors had higher increases in se- 17 6 Male sex Potassium supplements L. In patients on hemodialysis with hy- rum potassium preceding death (1.1 Non-black Penicillin G perkalemia, ECG-diagnosed T wave 1.3 versus 2.261.5 meq/L change in DM Digoxin “tenting” did not predict the serum serum potassium from admission, re- CVD NSAIDs potassium and substantially lost its sen- spectively). Most cases of hyperkalemia CHF ACEi/ARBs sitivity with increasing patient age and developed during hospitalization (in AKI MRAs presence of diabetes.18 Specificity for hy- 60% of the cohort) with a mean admis- CKD b-adrenergic blockers perkalemia and sudden death at follow- sion potassium level of 5.761.5 meq/L Acidosis Heparin up was improved with evaluation of the rising to 7.160.7 meq/L after an aver- Urinary obstruction Amiloride, Triamterene T:R wave amplitude in these patients, but ageof17daysoffollow-up. Trimethoprim, sensitivity was also diminished. In another retrospective review of Pentamidine Hyperkalemia has also been associ- .39,000 patients admitted to the inten- DM, diabetes mellitus; CVD, cardiovascular disease; NSAIDs, nonsteroidal anti-inflammatory ated with a host of nontraditional ECG sive care unit at two teaching hospitals in drugs; CHF, congestive heart failure; ACEi, changes including T wave inversions19 Boston, Massachusetts between 1997 angiotensin-converting enzyme inhibitor; ARB, and pseudonormalizations,20 bundle and 2007, incident hyperkalemia inde- angiotensin receptor blockade. branch,21 bifascicular,22 sinoatrial pendently predicted mortality at the exit,20 andatypicbundlebranch time of critical care initiation.32 This as- overall uncommon in humans. Reports blocks,8 and ST depressions and eleva- sociation was graded, with even minor of acute hyperkalemia precipitating car- tions.15,23,24 There are even reports of elevations in serum potassium (to levels diac arrest typically involve intravenous profound hyperkalemia with minimal 4.5–5.0 meq/L) conferring an increased potassium loading, massive cell turnover, or no discernable ECG changes.21,25,26 risk of death (OR for death within 30 or shift of potassium in the setting of Additionally, metabolic acidosis,27 left days, 1.49; 95% CI, 1.38 to 1.59), and 10–14 surgical anesthesia or critical illness. ventricular hypertrophy,28 early benign remained significant after adjusting for In these cases, the measured potas- repolarization,29 and acute coronary is- many potential confounders prevalent sium concentration was usually normal chemia30 are known to induce T wave in the critical care setting (adjusted OR, shortly before cardiopulmonary arrest; “tenting” in patients with normal serum 1.18; 95% CI, 1.09 to 1.27). Further- and only with rapid increases in serum potassium. Because there are currently more, failure of serum potassium to cor- fi potassium did the ndings of tachy- and inconsistent data supporting the utility rect by .1.0 meq/L within 48 hours after bradyarrhythmias associated with hy- of the ECG in predicting the degree of, initial measurement continued to pre- perkalemia become apparent. These and prognosis with, hyperkalemia, we dict death; whereas, this association extreme situations constitute a small must turn to published data that exam- was attenuated among patients achiev- minority of clinical hyperkalemia in ines the relationship between hyperkale- ing this degree of correction. Khanagavi humans which is often incidental, mia and cardiovascular outcomes. et al.33 reported on hospitalized patients asymptomatic, and of unknown duration. with serum potassium .5.1 meq/L, Additionally, there are many published Hyperkalemia in the Setting of finding that duration of hyperkalemia reports demonstrating a large disconnect Critical Illness and mortality increased substantially between degree of hyperkalemia and ex- Compelling data link hyperkalemia with with concomitant tissue necrosis [haz- pected ECG findings in humans. heightened adverse outcomes in the crit- ard ratio (HR) for death, 4.55; 95% CI, The ECG was observed to be some- ically ill population. In a retrospective 1.74 to 11.90], metabolic acidosis (HR, what unreliable in older studies of pa- analysis of 932 hospitalized adults in 4.84; 95% CI, 1.48 to 15.82), and AKI tients with potassium levels ,6.5 meq/ two Korean medical centers, high rates (HR, 3.89; 95% CI, 1.14 to 13.26). Total L.9,15 Modern studies and case reports of arrhythmia