New Guidelines for Potassium Replacement in Clinical Practice A Contemporary Review by the National Council on Potassium in Clinical Practice Jay N. Cohn, MD; Peter R. Kowey, MD; Paul K, Whelton, MD; L. Michael Prisant, MD his article is the result ofa meeting of the National Council on Potassium in Clinical Prac- tice. The Council, a multidisciplinary group comprising specialists in cardiology, hyper- tension, epidemiology, pharmacy, and compliance, was formed to examine the critical role of potassium in clinical practice. The goal of the Council was to assess the role of potas- sium in terms of current medical practice and future clinical applications. The primary outcome of the meeting was the development of guidelines for potassium replacement therapy. These guidelines represent a consensus of the Council members and are intended to provide a general approach to the prevention and treatment of hypokalemia. In re -nt years, studies of the potential pathogenetic role of potassitim defi- Glency in various medical conditions have underscored the importance of prevent- ing or correcting this deficiency. Al- though it has long been established that the maintenance of normal serum potas sium is essential in reducing the isk of life threatening cardiac arrhythmias, accumu lating evidence suggests thatthe increased, intake of potassium can also lower blood. pressure and reduce the risk of stroke ew clinicians attempt to monitor and augment potassium stores on a routine b- sis. One reason may be the inconve. inience of accurately measuring (otal body potassium, which entails a 24-hour uri- nary collection rather than a rapid labo- ratory serum measurement, Another rea- son is the practical difficulty of achieving and maintaining optimal potassium lev- cls, Therefore, many clinicians may not at- tempt to remedy subnormal potassium lev cls except in high-risk patients, The current lack of consensus on how to prevent and treat hypokalemia has led 10 From the Department of Medicine, University af Minnesota Medical Schoo, Minneapolis (Dr Cohn); Departmen of Cardiology, Lankenau Hospital and Medical Research Center, Wynnewood, Pa, and Department of Medicine, Jelersn Medical College, Philadelphia, Pa (Dr Kowey); Department of Epidemiology, Tulane University School of Public Heath and Tropical Medicine, New Orleans, La (Dr Whelton); and Department of Medicine, Medial College of Georgia, Augusta (Dr Print). Participants ofthe National Council on Potassium in Clinical Practice are listed Arch Intern Med. 2000;160:2429-2436 the neglect of a wide range of situations in which inereasing potassium intake might help prevent sequelae of cardiovascular dis cease. The multifactorial and interactive ‘mechanisms that are stimulated by hyper~ tension and even more so by heat failure, which mandate the introduction of drugs that disrupt electrolyte homeostasis, em- phasize the serious role of potassium. This article reviews contemporary thinking on potassium in clinical practice. (Of the total body potassium content {about 3500 mmol [mEq]), 90% is seques tered within cells” This compartmentalisa- tion depends on active transport through the cell membrane by a sodium-potassiuim pump, which maintains an intracellular eat- {on ratio of 1:10. Normal serum potassium levels are considered to lie roughly be- ‘oven 3.6 and 5.0 mmol/L, The loss of just 19 (35 mmol) of total body potassium con- tent would seriously disturb the delicate bal- ance between intracellular and extracell- lar potassium and would result in profound physiologic changes, On the other hand, the presence of hypokalemia (le, serum levels <3.6 mmol/L) is not necessarily synony- mous with whole-body potassium defi- ciency, because such asinall percentage of the total body stores is present in extmacel- lular fluid. Whereas it is generally ac- cepted that diuretic therapy ean decrease se- ‘rum polassiuin to hypokalemic levels, the subiler effects of inadequate dietary potas- inthe acknowledgments atthe end ofthe article sium are less well known, (ngpRa\TED) XRCHINTERN WEDIVOL 10, SEP 112000" WWWARCHINTERNMED COM (©2000 American Medical Association. Al rights reserved, ‘Downloaded From: https:/jamanetwork.com/ on 03/07/2022Table 1. Foods High Highest conten 000 mg [25 mel) 100g) Dri gs Nlasae ery high coer (>500 mg [125 mal} 100g) Dri tuts dates, prunes) ts voeadoe Bran cele Wheat germ Uma bene High contr, 250 mg (6.2 mal 00g) ‘Vogsales: spinach, mates, roceol, wintr squash, bet, ‘aro callow potatoes Fru bananae,cartaloupe, Kis oranges, argos Meats: ground be, steak, pork, ve, lamb ~Adoped om Gear For instance, although young adults may consume up to 3400 mg, (85 mmol) of potassium per day many elderly individuals, particu larly those living alone or those who are disabled may not have a sulficient amount of potassium in their diet. People who eat large amounts of fruits and vegetables tend to have a high potassium intake of approximately 8000 to 11.000 mg/d (200-250 mig). Urban whites typically consume approxi- mately 2500 mg (62.5 mEq) of potassium daily. In contrast, many African Americans have low intakes of about 1000 mg (25 mEg) per day.' The daily mini- mum requirement of potassium is considered to he approximately 1600 t0 2000 mg (40-50 mmol or mEq). Factors that affect potas- sium intake include the type of diet consumed (Table 1), age, race, and socioeconomic status, CLINICAL IMPLICATIONS OF POTASSIUM DEPLETION Potassium depletion is one of the most common electrolyte abnor- ‘malities encountered in clinial prac luce. More than 20% of hospitalized patients have hypokalemia, widely defined as a serum potassium level of less than 3.5 mmol/L. Low se- rum (or plasma) concentrations of potassium may occur in up to 40% (aepRnTED) ARCHINTERN MEDI VOL 16h SEP TT SOOO ‘Table 2, Potential Causes of Hypokalemia Inadaqatdetay potassium ake Dirt teapy High liatary sodium intake Hypomagnesemia Prolonged dares Voiing Primary or secondary aldostronism Cushing syndrome or dsase Large dss of conicostarois Ectopic cortcoropn Barter syndrome Lidl syndrome snarls in congste her are Catacalamines| Oars (excessive use of cari, insulin, ‘atbiaes) ‘of outpatients treated with thiazide diuretics? Because the kidneysare the ma- jor regulators of external potas- sium homeostasis, accounting for approximately S0% of potassium transit from the body, renal dysfune- tion ean result in gross abnormali- les in serum potassium levels.’ Transcellular potassiuim homeosta- sis depends toa large extent on acid base balance.'® Acidosis stimulates cellular efflux of potassium from cells, resulting in hyperkalemia, whereas alkalosis stimulates influx ‘of potassium, resulting in hypoks- lemia, without a simultaneous al- {eration in total body potassium. [n- ‘eases in insulin or catecholamines ‘canalso stimulate cells to import po- lassiuim and export sodium. In pa- ents with type 2 diabei creases in glucose or insulin ean allect potassium homeostasis, Smt lation of B,-adrenergic receptors by ‘sympathomimetic drugs (eg, decon- gestants and bronchodilators) can temporarily reduce serum potas- sium, A standard dose of nebulized albuterol reduces serum potassium by 0.21004 mmol/L Asecond dose administered within 1 hour re- duces it by approximately | mmol/ L2B,-Blockade, on the other hand, increases serum potassium, ‘Overt hypokalemia may be di- agnosed when the serum potas- sium level is less than 3.6 mmol/L. Potential causes include diuretic therapy, inadequate dietary potas- sium intake, high dietary sodium intake, and hypomagnesemia He 2). In most cases, hypoka- lemia is secondary to drug treat ‘ment, particularly diuretic therapy (fable 3).* Diuretics inhibit chlo- ride-associated sodium reabsorp- tion in the kidney, creating a favor- able electrochemical gradient for potassium secretion.** The degree of hypokalemia is directly related to the dose and half-life of the diuretic ad- ‘ministered.’ Hypokalemia occu in- frequently in patients with uncom- plicated hypertension who take a diuretic but is more common in pa tients with congestive heart failure (CHP), nephrotic syndrome, or cir thosis of the liver, who take an equivalent dose of a diuretic and constime approximately the same amount of potassium from food. Management of hypokalemia should begin with a thorough review of the patient’s medical record. If potassium-wasting drugs are not implicated, hypokalemia is most commonly caused either by abnormal loss through the kidney induced by metabolic alkalosis or by loss in the stool secondary to diarrhea Because potassium is a major intracellular cation, the tissues ‘most severely affected by potassium imbalance are muscle and renal tubular cells. Manifestations of hypokalemia include generalized muscle weakness, paralytic ileus, and cardiac arrhythmias (atrial tachycardia with or without block, atrioventricular dissociation, ven” tricular tachycardia, and ventricular fibrillation). Typical electrocardio- graphic changes include flat oF inverted T waves, ST-segment de- pression, and prominent U waves, In severe untreated hypokalemia, myopathy may progress to rhabdo- myolysis, myoglobinuria,and acute renal failure, Such complications are ‘most often seen in hypokalemia sec~ ondary to alcoholism PROTECTIVE EFFECT (OF POTASSIUM Data from animal experiments and epidemiologic studies suggest that high potassium may reduce the risk of stroke. Although patt of the pro- lective effect of potassium may be due to lowering of blood pressure, analysis of animal models suggests that potassium may have other pro- (©2000 American Medical Association. Al rights reserved,tective mechanisms, including in- hibitory effects on free radical for- mation, vascular smooth muscle proliferation, and arterial thrombo- sis©” It has also been shown ex- perimentally that potassiuin may reduce macrophage adherence to the vascular wall (an important factor in the development of arte- rial lesions, oxidative stress of the endothelium, oF vascular eicosa- noid production). In 1987, the results of a 12- year prospective popullation study. (N=859) showed that the relative risk of stroke-associated mortality ‘vas significantly lower with higher potassium intake." In fact, muli- variate analysis demonstrated that a 10-mmol higher level of daily po- tassiuim intake was associated with, 18 40% reduction in the relative risk of stroke mortality. This apparent protective elect of potassium was in- dependent of other nutritional vari ables, including energy (caloric) in- take; dietary levels of fat, protein, and. fiber; and intake of ealeium, mag- nesiuim, and alcohol. The authors also noted that the effect of potas siuum was greater than that which ‘would have been predicted from its ability to lower blood pressure." More recently, Ascherio etal re. ported the results ofan 8-year inves ligation of the association between di- etary potassium intake and subsequent risk of stroke in 43738 US men, aged 40 to 75 years, with- ‘out previously diagnosed cardiovas- celar disease or diabetes. During the study follow-up, 328 strokes were documented. The relative risk of stroke for men in the top filth of the range of potassium intake (median in- take, 43 g/d) vs those in the bottom ‘ith (median, 24 g/d) was0.62 (Pfor trend=.007). The inverse associa- don between potassium intake and subsequent stroke was more marked. ‘im hypertensive men and was not sig- nificantly altered by adjustment for baseline level of blood pressure." Ascherio etal? also found that the use of potassium supplements was inversely related to the risk of stroke, particularly among hyper- tensive men. They speculated that this relationship might be due, at least in part, ta reduction inthe risk for hypokalemia" The authors recommended increasing the in- ‘Table 3. Drugs That Induce Hypokalemia® ‘poate Tranecalarpotssim shit Be Adenrge agonist epneplvn), decongestants broncodistars, toca agents, theophyine cafe, veapariintoiaton, chloroquine Intestin, meuin overdose Inereasd rena potassium ss Diurets(acstazlamide,thiaies,clothaldne, ‘uroseie,mieaecorends ucrocartaone cal), substances ith mirsrlecortci ete high-osequcocoricoids, high-dose antes (pen, ‘fein, drape asocated wh magnesium dplton (aminoglycosides, elspa, fscaret sodium, ee naveing Ong amnphotern 8) cess ptasiumlossin stool Phanalphta, sium polystyrene sulonte Adapted ton Genarl® take of potassium by substituting potassium-rich fruits and veg- fruits, vegetables, and their natural etables was inversely related to sys- juices for low-potassiuim processed _tolic and diastolic pressure." Simi- foods and sodas and by consider- larly, 24-hour urinary potassium ing potassium supplements for per- excretion, 24-hour urinary sodium sons with hypertension.® excretion, and the ratio of urinary sodium to potassium were found 10 HYPOKALEMIA be independently related to blood pressure in the INTERSALT study," Clinical Implications ‘4 52-center international study of in Hypertension, electrolytes and blood pressure. Additional information was pr Evidence from epidemiologic and vided by the Rotterdam Study.’ clinical studies has implicated potas which evaluated the relationship. sium depletion in the pathogenesis between dietary electrolyte intake and maintenance of essential hyper and blood pressure in 3239 older tension." Increasing the intake ofpe- people (age, =55 years). A 1 g/d tassium appears to have an antihy- higher level of dietary potassium pertensive effect that is mediated by intake was associated with a 0.9 such mechanisms as increased nat mm Hg lower level of systolic Uuresis, improved baroreflex sensitiv. blood pressure (P=.11) and a 0.8 ity, direct vasodilation, and lower mm Hg lower level of diastolic cardiovascular reactivity to norepi-__ blood pressure (P=.01) nephrine or angiotensin IL.” Indi- Whelton et al! recently con- rect support for this hypothesiscomes ducted a meta-analysis of random- from observations of the effects ized controlled trials evaluating of primary aldosteronism (eg, __theelfects oforal potassium supple- aldosterone-producing hyperplasia mentation on blood pressure. This for adenoma) or secondary aldoste- analysis included 33 clinical tials in- ronism (eg, excessive ingestion of volving 2600 participants. In these licorice). Thesesyndromesare char- trials, the use of potassium supple- acterized by abnormally low serum mentation was the only difference potassium levelsandelevated blood between the intervention and con- pressure. Reversal of the underl ing cause results in increased 5 rum potassium levels and de cereased blood pressure. Similarl ol arms, Dosages of potassium (mostly in the form of potassium chloride) ranged from 60 mmol/d 10 greater than 100 mmol/d. The re- correction of diuretic or laxative sults demonstrated that potassium abuse can also raise potassium level supplementation was associated with, ‘and lower blood pressure significant reduction in mean sys- The large-scale Nurses’ Health tolic and diastolic blood pressure Study (N=41541) found that C44’ mm Hg and 2.4 mm Hg, re- dictary potassium intake was spectively;P=.001). The greatest ef Inversely associated with blood fects were observed in participants pressure, Specifically, intake of who had ahigh concurrent sodium (aepRa\ TED) ARCHINTERN MEDI VOL 1, SEP 11 S000" WOAWARCHINTERNMED CON (©2000 American Medical Association. Al rights reserved,intake. This analysis suggests that low potassium intake may play an important role in the genesis of high blood pressure. Thus, the authors recommended increased potas- sium intake for the prevention and teatment of hypertension.” Based on the strength ofthe available data, the Joint National Committee for Prevention, Detection, Evaluation, and Treatment of High Blood Pres sure JNC VI) included inereased potassium intake as a core recom- mendation for the prevention and weatment of hypertension, Among hypertensive patients, certain subgroups would derive spe cial benefit from increased potas- sium intake. Best recognized are AE rican Americans."" In the meta- analysis by Whelton et al,** the reduction of systolic blood pres- sure alter potassium supplementa- tion was approximately 3 times greater in blacks compared with whites. In addition, several studies have revealed lower urinary potas- sium excretion in blacks than in whites.” Watson etal reported that 24-hour urinary excretion of potas- sium was 28 mmol in black females ‘and 36 mmol in white females, The urinary sodium-to-potassium ratio was 4.1 in blacks and 2.9 in whites, difference that was statistically sig” nificant." The Veterans Adminis- tration Cooperative Study Group on Antihypertensive Agents (N=623) found potassium excretion to be 02% higher in whites than in blacks (73441 vs 45440 mmol); in addi- tion, serum potassium levels were negatively associated with systolic blood pressure. The study con- cluded that the difference in ut nary potassium excretion and in se- rum potassium levels between blacks and whites reflected a difference be- ‘owen the 2 groups in the intake of dietary potassium. Such a differ- fence may be an important factor in the greater prevalence of hyperten- sion in blacks.” Clinical Implications in CHF Not surprisingly, potassium deple- tion is commonly seen in patients with CHF, a condition that is char- acterized by several physiologie ab- ‘normalities that predispose to the de- velopment of electolyte disturbances. (aepRay TED) ARCHTINTERN MEDIVOL eo, SEP TT S00” WWARCT “Among the pathogenetic factors as- sociated with CHF are renal dys function and neurohormonal acti- vation, which embrace stimulation of the renin-angiotensin-aldoste- rone axis, enhanced sympathetic nervous tone, and hypersecretion of catecholamines." ‘A common misperception re- garding angiotensin-converting en- zyme (ACE) inhibitor therapy is that these drugs enhance potassium re- tention, thereby eliminating the need to add potassium of potassium sparing diuretics to ACE inhibitor therapy. In many cases, the pre- seribed dosages of ACE inhibitors in patients with CHE ate insullicient to protect against potassium loss. Se- rum potassium levels, therefore must be closely monitored in all pa” tients with CHF-—even those tak- ing ACE inibitors—to minimize the life-threatening risk of hypokale- mia in these patients, The arrhythmogenic potential of digoxin is enhanced by hypoka- lemia in patients with heart failure. When using digoxin in combina- tion witha loop diuretic and an ACE inhibitor, the decision of whether to administer potassiuim supplements ‘ean be complex. Leier et al recom- mend maintaining serum potas- sium levels in the range between 4.5 and 5.0 mmol/L. They suggest that llective potassium management ‘with properly targeted serum potas- sium concentrations... probably represents the most effective and sale antiarrhythmic intervention” in heart failure. Magnesium may also bbe administered to facilitate the re- versal of refractory hypokalemia, The importance of preventing hypokalemia is underscored by the finding that the risks of dysrhyth- mias, syncope, cardiac arrest, oF death are greater in patients with heart failure.» This result may be due in part to the cells of hypertro- phied and failing hearts often hav- ing prolonged action potential du- ration, which in most cases is due toa decrease in outward potassium Nolan et al found that low serum potassium levels were re- lated to sudden eardiae death in the United Kingdom Heart Failure Evali- ation and Assessment of Risk Trial (N=433). Grobbee and Hoes" r ported similar results in an examina tion of published randomized trials and recent case-control studies; pa tients with hypertension who wer prescribed non-potassium-sparing di- luretics had approximately twice the risk of sudden cardiac death com- pared with users of potassium- sparing therapy. The authors recom- mended using thiaside diuretics ata ow dose only, and adding a potas- sium-sparing diuretic drug when higher diuretic doses are needed. They estimated thatthe protective ef- {ect of antihypertensive treatment on ‘mortality might be halved by the in- duction of sudden death following po- tassiumn loss Leier et al suggested that vir- tually all patients with CHE should receive potassium supplementation, a potassium-sparing diuretic, or an ACEinhibitor. Thisis a prudent man- agement strategy in light of the po- tentially dire consequences of hypo- kkalemia in these patients Clinical Implications in Patients ‘With Arrhythmias Intheabsence of underlying hear dis- ease, major abnormalities in cardiac conduction secondary to hypokal mia are relatively unusual, How- ever, mild-to-moderate hypokale- mia can increase the likelihood of cardiac arrhythmias in patients who hhave eatdiae ischemia, heart failure, of eft ventricular hyperteophy.* As ‘mentioned earlier, this occurrence is. not surprising in light ofthe impor tant role that potassium plays inthe clectrophysiologic properties of the heart. The relation between extra and intracellular potassium levels is the primary determinant of the rest ing membrane potential (RMP) Changes in potassium level modify the electrophysiologic properties of the membrane and ean have pro- found effects on impulse geners- don and conduction throughout the heart.” Potassium deficiency, as well as, potassium channel blockade oF down-regulation, can cause pro- longed repolarization, the patho- genie factor in the genesis of tor- sades de pointes. The effects of hypokslemia on repolarization are ‘magnified in many disease states, in cluding left ventricular hypertro- (©2000 American Medical Association. Al rights reserved,phy, CHE, myocardial ischemia, and myocardial infarction, Such ef- fects, in turn, are compounded by agents with class IIL antiarrhyth- mic effects, such as sotalol" The Nernst equation de- scribes how the ratio of intracell- lar to extracellular potassium al- fects the RMP of myocardial cells: RMP=-61.5 log [K*/K°,]. Changes in this ratio, such as those induced by diuretic therapy, affect cardiac conduction and automaticity. As a result, low intracellular potassium levels ean increase spontaneous de- polarization, automaticity, and the emergence of ectopic foci.” Despite this compelling basic information, the link between hy- pokalemia and clinical arrhythmo- {genesis is not a strong one. Caralis, tab studied 17 hypertensive men to determine the relationship of di- uuretic-induced hypokalemia with ventricular ectopic activity. They {ound that the risk for ventricular ec topic activity was marked in a group of patients who were older and had clinial evidence of organic heart di cease, Patients with these characte fstics had increased frequency and complexity of ventricular ectopic activity during diuretic therapy In these patients, normalization of serum potassium levels with oral po- tassiuim supplements or potassium sparing agents reduced the complex ity and frequency of arrhythmias by 85%, even after discontinuation of diuretic therapy. Therefore, the au thors recommended tha clinical and laboratory observation should be used to identify those patients sus- ceptible to diuretic-induced ven- tricular ectopic activity (eg, older patients with organic heart disease) land that steps should be taken to normalize serum potassium levels. Caralis et al speculated that the finding of electrocardiographic abnormalities in a specific popula lion suggested that modest distur bances of potassium metabolism alone may not induce arrhythmia; rather, abnormalities of heart rhythm are most likely when underlying heart disease and low potassium occur together. => Although the relation be- ‘ween complex ventricular arehyth- mia and hypokalemia remains uncertain, there is evidence that hy- (aepRay ED) SRCHINTERN MEDIVOL 1, SEP TT Sn00”—WOWARCT pokslemia can trigger sustained ven- tricular tachyeardia or ventricular brillation, particularly in the setting ‘of acute myocardial infarction. How= ‘ever, the exact mechanism by which hypokalemia provokes ventricular fi- brillation or sudden eatdiac death in the absence of an acute myocardial infarction is unclear. In patients with ahistory of serious arrhythmias re ‘ceiving antiarrhythmic drugs, hy- pokalemia may reverse the benefi- ‘dal effects of these agents and render the patient vulnerable to a recur- rence of arrhythmia.” IL is prob- ably Important, therefore, to im- pose a stricter standard for treatment (potassium <4.0 mmol/L) espe- ‘ial in patients with heart disease ‘who are at risk for serious ventric lar tachyarthythmias. For exampl the risk of early ventricular ibrlla- tion in acute myocardial infarction is strikingly increased in patients ‘with serum potassium levels less than 3.9 mmol/L.” However, there are no data to prove that aggressive replenishment of potassium in pa- tients with heart disease necessar- ily leads to a better clinical out- POTASSIUM ‘SUPPLEMENTATION ‘STRATEGIES: PREVENTION VS REPLETION, Increasing potassium intake should he considered when serum potas- sium levels are between 3.5 and 4.0 mmol, Although treatment of ‘asymptomatic patients with border- line or “low normal” concentra- tions is controversial, very low lev- els (<3.0 mmol) are universally regarded as undesirable. Efforts to increase potassium intake are appropriate in certain populations who are vulnerable to cardiac arrhythmias (such as patients with heart failure, these taking digoxin, and patients with a history of myo- ‘eardial infarction oF ischemic heart disease). When the serum po- tassium level is below 3.5 mmol, potassium supplementation may be warranted even in asymptomatic patients with mild-to-moderate hypertension.* Strategies to minimize the risk ‘of potassium depletion include mint mizing the dosage of non-potassium- sparing diuretics and restricting so- dium intake. Increasing dietary potassium is the most straightfor- ward means of enhancing potas- sium intake, but the high content of some potassium-rich foods is a po- tential drawback to dietary potas sium supplementation (Table 1). Moreover, dietary potassium is almost entirely coupled with phos- phate, rather than with chloride; therefore, itis not elfective in correct- {ng potassium loss that is associated, with chloride depletion, such as in diuretic therapy, vomiting, and na- sogastric drainage For patients re- ceiving diuretic therapy, an at tempt should be made to reduce the dose or to discontinue therapy. the potassium depletion is not due to di- luretic therapy, the patient should be evaluated for other causes of potas- sium loss! When diuretic therapy is necessary, potassium balance should be protected by using low-dose di- uretics and by using diuretics in combination with drugs that have the potential for sparing potassium (such as B-blockers, potassium- sparing diuretics, ACE inhibitors, or angiotensin receptor blockers) Repletion strategies also should in- clude eating foods high in potas sium, using salt substitutes, or taking prescription potassium supplements (Table 4).* Potassium salts include potas- sium chloride, potassium phos- phate, and potassium bicarbonate Potassium phosphate is found primarily in food, and potassium bicarbonate is typically recom- mended when potassium depletion ‘oceutsin the setting of metabolic act- dosis (pH <7.4). In all other se tings, potassium chloride should be used becauise of ts unique effective ness against the most common causes of potassium depletion, Mot over, hypochloremia may develop if citrate, bicarbonate, gluconate, oran- other alkalinizing salt is adminis tered, particularly in patientsadher fing to diets that restrict the intake of chloride. Potassium chloride is available in ether liquid or tablet for- mulations (Table 4), and all potas sium formulations are readily ab- sorbed. Although liquid forms may beless expensive, they havea strong, unpleasant taste and often are not well tolerated, (©2000 American Medical Association. Al rights reserved,Table 4, Potassium Supplements Suppiement ‘Conzali-lase microenepauaed ‘abet Encapsulated contol ease ‘mironcapsultd partes Pela cori ir Potassium chloride (efrvescant alts) ‘or salon Warm enendd-elese alts oncapuatd mtoparicles: ss ‘heen an ase cohesive Fear rasan than vkematiblee*© Inowpensiv, tastes ta, poor compas ‘ew erosions; immediate tet * Comriant, bu mare expansive than “malate flat Easier a eval more gastrointestinal ‘act erosans compared with ‘meroancapsulted formulations *© COMPLIANCE ISSUES ‘AND POTASSIUM REPLACEMENT THERAPY As with many long-term therapies, compliance can be a challenge with potassium supplementation. Spe- cic characteristics of a medication, such as appearance, color, taste, size cease of swallowing, and cost can all influence patient compliance.” Std fes demonstrate that drug regimens should be simplified to the greatest ex- tent possible to enhance compli- ance. Forinstance, compliance rates ‘canbe improved by requiring the few est doses of medication per day. An examination of automated phar macy records by Halpern etal” docu- ‘mented this hypothesis, In their study fof more than 2000 patients, the in- vestigators determined the mean ad- hherence ratios for 1 pill vs 2 or more pills daly with an equivalent dosage ff potassium supplementation. At L year, the mean adherence ratio was significantly higher for patients take {ng 1 pill compared with those take ‘ng mulipl pills per day. The worst ratios were observed in patients who were treated with liquid potassium supplements, which the authors speculated may have been due to in- creased side elects, poor taste, andthe inconvenience of liquid supple- ments." In their conclusion, the att hherence is vitally important in the successful treatment of disease, espe- cially in asymptomatic long-term diseases... Siice potassium supple ‘ments are typically indicated forlong- {erm use, iL is important to optimize patient adherenc Reported adverse effects of polassitim supplements alfect pri- (aepRnED) ARCHINTERN MEDI VOL 16h SEP TT SOOO sarily the gastrointestinal act, and they include nausea, vomiting, di- arthea, flatulence, and abdominal oF discomfort. Ulcerations of the small bowel have been reported alter the administration of enteric ‘coated potassitim chloride tablets. A few cases of small bowel ulee ation, strieture, and perforation have Ibeen associated with wax-matex for- ulations.” Although slow-release tablets have been associated with {gastrointestinal tact ulcerations and bleeding, the risk of these compli- cations i low and seems t be low fst with the use of microeneapstt lated preparations POTASSIUM REPLETION AND. THE ROLE OF MAGNESIUM. Magnesium is an important cofac- ‘or for potassium uptake and for the maintenance of intracellular potas- sium levels. Recent studies using cel- lular models confirm the critical role ‘of magnesium in maintaining intea- cellular potassium and indicate that the mechanisms are multifacto- rial" Whang and colleagues" dem- onstrated that coexisting magn: ‘sium and potassium depletion could lead to refractory potassium repl tion, which is the inability to re- plete potassium in the presence of Unrecognized and continuing mag- nesium deficiency Many patients with potassium depletion may also have magne- sium deficiency. In particular, loop diuretics (eg, furosemide) produce substantial serum and intracellular potassium and magnesium loss, Di- goin accelerates the excretion of magnesium by reducing its reab- sorption at the renal tubules, The role of magnesium in maintaining in- tracellular potassium is particu- larly important in cardise myo- cytes because it desensitizes them to the calcium-induced arrhythmo- genic actions of cardiae glycosides, Routine determination of se- rum magnesium levels should be considered whenever the measure ‘ments of serum electrolytes are nes essary ina patient. Whang etal rec ‘ommend considering the repletion fof both magnesium and potassium for patients with hypokalemia, Di- etary sources of magnesium in- clude whole-grain cereals, peas, beans, nus, cocoa, seafood, and dark. green vegetables. CONSENSUS GUIDELINES FOR THE USE OF POTASSIUM REPLACEMENT IN CLINICAL PRACTICE Low serum potassium concentra lion is perhaps the most common electrolyte abnormality encoun- tered in clinical practice. Strategies aimed at achieving and maintain- {ing normokalemia must take into ac- count such factorsas (1) baseline po- tassium values, (2) the presence of underlying medical conditions (eg, CHP), (3) the use of medications that alter potassium levels (eg, non— potassium-sparing diuretics) or that lead to arrhythmias in the presence of hypokalemia (eg, cardiac glyco- sides), (4) patient variables such. as diet and salt intake, and (5) the ability to adhere to a therapeutic regimen, Because of the multiple fac~ tors involved, guidelines therefore should be directed toward patients with specific disease states, stich as those with cardiovascular condi- tions, and toward the general pa- tient population, The following list encompasses our general practices {or the use of potassium. The guide- lines were developedata 1908 meet {ng of the National Couneil on Po- ‘assim in Clinical Practice lis clear that controlled clinical studi necessary to determine the specific recommendations, General Guidelines 1, Dietary consumption of potassium- rch foods should be supplemented with (©2000 American Medical Association. Al rights reserved,potassium replacement therapy. Of ten, increasing dietary potassium in- take is not completely effective in re- placing the potassium loss associated. with chloride depletion (eg, that which occurs in diuretic therapy vomiting, or nasogastric drainage) because dietary potassium is al- ‘most entirely coupled with phos- phate, rather than with chloride. In addition, the consumption of potas- siuim-rich foods in amounts that are sulficient to increase the level of se- rum potassium level to acceptable concentrations may be costly, and it ‘may lead to weight gain, 2. Potassium replacement is recommended for individuals who are sensitive to sodium or who are tunable or unwilling to reduce salt intake; i€ is especially effective in reducing blood pressure in such per- sons, A high-sodium diet often resulls in excessive urinary potas- sium loss, 3. Potassium replacement is rec- ‘ommended for individuals who are subject to nausea, vomiting, diar~ rhea, bulimia, or diureticflaxative abuse, Potassium chloride has been shown tobe the most elfective means of replacing acute potassium loss. 4. Potassium supplements are best administered orally in a moder ate dosage aver a period of days to ‘weeks to achieve the full repletion of potassium, 5. Although laboratory measure- ‘ment of serum potassium is conve- nent, it is not always an accurate in- dicator of total body potassium ‘Measurement of 24-hour urinary po- tassitim excretion is appropriate for patients who are at high risk (eg, those with CHF). ‘8. Patient adherence to potas- sium supplementation may be in- creased with compliance-enhancing regimens, Microencapsulated formti- lations have no unpleasant taste and are associated with a relatively low. incidence of gastrointestinal side ellects 7. Potassium supplementation regimens should be as uncomplicated 4s possible to help optimize long- term compliance. 8. Adosage of 20 mmolid of po- tassium in oral form is generally suf Jicient for the prevention of hypoka- Tenia, and 40 to 100 mmol sulficient Jor its treatment (aepRay ED) ARCHTINTERN MEDIVOL oo, SEPT an00”—WWARCT Patients With Hypertension 1. Patients with drug-related hy pokalemia (ic, therapy with a non potassium-sparing diuretic) should receive potassium supplementation. 2. In patients with asymptom- ‘atic hypertension, an effort should be made to achieve andl maintain serum potassium levels oft leas 4.0 mmol/l. Low serum potassium levels (eg, 3.4 mmol/L) in asymptomatic patients ‘with uncomplicated hypertension, shouild not be regarded as inconse- ‘quential. Dietary consumption of po- lassium-rich foods and potassim supplementation should be insti- tuted as necessary. Patients With CHE Potassium replacement should be row- tinely considered in patients with CHE, ‘even f the initial potassium determi nation appears tobe normal (eg, 4.0 mmol/L). The majority of patients ‘with CHP are at increased risk for hypokalemi In patients with CHE ‘or myocardial ischemia, mild-to- moderate hypokalemia can in- cerease the risk of cardiac arthyth- mia. In addition, diuretic-induced hypokalemia can increase the risk of digitalis intoxication and life- threatening arthythmias, In light of the above informa- tion and the potential for hyperka- lemia to occur secondary to drug, therapy with ACE inbibitors or an- ‘glotensin Il receptor blockers, regu- lar monitoring of the serum potas- sium level is essential in these patients. Atany time, stress can trig- zger the secretion of aldosterone and the release of catecholamine in sponse to low cardiac output, thereby precipitating a fal in the se- rum potassium level Patients With Cardiac Arrhythmias ‘Maintenance of optimal potassium lev els (at least 4.0 mmol/L) is critical in these patients and routine potassium ‘monitoring is obligatory, Patients with heart disease are often susceptible to life-threatening ventriculararthyth- mias. In particular, such arrhyth- mmias are associated with heart fail- ure, left ventricular hypertrophy (characterized by an abnormal QRS complex), myocardial ischemi: and myocardial infarction (both in the acute phase and alter remod- cling). The coadministration of ‘magnesium should be considered 10 facilitate the cellular uptake of po- Patients Prone to Stroke I is prudent to maintain optimal po- tassium levels in patients at high risk {Jorstroke (including those with ahis- tory of atherosclerotic or hemor- rhagic cerebral vascular accidents) Although the effectiveness of potas sium supplementation in reducing the incidence of stroke in humans hhas not been demonstrated in ran- domized controlled trials, prospe: live studies suggest that the ine dence of fatal and nonfatal stroke correlates inversely with dietary po- tassium intake. In addition, the as sociation of stroke with hyperten- sion is well known, Patients With Diabetes Mellitus Potassium levels should be closely monitored in patients with diabetes ‘mellitus and potassium replacement therapy should be administered when ‘appropriate. Data underscore the ad- verse effects of glucose and instilin, oon potassium levels and the high in- idence of cardiovascular and renal ‘complications in patients with dia- betes mellitus, These factors are spe- cific to patients with type 2 diabe- tes who have poorly controlled serum glucose levels, Patients With Renal Impairment Data suggest a link between potas- sium levels and lesions of the kidneys. {in patients with renal disease or dia betes. Animal studies have demon- strated that potassium may offer a protective effect on the renal arteri- oles. The clinical implications of these findings are not yet clear. Accepted for publication February 28, 2000. This article is based on a sym- posium supported by a grant from Key Pharmaceuticals, Kenilworth, NJ The National Council on Potas- sium in Clinical Practice partici pants include: Jay N. Cohn, MD, (©2000 American Medical Association. Al rights reserved,Department of Medicine, University of ‘Minnesota Medical School, Minneapo- lis; Peter R. Kowey, MD, Department of Cardiology, Lankenau Hospital and Medical Research Center, Wy' newood, Pa, Department of Medicine, Jefferson Medical College, Phila- delphia, Pa; Barry J. Materson, MD, Department of Medicine, University of Miami, Miami, Fla; L. Michael Pris fant, MD, Department of Medicine, Director of Cardiology Fellowship Training, Medical College of Georgia, Augusta Elijah Saunders, MD, Depart- ‘ment of Medicine, Hypertension Divi- sion, University of Maryland School of Medicine, Baltimore; Dorothy L. ‘Smith, PharmD, President, Con- sumer Health Information Corpora tion, McLean, Va, Department of Community and Family Medicine Georgetown University School of Medicine, Washington, DC; Louis Tobian, MD, Department of Medi- cine, Division of Hypertension, Uni versity of Minnesota Medical School, Minneapolis; and Paul K. Whelton, MD, Tulane University School of Public Health and Tropical Medi- cine, New Orleans, La. Reprints: Jay N. Cohn, MD, Car- diovascular Division, MMC 508, Uni versity of Minnesota, 420 Delaware St SE, Minneapolis, MN 55455, SSS 1. Manda AK Hyplaemiana hyper. Mad Gln on Am oer 11-38, Gonna Fl pote. Eng J Med 1008 esis Felpe i KametKS Possum, area 1986 See “Tanan RL Potaesum orders: Kola J, Taman RL es ue on cre Sede Place P: WS Sanders: 1D chap 3 5 Hoes Al. Gatoes DE, Pet 1, Lube 1 Do onpoasiu-peing cues ese ik ‘aden care death in hyperens tens recent eens, Orgs 19844771 m 6. Asis Rin E8, Hera MA ot ake fausim, mages ral ane ang Fiske crake song US men. Crea. 086 ee ne 7 Mette RD dct A, Seat, Young (Dis Potseumiebs ede oman paren 194247 82. 8 fetate RD Yourg 08 Poasum nits eu ‘ured acer smoot muss pratt. Herens 1847 30680 9. Link YeungD8 raion tween plasm po ‘asum atc paephne corner rambo Indoge relator 104 2051-38, 10, his Toba, Supra Eso High (epRaNTED) XRCHINTERN MED VOL 16, SEP TT 3000 a 2 a a. posssion de rece ase andl fp rotenone spans yp lune ats Cin Exp Hypertens. 106 T89. en. IshnasuT, Tobin, Sugino. Large High potasum dnt ete macrophage seronee {0 th vacua yall sake pone sponta hypertensive rats Vase Res. 10952: ates Teta T, Toba Usha. 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