Hypokalemia and Cardiovascular Disease Michael Schulman,
MD,
A growing body of experimental,epidemiologicand physidogic evidencetestifiesto the hazards of hypokalemiaand other electrolytedisordersthat can complicatethe chronicuse of diureticdrugs in patientswith cardiovasculardisease.This study reviewsthe complexrenal and extrarenalmechanisms that regulatepotassiumbalancein normal personswith spsciaiattentionto the role of stressrelatedhormones.Disturbancesof potassiumbaiante are commonin patientstaking diuretics;indeed, the potentialnumber of peoplein this country at risk of diuretic-relatedhypokalemiaapproaches 9 million.The magnitudeof this problemis of particularconcern,becauseof the compellingdata that link hypokalemiain such patientsto electricalinstability of the heart and to a fatal outcomeafter an acutecardiacinjury. Therefore, aggressivecorrection of hypokalemiais warrantedin patientswith cardiovasculardisorders. (Am J Cardioi 1990;65AE-9E)
and Robert G. Narins, MD
?The
dangers of hypokalemia in patients with cardiovascular disease have become a matter of increasing concern, particularly to physicians working in critical care facilities. Such concern is heightened by the awareness that hypokalemia, long recognized as hazardous to cardiac patients receiving digitalis, can be life-threatening to other patients as well, and that even mild degrees of hypokalemia are associated with substantial risk.’ Potassium-wasting thiazide and loop-active diuretics are, of course, frequently used in volume-overloaded cardiac patients. Because hypertension is a common cause of heart disease and because most hypertensive patients receive diuretics, it follows that many patients with heart disease are at risk of hypokalemia developing. There is also growing evidence for the existence of complex neurohormonal events which, set in motion in the first moments after acute cardiac injury, interact to augment both the magnitude and the lethality of hypokalemia.2 The gravity of the problem is further heightened by the recognition that hypokalemia in the critically ill patient is often iatrogenic and almost always preventable.3 The pathogenesis and hazards of hypokalemia in cardiac patients are reviewed. Normal potassium balance is briefly summarized, and those areas of particular relevance to patients with heart disease receiving potassiumwasting diuretics are highlighted.
1
POTASSIUM METABOLISM IN HEALTH AND IN CARDIAC DISEASE
From the Department of Nephrology, Temple University, Health Sciences Center, Philadelphia, Pennsylvania. Address for reprints: Robert G. Narins, MD, Temple University Healthy Sciences Center, Department of Nephrology, Parkinson Pavilion, Room 580, Broad & Tioga Streets, Philadelphia, Pennsylvania 19140.
4E
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
65
The normal concentration of potassium in the extracellular fluid (Ko) is precisely regulated, ranging between 3.5 and 5.3 mEq/liter. Intracellular potassium concentration (Ki) is far greater-roughly 150 mEq/liter in most tissues; thus, approximately 98% of the body’s potassium is contained in cells. In absolute terms, the person weighing 70 kg with 28 liters of intracellular fluid stores 4,200 mE.q (28 liters X 150 mEq/liter) of potassium in his cells, while only 63 mEq (14 liters X 4.5 mEq/liter) reside in his extracellular space. Because clinical states of potassium depletion are often associated with deficits of 2QOto 400 mJ?q, cellular potassium stores must sustain greater absolute losses of the cation than the extracellular compartment. Whereas the loss of even several hundred mEq of intracellular potassium hardly changes Ki, the loss of a mere 30 mEq of extracellular potassium reduces Ko by half. Thus, in states of potassium depletion, KO is generally reduced much more than Ki. The pathophysiologic and clinical importance of these concentration changes and the importance of preventing deviations in the extracellular potassium concentration is suggested by the Nernst equation, which provides an approximate val-
ue for the resting cellular transmembrane electrical poPOTASSIUM BALANCE tential (Em): Em = -61 log Ki/Ko. Because the ratio of Ki/Ko strongly influences Em, and because the numerator Ki changes relatively little, even minor decrements in Ko produce significant degrees of cellular hyperpolarity. The altered excitability of CELLULAR cell membranes resulting from these increases in the Ki/ POTASSIUM Ko ratio underlies the hypokalemia-induced dysfunction CONCENTRATlON in skeletal muscles, the nervous system and the heart. The neuromuscular and dysrhythmic manifestations of potassium depletion are likely related to changes in Em. The preservation of a near-constant extraceullar po,GOWdoy PLAGMA GOOm.q,day I(* tassium concentration requires that daily potassium intake (normally 50 to 150 mEq) be more or less exactly matched by the renal and gastrointestinal excretion of potassium (Fig. 1). Stool losses are not critical to potassium balance in healthy persons, averaging about 10 mEq/ day. Thus, the kidneys must excrete an amount of potassium equal to the net absorption if external balance is to FIGURE 1. lntemd and external potassim balance: tnterd and extend baleme of pdassbn. See text be maintained. Since the kidneys filter 180 liters of plas- (Le., trm) ma water per day, the daily filtered load of potassium terdetas. averages 800 mEq (4 to 5 mEq/liter X 180 liters/day). Net tubular reabsorption must therefore occur, since the creased potassium secretion, perhaps because potassium chloride co-transport out of the lumen is inhibited.4 daily excretion of the 50 to 150 mEq required to maintain The peritubular factors augmenting distal potassium balance is far less than the filtered load. Micropuncture studies have shown that only a small fraction of the potas- secretion include increased dietary potassium intake, increased plasma potassium concentration and an elevated sium entering the proximal tubule remains by the time serum pH. It is the hormonal regulation of potassium the filtrate reaches the distal tubule.4 Thus, preservation secretion, however, that assumes major importance in the of potassium balance in the face of variable dietary intake is entirely dependent on the regulation of potassium se- cardiac patient, particularly after a catastrophic illness. cretion in the distal nephron. This secretory process is Chronically elevated levels of aldosterone stimulate potassium secretion in the cortical-collecting tubule and mediated by specific tubular epithelial cells (“principal cause hypokalemia. The hormone also stimulates extracells”) located in the collecting ducts in the superficial renal cells to take up potassium, thereby augmenting the cortex.4 development of the hypokalemia to a small degree.5 Potassium transport across the cell membrane is influMany patients with congestive heart failure manifest hyenced by 2 sets of factors: (1) those acting on the luminal perreninemia and hyperaldosteronism-as would be anmembrane, and (2) those acting on the contraluminal membrane.4 Among the most important luminal factors ticipated from the diminished renal perfusion that follows modifying potassium secretion are distal tubular flow the reduction in effective arterial blood volume caused by rate and sodium delivery. Although fluctuations in flow left ventricular failure. However, a significant number of rate and sodium delivery occur in parallel manner under such cardiac patients actually have normal renin and physiologic conditions, investigations using micropuncaldosterone levels.6 The reason for this surprising finding is unclear but may be related to high levels of atria1 ture techniques suggest that flow rate is the more critical determinant. The mechanism by which increased flow natriuretic hormone. The cardiac hormone is released in states of increased preload, and it impairs the secretion of augments net secretion is most likely by diluting luminal potassium, thereby eliminating concentration gradients renin and aldosterone.7 The acute infusion of glucocorticoids stimulates potassium secretion by virtue of their across the luminal membrane unfavorable to continued secretion of the cation. In vitro studies also suggest that action to increase glomerular filtration rate with conseluminal sodium concentrations of less than 35 mEq/liter quent increased distal sodium delivery. Antidiuretic horexert a rate-limiting effect on potassium secretion; how- mone (ADH) stimulates the secretion of potassium by ever, such concentrations are probably not encountered distal tubular epithelial cells by increasing their permeunder physiologic conditions. ability to the cation.8 Were it not for this countervailing The transepithelial potential in the distal tubule is kaliuretic action of ADH, the reduced distal flow caused negative and so favors potassium secretion. Thus, the by water deprivation might otherwise lead to renal potasdiuretic amiloride, which blocks sodium entry into distal sium retention. Conversely, the polyuric effect of excess tubular cells and thereby reduces luminal electronegativiwater intake might lead to renal potassium-wasting, were ty, exerts a “potassium-sparing” effect by indirectly in- it not for the associated suppression of the potassium hibiting secretion. Luminal concentrations of chloride, secretogogue ADH.8 when less than 20 mEq/liter, are associated with inEpinephrine exerts a minor inhibitory effect on distal THE AMERICAN JOURNAL OF CARDIOLOGY MARCH 6,199O
SE
A SYMPOSIUM:
HORMONE-ELECTROLYTE
INTERACTIONS
renal tubular potassiumsecretionbut strongly stimulates extrarenal potassium uptake, thereby causing hypokalemia.9 Insulin, like epinephrine, increasescell membrane adenosinetriphosphataseactivity which in turn increases cellular potassium uptake.to Thus, the increasedrelease of epinephrine and insulin during extreme stresspredisposesto redistributional hypokalemia. Patientswith mild, uncomplicated chronic congestive heart failure not receiving diuretics are not likely to have hypokalemia. Under such circumstances,the hypokalemia-producing effects of volume contraction and attendant hyperaldosteronism are usually offset by the potassium-retaining effects of renal hypoperfusion, reduced filtration and diminished distal salt and water delivery. However, when diuretics enhance distal flow and sodium delivery, substantial potassium-wasting and hypokalemia can occur, especiallyin thosepatients with preexisting hyperaldosteronism. The release of epinephrine in the wake of the severestressaccompanying an acute myocardial infarction may also cause redistributional hypokalemia (see later).” PREVALENCE
OF HYPOKALEMIA
The importance of hypokalemia in patients with cardiovascular diseasecan be estimated by considering the frequency with which this chemical abnormality is likely to be encountered.Between40 and 60 million Americans have sustained diastolic blood pressuregreater than 90 mm Hg and therefore are candidatesfor antihypertensive therapy.’ l Although the useof diuretics as initial therapy for hypertension is decreasing, many hypertensive patients still receive these agents alone or in combination with other drugs at some point in the course of their disease.Both the dose and half-life of thiazides and the duration of therapy influence the likelihood that hypokalemia (serum potassium
MD,
A growing body of experimental,epidemiologicand physidogic evidencetestifiesto the hazards of hypokalemiaand other electrolytedisordersthat can complicatethe chronicuse of diureticdrugs in patientswith cardiovasculardisease.This study reviewsthe complexrenal and extrarenalmechanisms that regulatepotassiumbalancein normal personswith spsciaiattentionto the role of stressrelatedhormones.Disturbancesof potassiumbaiante are commonin patientstaking diuretics;indeed, the potentialnumber of peoplein this country at risk of diuretic-relatedhypokalemiaapproaches 9 million.The magnitudeof this problemis of particularconcern,becauseof the compellingdata that link hypokalemiain such patientsto electricalinstability of the heart and to a fatal outcomeafter an acutecardiacinjury. Therefore, aggressivecorrection of hypokalemiais warrantedin patientswith cardiovasculardisorders. (Am J Cardioi 1990;65AE-9E)
and Robert G. Narins, MD
?The
dangers of hypokalemia in patients with cardiovascular disease have become a matter of increasing concern, particularly to physicians working in critical care facilities. Such concern is heightened by the awareness that hypokalemia, long recognized as hazardous to cardiac patients receiving digitalis, can be life-threatening to other patients as well, and that even mild degrees of hypokalemia are associated with substantial risk.’ Potassium-wasting thiazide and loop-active diuretics are, of course, frequently used in volume-overloaded cardiac patients. Because hypertension is a common cause of heart disease and because most hypertensive patients receive diuretics, it follows that many patients with heart disease are at risk of hypokalemia developing. There is also growing evidence for the existence of complex neurohormonal events which, set in motion in the first moments after acute cardiac injury, interact to augment both the magnitude and the lethality of hypokalemia.2 The gravity of the problem is further heightened by the recognition that hypokalemia in the critically ill patient is often iatrogenic and almost always preventable.3 The pathogenesis and hazards of hypokalemia in cardiac patients are reviewed. Normal potassium balance is briefly summarized, and those areas of particular relevance to patients with heart disease receiving potassiumwasting diuretics are highlighted.
1
POTASSIUM METABOLISM IN HEALTH AND IN CARDIAC DISEASE
From the Department of Nephrology, Temple University, Health Sciences Center, Philadelphia, Pennsylvania. Address for reprints: Robert G. Narins, MD, Temple University Healthy Sciences Center, Department of Nephrology, Parkinson Pavilion, Room 580, Broad & Tioga Streets, Philadelphia, Pennsylvania 19140.
4E
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
65
The normal concentration of potassium in the extracellular fluid (Ko) is precisely regulated, ranging between 3.5 and 5.3 mEq/liter. Intracellular potassium concentration (Ki) is far greater-roughly 150 mEq/liter in most tissues; thus, approximately 98% of the body’s potassium is contained in cells. In absolute terms, the person weighing 70 kg with 28 liters of intracellular fluid stores 4,200 mE.q (28 liters X 150 mEq/liter) of potassium in his cells, while only 63 mEq (14 liters X 4.5 mEq/liter) reside in his extracellular space. Because clinical states of potassium depletion are often associated with deficits of 2QOto 400 mJ?q, cellular potassium stores must sustain greater absolute losses of the cation than the extracellular compartment. Whereas the loss of even several hundred mEq of intracellular potassium hardly changes Ki, the loss of a mere 30 mEq of extracellular potassium reduces Ko by half. Thus, in states of potassium depletion, KO is generally reduced much more than Ki. The pathophysiologic and clinical importance of these concentration changes and the importance of preventing deviations in the extracellular potassium concentration is suggested by the Nernst equation, which provides an approximate val-
ue for the resting cellular transmembrane electrical poPOTASSIUM BALANCE tential (Em): Em = -61 log Ki/Ko. Because the ratio of Ki/Ko strongly influences Em, and because the numerator Ki changes relatively little, even minor decrements in Ko produce significant degrees of cellular hyperpolarity. The altered excitability of CELLULAR cell membranes resulting from these increases in the Ki/ POTASSIUM Ko ratio underlies the hypokalemia-induced dysfunction CONCENTRATlON in skeletal muscles, the nervous system and the heart. The neuromuscular and dysrhythmic manifestations of potassium depletion are likely related to changes in Em. The preservation of a near-constant extraceullar po,GOWdoy PLAGMA GOOm.q,day I(* tassium concentration requires that daily potassium intake (normally 50 to 150 mEq) be more or less exactly matched by the renal and gastrointestinal excretion of potassium (Fig. 1). Stool losses are not critical to potassium balance in healthy persons, averaging about 10 mEq/ day. Thus, the kidneys must excrete an amount of potassium equal to the net absorption if external balance is to FIGURE 1. lntemd and external potassim balance: tnterd and extend baleme of pdassbn. See text be maintained. Since the kidneys filter 180 liters of plas- (Le., trm) ma water per day, the daily filtered load of potassium terdetas. averages 800 mEq (4 to 5 mEq/liter X 180 liters/day). Net tubular reabsorption must therefore occur, since the creased potassium secretion, perhaps because potassium chloride co-transport out of the lumen is inhibited.4 daily excretion of the 50 to 150 mEq required to maintain The peritubular factors augmenting distal potassium balance is far less than the filtered load. Micropuncture studies have shown that only a small fraction of the potas- secretion include increased dietary potassium intake, increased plasma potassium concentration and an elevated sium entering the proximal tubule remains by the time serum pH. It is the hormonal regulation of potassium the filtrate reaches the distal tubule.4 Thus, preservation secretion, however, that assumes major importance in the of potassium balance in the face of variable dietary intake is entirely dependent on the regulation of potassium se- cardiac patient, particularly after a catastrophic illness. cretion in the distal nephron. This secretory process is Chronically elevated levels of aldosterone stimulate potassium secretion in the cortical-collecting tubule and mediated by specific tubular epithelial cells (“principal cause hypokalemia. The hormone also stimulates extracells”) located in the collecting ducts in the superficial renal cells to take up potassium, thereby augmenting the cortex.4 development of the hypokalemia to a small degree.5 Potassium transport across the cell membrane is influMany patients with congestive heart failure manifest hyenced by 2 sets of factors: (1) those acting on the luminal perreninemia and hyperaldosteronism-as would be anmembrane, and (2) those acting on the contraluminal membrane.4 Among the most important luminal factors ticipated from the diminished renal perfusion that follows modifying potassium secretion are distal tubular flow the reduction in effective arterial blood volume caused by rate and sodium delivery. Although fluctuations in flow left ventricular failure. However, a significant number of rate and sodium delivery occur in parallel manner under such cardiac patients actually have normal renin and physiologic conditions, investigations using micropuncaldosterone levels.6 The reason for this surprising finding is unclear but may be related to high levels of atria1 ture techniques suggest that flow rate is the more critical determinant. The mechanism by which increased flow natriuretic hormone. The cardiac hormone is released in states of increased preload, and it impairs the secretion of augments net secretion is most likely by diluting luminal potassium, thereby eliminating concentration gradients renin and aldosterone.7 The acute infusion of glucocorticoids stimulates potassium secretion by virtue of their across the luminal membrane unfavorable to continued secretion of the cation. In vitro studies also suggest that action to increase glomerular filtration rate with conseluminal sodium concentrations of less than 35 mEq/liter quent increased distal sodium delivery. Antidiuretic horexert a rate-limiting effect on potassium secretion; how- mone (ADH) stimulates the secretion of potassium by ever, such concentrations are probably not encountered distal tubular epithelial cells by increasing their permeunder physiologic conditions. ability to the cation.8 Were it not for this countervailing The transepithelial potential in the distal tubule is kaliuretic action of ADH, the reduced distal flow caused negative and so favors potassium secretion. Thus, the by water deprivation might otherwise lead to renal potasdiuretic amiloride, which blocks sodium entry into distal sium retention. Conversely, the polyuric effect of excess tubular cells and thereby reduces luminal electronegativiwater intake might lead to renal potassium-wasting, were ty, exerts a “potassium-sparing” effect by indirectly in- it not for the associated suppression of the potassium hibiting secretion. Luminal concentrations of chloride, secretogogue ADH.8 when less than 20 mEq/liter, are associated with inEpinephrine exerts a minor inhibitory effect on distal THE AMERICAN JOURNAL OF CARDIOLOGY MARCH 6,199O
SE
A SYMPOSIUM:
HORMONE-ELECTROLYTE
INTERACTIONS
renal tubular potassiumsecretionbut strongly stimulates extrarenal potassium uptake, thereby causing hypokalemia.9 Insulin, like epinephrine, increasescell membrane adenosinetriphosphataseactivity which in turn increases cellular potassium uptake.to Thus, the increasedrelease of epinephrine and insulin during extreme stresspredisposesto redistributional hypokalemia. Patientswith mild, uncomplicated chronic congestive heart failure not receiving diuretics are not likely to have hypokalemia. Under such circumstances,the hypokalemia-producing effects of volume contraction and attendant hyperaldosteronism are usually offset by the potassium-retaining effects of renal hypoperfusion, reduced filtration and diminished distal salt and water delivery. However, when diuretics enhance distal flow and sodium delivery, substantial potassium-wasting and hypokalemia can occur, especiallyin thosepatients with preexisting hyperaldosteronism. The release of epinephrine in the wake of the severestressaccompanying an acute myocardial infarction may also cause redistributional hypokalemia (see later).” PREVALENCE
OF HYPOKALEMIA
The importance of hypokalemia in patients with cardiovascular diseasecan be estimated by considering the frequency with which this chemical abnormality is likely to be encountered.Between40 and 60 million Americans have sustained diastolic blood pressuregreater than 90 mm Hg and therefore are candidatesfor antihypertensive therapy.’ l Although the useof diuretics as initial therapy for hypertension is decreasing, many hypertensive patients still receive these agents alone or in combination with other drugs at some point in the course of their disease.Both the dose and half-life of thiazides and the duration of therapy influence the likelihood that hypokalemia (serum potassium
