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Hyperkalemia Complicating Digoxin Toxicity in a Patient With Renal Failure
Hyperkalemia Complicating Digoxin Toxicity in a Patient With Renal Failure Maxine A. Papadakis, MD, Mark P. Wexman, MD, Cosmo Fraser, MD, and Scot M. Sedlacek, MD • We describe the occurrence of hyperkalemia in a stable hemodialysis patient who developed digoxin toxicity. The patient had been receiving digoxin for 2 years. His maintenance digoxin dose was increased from 0.125 to 0.25 mg three times a week, which resulted in a toxic serum level of 4.9 ng/mL (therapeutic range is 0.8 to 2.0 ng/ mL). As a consequence of the digoxin toxicity, he became hyperkalemic (7.8 mEq/L), and this value returned to normal only after the digoxin level was lowered by a combination of oral charcoal and dialysis. This study shows how readily hyperkalemia can occur in an anephric patient manifesting digoxin toxicity. Thus, potentially lethal hyperkalemia can occur in hemodialysis patients who ingest therapeutic quantities of digoxin. Digoxin toxicity should be added to the differential diagnosis of hyperkalemia in patients with renal failure. This can occur despite the absence of a history of massive ingestion of a cardiac glycoside. INDEX WORDS: Digoxin, hyperkalemia, renal failure.
H
YPERKALEMIA is well described as a complication of massive suicidal or accidental ingestion of digoxin. I Serum digoxin levels have usually been extremely high in these reports, ranging from 10 to 52 ng/mL after ingestion of at least 10 mg of the drug. 2 Associated hyperkalemia up to 13.5 mEq/L has been reported. 3 We describe digoxin toxicity and hyperkalemia in a patient who had been on hemodialysis for 2 years and had stable levels of serum potassium while taking maintenance doses of digoxin and propranolol. The patient's other medical conditions were hypertension and angina. MATERIALS AND METHODS Case Report A 76-year-old white man was admitted to the San Francisco Veterans Administration Hospital on February 8, 1983 for evaluation of a persistent left pleural effusion. In 1981, he underwent repair of a ruptured abdominal aortic aneurysm, which resulted in intraoperative renal failure that did not reverse. He has since undergone hemodialysis three times per week. He had chronically received digoxin 0 . 125 mg orally three times a week after each dialysis for intermittent atrial fibrillation , as well as isosorbide and propranolol 40 mg four times a day for From the Department of Medicine , University of California, San Francisco, and Veterans Administration Medical Center, San Francisco. Dr. Sedlacek's current address is Division of Oncology, University of Colorado, Denver, CO 80262. Address reprint requests to Maxine Papadakis, MD, Medical Service (IlIA), Veterans Administration Medical Center, 4150 Clement St. San Francisco. CA 94121. © 1985 by The National Kidney Foundation, Inc. 0272-63861851010064-03$3.0010
64
hypertension and stable angina. His potassium intake was stable and serum potassium levels were constant at 4.5 to 5.5 mEq/mL (normal 3.5 to 5.0 mEq/L) for 2 years despite his renal failure and digoxin and propranolol therapy. Three weeks before admission the digoxin dose was increased to .25 mg orally three times per week. Five days prior to admission the serum digoxin level was 2.4 ng/mL (therapeutic range 0.8 to 2.0 ng/mL). There was no history of diabetes mellitus and the patient's serum glucose level was 74 mg/dL in 1982. On physical examination, the pulse was 50/min and regular, and BP was 170/90; chest findings were consistent with left pleural effusion. The hematocrit was 29%, serum Na + = 140 mEq/L, K+ = 5.0 mEq/L, HCO, - = 19 mEq/L, BUN = 79 mg/ loo mL, creatinine = 14.3 mg/ loo mL , CA ++ = 9.7 mEq/L, po. ++ = 7.0 mEq/L, Mg ++ = 2.1 mEq/L. The ECG showed a sinus rate of 55/min , first-degree atrioventricular block, an old right bundle-branch block, and no peaked T waves . Chest x-ray revealed a small left pleural effusion and cardiomegaly. Two days after admission, the patient was found with a pulse of 30/min and an unobtainable BP Atropine and epinephrine had no effect on his heart rate. The serum potassium was 7.8 mEq/L , arterial pH = 7.30, and glucose = 144 mg/dL. He was treated with glucose, insulin, and sodium bicarbonate. After resuscitation, the ECG disclosed sinus bradycardia without peaked T waves and episodes of ventricular bigeminy. The digoxin level was 4.9 ng/mL. A temporary transvenous pacemaker was placed with good ventricular capture. In order to effectively treat the hyperkalemia, hemodialysis was immediately instituted . Postdialysis, the potassium level was 4.8 mEq/L but rose to 6.0 mEq/L in two and one-half hours (pH = 7.40). Because of the persistent hyperkalemia and elevated digoxin level , hemodialysis was reinstituted and activated charcoal with sorbitol was given every four hours per nasogastric tube.' Over the course of 24 hours (Fig I), the serum digoxin level fell from 5 to 2.8 ng/mL and, concomitantly, the serum potassium decreased from 7.8 to 4.5 mEq/L and remained stable thereafter. The patient was discharged ten day~ later in sinus rhythm with a heart rate of 70/min. The serum potassium level was 4.6 mEq/L.
American Journal of Kidney Diseases, Vol V, No 1, January 1985
HYPERKALEMIA IN DIGOXIN TOXICITY
I
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E
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65
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Fig 1. Relation of serum potassium to digoxin level. The dashed line represents the serum potassium level, and the solid line represents the serum digoxin level.
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DISCUSSION This case report demonstrates that digoxin toxicity, even from therapeutic doses, can cause hyperkalemia in a patient with end-stage renal failure while receiving {1-adrenergic blockade. We could find only one previous case of digoxin toxicity complicated by hyperkalemia (K + = 5.6 mEq/L) with a serum digoxin level less than 10 ng/mL, but that patient had taken 20 mg of digoxin in a suicidal attempt (usual digoxin dose .125 to .25 mg/ d). Our patient had no such history. His digoxin toxicity was due to a temporary increase in his therapeutic digoxin dose from .125 to .25 mg three times per week, which resulted in a toxic digoxin level of 4.9 ng/mL , most likely related to his renal failure . The hospital admission was elective for evaluation of a left pleural effusion, and other variables such as his cardiovascular status, dietary intake of potassium, sodium potassium levels, and hemodialysis regimen had been stable for 2 years. The main mode of excretion of digoxin is via the kidney as the unchanged glycoside. An increased half-life and decreased dosage requirement is to be expected in patients with impaired renal function. 5 The mechanism for hyperkalemia in digoxin toxicity may be related to the inhibition of sodiumpotassium-activated adenosine triphosphate (ATPase) enzyme 6 by the drug , not only in the myocar-
2 / 11
2/ 12
2/ 14
Time (days)
dium but in other cells as well. Even small amounts of digitalis may result in a slight elevation of serum potassium, due to inhibition of uptake of potassium by skeletal muscle and generalized release of potassium from many tissues , especially the liver.7 Also , digoxin may suppress the reninangiotensin system. 8 Propranolol, through {1-adrenergic blockade , can impair the cellular uptake of potassium, independent of renal potassium excretion or changing plasma aldosterone levels. 9 This inhibition of intracellular potassium transfer occurs even in nephrectomized animals. 10 The patient was elderly, which may have contributed to the propensity for hyperkalemia. With advancing age, there is decreased production of renin and aldosterone. II Also , conceivably, the insulin resistance in uremia may impair the ability to transport potassium intracellularly. However, the insulin effect on potassium uptake is normal in uremia l2 and should not be a factor in this case. In functionally anephric patients, one can expect an exaggerated hyperkalemic side effect to a drug as compared with normal patients , whose kidneys help to maintain potassium homeostasis . The pharmacologic combination of digoxin and propranolol is extremely common. Digoxin toxicity should be added to the differential diagnosis of hyperkalemia
66
PAPADAKIS ET AL
in patients with renal failure, especially if receiving iJ-adrengergic blockade, despite the absence of a history of massive ingestion of a cardiac glycoside.
ACKNOWLEDGMENT We gratefully acknowledge Dr Allen I. Arieff for his thoughtful assistance in preparation of this manuscript.
REFERENCES I . Willerson JT, Smith TW: Massive digoxin ingestion: Clinical experience and principles of management. Clin Med Ian:29- 31 , 1974 2. Smith TW, Butler Vp, Haber E, et al: Treatment of lifethreatening digital intoxication with digoxin-specific Fab antibody fragments: Experience in 26 cases. N Engl I Med 307: 1357-1362, 1982 3. Reza MI, Kovick RB , Shine Kl, et al: Massive intravenous digoxin overdosage. N Engl I Med 291:777-778, 1972 4. Levy G: Gastrointestinal clearance of drugs with activated charcoal. N Engl I Med 307:676-678, 1982 5. Finkelstein FO, Goffinet lA , Hendler ED, et al: Pharmacokinetics of digoxin and in patients undergoing hemodialysis. Am I Med 58:525-531, 1975 6. Smith TW: Quabain-specific antibodies: Immunochemical properties and reversal of Na + , K + -activated adenosine triphosphate inhibition. I Clin Invest 51: 1583-1593, 1972
7. Lown B, Black H, Moore F : Digitalis, electrolytes and the surgical patient. Am I Cardiol 6:309-337, 1960 8. Covit AB , Schaer GL, Sealey IE, et al : Suppression of the renin-angiotensin system by intravenous digoxin in chronic congestive heart failure. Am I Med 75:445-447 , 1983 9. Rosa RM, Silva P, Young JB , et al: Adrenergic modulation of extrarenal potassium disposal. N Engl J Med 302:431434, 1980 10. Hiatt N, Chapman LW, Davidson MB: Influence of epinephrine and propranolol on transmembrane K transfer in anuric dogs with hyperkalemia. J Phamacol Exp Ther 209 :282-286, 1979 II. Hegstad R , Brown RD, Jiang NS , et al: Aging and aldosterone. Am J Med 74:442-448, 1983 12. Westervelt FB Jr: Insulin effect in uremia. I Lab Clin Med 74 :79-84, 1969
H
YPERKALEMIA is well described as a complication of massive suicidal or accidental ingestion of digoxin. I Serum digoxin levels have usually been extremely high in these reports, ranging from 10 to 52 ng/mL after ingestion of at least 10 mg of the drug. 2 Associated hyperkalemia up to 13.5 mEq/L has been reported. 3 We describe digoxin toxicity and hyperkalemia in a patient who had been on hemodialysis for 2 years and had stable levels of serum potassium while taking maintenance doses of digoxin and propranolol. The patient's other medical conditions were hypertension and angina. MATERIALS AND METHODS Case Report A 76-year-old white man was admitted to the San Francisco Veterans Administration Hospital on February 8, 1983 for evaluation of a persistent left pleural effusion. In 1981, he underwent repair of a ruptured abdominal aortic aneurysm, which resulted in intraoperative renal failure that did not reverse. He has since undergone hemodialysis three times per week. He had chronically received digoxin 0 . 125 mg orally three times a week after each dialysis for intermittent atrial fibrillation , as well as isosorbide and propranolol 40 mg four times a day for From the Department of Medicine , University of California, San Francisco, and Veterans Administration Medical Center, San Francisco. Dr. Sedlacek's current address is Division of Oncology, University of Colorado, Denver, CO 80262. Address reprint requests to Maxine Papadakis, MD, Medical Service (IlIA), Veterans Administration Medical Center, 4150 Clement St. San Francisco. CA 94121. © 1985 by The National Kidney Foundation, Inc. 0272-63861851010064-03$3.0010
64
hypertension and stable angina. His potassium intake was stable and serum potassium levels were constant at 4.5 to 5.5 mEq/mL (normal 3.5 to 5.0 mEq/L) for 2 years despite his renal failure and digoxin and propranolol therapy. Three weeks before admission the digoxin dose was increased to .25 mg orally three times per week. Five days prior to admission the serum digoxin level was 2.4 ng/mL (therapeutic range 0.8 to 2.0 ng/mL). There was no history of diabetes mellitus and the patient's serum glucose level was 74 mg/dL in 1982. On physical examination, the pulse was 50/min and regular, and BP was 170/90; chest findings were consistent with left pleural effusion. The hematocrit was 29%, serum Na + = 140 mEq/L, K+ = 5.0 mEq/L, HCO, - = 19 mEq/L, BUN = 79 mg/ loo mL, creatinine = 14.3 mg/ loo mL , CA ++ = 9.7 mEq/L, po. ++ = 7.0 mEq/L, Mg ++ = 2.1 mEq/L. The ECG showed a sinus rate of 55/min , first-degree atrioventricular block, an old right bundle-branch block, and no peaked T waves . Chest x-ray revealed a small left pleural effusion and cardiomegaly. Two days after admission, the patient was found with a pulse of 30/min and an unobtainable BP Atropine and epinephrine had no effect on his heart rate. The serum potassium was 7.8 mEq/L , arterial pH = 7.30, and glucose = 144 mg/dL. He was treated with glucose, insulin, and sodium bicarbonate. After resuscitation, the ECG disclosed sinus bradycardia without peaked T waves and episodes of ventricular bigeminy. The digoxin level was 4.9 ng/mL. A temporary transvenous pacemaker was placed with good ventricular capture. In order to effectively treat the hyperkalemia, hemodialysis was immediately instituted . Postdialysis, the potassium level was 4.8 mEq/L but rose to 6.0 mEq/L in two and one-half hours (pH = 7.40). Because of the persistent hyperkalemia and elevated digoxin level , hemodialysis was reinstituted and activated charcoal with sorbitol was given every four hours per nasogastric tube.' Over the course of 24 hours (Fig I), the serum digoxin level fell from 5 to 2.8 ng/mL and, concomitantly, the serum potassium decreased from 7.8 to 4.5 mEq/L and remained stable thereafter. The patient was discharged ten day~ later in sinus rhythm with a heart rate of 70/min. The serum potassium level was 4.6 mEq/L.
American Journal of Kidney Diseases, Vol V, No 1, January 1985
HYPERKALEMIA IN DIGOXIN TOXICITY
I
I I
E
4 .0
"-
01
.s c
·x
3.0
0 01
0
2.0
'"
,
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I
,
, H
H
I I I, I
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7.0
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. /\:-----_._--_. I
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65
/
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I
,
I
5 .0
4 .0
:::J "c:r
W
E
3.0
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2.0
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1.0
Fig 1. Relation of serum potassium to digoxin level. The dashed line represents the serum potassium level, and the solid line represents the serum digoxin level.
6.0
I , \ I ,
~~ ( I~--~------~--~~~~ 1 / 222 / 32 / 10
DISCUSSION This case report demonstrates that digoxin toxicity, even from therapeutic doses, can cause hyperkalemia in a patient with end-stage renal failure while receiving {1-adrenergic blockade. We could find only one previous case of digoxin toxicity complicated by hyperkalemia (K + = 5.6 mEq/L) with a serum digoxin level less than 10 ng/mL, but that patient had taken 20 mg of digoxin in a suicidal attempt (usual digoxin dose .125 to .25 mg/ d). Our patient had no such history. His digoxin toxicity was due to a temporary increase in his therapeutic digoxin dose from .125 to .25 mg three times per week, which resulted in a toxic digoxin level of 4.9 ng/mL , most likely related to his renal failure . The hospital admission was elective for evaluation of a left pleural effusion, and other variables such as his cardiovascular status, dietary intake of potassium, sodium potassium levels, and hemodialysis regimen had been stable for 2 years. The main mode of excretion of digoxin is via the kidney as the unchanged glycoside. An increased half-life and decreased dosage requirement is to be expected in patients with impaired renal function. 5 The mechanism for hyperkalemia in digoxin toxicity may be related to the inhibition of sodiumpotassium-activated adenosine triphosphate (ATPase) enzyme 6 by the drug , not only in the myocar-
2 / 11
2/ 12
2/ 14
Time (days)
dium but in other cells as well. Even small amounts of digitalis may result in a slight elevation of serum potassium, due to inhibition of uptake of potassium by skeletal muscle and generalized release of potassium from many tissues , especially the liver.7 Also , digoxin may suppress the reninangiotensin system. 8 Propranolol, through {1-adrenergic blockade , can impair the cellular uptake of potassium, independent of renal potassium excretion or changing plasma aldosterone levels. 9 This inhibition of intracellular potassium transfer occurs even in nephrectomized animals. 10 The patient was elderly, which may have contributed to the propensity for hyperkalemia. With advancing age, there is decreased production of renin and aldosterone. II Also , conceivably, the insulin resistance in uremia may impair the ability to transport potassium intracellularly. However, the insulin effect on potassium uptake is normal in uremia l2 and should not be a factor in this case. In functionally anephric patients, one can expect an exaggerated hyperkalemic side effect to a drug as compared with normal patients , whose kidneys help to maintain potassium homeostasis . The pharmacologic combination of digoxin and propranolol is extremely common. Digoxin toxicity should be added to the differential diagnosis of hyperkalemia
66
PAPADAKIS ET AL
in patients with renal failure, especially if receiving iJ-adrengergic blockade, despite the absence of a history of massive ingestion of a cardiac glycoside.
ACKNOWLEDGMENT We gratefully acknowledge Dr Allen I. Arieff for his thoughtful assistance in preparation of this manuscript.
REFERENCES I . Willerson JT, Smith TW: Massive digoxin ingestion: Clinical experience and principles of management. Clin Med Ian:29- 31 , 1974 2. Smith TW, Butler Vp, Haber E, et al: Treatment of lifethreatening digital intoxication with digoxin-specific Fab antibody fragments: Experience in 26 cases. N Engl I Med 307: 1357-1362, 1982 3. Reza MI, Kovick RB , Shine Kl, et al: Massive intravenous digoxin overdosage. N Engl I Med 291:777-778, 1972 4. Levy G: Gastrointestinal clearance of drugs with activated charcoal. N Engl I Med 307:676-678, 1982 5. Finkelstein FO, Goffinet lA , Hendler ED, et al: Pharmacokinetics of digoxin and in patients undergoing hemodialysis. Am I Med 58:525-531, 1975 6. Smith TW: Quabain-specific antibodies: Immunochemical properties and reversal of Na + , K + -activated adenosine triphosphate inhibition. I Clin Invest 51: 1583-1593, 1972
7. Lown B, Black H, Moore F : Digitalis, electrolytes and the surgical patient. Am I Cardiol 6:309-337, 1960 8. Covit AB , Schaer GL, Sealey IE, et al : Suppression of the renin-angiotensin system by intravenous digoxin in chronic congestive heart failure. Am I Med 75:445-447 , 1983 9. Rosa RM, Silva P, Young JB , et al: Adrenergic modulation of extrarenal potassium disposal. N Engl J Med 302:431434, 1980 10. Hiatt N, Chapman LW, Davidson MB: Influence of epinephrine and propranolol on transmembrane K transfer in anuric dogs with hyperkalemia. J Phamacol Exp Ther 209 :282-286, 1979 II. Hegstad R , Brown RD, Jiang NS , et al: Aging and aldosterone. Am J Med 74:442-448, 1983 12. Westervelt FB Jr: Insulin effect in uremia. I Lab Clin Med 74 :79-84, 1969