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Profound Hypokalemia Secondary to Modest Potassium Depletion in a Patient With Coexisting Hyponatremia: Therapeutic Implications
VIGNETTE IN CLINICAL PATHOPHYSIOLOGY
Profound Hypokalemia Secondary to Modest Potassium Depletion in a Patient With Coexisting Hyponatremia: Therapeutic Implications William Aird, MD, Karen Douek, MD, and Mitchell L. Halperin, MD
P
ATIENTS with severe hyponatremia often have additional medical problems. For example, the patient described below had severe hypokalemia, a not uncommon finding in elderly patients treated with diuretics.1.2 This posed a diagnostic and therapeutic challenge. The purpose of this report is to provide quantitative data concerning the size of the K deficit that should prove useful in developing a treatment strategy for patients with a similar electrolyte disorder. CASE PRESENTATION
History An 87-year-old woman had a previous diagnosis of syndrome of inappropriate antidiuretic hormone secretion (SIADH) of the reset osmostat subtype (her usual plasma[Nal remained close to 128 mmol/L, and she could excrete a dilute urine when given a water load). She presented with a 2-week history of generalized weakness and fatigue. Her past history revealed well-controlled angina pectoris, hypertension, and congestive heart failure treated with isosorbide dinitrate, propranolol, digoxin, amitriptyUine, and chlorthalidone (25 mg/d).
Physical Examination The patient was oriented and although she was slow to respond to questions, her cognitive capactities were thought to be normal. BP was 140/100 mm Hg in both arms supine and sitting; heart rate was 90/min and regular, and the jugular venous pressure was 7 em absolute. She was afebrile. Chest examination revealed scattered bibasilar rales that cleared with coughing. The cardiac apex was displaced 12 cm to the left of the midclavicular line; the heart sounds were normal, and there was a grade I/VI systolic ejection murmur at the left lower sternal border. The remainder of the examination was normal. Initial and follow-up laboratory investigations are detailed in Table I. The heart size was slightly enlarged radiologically.
Calculations The CI space was used as a noninvasive estimate of the extracellular fluid (ECF) volume to determine the quantity of sodium (Na), potassium (K), and chloride (Cl) retained extracellulary. The initial ECF volume was thought to be normal and was estimated to be 20% of body weight. The rise in ECF volume during therapy (y L) was calculated from the quantity From the Renal Division, St. Michael's Hospital, Toronto. Address reprint requests to Mitchell L. Halperin, MD, Lab # 1, Research Wing, St. Michael's Hospital, 38 Shutter St, Toronto, Ont, Canada M5B lA6. © 1988 by the National Kidney Foundation, Inc. 0272-6386/88/1202-0013$3.00/0 164
of CI infused and excreted by using the following equation where Cl i and Clf are the plasma CI concentration before and after the infusions: [Clli
X
(10 L) + (Cl infused - excreted) = [ClIt x (10 + Y L)
The content of Na, K, and CI in the ECF were calculated as the product of their plasma concentrations and the ECF volume. For simplicity, Donnan effects were ignored.
Clinical Course Initial treatment included withdrawing the diuretic and giving oral KCl (30 mmol) plus intravenous (IV) saline (150 mmol/L) containing 40 mmol KCl/L. No changes were observed on serial neurological examinations. Her response to questions remained slow but appropriate; memory was excellent, and abstract thinking intact. A psychiatrist concluded that she was severely depressed. CAT scan of the brain raised the question of central pontine infarctions, but magnetic resonance imaging failed to substantiate this impression.
Questions I. What is the anticipated K deficit in this severely hypokalemic patient whose K loss was secondary to diuretic action? 2. What are the therapeutic implications of knowing the magnitude of this Kloss? 3. How might one explain the discrepancy in magnitude of the measured and anticipated K deficits in this patient?
DISCUSSION
Answer to Question 1 Although hypokalemia may be due to a K shift into cells (usually a result of anabolism, metabolic alkalosis, insulin or B2-adrenergic action), more often it results from K loss via the urinary or gastrointestinal (GI) tract. Renal K loss is dependent on adequate levels of aldosterone and distal nephron flow rate with Na delivery. These forces should be enhanced in a patient taking thiazide diuretics. Balance studies in K-deprived normals show that when the plasma [K] decreased from 4 to 3 mmol/ L, there was a mean K deficit of 350 mmol. A further reduction in [K] from 3 to 2 mmol/L is associated with an additional 400 mmol K deficit. 3 Two factors probably led to hypokalemia in this patient: (1) the urine flow and distal Na delivery were large due to diuretic action; and (2) aldosterone probably acted on the "cortical distal
American Journal of Kidney Diseases, Vol XII, No 2 (August), 1988: pp 164-166
165
HYPOKALEMIA AND HYPONATREMIA
Table 1.
Plasma and Urine Values on Admission and During Therapy Time (h)
a
2
Na (mmoI/L) K (mmoI/L) CI (mmoI/L) HC03 (mmoI/L) BUN (mmoI/L, mg/dL) Creatinine (mmoI/L, mg/dL) Glucose (mmoI/L, mg/dL)
100 1.9 62 21 6.2 (2.2) 0.5 (45) 117 (6.5)
106 1.7 66 24
Na (mmoI/L) K (mmoI/L) CI (mmoI/L) Osmolality (mosm/kg H2 O)
76 42 86 283
6
15
19
17
Plasma 114 3.8 86 19 0.6 (49)
119 4.0 87 17 5.0 (1.8) 0.7 (60)
119 3.3 87 18 5.0 (1.8) 0.7 (60)
119 3.6 89 19 5.0 (1.8) 0.6 (49) 88 (4.9)
73 51 83 329
52 68 81 374
68 56 122 311
118 39 145 335
Urine
The mmol/L values for urea, glucose, and creatinine are shown in parentheses.
nephron" as evidenced by the high urine K concentration (corrected for medullary water reabsorption) on admission. 4 Given this propensity for K loss, a K deficit of > 500 mmol in a 70 kg person, or at least 350 mmol in this 50 kg person was anticipated 3 ; Fishman et al observed a large K deficit in similarly hyponatremic patients treated with a thiazide diuretic. 5 Most patients on thiazide therapy develop only modest hypokalemia with a plasma K concentration that exceeds 3.0 mmol/L. This fall usually occurs within 1 week and only 7 % of these patients develop much more severe hypokalemia. 2
Answer to Question 2 The anticipation of such a large K deficit has two conflicting implications with regard to therapy: (1) severe hypokalemia should be corrected rapidly in a patient taking digitalis to prevent cardiac arrhythmias; and (2) there are risks associated with rapid K replacement that include sudden hyperkalemia in plasma returning to the heart and a Na shift from the intracellular fluid (ICF) to the ECF that could precipitate congestive heart failure (this Na shift might have contributed to the degree of hyponatremia). 6 Thus, exogenously administered Na or K salts should both lead to an increase in the ECF volume and the tonicity of body fluids. Since this patient had a history of congestive heart failure, it was important to correct the hyponatremia without overexpanding the ECF vol-
ume. If the K deficit was really> 350 mmol, then the retention of this quantity of K (together with the shift of an almost equivalent quantity of ICF Na to the ECF) would have led to a 2 L expansion of the ECF volume. When measured over the first 24 hours, the positive K balance was only 110 mmol in this patient, ie, < one third of the anticipated value.
Answer to Question 3 The large discrepancy between expected and observed positive K balance can be explained in one of three ways: (1) there may have been another factor that led to a K shift into cells; however, there was no evidence of marked hyperinsulinism, catecholamine excess, a hyperanabolic state, or metabolic alkalosis; (2) the loss of lean body mass with age diminishes the ICF K content; however, the K deficit in this paient was smaller than expected, even when taking this into consideration; and (3) there may have been a chronic ICF K deficit with less ICF K to "buffer" additional losses. If this were true, then a smaller renal K loss could lead to more profound hypokalemia. To explain why there might have been an ICF K deficit in this patient, we offer the following speculation: In steady state hyponatremia, ICF and ECF osmolalities must be equal since water movement rapidly dissipates osmolar gradients. Intracellular osmolality can be decreased either by water movement into cells (with cerebral cell swelling as the dangerous consequence), or by an adaptive reduction of cell solute (exporting KCl to the ECP). It
166
AIRD, DOUEK, AND HALPERIN
may be that other cells also regulate their ICF volume to some extent when the "osmostat is reset chronically"; this might lead to a lesser total body ICF K content. If the acute K deficit were less, then two important sequellae would follow: (1) therapy with K alone would not completely correct the hyponatremia; the shift of 100 mmol of Na from the ICF to the ECF compartment with adequate K replacement in our patient would have resulted in final serum Na concentration of 1,000 + 100 mmol/lO L or 110 mmol/L. Further, correction of hyponatremia could only be achieved by administering a solution with a higher Na concentration than ongoing losses or simply inducing a loss of water. (2) Diuretic therapy in patients with chronic ICF K depletion (perhaps in chronic hyponatremic states) may result in a larger fall in the plasma K concentration. This excessive degree of hypokalemia would be due to the limited degree of K-depleted
cells to "buffer" even small K losses. One could avoid potentially dangerous hypokalemia in this subset of elderly patients by screening for hyponatremia before initiating treatment with diuretics. CONCLUSION
Hyponatremia and hypokalemia occur with diuretic therapy. Hypokalemia is induced by several mechanisms (high urine flow and aldosterone action); it must be appreciated that its correction with K supplements will lead to Na shift to the ECF with a partial correction of the hyponatremia and expansion of ECF volume. However, in a patient with underlying chronic hyponatremia (SIADH), diuretic-induced hypokalemia may lead to more profound degrees of hypokalemia. This is an important finding, as it may add the syndrome of inappropriate antidiuretic hormone (ADH) secretion to the list of conditions in which diuretic therapy is potentially dangerous.
REFERENCES 1. Sterns RH: Severe symptomatic hyponatremia: Treatment and outcome. Ann Intern Med 107:656-664, 1987 2. Tannen RL: Diuretic-induced hypokalemia. Kidney Int 28:988-1000, 1985 3. Sterns RH, Cox M, Feig PU, et a1: Internal potassium balance and the control of the plasma potassium concentration. Medicine 60:339-354, 1981 4. West ML, Marsden PA, Richardson RMA, et al: New
clinical approach to evaluate disorders of potassium excretion. Miner Electrolyte Metab 12:234-238, 1986 5. Fishman Mp, Vorherr H, Kleeman CR, et al: Diureticinduced hyponatremia. Ann Intern Med 75:853-863, 1971 6. Laragh JH: The effect of potassium chloride on hyponatremia. J Clin Invest 33:807-8I8, 1954 7. Siebens AW: Cellular volume control, in Seldin DW; Giebisch G (eds): The Kidney: Physiology and Pathophysiology. New York, Raven, 1985, chap 5
Profound Hypokalemia Secondary to Modest Potassium Depletion in a Patient With Coexisting Hyponatremia: Therapeutic Implications William Aird, MD, Karen Douek, MD, and Mitchell L. Halperin, MD
P
ATIENTS with severe hyponatremia often have additional medical problems. For example, the patient described below had severe hypokalemia, a not uncommon finding in elderly patients treated with diuretics.1.2 This posed a diagnostic and therapeutic challenge. The purpose of this report is to provide quantitative data concerning the size of the K deficit that should prove useful in developing a treatment strategy for patients with a similar electrolyte disorder. CASE PRESENTATION
History An 87-year-old woman had a previous diagnosis of syndrome of inappropriate antidiuretic hormone secretion (SIADH) of the reset osmostat subtype (her usual plasma[Nal remained close to 128 mmol/L, and she could excrete a dilute urine when given a water load). She presented with a 2-week history of generalized weakness and fatigue. Her past history revealed well-controlled angina pectoris, hypertension, and congestive heart failure treated with isosorbide dinitrate, propranolol, digoxin, amitriptyUine, and chlorthalidone (25 mg/d).
Physical Examination The patient was oriented and although she was slow to respond to questions, her cognitive capactities were thought to be normal. BP was 140/100 mm Hg in both arms supine and sitting; heart rate was 90/min and regular, and the jugular venous pressure was 7 em absolute. She was afebrile. Chest examination revealed scattered bibasilar rales that cleared with coughing. The cardiac apex was displaced 12 cm to the left of the midclavicular line; the heart sounds were normal, and there was a grade I/VI systolic ejection murmur at the left lower sternal border. The remainder of the examination was normal. Initial and follow-up laboratory investigations are detailed in Table I. The heart size was slightly enlarged radiologically.
Calculations The CI space was used as a noninvasive estimate of the extracellular fluid (ECF) volume to determine the quantity of sodium (Na), potassium (K), and chloride (Cl) retained extracellulary. The initial ECF volume was thought to be normal and was estimated to be 20% of body weight. The rise in ECF volume during therapy (y L) was calculated from the quantity From the Renal Division, St. Michael's Hospital, Toronto. Address reprint requests to Mitchell L. Halperin, MD, Lab # 1, Research Wing, St. Michael's Hospital, 38 Shutter St, Toronto, Ont, Canada M5B lA6. © 1988 by the National Kidney Foundation, Inc. 0272-6386/88/1202-0013$3.00/0 164
of CI infused and excreted by using the following equation where Cl i and Clf are the plasma CI concentration before and after the infusions: [Clli
X
(10 L) + (Cl infused - excreted) = [ClIt x (10 + Y L)
The content of Na, K, and CI in the ECF were calculated as the product of their plasma concentrations and the ECF volume. For simplicity, Donnan effects were ignored.
Clinical Course Initial treatment included withdrawing the diuretic and giving oral KCl (30 mmol) plus intravenous (IV) saline (150 mmol/L) containing 40 mmol KCl/L. No changes were observed on serial neurological examinations. Her response to questions remained slow but appropriate; memory was excellent, and abstract thinking intact. A psychiatrist concluded that she was severely depressed. CAT scan of the brain raised the question of central pontine infarctions, but magnetic resonance imaging failed to substantiate this impression.
Questions I. What is the anticipated K deficit in this severely hypokalemic patient whose K loss was secondary to diuretic action? 2. What are the therapeutic implications of knowing the magnitude of this Kloss? 3. How might one explain the discrepancy in magnitude of the measured and anticipated K deficits in this patient?
DISCUSSION
Answer to Question 1 Although hypokalemia may be due to a K shift into cells (usually a result of anabolism, metabolic alkalosis, insulin or B2-adrenergic action), more often it results from K loss via the urinary or gastrointestinal (GI) tract. Renal K loss is dependent on adequate levels of aldosterone and distal nephron flow rate with Na delivery. These forces should be enhanced in a patient taking thiazide diuretics. Balance studies in K-deprived normals show that when the plasma [K] decreased from 4 to 3 mmol/ L, there was a mean K deficit of 350 mmol. A further reduction in [K] from 3 to 2 mmol/L is associated with an additional 400 mmol K deficit. 3 Two factors probably led to hypokalemia in this patient: (1) the urine flow and distal Na delivery were large due to diuretic action; and (2) aldosterone probably acted on the "cortical distal
American Journal of Kidney Diseases, Vol XII, No 2 (August), 1988: pp 164-166
165
HYPOKALEMIA AND HYPONATREMIA
Table 1.
Plasma and Urine Values on Admission and During Therapy Time (h)
a
2
Na (mmoI/L) K (mmoI/L) CI (mmoI/L) HC03 (mmoI/L) BUN (mmoI/L, mg/dL) Creatinine (mmoI/L, mg/dL) Glucose (mmoI/L, mg/dL)
100 1.9 62 21 6.2 (2.2) 0.5 (45) 117 (6.5)
106 1.7 66 24
Na (mmoI/L) K (mmoI/L) CI (mmoI/L) Osmolality (mosm/kg H2 O)
76 42 86 283
6
15
19
17
Plasma 114 3.8 86 19 0.6 (49)
119 4.0 87 17 5.0 (1.8) 0.7 (60)
119 3.3 87 18 5.0 (1.8) 0.7 (60)
119 3.6 89 19 5.0 (1.8) 0.6 (49) 88 (4.9)
73 51 83 329
52 68 81 374
68 56 122 311
118 39 145 335
Urine
The mmol/L values for urea, glucose, and creatinine are shown in parentheses.
nephron" as evidenced by the high urine K concentration (corrected for medullary water reabsorption) on admission. 4 Given this propensity for K loss, a K deficit of > 500 mmol in a 70 kg person, or at least 350 mmol in this 50 kg person was anticipated 3 ; Fishman et al observed a large K deficit in similarly hyponatremic patients treated with a thiazide diuretic. 5 Most patients on thiazide therapy develop only modest hypokalemia with a plasma K concentration that exceeds 3.0 mmol/L. This fall usually occurs within 1 week and only 7 % of these patients develop much more severe hypokalemia. 2
Answer to Question 2 The anticipation of such a large K deficit has two conflicting implications with regard to therapy: (1) severe hypokalemia should be corrected rapidly in a patient taking digitalis to prevent cardiac arrhythmias; and (2) there are risks associated with rapid K replacement that include sudden hyperkalemia in plasma returning to the heart and a Na shift from the intracellular fluid (ICF) to the ECF that could precipitate congestive heart failure (this Na shift might have contributed to the degree of hyponatremia). 6 Thus, exogenously administered Na or K salts should both lead to an increase in the ECF volume and the tonicity of body fluids. Since this patient had a history of congestive heart failure, it was important to correct the hyponatremia without overexpanding the ECF vol-
ume. If the K deficit was really> 350 mmol, then the retention of this quantity of K (together with the shift of an almost equivalent quantity of ICF Na to the ECF) would have led to a 2 L expansion of the ECF volume. When measured over the first 24 hours, the positive K balance was only 110 mmol in this patient, ie, < one third of the anticipated value.
Answer to Question 3 The large discrepancy between expected and observed positive K balance can be explained in one of three ways: (1) there may have been another factor that led to a K shift into cells; however, there was no evidence of marked hyperinsulinism, catecholamine excess, a hyperanabolic state, or metabolic alkalosis; (2) the loss of lean body mass with age diminishes the ICF K content; however, the K deficit in this paient was smaller than expected, even when taking this into consideration; and (3) there may have been a chronic ICF K deficit with less ICF K to "buffer" additional losses. If this were true, then a smaller renal K loss could lead to more profound hypokalemia. To explain why there might have been an ICF K deficit in this patient, we offer the following speculation: In steady state hyponatremia, ICF and ECF osmolalities must be equal since water movement rapidly dissipates osmolar gradients. Intracellular osmolality can be decreased either by water movement into cells (with cerebral cell swelling as the dangerous consequence), or by an adaptive reduction of cell solute (exporting KCl to the ECP). It
166
AIRD, DOUEK, AND HALPERIN
may be that other cells also regulate their ICF volume to some extent when the "osmostat is reset chronically"; this might lead to a lesser total body ICF K content. If the acute K deficit were less, then two important sequellae would follow: (1) therapy with K alone would not completely correct the hyponatremia; the shift of 100 mmol of Na from the ICF to the ECF compartment with adequate K replacement in our patient would have resulted in final serum Na concentration of 1,000 + 100 mmol/lO L or 110 mmol/L. Further, correction of hyponatremia could only be achieved by administering a solution with a higher Na concentration than ongoing losses or simply inducing a loss of water. (2) Diuretic therapy in patients with chronic ICF K depletion (perhaps in chronic hyponatremic states) may result in a larger fall in the plasma K concentration. This excessive degree of hypokalemia would be due to the limited degree of K-depleted
cells to "buffer" even small K losses. One could avoid potentially dangerous hypokalemia in this subset of elderly patients by screening for hyponatremia before initiating treatment with diuretics. CONCLUSION
Hyponatremia and hypokalemia occur with diuretic therapy. Hypokalemia is induced by several mechanisms (high urine flow and aldosterone action); it must be appreciated that its correction with K supplements will lead to Na shift to the ECF with a partial correction of the hyponatremia and expansion of ECF volume. However, in a patient with underlying chronic hyponatremia (SIADH), diuretic-induced hypokalemia may lead to more profound degrees of hypokalemia. This is an important finding, as it may add the syndrome of inappropriate antidiuretic hormone (ADH) secretion to the list of conditions in which diuretic therapy is potentially dangerous.
REFERENCES 1. Sterns RH: Severe symptomatic hyponatremia: Treatment and outcome. Ann Intern Med 107:656-664, 1987 2. Tannen RL: Diuretic-induced hypokalemia. Kidney Int 28:988-1000, 1985 3. Sterns RH, Cox M, Feig PU, et a1: Internal potassium balance and the control of the plasma potassium concentration. Medicine 60:339-354, 1981 4. West ML, Marsden PA, Richardson RMA, et al: New
clinical approach to evaluate disorders of potassium excretion. Miner Electrolyte Metab 12:234-238, 1986 5. Fishman Mp, Vorherr H, Kleeman CR, et al: Diureticinduced hyponatremia. Ann Intern Med 75:853-863, 1971 6. Laragh JH: The effect of potassium chloride on hyponatremia. J Clin Invest 33:807-8I8, 1954 7. Siebens AW: Cellular volume control, in Seldin DW; Giebisch G (eds): The Kidney: Physiology and Pathophysiology. New York, Raven, 1985, chap 5