Cation Exchange Resins in Congestive Heart Failure

Cation Exchange Resins in Congestive Heart Failure EDWARD S. ORGAIN, M.D.*

CONGESTIVE heart failure commonly occurs when the heart fails to pump an amount of blood adequate for body needs. Sodium and water retention by the kidney leads to expansion of extracellular fluid volume and tissue edema appears. Four basic principles in treatment are recognized: (1) rest in order to reduce the demands made by the tissues upon the heart for blood; (2) digitalis to increase cardiac output and cardiac efficiency; (3) diuretics to promote the excretion of sodium chloride and body water by the kidneys; (4) rigid restriction of dietary sodium to prevent salt and water retention. A regimen which includes rest, digitalis and diuretics is easily instituted and enforced but marked reduction in dietary sodium (300 to 500 mg. daily) is difficult for many patients and practically impossible for some. Cation exchange resins, because of their ability to bind both exogenous and endogenous sodium within the gastrointestinal tract, have proved clinically useful in the dietary management of patients exhibiting congestive heart failure. Historically, the principle of ionic change has been known by chemists and applied principally to the soil (fertilizers) for more than a century. Ion exchangers are substances which selectively will remove from solution either cations or anions and release one ion in exchange for another. Following the synthesis of cation and anion exchange resins by Adams and Holmes1 in 1935, extensive commercial uses of ion exchangers (water softening, metal recovery, sugar refining, etc.) have been made. In 1945, preliminary observations by Segal and associates,2 naturally led to. the use of anion exchange resins as antacids and pepsin inhibitors in the management of patients with peptic ulcer. However, it remained for Dock3 in 1946, to suggest that cation exchange resins be used for the removal of sodium ions from the body as a therapeutic procedure. In

, From the Department of Medicine, Duke University School of Medicine and D'uke '!lospital, Durham, N. C.

* Professor of Medicine, Duke University School of Medicine; Physician and Director of the Cardiovascular Service, Duke Hospital, Durham, N. C. 4-19

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1949 Irwin, Berger, Rosenberg and Jackenthal4 published the first extensive clinical study of cation exchange resins. They demonstrated clearly that a sulfonic resin effectively bound sodium and potassium in the gastrointestinal tract for excretion in the stool, decreased urinary excretion of sodium and potassium and promoted diuresis with loss of edema. Since then numerous clinical reports 5- 33 and several reviews34- 36 have appeared regarding the utility and dangers of the exchange resins in edematous states. PHARMACOLOGY The ion exchange resins are polymers of high molecular weight presenting llluitiple cross links to provide large areas for exchange purposes and divide into two general tytJes, cation and anion exchangers. The anion resin is a polyarnine-methylene (or polyamine-formaldehyde) resin, weakly basic in reaction, which possesses the property of binding anions (chloride, sulfate, phosphate, etc.) in solution. The cation resins are polyacrylic resins, weakly acid in reaction, MOUTH

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Fig. 27. Schematic diagram indicating the process of resin ionic exchange at various levels in the gastrointestinal tract.

commonly of carboxylic or sulfonic type, which exchange hydrogen (or aInmoniurn) ions for basic ions (calcium, magnesium, potassium, sodium, etc.). Cation exchangers initially may be saturated with either hydrogen ions (hydrogen cycle) or arnmonium ions (amrnonium cycle) alone, or in combination with potassium ions (hydrogen-potassium cycle, ammonium-potassium cycle) in ratios varying from 2 to 1 up to 5 to 1. The addition ·of potassium to the resin apparently decreases the efficiency of the resin in binding sodium. Sulfonic resins bind basic ions at pH 3 and above, act rapidly and effect maximal exchange capacity in the stomach. Early release of hydrogen ions may irritate the mouth or esophagus during ingestion of the resin. Carboxylic resins bind cations efficiently at pH 8 and above and therefore exchange ions most effectively in the alkaline intestine. When ammonium or ammonium-potassium forms of resin are employed, ammonium and potassium ions are released in the stomach in exchange for hydrogen ions. Ammonium ions are absorbed and converted to urea by the liver. Potassium ions, also absorbed, balance the uptake of potassium by resin in the intestine and prevent clinical hypokalemia. Hydrogen ions, bound to resin in the stomach, exchange for basic ions in the intestine; the latter are then excreted with the feces (Fig. 27). In the test tube the order of binding of different cations depends upon the concentration of the ion in solution, the valence of the ion and its molecular weight. Preference is given to ions of higher valence and higher molecular weight; calcium, magnesium, potassium and sodium are bound in this order. Although the capacity of a resin in vitro may approximate 10 mEq. of sodium

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per gram of resin, the amount of sodium bound in vivo depends primarily upon the level of sodium intake. 10 , 16 22 24 30 33 When dietary sodium is restricted to 0.5 gram (22 mEq.) to 1.5 gram (65 mEq.) per day, the resin will bind from 0.3 mEq. to 1 mEq. (23 mg.) of sodium per gram of resin. Even upon liberal sodium diets the capacity of the resin rarely exceeds 1.5 mEq. of sodium per gram. The release of hydrogen ions in the gut and their subsequent absorption into the blood stream and the loss of basic ions to the feces tends to create metabolic acidosis 4 17 18 22 characterized by decrease in CO 2 combining power of blood, rise in serum chloride and nitrogen and fall in bicarbonate. The ability of the normal kidney to maintain acid base balance by formation of ammonia and excretion of titratable acid37 prevents serious electrolyte disturbance. However, acidosis is a constant hazard when renal function is reduced,4 16 24 31, 32 owing principally to failure of the kidney to form ammon~a and thus retain basic ions. When hydrogen or ammonium resins without potassium are administered, sufficient potassium may be bound in the gut to produce clinical p.ypokalemia. 9 In a fully digitalized subject, drug intoxication may ensue. 9 , 19 Most resins now contain sufficient potassium to prevent such depletion and render additional potassium supplements unnecessary. Resins free of potassium have been used orally and by enemas to reduce clinical hypokalemia. 38 Balance studies during resin therapy exhibit increased fecal excretion of sodium and potassium but little increase in calcium,4, 16, 22 probably as a result of low concentration of available ionized calcium exposed to resin in the gut. Attention has been directed to possible deficiencies of other cations (magnesium, iron, cobalt, copper, etc.) as well as vitamins and amino acids,22, 39 but none as yet have been demonstrated. Characteristically, the blood electrolytes show little significant change, although sodium and potassium may fall slightly, while CO 2 combining power and bicarbonate decrease and chloride rises. Urinary sodium usually falls, frequently to levels below 10 mEq. per day, sometimes to less than 1 mEq. (23 mg.) per day, while urinary chloride excretion rises (Fig. 29) .13, 23 Although· a few investigators presume that exogenous sodium alone is bound by resin, 4 24 sufficient evidence from balance studies now obtains to indicate that endogenous sodium is likewise removed16 17. 26 31 32 from the "body sodium pool" since there is constant exchange of electrolytes across the gut wall between blood stream and intestinal tract. A recent study 40 suggests that the amount of sodium withdrawn by resin depends primarily upon amount of sodium present in the extracellular fluid space rather than dietary sodium intake, since fecal excretion' of sodium was not increased by added sodium until after weight gain and edema were evident. Fecal excretion of sodium also was increased by daily intravenous infusions of physiologic saline given to a normal subject without sustained weight gain. Desoxycorticosterone41 has been shown to decrease fecal excretion of sodium during resin therapy, presumably a result of depression of sodium transport across the gut wall, a conserving action similar to its reduction of sodium content in sweat. Of considerable interest is the fact that cation exchange. resin will potentiate the effect of mercury in producing diuresis. 9 , 22, 23, 24 The mechanism of this action is not clear but very probably it is similar to the acidifying action of ammonium chloride administered orally. Addition of an anion resin to a cation resin is thought by some to increase the efficiency of the cation exchanger and reduce the natural tendency toward acidosis by binding acid ions in the stomach. 22 The prevention of acidosis has particular significance for patients with renal diseas~. Other observers have J

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failed to demonstrate superior exchange capacity of the anion-cation mixture for basic ions as compared to cation resin alone. 17 , 31, 33 PREPARATIONS

At the present time four preparations of cation exchange resins are available commercially for prescription: 1. Resodec (Amberlite IRe-50) (Smith, Kline & French) is an inert, nonirritating, nonabsorbable, off-white powder whose action is restricted to the binding of cations. It is a polyacrylic carboxylic resin prepared by the polymerization of methacrylic acid with divinyl benzene to form sizeable molecules presenting large surface areas with available carboxylic acid radicals to which cations can be attached. It is saturated with ammonium and potassium ions in a ratio of 2 to 1. The amount of potassium supplied is approximately 2.3 grams (60 mEq.) in a daily ration of 45 grams of resin. The recommended daily dose is 15 grams (1 packet) of powder, three times daily, at mealtime administered in a chilled beverage or mixed with food. More than 60 grams per day is ingested with difficulty. 2. Carbo-Resin (Lilly) is a mildly flavored mixture containing 87.5 per cent of cation exchange resin and 12.5 per cent of anion exchange resin. The anion exchange resin is a polyamine-methylene resin. The cation exchange resin is a polyacrylic carboxylic acid resin of which twothirds is hydrogen resin and one-third potassium resin. The mixture is a buff-colored fine powder to which a wetting agent has been added to aid its dispersion in water and to facilitate administration. It is sold in packets containing 8 grams each or in powder form in one pound bottles. The recommended dose is 16 grams, three times daily, suspended in 6 ounces of water or fruit juice. No more than 24 grams is advisable as a single dose, and when it is necessary to exceed 72 grams per day, the number of doses rather than the size of individual doses is increased. 3. Natrinil (National Drug) is an insoluble, nontoxic, nonabsorbable cation exchange resin of the carboxylic type containing 80 per cent of resin in the hydrogen cycle and 20 per cent in the potassium cycle. The manufacturer recommends 40 grams per day divided into four equal doses of 10 grams each, administered with meals and at bedtime. The material i~ dispensed in 10 gram packets for this purpose. 4. Katonium (Winthrop-Stearns) is a light brown, finely divided powder, composed of a mixture of 75 per cent ammonium resin sulfonate and 25 per cent potassium resin sulfonate. Supplied in 15 gram packets, the·recommended dose is 15 grams administered three times daily with meals. DOSAGE AND ADMINISTRATION

The dose of the resin depends upon the product used, Resodec, 15 grams three times daily, Carbo-Resin, 16 grams three times daily,.

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Natrinil, 10 grams four times daily and Katonium, 15 grams three times daily. ()ur own experience using the first two forms, indicate that roost patients have difficulty exceeding these recommended doses. Adjustment of dosage must be individualized to each patient's needs. The resin is best given just before meals in a chilled beverage of strong flavor although many patients prefer water. The resin should be added to the beverage, stirred, and immediately swallowed. A few patients prefer mixing the resin with such foods as apple sauce or mashed potatoes. Most patients complain of the bulk to be ingested but little difficulty is encountered in those patients, long ill of heart failure, ·for whom conventional measures have failed to provide symptomatic relief. Although possible, no definite studies have been reported to indicate that extra resin given at bedtime on an empty stomach produces additional benefit. 20 Mild gastrointestinal disturbances are frequent, the principal one being constipation, which is usually controlled with mild laxatives. Bulk laxatives are preferably avoided. Fecal impaction should be carefully watched for but was not observed in our series. Calcium in the form of calcium lactate, 5 grams per day, is prescribed to forestall theoretical calcium depletion and along with supplementary vitamins, should be given between meals. It must be emphasized that the capacity of the exchanger does not allow a free salt intake with meals. 23 , 25, 30 Dietary sodium should not exceed approximately 1.5 grams (65 mEq.) daily. Sodium restriction to 500 mg. (22 mEq.) per day or less is mandatory for patients with uncontrolled chronic heart failure. It is best, when possible, to obtain control determinations of serum sodium, potassium, calcium, chloride, carbon dioxide combining power and nonprotein nitrogen and repeat these serially at weekly intervals for the first four weeks and monthly thereafter. These electrolyte observations are not important to the clinician treating uncomplicated congestive heart failure, but they are mandatory for those patients exhibiting any signs of renal disease, since the inability of the kidney to form ammonia may lead to severe uncompensated acidosis. When serum bicarbonate falls below 20 mEq.jL. (45 volumes per cent CO 2 combining power) and serum chloride rises, discontinuance of resin therapy must 3eriously be considered. In the absence of a flame photometer, the serum sodium can be estimated by adding the CO 2 combining power in milliequivalents to the serum chloride in milliequivalents and adding 10. 42 Alterations in potassium metabolism can be predicted from characteristic changes in serial electrocardiograms. 43 - 46 Additional potassium has been recommended 16 in the form of potassium chloride, 2 grams daily, even in the presence of a potassium exchanger, but this we have not found necessary. The resin may be administered continuously over prolonged periods with reasonable safety. 20, 23, 27, 28, 31 The intermittent use, that is, four

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days of resin therapy with three days rest, has been reported to be useful in the control of edema. 20 Alterations in body weight provide a simple clinical guide for determining the efficacy of resin therapy in edematous patients, for when sodium is removed from the body, diuresis follows and edema disappears. Adjustment in daily dosage requirement of resin for each individual may be made upon this basis. INDICATIONS AND CONTRAINDICATIONS

Use of cation exchange resin should be considered supplementary to conventional methods of therapy in heart failure. Resin administration is an adjunct to and not a replacement for accepted and usually effective therapeutic procedures. ll , 17, 20, 23, 25. 27, 30, 31 Resins are helpful in those patients with chronic heart failure who have difficulty in maintaining rigid dietary sodium restriction. After restoration to compensation, supplements in the form of increased dietary sodium may be made without return of heart failure. Resins are particularly useful for those patients who, in spite of an adequate regimen, require regular injections of mercurials in order to promote diuresis. The effect of the mercurial is potentiated by the exchange resin and the necessity for mercury is often eliminated. To those patients in whom mercurial diuretics no longer mobilize edema fluid, the administration of resin may induce diuresis. It should be emphasized that the cation exchange resin does not allow the cardiac who manifests chronic heart failure to enjoy a normal or unlimited salt intake. The prime indication, therefore, is exhibited by the patient with chronic heart failure who is responding poorly to conventional methods of therapy or who does not accept rigid sodium restriction or who exhibits sensitivity to mercurials. The outstanding contraindication to resin therapy is renal insufficiency. The failure of the kidney to maintain normal acid-base equilibril!m by the formation of ammonia leads to uncompensated acidosis. The acidifying effect of the resin is thought to be equivalent to approximately 8 to 10 grams of ammonium chloride daily. Close observation of serum electrolytes should be maintained for any patient with suspected or overt renal disease, for in addition to metabolic acidosis, the low salt syndrome 20 • 47 may appear. Resins should not be administered to patients who fail to eat well because the resin will bind circulating cations entering the bowel and produce serious disturbances in electrolyte balance. COMPLICArrIONS OF RESIN THERAPY

Patients often complain of the taste, the bulk and the consistency of the exchange mixture as well as its constipating effect. Others have epigastric burning, abdominal distention, cramping, diarrhea and occasionally fecal impaction may occur. Difficulties of this type have not

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assumed significant proportions in our experience. Urinary casts may appear in association with an acid urine but this is unimportant. 48 Metabolic acidosis due to excessive loss of base to the stool and retention of chloride ions must be watched for. The possible occurrence of the low sodium syndrome in which serum sodium falls and serum chloride rises with concomitant nitrogen retention must be appreciated along with such potentialities as hypokalemia and hypocalcemia. The addition of potassium in the exchanger prevents excessive loss of potassium except for occasional patients to whom additional potassium must be given in oral form. The administration of calcium has prevented both hypocalcemia and demineralization of bones even after prolonged use of resin in our series. However, attention has been called to the late development of hyponatremia, hypokalemia and hypocalcemia appearing after three to six months of continuous resin therapy.3o SUMMARY

The cation exchange resins have demonstrated clinical utility as an adjunct to conventional therapeutic measures in the treatment of congestive heart failure. The principal indications for resin administration are exemplified by patients who exhibit the following difficulties: (1) chronic congestive heart failure unresponsive to accepted therapeutic methods; (2) inability to accept or to follow low sodium diets; (3) necessity for frequent mercurial injections; (4) loss of expected diuretic effect from mercury; (5) sensitivity to mercurial compounds. The administration of cation exchange resin, although generally a 'safe procedure, is not without hazard. The hazard is greater with continued administration than with intermittent administration. Particular caution must be reserved for patients who exhibit renal insufficiency and for those placed upon marked restriction of dietary sodium. The possible c,omplications of acidosis, hyponatremia, hypokalemia and hypocalcemia resulting from prolonged resin therapy must be appreciated. Serial determinations of blood electrolytes, as well as serial electrocardiograms, should be performed when possible, in order to forestall and to correct the more serious, but fortunately infrequent, electrolyte disturbances which may appear during the course of resin treatment. CASE REPORTS CASE I. A 41 year old man with chronic rheumatic heart disease, mitral stenosis and insufficiency, and auricular fibrillation had been followed for 7 years in recurrent congestive heart failure necessitating several hospital admissions. Prior to the institution of resin therapy, failure was exhibited while on a regimen of rigid sodium restriction, continued digitalization, and at least weekly ~njections of mercuhydrin. After 2 months of controlled observations, cation exchange resin (Resodec) was started 15 grams, three times daily. No further

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mercurical injections were required. During the ensuing 6 months of continuous resin therapy, his weight gradually fell, edema cleared and he was able to resume part-time work. The urinary sodium fell to 0 to 2 mEq. per day while the urinary chlorides rose. In spite of some increase in diet, weight loss continued. Urinary excretion of sodium was stabilized at low levels and no electrolyte disturbance was exhibited. (See Fig. 28.) 135 130

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Fig. 28. I)emonstrates slow fall in weight, marked reduction in urinary sodium to less than 1 mEq. per day and the elimination of mercurial inj ections while taking resin (Resodec), 45 grams per day. The magnitude of rise in urinary chloride leads to suspicion of unauthorized additions to the low sodium diet of 500 mg. (22 mEq. [listed erroneously as 20 mEq. in the chart]) per day. (Case I.)

Comment. This patient exemplifies the picture of chronic congestive heart ""failure uncontrolled by conventional methods, including the frequent use of mercurial diuretics, until the addition of 45 grams of resin per day which, without other change in regimen, abolished completely the necessity for mercurial diuretics during a six months' period of continuous resin therapy. CASE II. A 57 year old man who presented the clinical picture of degenerative heart disease with hypertension, coronary disease, tremendous cardiac enlargement and nephrosclerosis with mild renal insufficiency (nonprotein nitrogen

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58 mg. per 100 cc.) was carefully followed for a period of 3 years during which time several periods of hospitalization were required to restore cOlnpensation. The patient found great difficulty adhering to rigid sodium restriction (500 mg. of sodium per day) which was required along with digitalis and mercurials two to three times weekly in order to control overt failure. During the first 3 months of resin therapy (Resodec), 45 grams per day, he remained compensated, free of edema, and was able to increase physical activity. Dietary breaks necessitated only 2 injections of mercurials during this period. Urinary sodium fell below 1 mEq. per day. Under continued resin therapy, sodium was added experimentally as crystalline sodium chloride, initially 500 mg. (22 mEq.) of sodium and later 1 gram (44 mEq.) of sodium without producing weight gain, edelna or necessitating mercurial diuretics and without significantly increasing urinary sodium excretion. Further additions of sodium chloride however, caused gain in weight, edema and increase in urinary sodium excretion, and mercurial injections were again required. During 13 months of continuous resin administration no electrolyte disturbances were encountered. The patient remained essentially well except for occasional dietary breaks. In order to test the efficacy of the resin, a 2 weeks' period away from resin therapy resulted in fairly rapid weight gain, dyspnea and overt edema. These signs disappeared when resin therapy was resumed.

Comment. This case illustrates the instance of a patient with chronic congestive heart failure and moderate renal insufficiency who under prolonged resin therapy failed to develop any electrolyte difficulty. The use of resin enabled the patient to remain fully compensated for the first time in several years and allowed the addition of a significant quantity of sodium to his diet. 1'his improved the palatability of the diet which in turn resulted in fewer dietary breaks. Of interest was the fact that this patient preferred to add crystalline sodium chloride to his diet for taste rather than broaden his choice of foods. CASE III. A 67 year old man with hypertensive heart disease, Inoderate cardiac enlargement, nephrosclerosis with mild renal insufficiency (nonprotein nitrogen 54 mg. per 100 cc.) had been followed for'5 years with congestive heart failure, during which three periods of hospitalization were required to restore compensation. In spite of rigid adherence to a reginlen of rest, digitalization and a low sodium diet (500 mg.), mercurials proved necessary at weekly intervals. When cat'ion exchange resin (Resodec), 45 grams per day, was instituted, weight loss was gradual and the urinary sodium declined to low levels, below 5 mEq. per day. Compensation was restored and the need for mercurial diuretics was abolished completely. After 8 months of continuous resin therapy during which no diuretics were required, a control period of 8 weeks away from resin therapy was instituted. Weight gain of 25 pounds resulted, dyspnea returned, edema reappeared and mercurial diuretics were again required. Resin therapy was then resumed. The patient has now followed 3 full years of continuous resin therapy except for a brief period when intermittent therapy was tested and found ineffective. The blood electrolyte pattern remains unchanged and the patient has been well except for one period when a hydrogen-potassium resin was substituted for 6 weeks. A marked drop in serum potassiunl and CO 2 combining power associated with a rise in serum chloride and nitrogen rapidly followed. This disturbance quickly disappeared when the ammonium-potassium resin was resumed. No further diuretics have been given. Mild fluctuations in nonprotein nitrogen have been observed but nitrogen retention sti~l persists. (See Fig. 29.)

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Comment. This patient demonstrates an instance of prolonged congestive heart failure in which control proved difficult on a rigid program including adequate salt restriction, digitalis and mercurial diuretics. Following the institution of resin therapy no further mercurial diuretics were necessary except during a control period away from resin. In spite of the prolonged three year administration of the resin, no electrolyte BLOOD ELECTROLYTES 140

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Fig. 29. Blood electrolyte pattern exhibited in Case III during first fifteen months of resin therapy. Note the stability of sodium, chloride and potassium and mildly fluctuating calcium, nitrogen and CO 2 combining power during the first eight months. During a control period of eight weeks, serum chloride fell slightly while CO 2 combining power rose. While taking the hydrogen-potassium resin, the chloride and nitrogen rose, and potassium and CO 2 combining power fell sharply. -

disturbance has been noted. There has been no fall in serum calcium or demineralization of bone. It is, therefore, possible for some patients to ingest cation resin continuously over prolonged periods without ill effects. In this patient and two others, a sudden shift from stability upon ammonium-potassium resin to an experimental period on hydrogenpotassium resin, created metabolic acidosis with considerable electroltye disturbance in each of the 3 patients. This experience has not been shared by others using the hydrogen form of resin. REFERENCES 1. Adams, B. A. and Holmes, E. L.: Absorptive Properties of Synthetic Resins. I. J. Soc. Chern. Ind. 54: IT, 1935. 2. Segal, H. L. and others: A Polyamine-Formaldehyde Resin: I. Its Effect upon the pH of Acidified Solutions and the pH and Pepsin of Gastric Juice in Vitro. II. Its Toxicity in Rats: Preliminary Feeding Tests. Gastroenterology 4: 484, 1945.

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3. Dock, W.: Sodium Depletion as a Therapeutic Procedure: The Value of Ion Exchange Resins in Withdrawing Sodium from the Body. T. A. Am. Physicians 59: 282, 1946. 4. Irwin, L. and others: The Effect of a Cation Exchange Resin on Electrolyte Balance and Its Use in Edematous States. J. Clin. Investigation 28: 1403, 1949. 5. Cohhey, T. S., Jr., and others: Biochemical and Clinical Effects of Cationic Exchange Resin. Fed. Proc. 8: 352, 1949. 6. Currens, J. H., Counihan, T. and Rourke, M.: Observations on the Administration of Ammonium Cation Exchange Resin to Patients with Cardiac Edema. J. Clin. Investigation 29: 807, 1950. '7. Danowski, T. S. and others: Carboxylic Cation Exchange Resin Studies in Animals and Humans. J. Clin. Investigation 29: 807,1950. 8. Kraus, H.: The Use of Cation Exchange Resin in Patients with Cardiac Edema. J. Clin. Investigation 29: 829, 1950. 9. Hay, S. H. and Wood, J. E., Jr.: Cation Exchange Resins in the Treatment of Congestive Heart Failure. Ann. Int. Med. 33: 1139, 1950. 10. Greenman, L. and others: Biochemical Changes Accompanying the Ingestion of a Carboxylic Cation Exchanger in the Hydrogen, Ammonium, Sodium, Potassium, or Calcium Form. J. Clin. Investigation 30: 995, 1951. 11. (jreenman, L. and others: Probable Clinical Utility of Cation Exchange Resins. J. Clin. Investigation 30: 1027, 1951. 12. Danowski, T. S. and others: The Use of Cation Exchange Resins in Clinical Situations. Ann. Int. Med. 35: 529, 1951. 13. Voyles, C. M., Jr., and Orgain, E. S.: Prolonged Cation-Exchange Resin Therapy in Congestive Heart Failure. New England J. Med. 245: 808, 1951. 14. Feinberg, A. W. and Rosenberg, B.: The Use of a Carboxylic Cation Exchange Resin in the Therapy of Congestive Heart Failure. Am. Heart J. 42: 698, 1951. 15. Chapman, D. W., Panill, F. C., Jr., and Skaggs, R. H.: A New Cation Exchange Resin in the Therapy of Edematous States. Am. Pract. 2: 945, 1951. 16. Emerson, K., Jr., and others: Oral Use of Cation Exchange Resins in Treatmen t of Edema. Arch. Int. Med. 88: 605, 1951. 17. Holmes, J. H., Hine, F. and Hlad, C. J.: Clinical and Laboratory Experience with Cation Exchange Resins. Tr. Am. Clin. Climatological A. 63: 187, 1951. 18. Friedman, I. S.: Problems of Cation Exchange Resin Therapy. Arch. Int. Med. 89: 99, 1952. 19. Callahan, E. J. and others: Clinical Use of Cation Exchange Resins in the Treatment of Congestive Heart Failure. Am. J. M. Sc. 223: 117, 1952. 20. Wood, J. E., Jr., Ferguson, D. H. and Lowrance, P.: Cation Exchange Resins as an Adjunct in the Treatment of Heart Failure. J.A.M.A. 148: 820,1952. 21. Best, M. M.: Use of an Anion Cation Exchange Resin in Edematous States Contraindicating Mercurial Diuretics. Am. Pract. & Digest Treat. 3: 274, 1952. 22. Martz, B.L., Kohlstaedt, K. G. and Helmer, O. M.: Use ofa Combination of Anion and Cation Exchange Resin in the Treatment of Edema and Ascites.Circulation 5: 524, 1952. 23. Voyles, C.M., Jr. and Orgain, E. S.: The Prolonged Administration of Cation Exchange ,Resin as a Supplementary Measure in Congestive Heart Failure. South. M. J.45:439, 1952. 24. Elkinton, J. R.,Squires, R. D. and Klingensmith, W. C., Jr.: Cation Exchange Resin in the Treatment of Congestive Heart Failure. I. Electrolyte Exchanges During Initial Periods of Resin Therapy. Circulation 5: 747, 1952. 25. Klingensmith, W. C., Jr. and Elkinton, J. R.: Cation Exchange Resin in the Treatment of Congestive Heart Failure. II. Clinical Effectiveness and Chemical Complications During Prolonged Periods of Use . Circulation 5: 842, 1952.

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