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Treatment of Hypercalcemia
Symposium on Endocrine Disorders
Treatment of Hypercalcemia Ralph S. Goldsmith, M.D.
Hypercalcemia is a serious and potentially lethal complication of many diseases. As a result, it is important to understand and to be familiar with the appropriate management of this condition which often is identified only accidentally. The approach to therapy must be tempered by an appreciation of the underlying disease state as well as by knowledge of whether or not emergency reduction of serum calcium is required. In regard to the latter, no firm rules based on serum calcium values can be applied. Rather, it is important to recognize that individual tolerance to hypercalcemia is variable and, furthermore, that it may reflect the rapidity with which the concentration of serum calcium increases. It is not uncommon, for example, to observe nearly asymptomatic patients with primary hyperparathyroidism and a serum calcium of 15 mg per 100 ml, yet virtually moribund patients with rapidly progressive cancer and a serum calcium of 12 mg per 100 ml. In these two extremes, of course, other factors, such as debility and impaired renal function, may contribute to the clinical manifestations observed. In any case, one must use judgment of the patient's clinical status in assessing therapeutic needs. Associated conditions, such as renal impairment or cardiac arrhythmias, may alter the approach to be utilized, and many of these will be discussed.
GENERAL SUPPORT The prime considerations in therapy are summarized as follows: general support, therapy for the underlying disorder, and therapy for the hypercalcemia itself. In the ambulatory, asymptomatic patient with mild hypercalcemia, heroic measures obviously are not warranted or indicated. As with any medical emergency, frank or potential, however, general supportive measures of the sick patient are of foremost importance (Table 1). Since patients with hypercalcemia often have had anorexia, nausea, and vomiting for some time prior to seeking medical assistance, severe dehydration and oliguria are common presenting features. As a result, perhaps the single most important measure in treatMedical Clinics of North America - Vo!. 56, No. 4, July 1972
951
952
RALPH
Table 1.
S.
GOLDSMITH
Treatment of Hypercalcemia
General support Hydration Correct electrolyte losses (frequently K) Maintain blood pressure , flow of urine Reduce digitalis dosage Increase mobilization, w~ight-bearing
ing the patient is the intravenous use of fluids, usually 0.9 per cent sodium chloride, with or without added glucose. In the patient with extreme contraction of extracellular fluid volume, in whom hypotension may be present, it may be necessary to add appropriate vasoconstrictor drugs until the blood volume has been repleted. Hypokalemia is not an infrequent concomitant of hypercalcemia and also may require the replacement of relatively large amounts of potassium. A special problem is the hypercalcemic patient who has been receiving digitalis or other cardiac glycosides. Since calcium and digitalis are synergistic in their effect on the myocardium and conducting system, the fully digitalized patient may manifest digitalis toxicity when he becomes hypercalcemic. Thus, in such a patient, it may be necessary temporarily to reduce or withdraw digitalis until the hypercalcemia is controlled. Similarly, the hypercalcemic patient who requires digitalization is likely to be fully digitalized at lower-than-average doses. Remember, of course, that after control of the hypercalcemia an increase in digitalis dosage may be indicated. In all cases, the effect of digitalis should be monitored both clinically and by electrocardiogram, with special attention to arrhythmias and conduction defects.
UNDERLYING DISORDER Paramount in the management of hypercalcemia must be the effective and specific therapy of the underlying disorder (Table 2). Whether medical or surgical therapy is indicated will be determined independently of the hypercalcemia, although certain interactions will be considered. Because of the increased hazard of general anesthesia in the ill, severely hypercalcemic patient, however, it is unwise to rush into emergency surgery. Since specific medical therapy for hypercalcemia is available and generally adequate, it is no longer necessary to perform even parathyroidectomy as an emergency procedure. It is often desirable Table 2.
Treatment of Hypercalcemia
Specific treatment of underlying disease Surgical extirpation of neoplasms Radiation Cytotoxic drugs Corticosteroids Withdrawal of milk and alkali
TREATMENT OF HYPERCALCEMIA
953
to reduce dangerous levels of hypercalcemia by medical means prior to a specific operation. Certainly, surgical treatment should never be contemplated without repletion of blood volume and reestablishment of adequate flow of urine, if at all possible. An infrequently recognized cause of severe hypercalcemia is "acute bone atrophy" as a result of immobilization. Mild, usually asymptomatic hypercalcemia develops in approximately 10 per cent of previously healthy people who are acutely immobilized as a result of injury, poliomyelitis, or some similar acute insult. In patients with increased bone turnover, such as Paget's disease or primary hyperparathyroidism, however, the increase in serum calcium occurring on immobilization may be of considerable magnitude and, rarely, may be life-threatening. In such cases, mobilization and weight-bearing may be the most effective, and certainly the most specific, form of therapy. Unfortunately, passive and active exercise is generally ineffective for the bedfast patient. In some conditions, as in thyrotoxicosis or adrenal insufficiency, hypercalcemia is but a relatively minor manifestation and sometimes can be ignored while specific treatment is being initiated. Under these circumstances, it is advisable to monitor the serum calcium frequently during treatment to assure one of its response.
THERAPY FOR HYPERCALCEMIA PER SE Although the goal of therapy must be directed ultimately at the underlying disorder, as already indicated, it is often impossible to delay reduction of the serum calcium by nonspecific means . The nonspecific measures can be classified into several broad categories (Tables 3, 4, and 5): gastrointestinal, renal, and skeletal.
Gastrointestinal Measures (Table 3) Efforts to reduce serum calcium by decreasing the availability of calcium from the gastrointestinal tract have perhaps the longest history of all treatment forms. It is still common to hear the suggestion that dietary calcium be reduced or eliminated as the first step in treatment. Although I have no quarrel with the concept of reducing dietary calcium in an atTable 3. Treatment of Hypercalcemia by Decreasing Gastrointestinal Absorption of Calcium Decrease dietary intake of calcium (reasonably effective only in sarcoidosis, vitamin D intoxication) Decrease availability of dietary calcium Oxalate-containing foods (such as rhubarb) Sodium phytate Cellulose phosphate Inhibit absorptive mechanisms Cortisone or congeners
954
RALPH
S.
GOLDSMITH
tempt to decrease calcium entry into the body, the usefulness of this maneuver is limited to those conditions in which gastrointestinal absorption of calcium is excessive and thus contributes significantly to the hypercalcemia. In practical terms, in fact, a substantial decrease in serum calcium in response to decreased dietary calcium strongly suggests the presence of sarcoidosis, vitamin D intoxication, or, perhaps, idiopathic hypercalcemia of infancy. It should be pointed out, however, that reduction of dietary calcium carries with it an undesirable feature. Since most dietary calcium is accompanied by phosphate, elimination of foods high in calcium, primarily dairy products, also eliminates much dietary phosphate. As discussed subsequently, this may have an effect opposite to that desired, in that serum calcium actually may increase. It is also possible to reduce calcium absorption by increasing the intake of foods that contain large amounts of complexing substances, such as oxalate. The formation of these relatively insoluble complexes necessarily decreases net calcium absorption. Unfortunately, such foods (for example, rhubarb and alfalfa) are not generally considered gourmet items by most people and, in any case, would have to be consumed in monumental amounts to produce the desired effects. Sodium phytate (inositol hexaphosphate), a common constituent of many cereals, is another dietary agent that has been recommended for its calcium-binding properties. It has been noted to produce reduction of serum calcium, but even more striking reduction of urinary calcium, especially in sarcoidosis." Since the intestine normally contains a substantial complement of phytase, which can hydrolyze phytate to its components, inositol and inorganic phosphate, it seems likely that the observed effects were due primarily to the phosphate moiety rather than to the intact molecule. In the presence of vitamin D deficiency, however, intestinal phytase may be inactive. Under such a circumstance, therefore, definite calcium-binding properties of the phytate may be manifest. Perhaps more suitable as a complexing agent is cellulose phosphate, which can be taken as a nearly tasteless wafer. Cellulose phosphate hydrolyzes to some extent, releasing inorganic phosphate, but much of it remains intact to bind calcium in the intestineY An additional advantage of this approach is that the cellulose phosphate also may bind calcium secreted into the intestine, so that fecal excretion of calcium actually may exceed dietary intake. Administration of cortisone, cortisol, or synthetic congeners results to some extent in inhibition of normal calcium-absorptive mechanisms, probably those that are mediated by vitamin D. Approximately half of normal calcium absorption appears to be dependent on vitamin D, so that steroid inhibition is not likely to have dramatic effects, except in those aforementioned diseases with excessive absorption. Renal Excretion and Dialysis (Table 4) Probably the most widely used and accepted techniques for treating hypercalcemia are those that depend on increasing the excretion of calcium from the body by way of the urine or through dialysis. This group of techniques may be considered under three categories : (1) increasing urinary excretion of sodium, (2) ch elating or complexing agents, and (3) dialysis.
TREATMENT OF HYPERCALCEMIA
955
Table 4. Treatment of Hypercalcemia by Increasing Renal Excretion of Calcium or by Dialysis Increase natriuri a Infuse saline solution Administer natriuretic agent Ethacrynic acid Furose mide Not thiazides Administer Sodium Sodium Sodium
chelating or binding agents citrate sulfate EDTA or EGTA
Dialyze Hemodialysis Peritoneal dialysis
It has been demonstrated both in experimental animals and in man that, other conditions remaining constant, renal calcium clearance is a linear function of sodium clearance. As a result, it is possible to increase urinary excretion of calcium by the simple expedient of increasing urinary excretion of sodium. Since intravenous hydration is so often a part of good supportive therapy, as mentioned, use of large amounts of sodium chloride solutions provides a simple but highly effective means of accomplishing both aims, the only limitation on the rate of infusion being the patient's tolerance. Some patients, of course, may be unable to accept large fluid loads because of myocardial insufficiency. This is especially true in the elderly, who, therefore, must be observed carefully for signs of fluid overload, manifested often by pulmonary edema. Largely as a result of attempting to circumvent such problems, certain natriuretic agents, most notably ethacrynic acid and furosemide, were found to promote natriuresis and calciuresis in concert, even without the intermediate of saline infusion.1l Thus, in the adequately hydrated patient, use of either of these natriuretics will greatly increase urinary excretion of calcium and can often decrease hypercalcemia substantially. To achieve optimal benefit, judicious combination of a natriuretic and a parenteral dose of saline may be employed. It is important to remember that these drugs are extremely potent, and it is necessary to replace volume and electrolyte losses incurred during their use. Strict avoidance of thiazide diuretics is important, since this class of agents is unique in dissociating natriuretic and calciuretic effects and, furthermore, may lead to increases in serum calcium. Ethylenediaminetetraacetate CEDTA) is foremost among the agents that increase urinary excretion of calcium by forming filtrable, soluble complexes, most of which are not reabsorbed by the renal tubule. EDTA has the specific property of chelating calcium in the blood, a process that directly decreases the ionized calcium concentration without being dependent on urinary excretion. It has been estimated that 1 gm of disodium EDTA will bind approximately 216 mg of calcium. As a result, there is the minor disadvantage that during EDTA infusion total serum
956
RALPH
S.
GOLDSMITH
calcium includes both bound and un bound calcium and thus does not reflect only the biologically active portion. During such treatment, therefore , serum calcium should be monitored by measurement of either ionized calcium directly (as by the calcium activity electrode) or total non-EDTA-bound calcium (by EDTA titration). A point of warning: EDTA infusions are usually painful at the site of infusion. Unfortunately, this extremely effective drug has a serious limitation: prolonged use or doses exceeding 3 gm have been reported to lead to renal tubular damage and renal insufficiency. Thus, although EDTA may be used for emergency reduction of life-threatening hypercalcemia, its use should not be continued beyond 24 to 48 hours. Sodium sulfate (isotonic) infusions have been reported to increase urinary excretion of calcium by production of a calcium sulfate complex, although it is not clear that the effect in man is substantially greater than would be expected from the natriuresis alone. Some patients certainly have shown an increased effect;l but responses have not been consistent. Sodium citrate also has been suggested as a complexing agent, but no systematic study of its value beyond that of the sodium alone has been reported. The efficacy of all of the foregoing methods depends on reasonable renal function. Dialysis, on the other hand, can be performed irrespective of renal functional status and depends solely on the calcium gradient established across an artificial membrane (hemodialysis) or the peritoneum. By utilizing a calcium-free dialysate, a large gradient is produced and correspondingly large fluxes of calcium can be created. A recent report has demonstrated the potential value of continued peritoneal dialysis. s Although not extensive, my own experience cautions against being overly dependent on this treatment modality. Recently, a severely hypercalcemic patient underwent hemodialysis in preparation for parathyroid surgery.JO Despite removal of 3000 mg of calcium in 4 hours , the value for serum calcium was 16 mg per 100 ml at the end of dialysis and had increased to 19 m p.: per 100 ml within another 3 hours. Thus, an unusually large amount of calcium was removed, with a relatively small and transient effect. I am compelled to suggest, therefore, that dialysis may be a useful temporizing measure, but that alternate therapy should be sought for more prolonged maintenance. Skeletal Factors (Table 5) The obvious fallacy with the foregoing approaches to therapy of hypercalcemia is that they fail to attack the primary source of most hypercalcemia, that is, the skeleton. With the possible exception of viTable 5. Treatment of Hypercalc emia by Increasing Ratio of Bone Accretion to Resorption Cortisone or congeners Phosphate Calcitonin Mithramycin
TREATMENT OF HYPERCALCEMIA
957
tamin D intoxication and sarcoidosis, hypercalcemia is due to an imbalance between skeletal calcium accretion and resorption, usually an increase in resorption. The most efficacious therapy, therefore, must be one that restores this balance, for that is where the trouble is. Without question the most exciting event in treatment of hypercalcemia was the discovery of calcitonin, a hypocalcemic hormone that specifically inhibits osteoclastic bone resorption. The availability of such an agent should by all odds have resolved this therapeutic problem, yet early experience indicated that it is usually far less effective than was predicted. It is possible, however, that salmon calcitonin, which is more potent than the porcine variety, may be more efficacious.'" Cortisol, cortisone, and various synthetic congeners have been utilized for many years in the therapy of hypercalcemia due to causes other than hyperparathyroidism. The usual resistance of patients with hyperparathyroidism to steroid therapy has resulted in the common use of steroids as a diagnostic aid, especially when coexistence of two diseases is suspected. Decrease of hypercalcemia may not be rapid, however, and a lag of 7 to 10 days is not exceptional. The best response to steroids is seen most commonly in patients who have sarcoidosis, vitamin D intoxication, myeloma, or various lymphomas and leukemias. Patients with solid malignant tumors respond much less predictably, but the majority do show at least a moderate decrease in hypercalcemia. The mechanism of the steroid effect is probably a combination of both antagonism to vitamin D in the gastrointestinal tract and a direct effect on bone. It has been reported 7 that, in myeloma, steroids increase both calcium accretion and resorption rates, but the balance is tilted in favor of an increasing ratio of accretion to resorption. This provides little insight into the precise cellular or molecular mechanisms involved, but at least it appears that steroids have a direct skeletal effect. One of the major problems with steroid therapy, however, is the well-known long-term effect of promoting osteoporosis. As a result, steroid therapy probably should not be continued for prolonged periods. The effectiveness of oral doses of phosphate in decreasing hypercalcemia in hyperparathyroidism was first reported 40 years ago,1 but the use of phosphate as a therapeutic agent received little attention until recently.' The long delay was due largely to the concern expressed by Albright and his colleagues, and recently reiterated by other authors," that the use of phosphate might lead to extraskeletal calcification and urinary tract calculi. Phosphate is now known to be an excellent therapeutic agent for calcium calculi, so this objection seems obviated. Soft-tissue calcification is another matter, however, and it is clear that this complication may well occur in patients who are treated too vigorously without heed to the usual standards of good practice. Within such limits as avoiding excessive increases in serum concentration of phosphorus for prolonged periods, administration of phosphate by either the oral or the intravenous route is at least as safe as other forms of therapy. I have not seen any significant complications of this medication when utilizing recommended doses and rates of administration (Table 6). Two major advantages for phosphate therapy may be mentioned. First, it is almost univer-
Intravenous
Oral or parenteral
Intravenous
Intravenous
EDTA
Cortisone
Mithramycin
Phosphate
Parenteral
weight daily
body weight/day
1-5 MRC units/kg
1 millimolet/kg body weight over 6-8 hr 1-2 millimolest/kg body
25 Ilg/kg body weight
penia, nausea, vomiting
Nausea, vomiting
Extraskeletal calcification, hypoca1cemia
Hemorrhage , thrombocyto-
Hypercorticism
Pulmonary edema, hypernatremia Volume depletion, hypokalemia Renal failure, hypotension
Pulmonary edema
REPORTED COMPLICATIONS
Thrombotic disorders
Emergency reduction of serum calcium required Bleeding disorder, renal insufficiency, liver impairment Renal insufficiency, hyperphosphatemia
Renal insufficiency
Congestive heart failure, renal insufficiency, hypertension Congestive heart failure, renal insufficiency, hypertension Renal insufficiency
CONTRAINDICATIONS
t 1 millimole of phosphate is equivalent to 31 mg of phosphorus.
1970.
"'Modified from Suki WN, Yium JJ, Von Minden M, et al: Acute treatment of hyperca1cemia with furosemide. N Engl J Med 283:836-840,
Calcitonin
100 mg/hr
Intravenous
Oral
3 liters over 9 hr
Intravenous
50 mg/kg body weight over 4-6 hr 150 mg/day
1 liter every 3-4 hr
DOSAGE
Intravenous
ROUTE
Usual Doses of Hypocalcemic Agents':'
Sodium chloride solution (isotonic) Sodium sulfate solution (isotonic) Furosemide
DRUG
Table 6.
~
~
s: ::l
[JJ
I;j
t"
oo
[J)
~
'"
t"
:r>
t.C tJl 00
959
TREATMENT OF HYPERCALCEMIA
Table 7.
Comparison of Hypocalcemic Agents
Sodium sulfate (i.v.) Furosemide, e thacrynic acid EDTA (i.v. ) Dialysis Calcitonin Phosphate (p.o. ) Phosphate (i. v.) Mithramycin Cortisone
SPEED
EFFICACY
REBOUND
+ + + +++ ++ +++ + +++ ++ +
+ ++ +++ + ++ ++ ++ +++ +++ ++
+ +++ ++ ++ ++++ ++++
LO NG- T E R M
:!:
+ ?+++ +++
:!:
:!:
+++ ++
+++ ++
sally effective and can be used as emergency therapy intravenously or, less heroically, by the oral route. Because of the predictable and rapid response that can be obtained, valuable time can be gained for appropriate diagnostic studies or more specific therapy for the underlying disorder. Second, and of nearly equal value, is the fact that satisfactory suppression of hypercalcemia can be maintained for prolonged periods with daily oral dosage or periodic intravenous infusion. Cytotoxic drugs, especially those of the actinomycin D genre, have been reported from time to time as hypocalcemic agents. Recently, however, it has been found that mithramycin, a drug used frequently in therapy of testicular neoplasms , almost uniformly causes a reduction in serum calcium during the usual course of its administration. 6 Side-effects have varied from mild (nausea and vomiting) to severe (hemorrhagic tendency), depending on dosage and frequency. A further limitation of its use has been the fact that the decrease in serum calcium often has not been rapid enough to consider the drug sufficiently dependable for use in emergencies. Rebound in serum calcium usually occurs on cessation of therapy, but the drug can be given repeatedly as long as hemorrhagic complications do not occur. My personal prejudice is that this agent should be reserved for hypercalcemia due to malignant tumors, although its use in other circumstances may sometimes be warranted.
COMPARISON OF AVAILABLE MODALITIES Tables 6 and 7 summarize my experience plus tha t culled from the literature on the comparative speed, efficacy, and other characteristics of the various therapeutic modalities already discussed. Although I have made every effort to be objective, such a comparison must of necessity be heavily biased by personal experience. The major limitations of this comparison are that (1) few comparative studies have been published, and (2) much of the literature on some agents consists primarily of individual case reports. Also as a result of my experience I am suggesting the following schedule for the emergency treatment of the hypercalcemic patient.
960
RALPH
S.
GOLDSMITH
A RECOMMENDED SCHEDULE FOR EMERGENCY TREATMENT OF HYPERCALCEMIA 1. Begin electrocardiographic monitoring 2. Institute appropriate supportive measures a. Intravenous saline infusion b. Potassium replacement as needed c. Vasopressor agents as needed 3. Furosemide (100 mg/hr) intravenously 4 . If response is inadequate, proceed with one of the following measures a. EDTA infusion-do not continue beyond 24 hours b. Phosphate infusion (1.5 gm of phosphorus infused over 6 to 8 hours) may be repeated daily, but more than two infusions usually are not required. Follow with phosphate given orally c. Mithramycin (25 ~g/ kg) intravenously 5. If renal failure unresponsive to diuretics and fluid is present, corticosteroids and calcitonin are the only modalities that can be used safely.
APPENDIX The following drugs discussed in this paper are still under investigation and can be obtained from the appropriate pharmaceutical companies only: (1) calcitonin-Armour; (2) Hyper-Phos-K (a phosphate for oral use) - Davies Rose Hoyt ; and (3) In Phos (a phosphate for intravenous use)-Davies Rose Hoyt. A phosphate solution given orally (Neutraphos), marketed as a dietary supplement by Willen Drug Co., also has been used.
REFERENCES l. Albright F , Bauer W, Claflin D, et al: Studies in parathyroid physiology. Ill. The effect of phospha te ingestion in clinical hyperparathyroidism. J Clin Invest 11 :411-435, 1932 2. Brewer RI , LeBauer J: Caution in the use of phosphates in the treatment of severe hypercalcemia. J Clin Endocrinol Metab 27:695-705, 1967 3. Chakma kjian ZH, Bethune JE: Sodium sulfa te treatment of hypercalcemia. N Engl J Med 275 :862-869, 1966 4. Goldsmith RS , Ingbar SH: Inorganic phospha te treatment of hypercalcemia of diverse etiologies. N Engl J Med 274:1-7,1966 5. Henneman PH, Dempsey EF , Carroll EL, et al: The cause of hypercalcuria in sarcoid and its treatment with cortisone and sodium phytate. J Clin Invest 35:1229- 1242, 1956 6. Kennedy BJ: Metabolic and toxic effects of mithramycin during tumor therapy. Am J Med 49:494-503 , 1970 7. Lazar MZ , Rosenberg LE: Mechanism of adrenal-steroid reversal of hyperca lcemia in multiple myeloma. N Engl J Med 270:749-755, 1964 8. Nolph KD, Stoltz ML: Treatment of hypercalce mia with calcium free peritoneal dialysis (CFPD) (abstract). Clin Re s 19:481, 1971 9. Pak CYC , Wortsman J, Bennett JE, et al: Control of hypercalcemia with cellulose phosphate (letter to the editor). J Clin Endocrinol Metab 28: 1829-1832, 1968 10. Steffee W, et al: Unpublished data 1l. Suki WN , Yium JJ, Von Minden M, et al: Acute treatment of hypercalcemia with furosemide. N Engl J Med 283:836-840 , 1970 12. West TET, Joffe M, Sinclair L, et al: Treatment of hypercalca emia with calcitonin. Lancet 1 :675-678, 1971 Mayo Clinic Rochester, Minnesota 55901
Treatment of Hypercalcemia Ralph S. Goldsmith, M.D.
Hypercalcemia is a serious and potentially lethal complication of many diseases. As a result, it is important to understand and to be familiar with the appropriate management of this condition which often is identified only accidentally. The approach to therapy must be tempered by an appreciation of the underlying disease state as well as by knowledge of whether or not emergency reduction of serum calcium is required. In regard to the latter, no firm rules based on serum calcium values can be applied. Rather, it is important to recognize that individual tolerance to hypercalcemia is variable and, furthermore, that it may reflect the rapidity with which the concentration of serum calcium increases. It is not uncommon, for example, to observe nearly asymptomatic patients with primary hyperparathyroidism and a serum calcium of 15 mg per 100 ml, yet virtually moribund patients with rapidly progressive cancer and a serum calcium of 12 mg per 100 ml. In these two extremes, of course, other factors, such as debility and impaired renal function, may contribute to the clinical manifestations observed. In any case, one must use judgment of the patient's clinical status in assessing therapeutic needs. Associated conditions, such as renal impairment or cardiac arrhythmias, may alter the approach to be utilized, and many of these will be discussed.
GENERAL SUPPORT The prime considerations in therapy are summarized as follows: general support, therapy for the underlying disorder, and therapy for the hypercalcemia itself. In the ambulatory, asymptomatic patient with mild hypercalcemia, heroic measures obviously are not warranted or indicated. As with any medical emergency, frank or potential, however, general supportive measures of the sick patient are of foremost importance (Table 1). Since patients with hypercalcemia often have had anorexia, nausea, and vomiting for some time prior to seeking medical assistance, severe dehydration and oliguria are common presenting features. As a result, perhaps the single most important measure in treatMedical Clinics of North America - Vo!. 56, No. 4, July 1972
951
952
RALPH
Table 1.
S.
GOLDSMITH
Treatment of Hypercalcemia
General support Hydration Correct electrolyte losses (frequently K) Maintain blood pressure , flow of urine Reduce digitalis dosage Increase mobilization, w~ight-bearing
ing the patient is the intravenous use of fluids, usually 0.9 per cent sodium chloride, with or without added glucose. In the patient with extreme contraction of extracellular fluid volume, in whom hypotension may be present, it may be necessary to add appropriate vasoconstrictor drugs until the blood volume has been repleted. Hypokalemia is not an infrequent concomitant of hypercalcemia and also may require the replacement of relatively large amounts of potassium. A special problem is the hypercalcemic patient who has been receiving digitalis or other cardiac glycosides. Since calcium and digitalis are synergistic in their effect on the myocardium and conducting system, the fully digitalized patient may manifest digitalis toxicity when he becomes hypercalcemic. Thus, in such a patient, it may be necessary temporarily to reduce or withdraw digitalis until the hypercalcemia is controlled. Similarly, the hypercalcemic patient who requires digitalization is likely to be fully digitalized at lower-than-average doses. Remember, of course, that after control of the hypercalcemia an increase in digitalis dosage may be indicated. In all cases, the effect of digitalis should be monitored both clinically and by electrocardiogram, with special attention to arrhythmias and conduction defects.
UNDERLYING DISORDER Paramount in the management of hypercalcemia must be the effective and specific therapy of the underlying disorder (Table 2). Whether medical or surgical therapy is indicated will be determined independently of the hypercalcemia, although certain interactions will be considered. Because of the increased hazard of general anesthesia in the ill, severely hypercalcemic patient, however, it is unwise to rush into emergency surgery. Since specific medical therapy for hypercalcemia is available and generally adequate, it is no longer necessary to perform even parathyroidectomy as an emergency procedure. It is often desirable Table 2.
Treatment of Hypercalcemia
Specific treatment of underlying disease Surgical extirpation of neoplasms Radiation Cytotoxic drugs Corticosteroids Withdrawal of milk and alkali
TREATMENT OF HYPERCALCEMIA
953
to reduce dangerous levels of hypercalcemia by medical means prior to a specific operation. Certainly, surgical treatment should never be contemplated without repletion of blood volume and reestablishment of adequate flow of urine, if at all possible. An infrequently recognized cause of severe hypercalcemia is "acute bone atrophy" as a result of immobilization. Mild, usually asymptomatic hypercalcemia develops in approximately 10 per cent of previously healthy people who are acutely immobilized as a result of injury, poliomyelitis, or some similar acute insult. In patients with increased bone turnover, such as Paget's disease or primary hyperparathyroidism, however, the increase in serum calcium occurring on immobilization may be of considerable magnitude and, rarely, may be life-threatening. In such cases, mobilization and weight-bearing may be the most effective, and certainly the most specific, form of therapy. Unfortunately, passive and active exercise is generally ineffective for the bedfast patient. In some conditions, as in thyrotoxicosis or adrenal insufficiency, hypercalcemia is but a relatively minor manifestation and sometimes can be ignored while specific treatment is being initiated. Under these circumstances, it is advisable to monitor the serum calcium frequently during treatment to assure one of its response.
THERAPY FOR HYPERCALCEMIA PER SE Although the goal of therapy must be directed ultimately at the underlying disorder, as already indicated, it is often impossible to delay reduction of the serum calcium by nonspecific means . The nonspecific measures can be classified into several broad categories (Tables 3, 4, and 5): gastrointestinal, renal, and skeletal.
Gastrointestinal Measures (Table 3) Efforts to reduce serum calcium by decreasing the availability of calcium from the gastrointestinal tract have perhaps the longest history of all treatment forms. It is still common to hear the suggestion that dietary calcium be reduced or eliminated as the first step in treatment. Although I have no quarrel with the concept of reducing dietary calcium in an atTable 3. Treatment of Hypercalcemia by Decreasing Gastrointestinal Absorption of Calcium Decrease dietary intake of calcium (reasonably effective only in sarcoidosis, vitamin D intoxication) Decrease availability of dietary calcium Oxalate-containing foods (such as rhubarb) Sodium phytate Cellulose phosphate Inhibit absorptive mechanisms Cortisone or congeners
954
RALPH
S.
GOLDSMITH
tempt to decrease calcium entry into the body, the usefulness of this maneuver is limited to those conditions in which gastrointestinal absorption of calcium is excessive and thus contributes significantly to the hypercalcemia. In practical terms, in fact, a substantial decrease in serum calcium in response to decreased dietary calcium strongly suggests the presence of sarcoidosis, vitamin D intoxication, or, perhaps, idiopathic hypercalcemia of infancy. It should be pointed out, however, that reduction of dietary calcium carries with it an undesirable feature. Since most dietary calcium is accompanied by phosphate, elimination of foods high in calcium, primarily dairy products, also eliminates much dietary phosphate. As discussed subsequently, this may have an effect opposite to that desired, in that serum calcium actually may increase. It is also possible to reduce calcium absorption by increasing the intake of foods that contain large amounts of complexing substances, such as oxalate. The formation of these relatively insoluble complexes necessarily decreases net calcium absorption. Unfortunately, such foods (for example, rhubarb and alfalfa) are not generally considered gourmet items by most people and, in any case, would have to be consumed in monumental amounts to produce the desired effects. Sodium phytate (inositol hexaphosphate), a common constituent of many cereals, is another dietary agent that has been recommended for its calcium-binding properties. It has been noted to produce reduction of serum calcium, but even more striking reduction of urinary calcium, especially in sarcoidosis." Since the intestine normally contains a substantial complement of phytase, which can hydrolyze phytate to its components, inositol and inorganic phosphate, it seems likely that the observed effects were due primarily to the phosphate moiety rather than to the intact molecule. In the presence of vitamin D deficiency, however, intestinal phytase may be inactive. Under such a circumstance, therefore, definite calcium-binding properties of the phytate may be manifest. Perhaps more suitable as a complexing agent is cellulose phosphate, which can be taken as a nearly tasteless wafer. Cellulose phosphate hydrolyzes to some extent, releasing inorganic phosphate, but much of it remains intact to bind calcium in the intestineY An additional advantage of this approach is that the cellulose phosphate also may bind calcium secreted into the intestine, so that fecal excretion of calcium actually may exceed dietary intake. Administration of cortisone, cortisol, or synthetic congeners results to some extent in inhibition of normal calcium-absorptive mechanisms, probably those that are mediated by vitamin D. Approximately half of normal calcium absorption appears to be dependent on vitamin D, so that steroid inhibition is not likely to have dramatic effects, except in those aforementioned diseases with excessive absorption. Renal Excretion and Dialysis (Table 4) Probably the most widely used and accepted techniques for treating hypercalcemia are those that depend on increasing the excretion of calcium from the body by way of the urine or through dialysis. This group of techniques may be considered under three categories : (1) increasing urinary excretion of sodium, (2) ch elating or complexing agents, and (3) dialysis.
TREATMENT OF HYPERCALCEMIA
955
Table 4. Treatment of Hypercalcemia by Increasing Renal Excretion of Calcium or by Dialysis Increase natriuri a Infuse saline solution Administer natriuretic agent Ethacrynic acid Furose mide Not thiazides Administer Sodium Sodium Sodium
chelating or binding agents citrate sulfate EDTA or EGTA
Dialyze Hemodialysis Peritoneal dialysis
It has been demonstrated both in experimental animals and in man that, other conditions remaining constant, renal calcium clearance is a linear function of sodium clearance. As a result, it is possible to increase urinary excretion of calcium by the simple expedient of increasing urinary excretion of sodium. Since intravenous hydration is so often a part of good supportive therapy, as mentioned, use of large amounts of sodium chloride solutions provides a simple but highly effective means of accomplishing both aims, the only limitation on the rate of infusion being the patient's tolerance. Some patients, of course, may be unable to accept large fluid loads because of myocardial insufficiency. This is especially true in the elderly, who, therefore, must be observed carefully for signs of fluid overload, manifested often by pulmonary edema. Largely as a result of attempting to circumvent such problems, certain natriuretic agents, most notably ethacrynic acid and furosemide, were found to promote natriuresis and calciuresis in concert, even without the intermediate of saline infusion.1l Thus, in the adequately hydrated patient, use of either of these natriuretics will greatly increase urinary excretion of calcium and can often decrease hypercalcemia substantially. To achieve optimal benefit, judicious combination of a natriuretic and a parenteral dose of saline may be employed. It is important to remember that these drugs are extremely potent, and it is necessary to replace volume and electrolyte losses incurred during their use. Strict avoidance of thiazide diuretics is important, since this class of agents is unique in dissociating natriuretic and calciuretic effects and, furthermore, may lead to increases in serum calcium. Ethylenediaminetetraacetate CEDTA) is foremost among the agents that increase urinary excretion of calcium by forming filtrable, soluble complexes, most of which are not reabsorbed by the renal tubule. EDTA has the specific property of chelating calcium in the blood, a process that directly decreases the ionized calcium concentration without being dependent on urinary excretion. It has been estimated that 1 gm of disodium EDTA will bind approximately 216 mg of calcium. As a result, there is the minor disadvantage that during EDTA infusion total serum
956
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calcium includes both bound and un bound calcium and thus does not reflect only the biologically active portion. During such treatment, therefore , serum calcium should be monitored by measurement of either ionized calcium directly (as by the calcium activity electrode) or total non-EDTA-bound calcium (by EDTA titration). A point of warning: EDTA infusions are usually painful at the site of infusion. Unfortunately, this extremely effective drug has a serious limitation: prolonged use or doses exceeding 3 gm have been reported to lead to renal tubular damage and renal insufficiency. Thus, although EDTA may be used for emergency reduction of life-threatening hypercalcemia, its use should not be continued beyond 24 to 48 hours. Sodium sulfate (isotonic) infusions have been reported to increase urinary excretion of calcium by production of a calcium sulfate complex, although it is not clear that the effect in man is substantially greater than would be expected from the natriuresis alone. Some patients certainly have shown an increased effect;l but responses have not been consistent. Sodium citrate also has been suggested as a complexing agent, but no systematic study of its value beyond that of the sodium alone has been reported. The efficacy of all of the foregoing methods depends on reasonable renal function. Dialysis, on the other hand, can be performed irrespective of renal functional status and depends solely on the calcium gradient established across an artificial membrane (hemodialysis) or the peritoneum. By utilizing a calcium-free dialysate, a large gradient is produced and correspondingly large fluxes of calcium can be created. A recent report has demonstrated the potential value of continued peritoneal dialysis. s Although not extensive, my own experience cautions against being overly dependent on this treatment modality. Recently, a severely hypercalcemic patient underwent hemodialysis in preparation for parathyroid surgery.JO Despite removal of 3000 mg of calcium in 4 hours , the value for serum calcium was 16 mg per 100 ml at the end of dialysis and had increased to 19 m p.: per 100 ml within another 3 hours. Thus, an unusually large amount of calcium was removed, with a relatively small and transient effect. I am compelled to suggest, therefore, that dialysis may be a useful temporizing measure, but that alternate therapy should be sought for more prolonged maintenance. Skeletal Factors (Table 5) The obvious fallacy with the foregoing approaches to therapy of hypercalcemia is that they fail to attack the primary source of most hypercalcemia, that is, the skeleton. With the possible exception of viTable 5. Treatment of Hypercalc emia by Increasing Ratio of Bone Accretion to Resorption Cortisone or congeners Phosphate Calcitonin Mithramycin
TREATMENT OF HYPERCALCEMIA
957
tamin D intoxication and sarcoidosis, hypercalcemia is due to an imbalance between skeletal calcium accretion and resorption, usually an increase in resorption. The most efficacious therapy, therefore, must be one that restores this balance, for that is where the trouble is. Without question the most exciting event in treatment of hypercalcemia was the discovery of calcitonin, a hypocalcemic hormone that specifically inhibits osteoclastic bone resorption. The availability of such an agent should by all odds have resolved this therapeutic problem, yet early experience indicated that it is usually far less effective than was predicted. It is possible, however, that salmon calcitonin, which is more potent than the porcine variety, may be more efficacious.'" Cortisol, cortisone, and various synthetic congeners have been utilized for many years in the therapy of hypercalcemia due to causes other than hyperparathyroidism. The usual resistance of patients with hyperparathyroidism to steroid therapy has resulted in the common use of steroids as a diagnostic aid, especially when coexistence of two diseases is suspected. Decrease of hypercalcemia may not be rapid, however, and a lag of 7 to 10 days is not exceptional. The best response to steroids is seen most commonly in patients who have sarcoidosis, vitamin D intoxication, myeloma, or various lymphomas and leukemias. Patients with solid malignant tumors respond much less predictably, but the majority do show at least a moderate decrease in hypercalcemia. The mechanism of the steroid effect is probably a combination of both antagonism to vitamin D in the gastrointestinal tract and a direct effect on bone. It has been reported 7 that, in myeloma, steroids increase both calcium accretion and resorption rates, but the balance is tilted in favor of an increasing ratio of accretion to resorption. This provides little insight into the precise cellular or molecular mechanisms involved, but at least it appears that steroids have a direct skeletal effect. One of the major problems with steroid therapy, however, is the well-known long-term effect of promoting osteoporosis. As a result, steroid therapy probably should not be continued for prolonged periods. The effectiveness of oral doses of phosphate in decreasing hypercalcemia in hyperparathyroidism was first reported 40 years ago,1 but the use of phosphate as a therapeutic agent received little attention until recently.' The long delay was due largely to the concern expressed by Albright and his colleagues, and recently reiterated by other authors," that the use of phosphate might lead to extraskeletal calcification and urinary tract calculi. Phosphate is now known to be an excellent therapeutic agent for calcium calculi, so this objection seems obviated. Soft-tissue calcification is another matter, however, and it is clear that this complication may well occur in patients who are treated too vigorously without heed to the usual standards of good practice. Within such limits as avoiding excessive increases in serum concentration of phosphorus for prolonged periods, administration of phosphate by either the oral or the intravenous route is at least as safe as other forms of therapy. I have not seen any significant complications of this medication when utilizing recommended doses and rates of administration (Table 6). Two major advantages for phosphate therapy may be mentioned. First, it is almost univer-
Intravenous
Oral or parenteral
Intravenous
Intravenous
EDTA
Cortisone
Mithramycin
Phosphate
Parenteral
weight daily
body weight/day
1-5 MRC units/kg
1 millimolet/kg body weight over 6-8 hr 1-2 millimolest/kg body
25 Ilg/kg body weight
penia, nausea, vomiting
Nausea, vomiting
Extraskeletal calcification, hypoca1cemia
Hemorrhage , thrombocyto-
Hypercorticism
Pulmonary edema, hypernatremia Volume depletion, hypokalemia Renal failure, hypotension
Pulmonary edema
REPORTED COMPLICATIONS
Thrombotic disorders
Emergency reduction of serum calcium required Bleeding disorder, renal insufficiency, liver impairment Renal insufficiency, hyperphosphatemia
Renal insufficiency
Congestive heart failure, renal insufficiency, hypertension Congestive heart failure, renal insufficiency, hypertension Renal insufficiency
CONTRAINDICATIONS
t 1 millimole of phosphate is equivalent to 31 mg of phosphorus.
1970.
"'Modified from Suki WN, Yium JJ, Von Minden M, et al: Acute treatment of hyperca1cemia with furosemide. N Engl J Med 283:836-840,
Calcitonin
100 mg/hr
Intravenous
Oral
3 liters over 9 hr
Intravenous
50 mg/kg body weight over 4-6 hr 150 mg/day
1 liter every 3-4 hr
DOSAGE
Intravenous
ROUTE
Usual Doses of Hypocalcemic Agents':'
Sodium chloride solution (isotonic) Sodium sulfate solution (isotonic) Furosemide
DRUG
Table 6.
~
~
s: ::l
[JJ
I;j
t"
oo
[J)
~
'"
t"
:r>
t.C tJl 00
959
TREATMENT OF HYPERCALCEMIA
Table 7.
Comparison of Hypocalcemic Agents
Sodium sulfate (i.v.) Furosemide, e thacrynic acid EDTA (i.v. ) Dialysis Calcitonin Phosphate (p.o. ) Phosphate (i. v.) Mithramycin Cortisone
SPEED
EFFICACY
REBOUND
+ + + +++ ++ +++ + +++ ++ +
+ ++ +++ + ++ ++ ++ +++ +++ ++
+ +++ ++ ++ ++++ ++++
LO NG- T E R M
:!:
+ ?+++ +++
:!:
:!:
+++ ++
+++ ++
sally effective and can be used as emergency therapy intravenously or, less heroically, by the oral route. Because of the predictable and rapid response that can be obtained, valuable time can be gained for appropriate diagnostic studies or more specific therapy for the underlying disorder. Second, and of nearly equal value, is the fact that satisfactory suppression of hypercalcemia can be maintained for prolonged periods with daily oral dosage or periodic intravenous infusion. Cytotoxic drugs, especially those of the actinomycin D genre, have been reported from time to time as hypocalcemic agents. Recently, however, it has been found that mithramycin, a drug used frequently in therapy of testicular neoplasms , almost uniformly causes a reduction in serum calcium during the usual course of its administration. 6 Side-effects have varied from mild (nausea and vomiting) to severe (hemorrhagic tendency), depending on dosage and frequency. A further limitation of its use has been the fact that the decrease in serum calcium often has not been rapid enough to consider the drug sufficiently dependable for use in emergencies. Rebound in serum calcium usually occurs on cessation of therapy, but the drug can be given repeatedly as long as hemorrhagic complications do not occur. My personal prejudice is that this agent should be reserved for hypercalcemia due to malignant tumors, although its use in other circumstances may sometimes be warranted.
COMPARISON OF AVAILABLE MODALITIES Tables 6 and 7 summarize my experience plus tha t culled from the literature on the comparative speed, efficacy, and other characteristics of the various therapeutic modalities already discussed. Although I have made every effort to be objective, such a comparison must of necessity be heavily biased by personal experience. The major limitations of this comparison are that (1) few comparative studies have been published, and (2) much of the literature on some agents consists primarily of individual case reports. Also as a result of my experience I am suggesting the following schedule for the emergency treatment of the hypercalcemic patient.
960
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A RECOMMENDED SCHEDULE FOR EMERGENCY TREATMENT OF HYPERCALCEMIA 1. Begin electrocardiographic monitoring 2. Institute appropriate supportive measures a. Intravenous saline infusion b. Potassium replacement as needed c. Vasopressor agents as needed 3. Furosemide (100 mg/hr) intravenously 4 . If response is inadequate, proceed with one of the following measures a. EDTA infusion-do not continue beyond 24 hours b. Phosphate infusion (1.5 gm of phosphorus infused over 6 to 8 hours) may be repeated daily, but more than two infusions usually are not required. Follow with phosphate given orally c. Mithramycin (25 ~g/ kg) intravenously 5. If renal failure unresponsive to diuretics and fluid is present, corticosteroids and calcitonin are the only modalities that can be used safely.
APPENDIX The following drugs discussed in this paper are still under investigation and can be obtained from the appropriate pharmaceutical companies only: (1) calcitonin-Armour; (2) Hyper-Phos-K (a phosphate for oral use) - Davies Rose Hoyt ; and (3) In Phos (a phosphate for intravenous use)-Davies Rose Hoyt. A phosphate solution given orally (Neutraphos), marketed as a dietary supplement by Willen Drug Co., also has been used.
REFERENCES l. Albright F , Bauer W, Claflin D, et al: Studies in parathyroid physiology. Ill. The effect of phospha te ingestion in clinical hyperparathyroidism. J Clin Invest 11 :411-435, 1932 2. Brewer RI , LeBauer J: Caution in the use of phosphates in the treatment of severe hypercalcemia. J Clin Endocrinol Metab 27:695-705, 1967 3. Chakma kjian ZH, Bethune JE: Sodium sulfa te treatment of hypercalcemia. N Engl J Med 275 :862-869, 1966 4. Goldsmith RS , Ingbar SH: Inorganic phospha te treatment of hypercalcemia of diverse etiologies. N Engl J Med 274:1-7,1966 5. Henneman PH, Dempsey EF , Carroll EL, et al: The cause of hypercalcuria in sarcoid and its treatment with cortisone and sodium phytate. J Clin Invest 35:1229- 1242, 1956 6. Kennedy BJ: Metabolic and toxic effects of mithramycin during tumor therapy. Am J Med 49:494-503 , 1970 7. Lazar MZ , Rosenberg LE: Mechanism of adrenal-steroid reversal of hyperca lcemia in multiple myeloma. N Engl J Med 270:749-755, 1964 8. Nolph KD, Stoltz ML: Treatment of hypercalce mia with calcium free peritoneal dialysis (CFPD) (abstract). Clin Re s 19:481, 1971 9. Pak CYC , Wortsman J, Bennett JE, et al: Control of hypercalcemia with cellulose phosphate (letter to the editor). J Clin Endocrinol Metab 28: 1829-1832, 1968 10. Steffee W, et al: Unpublished data 1l. Suki WN , Yium JJ, Von Minden M, et al: Acute treatment of hypercalcemia with furosemide. N Engl J Med 283:836-840 , 1970 12. West TET, Joffe M, Sinclair L, et al: Treatment of hypercalca emia with calcitonin. Lancet 1 :675-678, 1971 Mayo Clinic Rochester, Minnesota 55901