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Clinical Aspects and Management of Hypercalcemia
Clinical Aspects and Management of H ypercalcemia w.
P. LAIRD MYERS, M.D.
PATIENTS with disseminated cancer are subject to a wide variety of medical and metabolic complications which at times may be of such magnitude as to threaten life. If the dissemination involves the skeletal system, hypercalcemia may develop as a result of osteolysis secondary to the growth of tumor in bone. This phenomenon, particularly as seen in patients with metastatic mammary carcinoma, has been recognized for a number of years but still has not received the emphasis it deserves. It is the purpose of this paper to review the various aspects of hypercalcemia including clinical manifestations and treatment.
CALCIUM HOMEOSTASIS AND NEOPLASTIC CAUSES OF HYPERCALCEMIA
Figure 113 illustrates diagrammatically the various factors relating to calcium homeostasis. The diagram has been oversimplified for the sake of emphasis and no attempt has been made to indicate the exact sites of action of vitamin D and parathormone nor to include all possible factors in bone metabolism (protein intake, sex hormones, thyroid hormone, etc.). Nevertheless, the major factors are shown. Elevation of the serum calcium above normal will result, then, "whenever more calcium enters the blood stream than leaves it."! This calcium may enter the vascular system from the bones, the gastrointestinal tract or by the parenteral route. If the rate of excretion by the kidneys is equal to the calcium load, hypercalcemia is averted. Data indicate that the critical level of renal excretion is about 500 mg./24 hours.2 Amounts in excess of this value are usually associated with hypercalcemia. Amounts less than this may also be associated with hypercalcemia, if renal insufficiency is present. Renal From the Chemotherapy Service, Department of Medicine, Memorial Hospital; and Division of Clinical Chemotherapy, Sloan-Kettering Institute. This study was supported in part by the following grants: Grant C-1889 from the National Cancer Institute of the National Institutes of Health, U. S. Public Health Service; the American Cancer Society; the Damon Runyon Memorial Fund for Medical Resenrch; and the Lasker Foundation. 871
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W. P. Laird Myers
insufficiency alone, through retention of phosphate, leads to hypocalcemia not hypercalcemia, but if it is present in addition to uncontrolled entry of calcium into the blood, hypercalcemia will result or become more marked if already present. Under normal conditions, the dietary restriction of calcium to 200 mg. per day will result in the excretion of about 50 mg./24 hours in the urine and about 200 mg./24 hours in the CALCIUM
HOMEOSrASIS
;l ~"\
:·ff '~
USI
e
Protein Bound
Serum Calcium
Renal Excretion
Fig. 113. The bone, kidney, gastrointestinal tract and para thyroids are shown in the medium of extracellular fluid. The reversible arrows indicate that ionizable calcium of the serum is in equilibrium with extracellular calcium and with the systems shown. Thus calcium is continuously being deposited in and resorbed from bone, being filtered and resorbed by the kidney and absorbed from and excreted into the gastrointestinal tract. However, most of the fecal calcium simply represents unabsorbed calcium in the diet and is not the product of active excretion. The ionizable fraction is also in equilibrium with the protein-bound fraction, with the functional activity of the parathyroid glands and with the level of serum phosphorus. The single arrows at the top of the diagram indicate a direct action of the parathyroid glands on bone and kidney. Lowered blood pH favors an increase in ionizable calcium and an alkaline pH the reverse. The serum calcium will be elevated in hyperproteinemia and lowered in hypoproteinemia and hence it is necessary to know the level of the serum proteins for proper interpretation of the serum calcium. Thus an apparently normal serum calcium may actually represent hypercalcemia if the total serum protein is low.
stooJ.2 The upper limit of normal urinary calcium excretion on a 200 mg. intake is about 150 mg./24 hours. 2 With normal intakes of calcium (600 to 800 mg. per day in the average adult) the urinary calcium rises somewhat but most of the excess calcium is unabsorbed and leaves the body as fecal calcium. The calcium in the body amounts to about 2 per cent of the body weight. 3 Over 99 per cent of this calcium is in the skeleton while about
Clinical Aspects and Management of Hypercalcemia
873
1 gram of calcium is present in the extracellular fluid. 4 The growth of a tumor in bone (Fig. 113) may initially proceed at such a rate as to enable the kidney to excrete the displaced calcium with resultant hypercalciuria but without hypercalcemia. This has been described 2. 5 in detail and it has been suggested by Pearson,2 as an approximation, that when a tumor increases in size by 1 gram, about 1 gram of bone containing 100 mg. of calcium is destroyed and the calcium is excreted into the urine. This analysis of urinary calcium as an indirect measure of progression or regression of tumor growth in bone has developed into a convenient means Table 1 SIXTY-ONE CASES OF HYPERCALCEMIA ANALYZED FROM THE STANDPOINT OF UNDERLYING CAUSE, HIGHEST SERUM CALCIUM LEVEL, AND ROENTGEN SURVEYS OF THE SKELETON DIAGNOSIS
No. CoIos 9
Kidney
5
Myelomo
2
LunQ
3
Lymphoma
4
Stomach
I
Cervl.
2
J
~1~Wlr a"a.'
2
26
Neuroblastoma
2
U'erus
I
~:~~~~-
I
AcuM Leukemia
I
Tonsil
I
Ca, primary unknown
2
Exceal Calcium
4
M~a.'atoc
and Vitamin D HyperThvroldism
I
~X~{hyrOidISm
2
Cause unknown
I
NORMAL RANGE
I
HIGHEST SERUM
10
11
12
~~
Wh W I@ ~ I~ W • I~ ~ I~ W I~ W
I~ W
!m W
•
t
13
~ W,
WW
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@@ ~~
.
•
@; ~ • W, W, ~
•
1&
•
17
18
19
•• • • • •
• • • •
~ W,
@~
le
14
CALC I UM MG.lIOOCC.
•
..: •
-
20
•
• •
'5~H~L 21
25
I Pos. 4
No' NeQ. Done I
2 3
•
3
I
I
I
I
•
23
I
I
I
2
2 I I I
• •
• •
•
•
I
2 3
I
I
2 I
of evaluation of therapy. As noted above, when the renal mechanisms for calcium excretion are exceeded by the load, hypercalcemia will result. Table 1 shows some of the diseases associated with hypercalcemia encountered at Memorial Center in the 13 month period from July 1954 to August 1955. It was not possible to analyze all the cases of hypercalcemia nor was it possible to calculate the incidence of hypercalcemia among various tumors. The data have been compiled merely to illustrate some of the types of tumors which may be associated with hypercalcemia as well as some of the miscellaneous causes of hypercalcemia which have been encountered. The normal range of serum calcium in our hospital is 9.2 to 10.8 mg./100 cc. For the purposes of this
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W. P. Laird Myers
case analysis a level of 11.5 mg./IOO cc. or higher was regarded as an elevation. Undoubtedly the recognition of a large number of cases of metastatic breast cancer with hypercalcemia is in part due to an increasing awareness of this complication in breast cancer and to the frequent determinations of serum calcium in this group. However, in a series of 445 cases of breast cancer metastatic to bone, Woodard1 found an over-all incidence of hypercalcemia (12.1 mg./IOO cc. or above) of 9.4 per cent compared to an incidence of 8.9 per cent in 135 patients with miscellaneous cancers metastatic to bone (excluding multiple myeloma). In general, the tumors which commonly involve bone are those of breast, lung and kidney origin in addition to multiple myeloma and lymphomatous diseases. When a patient with metastatic disease presents any of the symptoms discussed below the possibility of hypercalcemia should be considered. Multiple determinations of serum calcium are often necessary to establish the diagnosis with certainty. The skeletal survey proved to be positive for metastatic disease in most instances recorded in Table 1, but it is well to note that there were a few patients who had hypercalcemia despite normal bone surveys. Cancer may involve the skeleton widely and yet initially may produce no changes in the x-ray if the lesions are small. The extent of involvement by x-ray cannot be correlated with the degree of hypercalcemia. Some patients with extensive bone disease showed only slight elevation in calcium while others with a single lesion showed marked elevations. The nonmalignant causes of hypercalcemia are of interest. There were three patients who had hypoparathyroidism which developed following sacrifice of the parathyroid glands during neck dissections for carcinoma of the thyroid gland. In the management of their hypoparathyroidism, excessive administration of calcium and vitamin Dzled to hypercalcemia. A fourth patient developed hypercalcemia when he received too vigorous parenteral replacement therapy in an attempt to treat hypocalcemia secondary to large losses of calcium through a small bowel fistula. Hyperparathyroidism was due in one instance to a single adenoma and in another to multiple adenomas. Although metastatic osseous cancer is usually accompanied by slight elevations in serum phosphorus, occasionally, the chemical findings of hyperparathyroidism (hypercalcemia in association with hypercalciuria and hypophosphatemia) are seen and may lead to confusion in diagnosis. Albright and Reifenstein 6 have described such a patient with metastatic renal carcinoma and we have encountered the same problem in two patients, one with lymphosarcoma and one with metastatic renal carcinoma. The diagnosis can sometimes be established by the demonstration of tumor cells in the patient's marrow. Patients with metastatic breast cancer under treatment with estrogens may show a lowering of the serum phosphorus as a result of treatment. 7 Hyperthyroidism was observed in one instance and has been described
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875
fully in a recent reviews as a cause of hypercalcemia. Other well recognized, nonmalignant causes of hypercalcemia including sarcoidosis,9 the milk and alkali syndrome,lO and osteoporosis with immobilization 6 were not encountered in this brief case review. CLINICAL MANIFESTATIONS OF HYPERCALCEMIA
The various roles which calcium fulfills in bone formation, blood coagulation, cardiac contractility and lactation have long been established. In addition it is known that calcium decreases cell membrane permeability, that it may block ganglionic transmission in high concentrations and that "it is indispensable for the maintenance of the functional integrity of the somatic and autonomic nervous systems."ll In clinical situations where there is an excess of circulating calcium it might be supposed that all of these various functions would be disturbed. Practically speaking, however, the major symptoms are as follows: Nervous System. Drowsiness and lethargy are usually the earliest signs. The lethargy may become pronounced and may be accompanied by confusion and disorientation. Eventually semistupor and coma may result. There is generalized muscular weakness with hypotonia and the deep tendon reflexes are hypoactive or absent. The neurological signs suggest no localization although at times thick speech and transient aphasia have been observed. In these latter instances, however, the possibility of cerebral metastases could not be excluded as the underlying cause. In some patients it has appeared as though previously latent cerebral metastases became manifest during hypercalcemia. For example, one patient was observed to have a generalized convulsion when his serum calcium rose to 15.1 mg./lOO cc. This seizure was due to cerebral metastases but the role of the elevated serum calcium as a possible precipitating factor must be considered. Convulsions are not a symptom of hypercalcemia per se but rather of hypocalcemia. Renal. The increased load of filtered calcium results in an osmotic diuresis so that patients usually have polyuria. With the loss of water via this route (and because of vomiting) they become dehydrated and thirsty. With long-continued hypercalciuria, deposition of calcium in the renal tubules may lead to nephrocalcinosis with hyposthenuria and albuminuria.1 2 Water loss by the kidneys is thereby aggravated and eventually azotemia and renal failure may occur. Gastrointestinal. Anorexia, nausea, vomiting and constipation are usually part of the symptomatology of hypercalcemia. The exact mechanisms involved are obscure but presumably the symptoms are related to the effects of calcium on the autonomic nervous system or to effects on the central nervous system. Cardiac. In man, infusions of calcium result in changes which resemble vagal stimulation. ll . 13 Thus sinus bradycardia, sinus arrhythmia, shifting pacemaker and varying degrees of auriculoventricular block have been
876
W. P. Laird Mycrs
observed with such infusions and might be expected to occur in clinical hypercalcemia. In our experience tachycardia rather than bradycardia has been the rule and disturbances in rhythm have not usually been encountered. With increasing levels of serum calcium a direct effect on the myocardium may result in premature ventricular contractions or ventricular tachycardia. Cardiac failure has been observed in the course of hypercalcemia and the management of this complication will be discussed shortly. The electrocardiographic changes, in addition to revealing any possible disturbances in rhythm, may show shortened QT intervals and T wave depressions.14 General. There appears to be a marked individual variation from patient to patient in the signs and symptoms they will show at any particular level of serum calcium. Thus one patient became comatose when the serum calcium rose to 18.3 mg./IOO cc. while another patient tolerated a similar elevation for several weeks with only mild lethargy. There was, however, a general parallelism in that the symptoms noted above tended to be minimal with slight to moderate elevations of serum calcium and were usually marked with higher levels. It is important to note that fatalities may result from hypercalcemia probably due to the direct action of the calcium on the myocardium. Some authors have reported 15 the occurrence of hyperbilirubinemia in patients with hypercalcemia secondary to metastatic mammary carcinoma. This in all likelihood is a reflection of advancing metastatic disease in the liver and not related to the hypercalcemia. Corneal calcifications have been reported 16 in some diseases associated with hypercalcemia. Our patients have not had slit-lamp examinations but it would seem possible that metastatic disease leading to hypercalcemia could produce such changes. MANAGEMENT OF HYPERCALCEMIA
Inasmuch as hypercalcemia may in itself cause death it is essential not only to be aware of its possible occurrence but also to know what measures are useful in treating it. Although we are dealing with ultimately fatal situations in patients with skeletal metastases, some patients may die prematurely if hypercalcemia is uncorrected. A brief case experience will serve to illustrate this point: A 35 year old housewife was under treatment with testosterone propionate for metastatic mammary carcinoma. After 3 weeks of treatment she showed a progressive increase in urinary calcium~the first sign of impending hypercalcemia. The hormone therapy was stopped prior to an increase in the level of serum calcium but this subsequently rose to 12.8 mg./IOO cc. and then gradually returned to normal. The patient had no symptoms of hypercalcemia, the hormone therapy having been stopped solely on the basis of the rising urinary calcium. She later had a striking remission in her disease following radiation castration. She returned home and was able to resume her usual household duties and the care of her 3 children. It is true that she succumbed to her disease a year later
Clinical Aspects and M anagernent of Hypercalcernia
877
but she might have died prematurely if the hypercalcemia had not been recognized early and treated.
The management is best considered in the following way: (a) the use of nonspecific measures, (b) treatment of the cause and (c) treatment of associated problems. The Use of Nonspecific Measures
The nonspecific measures in the treatment of any patient with hypercalcemia are chiefly those of reduction of intake and promotion of calcium output. Diet. The calcium in the diet should be limited to 200 mg. per day or less. For practical purposes this means elimination of milk and milk products; cheese and eggs. At times patients are too drowsy or have too much vomiting to permit oral feedings and nutrition must be maintained parenterally. Parenteral feeding, however, is difficult to maintain over long periods and in some patients who have been hypercalcemic for long per:oJs tube feedings have been used. Tube feedings pose a special problem since most are made with milk as a base. To avoid this, a low calcium diet can be homogenized in a Waring Blendor and thinned with water for tube administration or an artificial low calcium formula can be made up. One such formula is as follows: Dextrose 200 grams = 800 calories Fat (Lipomul, for example) 80 grams = 720 calories Protein (Protinal, for example) 40 grams = 160 calories Total calories = 1680 Add a liquid vitamin preparation (one which contains no vitamin D) and water q.s. ad 1500 cc. Supplementary nourishment (fluids, broths) can be given via the tube to bring the total fluid and electrolyte intake to any desired amount.
Some protein supplements contain large amounts of calcium and care in the selection of a proper product is necessary. The calcium content of the above formula is approximately 160 mg. Such a formula may be divided into multiple feedings throughout a 24 hour period. In order to promote output, intravenous fluids should be administered to hypercalcemic patients in amounts sufficient to insure a daily urinary volume of at least 1500 to 2000 ml. These patients are dehydrated and need water to correct their deficits as well as to promote calcium excretion. When patients are incontinent or when there is doubt about the adequacy of the urinary volume, a catheter should be inserted in the bladder for a few days until the more severe stages of hypercalcemia have passed. Infusions should consist principally of dextrose in water with supplementary potassium and sodium chloride as the clinical situation indicates. Caution in the administration of potassium by vein is warranted until it is established that the patient is capable of voiding adequate amounts of urine. Use of so-called "balanced solutions" should be
878
w. P. Laird Myers
avoided in treating hypercalcemia as some of these solutions may contain calcium. Inasmuch as calcium and potassium have opposing actions on the myocardium, the potential cardiac toxicity of a given level of hypercalcemia will be enhanced by a simultaneous reduction in the level of serum potassium. Thus, hypokalemia must be avoided or corrected if already present. Potassium depletion with alkalosis has been observed to develop concomitantly with hypercalcemia17 (for reasons which are obscure) and hence this added complication should be looked for in each patient. There is a theoretical reason for the administration of alkali to hypercalcemic patients because of the reduction of the ionizable fraction with an alkaline pH. However, practically speaking, such infusions are unnecessary and are attended by the hazard of alkalosis with a possible increase in renal damage. Thus, unless marked azotemia with acidosis demands the use of such infusions, the best and simplest plan is to administer dextrose in water in treating uncomplicated hypercalcemia. Treatment of the Cause
The above measures obviously are designed for immediate use and trovide only temporary benefit. The most important step, then, is to analyze and treat the cause of hypercalcemia. Once it has been depermined that osseous metastases are the underlying cause, there are certain specific measures which may be undertaken. Figure 114 illustrates the case of a 59 year old woman who had hypercalcemia complicating lymphosarcoma. Skeletal surveys were negative but the hypercalcemia was regarded as secondary to the presence of rapidly advancing lymphosarcoma in the skeleton since, as has been noted, x-ray evidence of neoplastic disease in the skeleton may not necessarily be present in conjunction with the hypercalcemia. Nitrogen mustard (0.3 mg./kg.) was administered intravenously at a time when the patient was comatose with a serum calcium of 20.2 mg./IOO cc. and a urine calcium ranging between 600 and SOO mg./24 hours. She had previously received intravenous fluids without any lowering of her serum calcium. The effect after nitrogen mustard was striking. There was a remarkable reduction of the serum and urinary calcium to normal. She regained consciousness and in about ten days had improved so much that she was able to be up in a wheelchair. This effect was interpreted as having been due to cessation of growth of the lymphosarcoma in the skeleton with consequent elimination of active osteolysis. Unfortunately the hypercalcemia recurred and the patient became comatose a second time. On this occasion, cortisone was given in doses of 75 mg. intramuscularly every six hours along with intravenous fluids. Again hypercalcemia and hypercalciuria were reversed as shown in the diagram. There was clearing of her mental status a second time but she did not improve as much generally as she had following the nitrogen mustard. The cerebrospinal fluid calcium was determined on each occasion that the patient became comatose and elevations were noted (7.S mg./IOO cc. with a serum level of 21.9 mg./IOO cc., and 7.5 mg./IOO cc. with a serum level of lS.3 mg./IOO cc.). The spinal fluid protein was normal in each instance. Elevation in cerebrospinal fluid calcium may, in part, be responsible for the neurological signs and symptoms of hypercalcemia. The marked
Clinical Aspects and Management of Hypercalcemia I.e.
59yrs.
879
$ Lymphosarcoma
~~
45 mg."I.
25
5~------~--------~==~~-r-------------rBodansky 5 Units
O~-------r------------------~--------------'--
50
O~~-----r------------------~--------------'-20
mg. %
15
o
Days 0
1955 4·29
20
40
60
·Calcium intake approximately 200 mg /day
Fig. 114. Fifty-nine year old patient with generalized lymphosarcoma and hypercalcemia. The effect of nitrogen mustard and cortisone on serum and urinary calcium is shown.
hypophosphatemia in association with the hypercalcemia led to the suspicion that the patient might have had an independent primary hyperparathyroidism but a subsequent postmortem examination revealed four normal parathyroid glands.
Nitrogen mustard is most useful in the lymphomatous diseases and its effectiveness in the treatment of those cases with an accompanying hypercalcemia indicates even broader usefulness. The usual precautions
880
W. P. Laird Myers
in the administration of this compound should be followed, namely, that if there is marked hematological depression from a previous course of treatment it should not be used or if the depression is a result of the lymphomatous disease process within the marrow and the bone marrow is not hypoplastic; it should be used in smaller doses and cautiously. The presence of definite myelophthisic anemia which may be seen in some carcinomas metastatic to bone should lead to great caution in the use of any chemical agent which can cause further bone marrow depression. In such instances the use of hormonal therapy is safer. The use of cortisone or related compounds requires close observation of the patient and the usual attention to the well-known side effects of these adrenal steroids. The mechanism of action of nitrogen mustard and adrenal steroids in the correction of hypercalcemia of malignant disease appears to be due to their inhibition of tumor growth in the skeleton. The possibility that cortisone may favorably influence hypercalcemia by enhancing fecal excretion of calcium has not been substantiated experimentally thus far in neoplastic disease. Both adrenal steroids and nitrogen mustard should be considered in the treatment of hypercalcemia accompanying any tumor metastatic to bone. Although most effective in the lymphomatous group of diseases, reductions of elevated serum calciums have been achieved with these agents in patients with metastatic osseous cancer. For examp'e, in a critically ill patient with metastatic breast cancer and hypercalcemia, the use of hydrocortisone intravenously (200 mg. in 1000 cc. of 5 per cent glucose in water given over an 18 hour period) combined with cortisone given intramuscularly 300 mg. per 24 hours resulted in a reversal of these changes and the general condition of the patient improved sufficiently to permit her to undergo radiation castration. Cortisone has also been effective in the treatment of hypercalcemia associated with multiple myeloma. These experiences and others with both nitrogen mustard and cortisone have led us to try these agents in the treatment of metastatic bone disease with hypercalcemia if other accepted measures have failed, although it must be admitted that reductions in serum calcium do not by any means occur uniformly. Radiation therapy may sometimes result in disappearance of hypercalcemia and hypercalciuria. In patients who have localized osteolytic tumors causing hypercalcemia, radiation to such an area would be the treatment of choice unless the hypercalcemia were so marked that more prompt action was desirable. In such instances nitrogen mustard or intravenous hydrocortisone might be considered. Figure 115 illustrates an important principle in the management of hypercalcemia, namely that of knowing when to stop treatment. The patient, a 48 year old married woman, had extensive osteolytic metastases from carcinoma of the breast. Testosterone therapy resulted in both
Clinical Aspects and Management of Hypercalcemia
881
hypercalcemia and hypercalciuria which were effectively treated simply by stopping the testosterone, continuing the restricted calcium intake and administering infusions of dextrose in water during the period of hypercalcemia. This complication of the therapy of metastatic breast cancer has been observed with both androgen and estrogenlS and constitutes one of the hazards attending the use of these hormones. The figure also illustrates the value of urinary calcium data in anticipating the development of hypercalcemia. Hormone therapy was discontinued NK. 48yrs.!f Co. Breost
~~~t:i:~~~~e
=;;;=;=;=;=111=1
f'ZZZJ I.V. Fluids
50mg/day
15 '13
9----
mg% 11
Serum Calcium
Urinary Calcium·
DAYS 0 40 80 ·Calcium intake approximately 200mglday Fig. 115. Forty-eight year old woman with metastatic breast carcinoma. Exacerbation of skeletal disease with resultant hypercalcemia followed treatment with testosterone propionate.
because of the rising urinary calcium at a time when the serum calcium was still normal. In spite of stopping the hormone, the delayed effects still resulted in subsequent striking hypercalcemia which might have been considerably worse without the warning afforded by the urinary calcium. In women with metastatic breast cancer who demonstrate the phenomenon of cyclic hypercalcemia with their menstrual periods 2 (due to endogenous estrogen stimulation of the mammary cancer), the treatment is to remove the source of estrogen by castration. Surgical castration should be performed before the next menstrual cycle results in recurrent hypercalcemia. The presence of moderate hypercalcemia itself does not contraindicate surgery. Figure 116 illustrates a final treatment modality, namely the use of disodium ethylen~diamine tetra-acetate* (sodium EDTA). This drug has no known tumor-inhibitory properties in man and its action is simply to
* Kindly supplied
by Riker Laboratories, Inc., Los Angeles, California.
W. P. Laird Myers
882
form a soluble chelate with calcium and enhance its renal excretion. 19 The patient, a 38 year old man, had hypercalcemia secondary to metastatic cancer the primary site of which could not be determined. Six grams were diluted in 500 cc. of 5 per cent glucose in water and the intravenous infusion was given slowly over a period of one hour. The serum calcium decreased and there was a slight rise in the calcium output in the urine. Despite this, there was no change in the patient's condition or mental status. The serum calcium decrease was an apparent one since the chelated calcium was present in the serum but was not detectable A.J. "S8 YRS. OSSEOUS MET. '·UNKNOWN
mg.%
16j 12
mg.%
mg.%
Fig. 116. Thirty-eight year old man with metastatic carcinoma and hypercalcemia. Sodium EDTA (Versene) resulted in definite but transient decrease in serum calcium.
by the usual oxalate precipitation method of serum calcium analysis. However, this EDTA-bound calcium is presumably physiologically inert and from this standpoint the decrease was a real one. The serum calcium gradually returned to pretreatment values over a 24 hour period following the infusion. To overcome this limitation, repeated daily infusions of Versene could be given, but there have been reports of renal tubular vacuolization20 • 21 with repeated use. It seems best in our present state of knowledge to reserve the use of sodium EDTA for those situations where other measures have failed and to use it only as a temporary measure for a few days at most. Its use
Chnical Aspects and Management of Hypercalcemia
883
should not be considered in patients with mild hypercalcemia but only in those with marked hypercalcemia (17 or 18 mg./lOO cc. or above) which is also symptomatic. As a temporary measure, then, it must be accompanied by efforts designed to treat the underlying cause of the hypercalcemia. In general, preliminary data suggest that doses of 90 to 100 mg./kg./day should not be exceeded and that a total of 6 grams per infusion per day should be the maximum adult dose. Although the patient discussed received the dose in a one hour period, otherslQ • 20 have given the infusions over periods of four to six hours in length. Theoretically and in actuality 6 grams of sodium EDTA will lower the serum calcium about 4 mg./lOO cc. in a 70 kg. person with an estimated extracellular space of 14 liters (20 per cent of body weight). Smaller patients will obviously have smaller extracellular volumes and the expected decrease in serum calcium for the same dose of sodium EDTA will be greater. It must be stressed that while sodium EDTA is being administered the physician must not leave the bedside of the patient. The Chvostek and Trousseau signs and the blood pressure should be tested repeatedly during the infusion. When any suggestion of hypocalcemia or hypotension is noted the infusion must be stopped promptly. La.stly, it must be remembered that the EDTA used in the treatment of lead intoxication is already chelated with respect to calcium and it will have no effect at all in hypercaloomia. Management of Associated Problems
Certain associated problems arise in the course of hypercalcemia and these are often of importance in the total management. The first one relates to digitalization of a pqtient whose serum calcium is elevated. The fact that synergism exists between digitalis and calcium with respect to their effects on the myocardium has long been known. Although differences of opinion exist,22 reports have been published cautioning the physician not to use calcium intrav~mously in a digitalized patient. l3 What hazards exist, then, in the use of intravenous digitalis in a patient with hypercalcemia? There is insufficient data at present on this point but we have digitalized two patients recently with serum calciums ranging between 12 and 14 mg./lOO cc. at the time of digitalization. In one patient this was done by giving one-half the usual digitalizing dose of digitoxin in divided doses over a two day period followed by a daily maintenance dose of 0.1 mg. In the other patient 0.8 mg. Cedilanid was given initially and the following day two doses of 0.4 mg. each were given with a four hour interval between doses. Neither patient had any untoward effects. Further observations must be made but at present it would seem best to fractionate the doses of digitalis in any situation of hypercalcemia and to carry out digitalization with the help of serial electrocardiograms. If the clinical situation permits, digitalization by the oral route is preferable to the parenteral route. Recognition of coexistent
w.
884
P. Laird Myers
hypopotassemia is important when digitalization is contemplated because of the enhanced effects of digitalis in the presence of potassium depletion. Renal insufficiency with azotemia and acidosis may present problems in management. The same principles apply in these situations as with renal failure due to other causes. Although renal shutdown is theoretically possible we have not encountered it and since other measures are available to control serum calcium levels the question of extracorporeal dialysis has never arisen in our patients for the control of hypercalcemia. Renal lithiasis is likewise a theoretical complication which has not proved a problem in our experience. The central nervous system signs and symptoms which these patients present always raises the question as to whether they are due to hypercalcemia per se or to brain metastases or to both. Cerebrospinal fluid examinations should be done in those patients where this confusion arises since elevation of the spinal fluid protein is supporting evidence for the presence of central nervous system metastases. The spinal fluid calcium in some of our patients has been elevated. Its role in the production of these symptoms remains to be determined. The other factors complicating the management of these patients usually relate to the disease in the skeleton. Skeletal pain, pathological fractures, superimposed osteoporosis, and myelophthisic anemia do not arise as a result of hypercalcemia itself but like it they are end results of the same neoplastic process and demand appropriate treatment. SUMMARY
The various factors in calcium homeostasis have been reviewed as well as the 3igns and symptoms of hypercalcemia. A brief analysis of 61 cases of hypercalcemia has been presented. The various modalities of treatment of hypercalcemia, including nonspecific measures, treatment of the underlying cause and treatment of associated problems have been considered. REFERENCES 1. Woodard, H. Q.: Changes in Blood Chemistry Associated with Carcinoma Metastatic to Bone. Cancer 6: 1219-1227 (Nov.) 1953. 2. Pearson, O. H., West, C. D., Hollander, V. P. and Treves, N. E.: Evaluation of Endocrine Therapy for Advanced Breast Cancer. J.A.M.A. 154: 234-239 (Jan. 16) 1954. 3. Best, C. H. and Taylor, N. B.: Physiological Basis of Medical Practice. 5th Ed. Baltimore, WiJliams & Wilkins Co., 1950. 4. Howard, J. E.: Metabolism of Calcium and Phosphorus in Bone. Bull. New York Acad. Med. 27: 24-41 (Jan.) 1951. 5. Laszlo, D. and others: Mineral and Protein Metabolism in Osteolytic Metastases. J.A.M.A. 148: 1027-1032 (March) 1952. 6. Albright, F. and Reifenstein, E. C. Jr.: The Parathyroid Glands and Metabolic Bone Disease. Baltimore, Williams & Wilkins Co., 1948. 7. Woodard, H. Q., Escher, G. C. and Farrow, J. H.: Changes in Blood Chemistry of Patients with Disseminated Carcinoma of Breast During Endocrine Therapy. Cancer 7: 744-757 (July) 1954.
Clinical Aspects and Management of Hypercalcemia
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8. Rose, E. and Boles, R. S. Jr.: IIypercaleemia in Thyrotoxicosis. IV!. CLIN. NORTH AMERICA 37: 1715-1724 (Nov.) 1953. D. Longcope, W. T. and Freiman, D. G.: A Study of Sarcoidosis. Mediciue 31: 1-132, 1D52.
10. Burnctt, C. H., Commons, R. R., Albright, F. and Howard, J. K: Hypercalcemia Without Hypercalciuria or lIypophosphatemh, Calcinosis and Renal Insufficiency. Kew England J. Med. 240: 7S1-7!i4 (May) Ul4U. It. Goodman, L. S. and Gilman, A.: PharmacoJ;,.~i",d Basis of Therapeutics. 2nd Ed. New York, Macmillan Co., 1D5.5. 12. Roch, M., Berthoud, Eo and Koralnik, 0.: De diverses causes de I'hypercalcemie et de son expression clinique. Bull. et mem. Soc. med. d. hop. de Paris 69: 2\)2-2D5 (March 20) 1953. 13. Clarke, N. Eo: Action of Calcium on Human Electrocardiogram. Am. Heart J. 22: 367-373 (Sept.) 1D41. 14. Levine, H. D.: Electrolyte Imbalance and Electrocardiogram. Modern Concepts of Cardiovascular Disease 23: 246-249 (Nov.) 1954. 15. Kennedy, B. J., Tibbetts, D. M., Nathanson, I. T. and Aub, J. C.: Hypercalcemia, a Complication of Hormone Therapy of Advanced Breast Cancer. Cancer Research 13: 445-459 (June) 1953. lG. Walsh, F. B. and Murray, R. G.: Ocular Manifestations of Disturbances in Calcium Metabolism. Am. J. Ophth. 36: 1657-1676 (Dec ) 1\)53. 17. Pearson, O. H. and Eliel, L. P.: Hormone Therapy in Cancer. Experimental Studies with ACTH and Cortisone in Patients with Neoplastie Disease. Recent Progress in Hormone Research, N ew York, Academic Press Inc., 1!J51, pp. 373-416. IS. Mycrs, W. P. L., West, C. D., Pearson, O. H. and Karnofsky, D. A.: AndrogenInduced Exacerbation of Human Breast Cancer as Measured by Calciulll Excretion: Conversion of Androgen to Estrogen as a Possible Underlying Mechanism. J.A.M.A. (In press.) ID. Spencer, H., Vankinscott, V., Lewin, 1. and Laszlo, D.: Removal of Calcium in Man by Ethylenediamine Tetra-acetic Acid. A Metabolic Study. J. Clin. Tnvestigation 31: 1023-1027 (Dec.) 1952. 20. Dudky, H. R., Ritchie, A. C., Schilling, A. and Baker, W. H.: Pathologic Changes Associated with Use of Sodium Ethylene Diamine Tetra-acetate in TreatIllent of Hypercalcemia: Report of Two Cases with Autopsy Findings. New England J. Med. 252: 331-337 (March 3) 1955. 21. Holland, J. F., Danielson, E. and Sabagian-Edwards, A.: Use of Ethylene Diamine Tetra-acetic Acid in Hypercalcemic Patients. Proc. Soc. Exper. BioI. & Med. 8~: 359-364 (Nov.) 1954. 22. Smith, P. K., Winkler, A. W. and Hoff, H. E.: Calcium and Digitalis Synergism. Toxicity of Calcium Salts Injected Intravenously into Digitalized Animals. Arch. Int. Med. 64: 322-329, 1939.
P. LAIRD MYERS, M.D.
PATIENTS with disseminated cancer are subject to a wide variety of medical and metabolic complications which at times may be of such magnitude as to threaten life. If the dissemination involves the skeletal system, hypercalcemia may develop as a result of osteolysis secondary to the growth of tumor in bone. This phenomenon, particularly as seen in patients with metastatic mammary carcinoma, has been recognized for a number of years but still has not received the emphasis it deserves. It is the purpose of this paper to review the various aspects of hypercalcemia including clinical manifestations and treatment.
CALCIUM HOMEOSTASIS AND NEOPLASTIC CAUSES OF HYPERCALCEMIA
Figure 113 illustrates diagrammatically the various factors relating to calcium homeostasis. The diagram has been oversimplified for the sake of emphasis and no attempt has been made to indicate the exact sites of action of vitamin D and parathormone nor to include all possible factors in bone metabolism (protein intake, sex hormones, thyroid hormone, etc.). Nevertheless, the major factors are shown. Elevation of the serum calcium above normal will result, then, "whenever more calcium enters the blood stream than leaves it."! This calcium may enter the vascular system from the bones, the gastrointestinal tract or by the parenteral route. If the rate of excretion by the kidneys is equal to the calcium load, hypercalcemia is averted. Data indicate that the critical level of renal excretion is about 500 mg./24 hours.2 Amounts in excess of this value are usually associated with hypercalcemia. Amounts less than this may also be associated with hypercalcemia, if renal insufficiency is present. Renal From the Chemotherapy Service, Department of Medicine, Memorial Hospital; and Division of Clinical Chemotherapy, Sloan-Kettering Institute. This study was supported in part by the following grants: Grant C-1889 from the National Cancer Institute of the National Institutes of Health, U. S. Public Health Service; the American Cancer Society; the Damon Runyon Memorial Fund for Medical Resenrch; and the Lasker Foundation. 871
872
W. P. Laird Myers
insufficiency alone, through retention of phosphate, leads to hypocalcemia not hypercalcemia, but if it is present in addition to uncontrolled entry of calcium into the blood, hypercalcemia will result or become more marked if already present. Under normal conditions, the dietary restriction of calcium to 200 mg. per day will result in the excretion of about 50 mg./24 hours in the urine and about 200 mg./24 hours in the CALCIUM
HOMEOSrASIS
;l ~"\
:·ff '~
USI
e
Protein Bound
Serum Calcium
Renal Excretion
Fig. 113. The bone, kidney, gastrointestinal tract and para thyroids are shown in the medium of extracellular fluid. The reversible arrows indicate that ionizable calcium of the serum is in equilibrium with extracellular calcium and with the systems shown. Thus calcium is continuously being deposited in and resorbed from bone, being filtered and resorbed by the kidney and absorbed from and excreted into the gastrointestinal tract. However, most of the fecal calcium simply represents unabsorbed calcium in the diet and is not the product of active excretion. The ionizable fraction is also in equilibrium with the protein-bound fraction, with the functional activity of the parathyroid glands and with the level of serum phosphorus. The single arrows at the top of the diagram indicate a direct action of the parathyroid glands on bone and kidney. Lowered blood pH favors an increase in ionizable calcium and an alkaline pH the reverse. The serum calcium will be elevated in hyperproteinemia and lowered in hypoproteinemia and hence it is necessary to know the level of the serum proteins for proper interpretation of the serum calcium. Thus an apparently normal serum calcium may actually represent hypercalcemia if the total serum protein is low.
stooJ.2 The upper limit of normal urinary calcium excretion on a 200 mg. intake is about 150 mg./24 hours. 2 With normal intakes of calcium (600 to 800 mg. per day in the average adult) the urinary calcium rises somewhat but most of the excess calcium is unabsorbed and leaves the body as fecal calcium. The calcium in the body amounts to about 2 per cent of the body weight. 3 Over 99 per cent of this calcium is in the skeleton while about
Clinical Aspects and Management of Hypercalcemia
873
1 gram of calcium is present in the extracellular fluid. 4 The growth of a tumor in bone (Fig. 113) may initially proceed at such a rate as to enable the kidney to excrete the displaced calcium with resultant hypercalciuria but without hypercalcemia. This has been described 2. 5 in detail and it has been suggested by Pearson,2 as an approximation, that when a tumor increases in size by 1 gram, about 1 gram of bone containing 100 mg. of calcium is destroyed and the calcium is excreted into the urine. This analysis of urinary calcium as an indirect measure of progression or regression of tumor growth in bone has developed into a convenient means Table 1 SIXTY-ONE CASES OF HYPERCALCEMIA ANALYZED FROM THE STANDPOINT OF UNDERLYING CAUSE, HIGHEST SERUM CALCIUM LEVEL, AND ROENTGEN SURVEYS OF THE SKELETON DIAGNOSIS
No. CoIos 9
Kidney
5
Myelomo
2
LunQ
3
Lymphoma
4
Stomach
I
Cervl.
2
J
~1~Wlr a"a.'
2
26
Neuroblastoma
2
U'erus
I
~:~~~~-
I
AcuM Leukemia
I
Tonsil
I
Ca, primary unknown
2
Exceal Calcium
4
M~a.'atoc
and Vitamin D HyperThvroldism
I
~X~{hyrOidISm
2
Cause unknown
I
NORMAL RANGE
I
HIGHEST SERUM
10
11
12
~~
Wh W I@ ~ I~ W • I~ ~ I~ W I~ W
I~ W
!m W
•
t
13
~ W,
WW
• :1:-
~~
@@ ~~
.
•
@; ~ • W, W, ~
•
1&
•
17
18
19
•• • • • •
• • • •
~ W,
@~
le
14
CALC I UM MG.lIOOCC.
•
..: •
-
20
•
• •
'5~H~L 21
25
I Pos. 4
No' NeQ. Done I
2 3
•
3
I
I
I
I
•
23
I
I
I
2
2 I I I
• •
• •
•
•
I
2 3
I
I
2 I
of evaluation of therapy. As noted above, when the renal mechanisms for calcium excretion are exceeded by the load, hypercalcemia will result. Table 1 shows some of the diseases associated with hypercalcemia encountered at Memorial Center in the 13 month period from July 1954 to August 1955. It was not possible to analyze all the cases of hypercalcemia nor was it possible to calculate the incidence of hypercalcemia among various tumors. The data have been compiled merely to illustrate some of the types of tumors which may be associated with hypercalcemia as well as some of the miscellaneous causes of hypercalcemia which have been encountered. The normal range of serum calcium in our hospital is 9.2 to 10.8 mg./100 cc. For the purposes of this
874
W. P. Laird Myers
case analysis a level of 11.5 mg./IOO cc. or higher was regarded as an elevation. Undoubtedly the recognition of a large number of cases of metastatic breast cancer with hypercalcemia is in part due to an increasing awareness of this complication in breast cancer and to the frequent determinations of serum calcium in this group. However, in a series of 445 cases of breast cancer metastatic to bone, Woodard1 found an over-all incidence of hypercalcemia (12.1 mg./IOO cc. or above) of 9.4 per cent compared to an incidence of 8.9 per cent in 135 patients with miscellaneous cancers metastatic to bone (excluding multiple myeloma). In general, the tumors which commonly involve bone are those of breast, lung and kidney origin in addition to multiple myeloma and lymphomatous diseases. When a patient with metastatic disease presents any of the symptoms discussed below the possibility of hypercalcemia should be considered. Multiple determinations of serum calcium are often necessary to establish the diagnosis with certainty. The skeletal survey proved to be positive for metastatic disease in most instances recorded in Table 1, but it is well to note that there were a few patients who had hypercalcemia despite normal bone surveys. Cancer may involve the skeleton widely and yet initially may produce no changes in the x-ray if the lesions are small. The extent of involvement by x-ray cannot be correlated with the degree of hypercalcemia. Some patients with extensive bone disease showed only slight elevation in calcium while others with a single lesion showed marked elevations. The nonmalignant causes of hypercalcemia are of interest. There were three patients who had hypoparathyroidism which developed following sacrifice of the parathyroid glands during neck dissections for carcinoma of the thyroid gland. In the management of their hypoparathyroidism, excessive administration of calcium and vitamin Dzled to hypercalcemia. A fourth patient developed hypercalcemia when he received too vigorous parenteral replacement therapy in an attempt to treat hypocalcemia secondary to large losses of calcium through a small bowel fistula. Hyperparathyroidism was due in one instance to a single adenoma and in another to multiple adenomas. Although metastatic osseous cancer is usually accompanied by slight elevations in serum phosphorus, occasionally, the chemical findings of hyperparathyroidism (hypercalcemia in association with hypercalciuria and hypophosphatemia) are seen and may lead to confusion in diagnosis. Albright and Reifenstein 6 have described such a patient with metastatic renal carcinoma and we have encountered the same problem in two patients, one with lymphosarcoma and one with metastatic renal carcinoma. The diagnosis can sometimes be established by the demonstration of tumor cells in the patient's marrow. Patients with metastatic breast cancer under treatment with estrogens may show a lowering of the serum phosphorus as a result of treatment. 7 Hyperthyroidism was observed in one instance and has been described
Clinical Aspects and Management of Hypercalcemia
875
fully in a recent reviews as a cause of hypercalcemia. Other well recognized, nonmalignant causes of hypercalcemia including sarcoidosis,9 the milk and alkali syndrome,lO and osteoporosis with immobilization 6 were not encountered in this brief case review. CLINICAL MANIFESTATIONS OF HYPERCALCEMIA
The various roles which calcium fulfills in bone formation, blood coagulation, cardiac contractility and lactation have long been established. In addition it is known that calcium decreases cell membrane permeability, that it may block ganglionic transmission in high concentrations and that "it is indispensable for the maintenance of the functional integrity of the somatic and autonomic nervous systems."ll In clinical situations where there is an excess of circulating calcium it might be supposed that all of these various functions would be disturbed. Practically speaking, however, the major symptoms are as follows: Nervous System. Drowsiness and lethargy are usually the earliest signs. The lethargy may become pronounced and may be accompanied by confusion and disorientation. Eventually semistupor and coma may result. There is generalized muscular weakness with hypotonia and the deep tendon reflexes are hypoactive or absent. The neurological signs suggest no localization although at times thick speech and transient aphasia have been observed. In these latter instances, however, the possibility of cerebral metastases could not be excluded as the underlying cause. In some patients it has appeared as though previously latent cerebral metastases became manifest during hypercalcemia. For example, one patient was observed to have a generalized convulsion when his serum calcium rose to 15.1 mg./lOO cc. This seizure was due to cerebral metastases but the role of the elevated serum calcium as a possible precipitating factor must be considered. Convulsions are not a symptom of hypercalcemia per se but rather of hypocalcemia. Renal. The increased load of filtered calcium results in an osmotic diuresis so that patients usually have polyuria. With the loss of water via this route (and because of vomiting) they become dehydrated and thirsty. With long-continued hypercalciuria, deposition of calcium in the renal tubules may lead to nephrocalcinosis with hyposthenuria and albuminuria.1 2 Water loss by the kidneys is thereby aggravated and eventually azotemia and renal failure may occur. Gastrointestinal. Anorexia, nausea, vomiting and constipation are usually part of the symptomatology of hypercalcemia. The exact mechanisms involved are obscure but presumably the symptoms are related to the effects of calcium on the autonomic nervous system or to effects on the central nervous system. Cardiac. In man, infusions of calcium result in changes which resemble vagal stimulation. ll . 13 Thus sinus bradycardia, sinus arrhythmia, shifting pacemaker and varying degrees of auriculoventricular block have been
876
W. P. Laird Mycrs
observed with such infusions and might be expected to occur in clinical hypercalcemia. In our experience tachycardia rather than bradycardia has been the rule and disturbances in rhythm have not usually been encountered. With increasing levels of serum calcium a direct effect on the myocardium may result in premature ventricular contractions or ventricular tachycardia. Cardiac failure has been observed in the course of hypercalcemia and the management of this complication will be discussed shortly. The electrocardiographic changes, in addition to revealing any possible disturbances in rhythm, may show shortened QT intervals and T wave depressions.14 General. There appears to be a marked individual variation from patient to patient in the signs and symptoms they will show at any particular level of serum calcium. Thus one patient became comatose when the serum calcium rose to 18.3 mg./IOO cc. while another patient tolerated a similar elevation for several weeks with only mild lethargy. There was, however, a general parallelism in that the symptoms noted above tended to be minimal with slight to moderate elevations of serum calcium and were usually marked with higher levels. It is important to note that fatalities may result from hypercalcemia probably due to the direct action of the calcium on the myocardium. Some authors have reported 15 the occurrence of hyperbilirubinemia in patients with hypercalcemia secondary to metastatic mammary carcinoma. This in all likelihood is a reflection of advancing metastatic disease in the liver and not related to the hypercalcemia. Corneal calcifications have been reported 16 in some diseases associated with hypercalcemia. Our patients have not had slit-lamp examinations but it would seem possible that metastatic disease leading to hypercalcemia could produce such changes. MANAGEMENT OF HYPERCALCEMIA
Inasmuch as hypercalcemia may in itself cause death it is essential not only to be aware of its possible occurrence but also to know what measures are useful in treating it. Although we are dealing with ultimately fatal situations in patients with skeletal metastases, some patients may die prematurely if hypercalcemia is uncorrected. A brief case experience will serve to illustrate this point: A 35 year old housewife was under treatment with testosterone propionate for metastatic mammary carcinoma. After 3 weeks of treatment she showed a progressive increase in urinary calcium~the first sign of impending hypercalcemia. The hormone therapy was stopped prior to an increase in the level of serum calcium but this subsequently rose to 12.8 mg./IOO cc. and then gradually returned to normal. The patient had no symptoms of hypercalcemia, the hormone therapy having been stopped solely on the basis of the rising urinary calcium. She later had a striking remission in her disease following radiation castration. She returned home and was able to resume her usual household duties and the care of her 3 children. It is true that she succumbed to her disease a year later
Clinical Aspects and M anagernent of Hypercalcernia
877
but she might have died prematurely if the hypercalcemia had not been recognized early and treated.
The management is best considered in the following way: (a) the use of nonspecific measures, (b) treatment of the cause and (c) treatment of associated problems. The Use of Nonspecific Measures
The nonspecific measures in the treatment of any patient with hypercalcemia are chiefly those of reduction of intake and promotion of calcium output. Diet. The calcium in the diet should be limited to 200 mg. per day or less. For practical purposes this means elimination of milk and milk products; cheese and eggs. At times patients are too drowsy or have too much vomiting to permit oral feedings and nutrition must be maintained parenterally. Parenteral feeding, however, is difficult to maintain over long periods and in some patients who have been hypercalcemic for long per:oJs tube feedings have been used. Tube feedings pose a special problem since most are made with milk as a base. To avoid this, a low calcium diet can be homogenized in a Waring Blendor and thinned with water for tube administration or an artificial low calcium formula can be made up. One such formula is as follows: Dextrose 200 grams = 800 calories Fat (Lipomul, for example) 80 grams = 720 calories Protein (Protinal, for example) 40 grams = 160 calories Total calories = 1680 Add a liquid vitamin preparation (one which contains no vitamin D) and water q.s. ad 1500 cc. Supplementary nourishment (fluids, broths) can be given via the tube to bring the total fluid and electrolyte intake to any desired amount.
Some protein supplements contain large amounts of calcium and care in the selection of a proper product is necessary. The calcium content of the above formula is approximately 160 mg. Such a formula may be divided into multiple feedings throughout a 24 hour period. In order to promote output, intravenous fluids should be administered to hypercalcemic patients in amounts sufficient to insure a daily urinary volume of at least 1500 to 2000 ml. These patients are dehydrated and need water to correct their deficits as well as to promote calcium excretion. When patients are incontinent or when there is doubt about the adequacy of the urinary volume, a catheter should be inserted in the bladder for a few days until the more severe stages of hypercalcemia have passed. Infusions should consist principally of dextrose in water with supplementary potassium and sodium chloride as the clinical situation indicates. Caution in the administration of potassium by vein is warranted until it is established that the patient is capable of voiding adequate amounts of urine. Use of so-called "balanced solutions" should be
878
w. P. Laird Myers
avoided in treating hypercalcemia as some of these solutions may contain calcium. Inasmuch as calcium and potassium have opposing actions on the myocardium, the potential cardiac toxicity of a given level of hypercalcemia will be enhanced by a simultaneous reduction in the level of serum potassium. Thus, hypokalemia must be avoided or corrected if already present. Potassium depletion with alkalosis has been observed to develop concomitantly with hypercalcemia17 (for reasons which are obscure) and hence this added complication should be looked for in each patient. There is a theoretical reason for the administration of alkali to hypercalcemic patients because of the reduction of the ionizable fraction with an alkaline pH. However, practically speaking, such infusions are unnecessary and are attended by the hazard of alkalosis with a possible increase in renal damage. Thus, unless marked azotemia with acidosis demands the use of such infusions, the best and simplest plan is to administer dextrose in water in treating uncomplicated hypercalcemia. Treatment of the Cause
The above measures obviously are designed for immediate use and trovide only temporary benefit. The most important step, then, is to analyze and treat the cause of hypercalcemia. Once it has been depermined that osseous metastases are the underlying cause, there are certain specific measures which may be undertaken. Figure 114 illustrates the case of a 59 year old woman who had hypercalcemia complicating lymphosarcoma. Skeletal surveys were negative but the hypercalcemia was regarded as secondary to the presence of rapidly advancing lymphosarcoma in the skeleton since, as has been noted, x-ray evidence of neoplastic disease in the skeleton may not necessarily be present in conjunction with the hypercalcemia. Nitrogen mustard (0.3 mg./kg.) was administered intravenously at a time when the patient was comatose with a serum calcium of 20.2 mg./IOO cc. and a urine calcium ranging between 600 and SOO mg./24 hours. She had previously received intravenous fluids without any lowering of her serum calcium. The effect after nitrogen mustard was striking. There was a remarkable reduction of the serum and urinary calcium to normal. She regained consciousness and in about ten days had improved so much that she was able to be up in a wheelchair. This effect was interpreted as having been due to cessation of growth of the lymphosarcoma in the skeleton with consequent elimination of active osteolysis. Unfortunately the hypercalcemia recurred and the patient became comatose a second time. On this occasion, cortisone was given in doses of 75 mg. intramuscularly every six hours along with intravenous fluids. Again hypercalcemia and hypercalciuria were reversed as shown in the diagram. There was clearing of her mental status a second time but she did not improve as much generally as she had following the nitrogen mustard. The cerebrospinal fluid calcium was determined on each occasion that the patient became comatose and elevations were noted (7.S mg./IOO cc. with a serum level of 21.9 mg./IOO cc., and 7.5 mg./IOO cc. with a serum level of lS.3 mg./IOO cc.). The spinal fluid protein was normal in each instance. Elevation in cerebrospinal fluid calcium may, in part, be responsible for the neurological signs and symptoms of hypercalcemia. The marked
Clinical Aspects and Management of Hypercalcemia I.e.
59yrs.
879
$ Lymphosarcoma
~~
45 mg."I.
25
5~------~--------~==~~-r-------------rBodansky 5 Units
O~-------r------------------~--------------'--
50
O~~-----r------------------~--------------'-20
mg. %
15
o
Days 0
1955 4·29
20
40
60
·Calcium intake approximately 200 mg /day
Fig. 114. Fifty-nine year old patient with generalized lymphosarcoma and hypercalcemia. The effect of nitrogen mustard and cortisone on serum and urinary calcium is shown.
hypophosphatemia in association with the hypercalcemia led to the suspicion that the patient might have had an independent primary hyperparathyroidism but a subsequent postmortem examination revealed four normal parathyroid glands.
Nitrogen mustard is most useful in the lymphomatous diseases and its effectiveness in the treatment of those cases with an accompanying hypercalcemia indicates even broader usefulness. The usual precautions
880
W. P. Laird Myers
in the administration of this compound should be followed, namely, that if there is marked hematological depression from a previous course of treatment it should not be used or if the depression is a result of the lymphomatous disease process within the marrow and the bone marrow is not hypoplastic; it should be used in smaller doses and cautiously. The presence of definite myelophthisic anemia which may be seen in some carcinomas metastatic to bone should lead to great caution in the use of any chemical agent which can cause further bone marrow depression. In such instances the use of hormonal therapy is safer. The use of cortisone or related compounds requires close observation of the patient and the usual attention to the well-known side effects of these adrenal steroids. The mechanism of action of nitrogen mustard and adrenal steroids in the correction of hypercalcemia of malignant disease appears to be due to their inhibition of tumor growth in the skeleton. The possibility that cortisone may favorably influence hypercalcemia by enhancing fecal excretion of calcium has not been substantiated experimentally thus far in neoplastic disease. Both adrenal steroids and nitrogen mustard should be considered in the treatment of hypercalcemia accompanying any tumor metastatic to bone. Although most effective in the lymphomatous group of diseases, reductions of elevated serum calciums have been achieved with these agents in patients with metastatic osseous cancer. For examp'e, in a critically ill patient with metastatic breast cancer and hypercalcemia, the use of hydrocortisone intravenously (200 mg. in 1000 cc. of 5 per cent glucose in water given over an 18 hour period) combined with cortisone given intramuscularly 300 mg. per 24 hours resulted in a reversal of these changes and the general condition of the patient improved sufficiently to permit her to undergo radiation castration. Cortisone has also been effective in the treatment of hypercalcemia associated with multiple myeloma. These experiences and others with both nitrogen mustard and cortisone have led us to try these agents in the treatment of metastatic bone disease with hypercalcemia if other accepted measures have failed, although it must be admitted that reductions in serum calcium do not by any means occur uniformly. Radiation therapy may sometimes result in disappearance of hypercalcemia and hypercalciuria. In patients who have localized osteolytic tumors causing hypercalcemia, radiation to such an area would be the treatment of choice unless the hypercalcemia were so marked that more prompt action was desirable. In such instances nitrogen mustard or intravenous hydrocortisone might be considered. Figure 115 illustrates an important principle in the management of hypercalcemia, namely that of knowing when to stop treatment. The patient, a 48 year old married woman, had extensive osteolytic metastases from carcinoma of the breast. Testosterone therapy resulted in both
Clinical Aspects and Management of Hypercalcemia
881
hypercalcemia and hypercalciuria which were effectively treated simply by stopping the testosterone, continuing the restricted calcium intake and administering infusions of dextrose in water during the period of hypercalcemia. This complication of the therapy of metastatic breast cancer has been observed with both androgen and estrogenlS and constitutes one of the hazards attending the use of these hormones. The figure also illustrates the value of urinary calcium data in anticipating the development of hypercalcemia. Hormone therapy was discontinued NK. 48yrs.!f Co. Breost
~~~t:i:~~~~e
=;;;=;=;=;=111=1
f'ZZZJ I.V. Fluids
50mg/day
15 '13
9----
mg% 11
Serum Calcium
Urinary Calcium·
DAYS 0 40 80 ·Calcium intake approximately 200mglday Fig. 115. Forty-eight year old woman with metastatic breast carcinoma. Exacerbation of skeletal disease with resultant hypercalcemia followed treatment with testosterone propionate.
because of the rising urinary calcium at a time when the serum calcium was still normal. In spite of stopping the hormone, the delayed effects still resulted in subsequent striking hypercalcemia which might have been considerably worse without the warning afforded by the urinary calcium. In women with metastatic breast cancer who demonstrate the phenomenon of cyclic hypercalcemia with their menstrual periods 2 (due to endogenous estrogen stimulation of the mammary cancer), the treatment is to remove the source of estrogen by castration. Surgical castration should be performed before the next menstrual cycle results in recurrent hypercalcemia. The presence of moderate hypercalcemia itself does not contraindicate surgery. Figure 116 illustrates a final treatment modality, namely the use of disodium ethylen~diamine tetra-acetate* (sodium EDTA). This drug has no known tumor-inhibitory properties in man and its action is simply to
* Kindly supplied
by Riker Laboratories, Inc., Los Angeles, California.
W. P. Laird Myers
882
form a soluble chelate with calcium and enhance its renal excretion. 19 The patient, a 38 year old man, had hypercalcemia secondary to metastatic cancer the primary site of which could not be determined. Six grams were diluted in 500 cc. of 5 per cent glucose in water and the intravenous infusion was given slowly over a period of one hour. The serum calcium decreased and there was a slight rise in the calcium output in the urine. Despite this, there was no change in the patient's condition or mental status. The serum calcium decrease was an apparent one since the chelated calcium was present in the serum but was not detectable A.J. "S8 YRS. OSSEOUS MET. '·UNKNOWN
mg.%
16j 12
mg.%
mg.%
Fig. 116. Thirty-eight year old man with metastatic carcinoma and hypercalcemia. Sodium EDTA (Versene) resulted in definite but transient decrease in serum calcium.
by the usual oxalate precipitation method of serum calcium analysis. However, this EDTA-bound calcium is presumably physiologically inert and from this standpoint the decrease was a real one. The serum calcium gradually returned to pretreatment values over a 24 hour period following the infusion. To overcome this limitation, repeated daily infusions of Versene could be given, but there have been reports of renal tubular vacuolization20 • 21 with repeated use. It seems best in our present state of knowledge to reserve the use of sodium EDTA for those situations where other measures have failed and to use it only as a temporary measure for a few days at most. Its use
Chnical Aspects and Management of Hypercalcemia
883
should not be considered in patients with mild hypercalcemia but only in those with marked hypercalcemia (17 or 18 mg./lOO cc. or above) which is also symptomatic. As a temporary measure, then, it must be accompanied by efforts designed to treat the underlying cause of the hypercalcemia. In general, preliminary data suggest that doses of 90 to 100 mg./kg./day should not be exceeded and that a total of 6 grams per infusion per day should be the maximum adult dose. Although the patient discussed received the dose in a one hour period, otherslQ • 20 have given the infusions over periods of four to six hours in length. Theoretically and in actuality 6 grams of sodium EDTA will lower the serum calcium about 4 mg./lOO cc. in a 70 kg. person with an estimated extracellular space of 14 liters (20 per cent of body weight). Smaller patients will obviously have smaller extracellular volumes and the expected decrease in serum calcium for the same dose of sodium EDTA will be greater. It must be stressed that while sodium EDTA is being administered the physician must not leave the bedside of the patient. The Chvostek and Trousseau signs and the blood pressure should be tested repeatedly during the infusion. When any suggestion of hypocalcemia or hypotension is noted the infusion must be stopped promptly. La.stly, it must be remembered that the EDTA used in the treatment of lead intoxication is already chelated with respect to calcium and it will have no effect at all in hypercaloomia. Management of Associated Problems
Certain associated problems arise in the course of hypercalcemia and these are often of importance in the total management. The first one relates to digitalization of a pqtient whose serum calcium is elevated. The fact that synergism exists between digitalis and calcium with respect to their effects on the myocardium has long been known. Although differences of opinion exist,22 reports have been published cautioning the physician not to use calcium intrav~mously in a digitalized patient. l3 What hazards exist, then, in the use of intravenous digitalis in a patient with hypercalcemia? There is insufficient data at present on this point but we have digitalized two patients recently with serum calciums ranging between 12 and 14 mg./lOO cc. at the time of digitalization. In one patient this was done by giving one-half the usual digitalizing dose of digitoxin in divided doses over a two day period followed by a daily maintenance dose of 0.1 mg. In the other patient 0.8 mg. Cedilanid was given initially and the following day two doses of 0.4 mg. each were given with a four hour interval between doses. Neither patient had any untoward effects. Further observations must be made but at present it would seem best to fractionate the doses of digitalis in any situation of hypercalcemia and to carry out digitalization with the help of serial electrocardiograms. If the clinical situation permits, digitalization by the oral route is preferable to the parenteral route. Recognition of coexistent
w.
884
P. Laird Myers
hypopotassemia is important when digitalization is contemplated because of the enhanced effects of digitalis in the presence of potassium depletion. Renal insufficiency with azotemia and acidosis may present problems in management. The same principles apply in these situations as with renal failure due to other causes. Although renal shutdown is theoretically possible we have not encountered it and since other measures are available to control serum calcium levels the question of extracorporeal dialysis has never arisen in our patients for the control of hypercalcemia. Renal lithiasis is likewise a theoretical complication which has not proved a problem in our experience. The central nervous system signs and symptoms which these patients present always raises the question as to whether they are due to hypercalcemia per se or to brain metastases or to both. Cerebrospinal fluid examinations should be done in those patients where this confusion arises since elevation of the spinal fluid protein is supporting evidence for the presence of central nervous system metastases. The spinal fluid calcium in some of our patients has been elevated. Its role in the production of these symptoms remains to be determined. The other factors complicating the management of these patients usually relate to the disease in the skeleton. Skeletal pain, pathological fractures, superimposed osteoporosis, and myelophthisic anemia do not arise as a result of hypercalcemia itself but like it they are end results of the same neoplastic process and demand appropriate treatment. SUMMARY
The various factors in calcium homeostasis have been reviewed as well as the 3igns and symptoms of hypercalcemia. A brief analysis of 61 cases of hypercalcemia has been presented. The various modalities of treatment of hypercalcemia, including nonspecific measures, treatment of the underlying cause and treatment of associated problems have been considered. REFERENCES 1. Woodard, H. Q.: Changes in Blood Chemistry Associated with Carcinoma Metastatic to Bone. Cancer 6: 1219-1227 (Nov.) 1953. 2. Pearson, O. H., West, C. D., Hollander, V. P. and Treves, N. E.: Evaluation of Endocrine Therapy for Advanced Breast Cancer. J.A.M.A. 154: 234-239 (Jan. 16) 1954. 3. Best, C. H. and Taylor, N. B.: Physiological Basis of Medical Practice. 5th Ed. Baltimore, WiJliams & Wilkins Co., 1950. 4. Howard, J. E.: Metabolism of Calcium and Phosphorus in Bone. Bull. New York Acad. Med. 27: 24-41 (Jan.) 1951. 5. Laszlo, D. and others: Mineral and Protein Metabolism in Osteolytic Metastases. J.A.M.A. 148: 1027-1032 (March) 1952. 6. Albright, F. and Reifenstein, E. C. Jr.: The Parathyroid Glands and Metabolic Bone Disease. Baltimore, Williams & Wilkins Co., 1948. 7. Woodard, H. Q., Escher, G. C. and Farrow, J. H.: Changes in Blood Chemistry of Patients with Disseminated Carcinoma of Breast During Endocrine Therapy. Cancer 7: 744-757 (July) 1954.
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8. Rose, E. and Boles, R. S. Jr.: IIypercaleemia in Thyrotoxicosis. IV!. CLIN. NORTH AMERICA 37: 1715-1724 (Nov.) 1953. D. Longcope, W. T. and Freiman, D. G.: A Study of Sarcoidosis. Mediciue 31: 1-132, 1D52.
10. Burnctt, C. H., Commons, R. R., Albright, F. and Howard, J. K: Hypercalcemia Without Hypercalciuria or lIypophosphatemh, Calcinosis and Renal Insufficiency. Kew England J. Med. 240: 7S1-7!i4 (May) Ul4U. It. Goodman, L. S. and Gilman, A.: PharmacoJ;,.~i",d Basis of Therapeutics. 2nd Ed. New York, Macmillan Co., 1D5.5. 12. Roch, M., Berthoud, Eo and Koralnik, 0.: De diverses causes de I'hypercalcemie et de son expression clinique. Bull. et mem. Soc. med. d. hop. de Paris 69: 2\)2-2D5 (March 20) 1953. 13. Clarke, N. Eo: Action of Calcium on Human Electrocardiogram. Am. Heart J. 22: 367-373 (Sept.) 1D41. 14. Levine, H. D.: Electrolyte Imbalance and Electrocardiogram. Modern Concepts of Cardiovascular Disease 23: 246-249 (Nov.) 1954. 15. Kennedy, B. J., Tibbetts, D. M., Nathanson, I. T. and Aub, J. C.: Hypercalcemia, a Complication of Hormone Therapy of Advanced Breast Cancer. Cancer Research 13: 445-459 (June) 1953. lG. Walsh, F. B. and Murray, R. G.: Ocular Manifestations of Disturbances in Calcium Metabolism. Am. J. Ophth. 36: 1657-1676 (Dec ) 1\)53. 17. Pearson, O. H. and Eliel, L. P.: Hormone Therapy in Cancer. Experimental Studies with ACTH and Cortisone in Patients with Neoplastie Disease. Recent Progress in Hormone Research, N ew York, Academic Press Inc., 1!J51, pp. 373-416. IS. Mycrs, W. P. L., West, C. D., Pearson, O. H. and Karnofsky, D. A.: AndrogenInduced Exacerbation of Human Breast Cancer as Measured by Calciulll Excretion: Conversion of Androgen to Estrogen as a Possible Underlying Mechanism. J.A.M.A. (In press.) ID. Spencer, H., Vankinscott, V., Lewin, 1. and Laszlo, D.: Removal of Calcium in Man by Ethylenediamine Tetra-acetic Acid. A Metabolic Study. J. Clin. Tnvestigation 31: 1023-1027 (Dec.) 1952. 20. Dudky, H. R., Ritchie, A. C., Schilling, A. and Baker, W. H.: Pathologic Changes Associated with Use of Sodium Ethylene Diamine Tetra-acetate in TreatIllent of Hypercalcemia: Report of Two Cases with Autopsy Findings. New England J. Med. 252: 331-337 (March 3) 1955. 21. Holland, J. F., Danielson, E. and Sabagian-Edwards, A.: Use of Ethylene Diamine Tetra-acetic Acid in Hypercalcemic Patients. Proc. Soc. Exper. BioI. & Med. 8~: 359-364 (Nov.) 1954. 22. Smith, P. K., Winkler, A. W. and Hoff, H. E.: Calcium and Digitalis Synergism. Toxicity of Calcium Salts Injected Intravenously into Digitalized Animals. Arch. Int. Med. 64: 322-329, 1939.