Medical and Pediatric Oncology 1:289-295 (1975)

HYPOCALCEMIA COMPLICATING ACUTE LEUKEMIA David S. Alberts, M.D., Arthur A. Serpick, M.D., and W. Leigh Thompson, M.D. Baltimore Cancer Research Center, National Cancer Institute, United States Public Health Service Hospital, Baltimore

Eighteen of 54 adults with acute leukemia developed severe hypocalcemia during a 20 month period. Hypocalcemia (mean lowest serum calcium 6.3 mg/lOO ml with a range of 4.1 to 7.0 mg/100 ml) lasted 2-29 days and was symptomatic in all but one patient. Six patients were hypocalcemic at the time of death, 5 died within 1 week of hypocalcemia, and 2 had antibiotic-induced respiratory arrest. All patients had severe infections; 17 of 18 were with gram-negative organisms. No patient had severe azotemia, diarrhea, alkalosis, or hypoalbuminemia. Hypophosphatemia was seen in 14 patients, suggesting no hypoparathyroidism. The serum calcium of patients with acute leukemia should be measured frequently, especially when they have infection. Hypocalcemia is a sign of poor prognosis and should signal the need for careful observation of ventilation, caution in the use of aminoglycoside antibiotics, and vigorous attempts at calcium administration.

KEY WORDS: acute leukemia, hypocalcemia, gram negative infections, gram negative sepsis INTRODUCTION

Hypocalcemia is a life-threatening complication in patients with acute leukemia (I, 2). Causing weakness, lethargy, disorientation, and tetany, it may seriously compromise pulmonary function and potentiate the risks of bacterial pneumonia and antibiotic-induced respiratory arrest (3-5). Furthermore, a high percentage of leukemic patients die within a few days of becoming hypocalcemic (1,2). Recently two groups have reported the occurrence of hypocalcemia in children with acute leukemia ( 2 , 6 ) . This report is a retrospective study of 54 adults with acute leukemia admitted to the Baltimore Cancer Research Center, during a 20 month period, 18 of whom developed severe hypocalcemia. D.S. Alberts, Department of Medicine, University of Arizona, Tuscon. A.A. Serpick, Department of Medicine, University of Maryland Medical School, and Division of Hematology and Oncology, Maryland General Hospital, Baltimore, Maryland. W.L.Thompson, Case Western Reserve, University of Cleveland, Cleveland, Ohio. Address reprint requests to Dr. D.S. Alberts, Section of Hematology-Oncology, Department of Medicine, College of Medicine, University of Arizona, Tuscon, Arizona 85724.

0 1975 Alan R. Liss, Inc., 150 Fifth Avenue, New York, N.Y. 10011

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Alberts, Serpick, and Thompson

METHODS

The diagnosis of acute leukemia in all 54 patients was based on morphologic examination of peripheral blood smears, bone marrow aspirates and biopsies. Serum calcium (7), phosphorus (7), protein (8,9),urea nitrogen, and electrolytes were measured every 1-3 days in all patients who were admitted with leukemia. Urinary excretion of calcium or phosphorus or both were measured in 11 of the hypocalcemic patients. Serum unbound calcium [Bio-Science Laboratories, Schatz method (1 O ) ] was measured in 3 patients, and in all patients, serum ionized calcium was estimated from the serum calcium and protein concentrations IZeisler equation ( 1 l)] . All patients were eating a standard hospital diet including milk. Calorie counts were kept to assure normal food intake. No patient was on diuretic therapy, and parenteral fluids contained magnesium, potassium. and vitamin supplementation. RESULTS Clinical Features

Among the 18 hypocalcemic patients (serum calcium of 7.0 mg/lOO ml or less), 4 had not received prior cancer chemotherapy (Table I). No patient had received actinornycin-D, mithramycin, or busulfan. Only 1 patient (no. 6) was in remission during hypocalcemia. All 18 patients had serious bacterial infections before or during hypocalcemia (Table I). Blood cultures from 7 patients contained Ps. aeruginosa or E. coli. Ten others had serious localized gram-negative infections. The remaining patient had “phlebitis” with fever and was given polymyxin-B and kanamycin for 2 days before hypocalcemia was recognized. Although 13 of 18 had received kanamycin or a polymyxin or both within 7 days before hypocalcemia, 5 patients had been given no antibiotics. Seventeen of 18 patients had signs or symptoms of hypocalcemia. Ten had Chvostek signs, 4 were disoriented and lethargic, 1 was comatose, and 2 stopped breathing after injections of polymyxin-B (patient 12 was resuscitated and patient 14 died). Six patients were hypocalcemic at death, and 5 others died within 1 week after resolution of hypocalcemia. LABORATORY STUD1ES

The representative serum calcium concentrations (Table 11) were chosen from values recorded before onset of acute renal failure or septic shock and were measured at the time of urine collections. These serum calcium values ranged from 4.1 to 7.0 mg/100 ml (mean 6.3). Overall duration of hypocalcemia was 2-29 days. The mean serum calcium concentration of samples submitted to the laboratories of the Baltimore U.S. Public Health Service Hospital was 10.1 (SD f 0.4)mg/l00 ml. The last serum calcium value measured before death in 184 consecutive patients with cancer at this hospital during 1966-1968, but excluding the patients presently reported, averaged 8.53 (SD f 1.32) mg/100 ml. Serum albumin concentrations were similar in 18 hypocalcemic patients (mean 2.0 gm/lOO ml) and 193 other patients with cancer [mean 2.14 (SD ? 0.65) gm/lOO ml] . Serum unbound calcium concentrations of 3 patients (nos. 13, 16 and 17) were 3.8,3.8, and 4.4 mg/lOO ml (normal 4.8 to 5.8 mg/lOO ml), and the estimated serum ionic calcium concentrations of all 18 patients ranged between 2.1 to 3.8 mg/100 ml with a mean of 3.2 mg/100 ml.

AML AMOL AMOL AMML ALL AML

AML

AML AMOL AML AMOL

ALL AMOL AMML AML BCC AML

ALL

M, 46 F, 63 F, 28 F, 46 F, 21 F, 20

F, 37

M, 24 M, 48 F, 14 F, 52

M, 25 M, 36 F, 1 3 M, 28 F, 18 F, 27

F. 58 -

5 98 88

-

75

54 59 12 90

60

1

-

80 67 15 15

7% Bone marrow blasts Culture source and result

Daunomycin Daunom ycin Daunomycin Daunomycin None Daunomycin

Blood, P. aeruginosa Blood, P. aeruginosa Phlebitis, no culture Urine, P. aeruginosa Blood, E. coli Anal abscess, P. aeruginosa Vaginal infection, Ara-Ct E. coli Mercaptopurine Sputum P. aeruginosa Blood, P. aeruginosa Daunomycin Liver abscess, E. coli None Breast abscess, None A. aeruginosa Glutamine Blood, P. aeruginosa Sputum, P. aeruginosa Ara-C? 4 Drugs** Sputum, P. aeruginosa Blood, P. aeruginosa None 5 Drugs$ Blood, P. aeruginosa Daunomycin Thigh abscess, P. aeruginosa 3 Drugsf Sputum, A. aeruginosa

Antileukemia chemotherapy

7.0 7.0 2.4 1.8 12.0 5.0 None

0.8 1.4 1.2 None 1.1 1.o None

102 (38.9)

101 (38.3) 104 (40.0) 97 (36.1) 103 (39.4) 101 (38.3)

100 (37.8)

None

None 2.7 None None

104 (40.0) 101 (38.3) 99 (37.2) 102 (38.9)

15.0

None 23.0

36.0

4.6

103 (39.4)

1 .o

2.0 None None

2.4 2.0

12.0 7.2 4.8 9.5 None None

Kanamycin total gm

103 (39.4) 99 (37.2) 98 (36.7) 103 (39.4) 104 (40.0) 98 (36.7)

Peak temp Polymyxin "F f c ) - total gm

*AML: acute myelocytic leukemia; AMOL: acute monocytic leukemia; AMML: acute myelomonocytic leukemia; ALL: acute lymphocytic leukemia; BCC: blast cell crisis of chronic myelocytic leukemia. tCytosine Arabinoside **Methotrexate, 6mercaptopurine, vincristine, prednisone. $1-asparaginas, cytosine arabinoside, daunomycin, vincristine, prednisone. $ Daunomycin, vincristine, prednisone.

Diagnosis*

Sex, age (patients 1-18)

TABLE I. Characteristics of Patients with Hypocalcemia

5'

ii

6

E n,

2

L

W

N

10 14

2 12 34 2 7 28 2 8 29 12 6 12 12

7 4 15 21

6.1 6.4 6.5 6.2 6.4 6.1 6.3 7.0 6.3 6.8 6.7 7.0 4.1 6.4 5.6 6.0 6.4 6.6 6.3

3.22 3.52 2.94 3.06 3.22 2.64 3.32 3.68 3.06 3.48 3.26 3.58 2.13 3.16 2.94 3.10 3.03 3.64 3.26 3.1 2.0 2.0 2.0

1.8

1.5 0.8 3.2 1.5 2.3 2.9 1.9 1.2 0.9 1.5 4.0 2.9 1.4 0.8

15 15 12 38 18 20 15 48 15 19.5

9 14

3

31 40 21 23 9 43

-

2** 10 141

-

-

4 ** 200** 2 144**

-

179**

1 I0

-

49 29

-

-

Urine calcium mglday

*Estimated by Zeisler equation on basis of serum calcium and protein concentrations (27). tRespiratory arrest occurred during or immediately following polymyxin-B administration. **Diet supplemented with 2-6 gm calcium gluconate/day.

Chvostek Coma Lethargy Chvostek None Chvostek Lethargy Chvostek Chvostek Chvostek Lethargy R. arrestt Chvostek R. arrestt Chvostek Chvostek Chvostek Lethargy Mean

- .

TABLE 11. Laboratow Studies of Patients with HyDocalcemia Associated Serum Davs of Serum calcium Urea svmotoms or signs hypoTotal Ionic* Phosphorus nitrogen calcemia mg/100 ml mg/lOO ml (patients 1-18) Serum protein

1.7 1.4 2.3 2.1 2.1 2.6 1.9 2.4 2.3 2.4 2.6 I .9 1.7 1.2 2.4 2.0 2.1 1.7 2.0 5.4 5.9 5.4 4.9 4 .O 5.1 5.2 6.2 4.6 5.5

5.9

5 .O 4.6 6.7 5.7 5.5 7.2 5 .o 5.4

Albumin Total gm/100 ml

E

293

Hypocalcemia Complicating Acute Leukemia

Average urinary calcium excretion was 57 mg/24 hr in 6 patients eating regular diets and 106 mg/24 hr in 5 patients receiving calcium gluconate intravenously (2-6 gm daily). Average urinary phosphate excretion was 149 mg/day in 6 patients on regular diets and 567 mglday in 3 patients receiving calcium gluconate. Serum phosphorus was 0.8-4.0 mg/100 ml (mean 2.0), serum carbon dioxide combining power was 18-38 meq/L (mean 29), serum creatinine was 0.6-4.0 mg/lOO ml (mean 1.6), and serum urea nitrogen was 3-48 mg/l00 ml (mean 19) in hypocalcemic patients. Stool collections were not performed, but 17 patients had no evidence of abnormal number or volume of stool. One patient (no. 4) had a serum calcium concentration of 7.0 mg/100 ml for 5 days before onset of diarrhea; serum calcium levels then decreased to 6.2 mg/l00 ml. Three patients (nos. 6, 11, and 15) excreted 10,25, and 40% of d-xylose (25 gm orally) during 5 hr (normal 2 4 4 8 % ) . DISCUSSlON

The pathogenesis of hypocalcemia in patients with acute leukemia is multifactorial. Zusman et al. (6) have identified hyperphosphatemia secondary to the destruction of lymphoblasts in children on chemotherapy for their acute leukemia as a cause of mild hypocalcemia. The majority of our patients, however, were hypophosphatemic. There have been case reports of elevated levels of plasma-immunoreactive calcitonin in patients with oat cell carcinoma of the lung (12), carcinoid tumor of the bowel (1 3), and recently, Coombes et al. (14) demonstrated increased concentrations of immunoreactive calcitonin in plasma samples from 21 of 46 patients with nonthyroid tumors. None of these patients were hypocalcemic when calcitonin levels were high. In a patient with acute myelocytic leukemia not included in this series but studied by one of us (D.S.A.), Deftos et al. (1 5) reported extremely high levels of both immunoreactive calcitonin (646 pg/ml) and parathormone (1,100 pg/ml) at the time of hypocalcemia. Although probably not a major factor in the pathogenesis of hypocalcemia in our patients, calcitonin secretion from leukemic cells may have been a contributory factor in some of them. All our patients had serious infections, gram-negative bacteria being isolated from 17 of 18. Hypocalcemia has been demonstrated in rabbits following endotoxin injection (16), and hypophosphatemia develops in most patients who have documented gram-negative septicemia (1 7). Of 17 patients with absolute hypophosphatemia and gram-negative sepsis in one study, 12 were found to have serum calcium values of less than 9 mg/100 ml(l7). The hypophosphatemia in our infected patients could be caused by endotoxin inhibition of the fructose-1-phosphate-splitting enzyme, aldolase, as is seen in hereditary fructose intolerance (18). The mechanism of hypocalcemia occurring during infection is unknown (2). The antitumor antibiotics, actinomycin-D and mithramycin, are well known to lower serum calcium concentrations (19-21), but daunomycin, an anthracycline antitumor antibiotic (22), in the past hasnot been associated withhypocalcemia. Seven of these 18 patients received daunomycin prior to their development of hypocalcemia. Fourteen of the patients had cancer chemotherapeutic agents prior to or during hypocalcemia, but 4 of the patients were hypocalcemic before cancer chemotherapy. Hypoparathyroidism is unlikely in these patients because all were hypophosphatemic, and in the 9 who were examined at autopsy parathyroid glands appeared normal histologically. Hypoalbuminemia contributed to hypocalcemia, but measured values of un-

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Alberts, Serpick, and Thompson

bound calcium and estimated ionic calcium concentrations were much less than normal (10,l l), and most patients had symptoms of hypocalcemia. Gastrointestinal absorption of calcium is reduced in patients with multiple myeloma (23). Only 1 of our patients had diarrhea, but 1 of 3 patients studied had reduced d-xylose absorption; however, malabsorption may not have been detected in others. Finally, renal failure with renal tubular damage and hypercalciuria was not present in this patient population. The mean blood urea nitrogen for these 18 patients was 19 mg/100 ml. Five patients did have values in the range of 3 1-48 mg/ 100 ml, but prerenal factors adequately explained these elevations. Although serum magnesium levels were not measured in these patients, magnesium was included in parenteral fluids, and all patients were eating standard hospital diets; however, hypomagnesemia cannot be ruled out as a causative factor of the observed hypocalcemia (24). Hypocalcemia potentiates the neuromuscular-blocking action of some antibiotics (3,s). In addition, hypocalcemia may inhibit hepatic microsomal drug-metabolizing enzymes and increase the effect of common sedatives (25). The patient with acute leukemia may have cachexia, fatigue, and increased metabolic requirements. Serious infection with fever further increases metabolic requirements, and, in septic shock, pulmonary dead space is increased. pulmonary and peripheral arteriovenous shunting is prominent, and heart failure with pulmonary edema may further diminish respiratory reserve. Hypocalcemia, causing weakness, lethargy, disorientation, and tetany, may seriously compromise the pulmonary function of these patients, and the concomitant administration of aminoglycoside antibiotics may precipitate apnea (5,26). Although calcium administration may reverse antibiotic-induced respiratory failure (3,5)possibly by enhancing release of acetylocholine (27), it should not be given indiscriminantly because calcium can also attenuate the antibacterial action of polymyxin and aminoglycoside antibiotics (28,29). ACKNOWLEDGMENTS

The authors are grateful to Dorothy Metcalf and Donna Mei for typing the manuscript. REFERENCES 1. Alberts, D.S., Serpick, A.A., and Thompson, W.L. Hypocalcemia complicating acute leukemia. Clin. Res. 17:399 (1969). 2. Jaffe, N., So0 Kim, B., and Vawter, G.F. Hypocalcemia - a complication of childhood leukemia. Cancer 29:392-398 (1972). 3. Corrado, A.P., Ramos, A.O., and DeEscobar, C.T. Neuro-muscular blockage by neomycin, potentiation by ether anesthesia and d-tubo-curarine and antagonism by calcium and prostigmine. Arch. Int. Pharmacodyn. 121:380-394 (1959). 4. Lindesmith, L.A., Baines, R.D., Jr., Bigelow, D.B., and Petty, T.L. Reversible respiratory paralysis associated with polymyxin therapy. Ann. Intern. Med. 68:318-327 (1968). 5 . McQuillen, M.P., Cantor, H.E., and ORourke, J.R. Myasthenic syndrome associated with antibiotics. Arch. Neurol. 18:402-415 (1968). 6. Zusman, J., Brown, D.M., and Nesbit, M.E. Hyperphosphatemia, hyperphosphaturia and hypocalcemia in acute lymphoblastic leukemia. New Eng. J. Med. 289:1335-1340 (1973). 7. Kessler, G., and Wolfman, M. An automated procedure for simultaneous determination of calcium and phosphorus. Clin.Chem. 10:686-703 (1964). 8. Weichsetbaum, T.E. Accurate and rapid method for determination of proteins in small amounts of blood, serum and plasma. Amer. J. Clin. Path. Tech. Sect. 10:40-49 (1946).

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9. Failing, J.F., Jr. , Buckley, M.W., and Zak, B. Automatic determination of serum proteins. Tech. Bull. Regist. Med. Tech. 29:205-210 (1959). 10. Schatz, B.C. Thesis, graduate school, Univ. S. Calif., 1962. 1 1 . Zeisler, E.B. Determination of diffusable serum calcium. Amer. J. Clin. Path. 24588-593 (1954). 12. Silva, O.L.,Becker, K.L., Primack, A., Doppman, J.. Snider. R.H. Ectopic production of calcitonin. Lancet 2:317-319 (1973). 13. Rosen, S.W., and Weintraub, B.D. Ectopic production of the isolated alpha subunit of the glycoprotein hormones. New Eng. J. Med. 290:1441-1446 (1974). 14. Coombes, R.C., Hillyard, C., Greenberg, P.B., and Maclntyre, I. Plasma-immunorea&tive-calcitonin in patients with non-thyroid tumours. Lancet 1:1080-1093 (1974). 15. Deftos, L.J., McMillan, P.J., Sartiano, G.P., Robinson, A.G., Xbuid, J., and Alberts, D.S. Simultaneous ectopic production of parathyroid hormone and calcitonin. (Submitted to J. Clin. Endocr. Metab., 1975). 16. Peterson, C.R., and Brunson, J.G. Effects of endotoxin on serum clacium; relationship to breakdown of blood brain barrier. Fed. Roc. 18:499 (1959) (abstr.) 17. Riedler, G.F., and Scheitlin, W.A. Hypophosphataemia in septicaemia: higher incidence in gramnegative than in gram-positive infections. Br. Med. J. 1:753-756 (1969). 18. Froesch, E.R., Wolf, H.P., Baitsch, H., Rader, A., and Labhart, A. Hereditary fructose intolerance an inborn defect of hepatic fructose-1-phosphate splitting aldolase. Amer. J. Med. 34: 151- 167 (1963). 19. Harrison, H.E., and Harrison, H.C. Actinomycin-D inhibition of intestinal transport of calcium and of vitamin-D action. Proc. SOC.Exp. Biol. Med. 121:312-317 (1966). 20. Khoo, E.C., and Kowalewski, K. The hypocalcemic effect of actinomycin-D. Arch. Int. Pharmacodyn. 160:96-98 (1966). 21. Parsons, V., Baum, M., and Self, M. Effect of mithramycin on calcium and hydroxyproline metabolism in patients with malignant disease. Brit. Med. J. 1:474-477 (1967). 22. Tan, C., Tasaka, H., Yu,K.P., Murphy, M.L., and Karnofsky, D.A. Daunomycin, anantitumor antibiotic, in the treatment of neoplastic disease. Cancer 20:333-35 3 (1967). 23. Bentzel, C.J., Carbone, P., and Rosenberg, L. The effect of prednisone on calcium metabolism and Ca47 kinetics in patients with multiple myeloma and hypercalcemia. J. Clin. Invest. 43:2132-2145 (1964). 24. Medalle, R., and Waterhouse, C. A magnesiumdeficient patient presenting with hypocalcemia and hyperphosphatemia. Ann. Intern. Med. 79:76-79 (1973). 25. Dingell, J.V., Joiner, P.D.. and Hurwitz. L. Impairment of hepatic drug metabolism in calcium deficiency. Biochem. Pharm. 15:971-976 (1966). 26. Ream, C.R. Respiratory and cardiac arrest after intravenous administration of kanamycin with reversal of toxic effects by neostigmine. Ann. Intern. Med. 59:384-387 (1963). 27. Del Castillo, J., and Stark, L. The effect of calcium ions on the motor end plate potentials. J. Physiol. 116:507-515 (1952). 28. Newton, B.A. Site of action of polymyxin on Pseudomonas aeruginosa: antagonism by cations. J. Gen. Microbiol. 10:491-499 (1954). 29. Zimelis, V.M., and Jackson, G.G. Activity of aminoglycoside antibiotics against Pseudomonas aeruginosa: Specificity and site of calcium and magnesium antagonism. J. Infect. Dis. 127:663669 (1973).