Hypercalcemia in early traumatic quadriplegia

J Chron Dis 1975, Vol. 28, pp. 81-90. Pergamon Press. Printed in Great Britain

HYPERCALCEMIA IN EARLY TRAUMATIC QUADRIPLEGIA JACQUELINE CLAUS-WALKER,* R. EDWARDCARTER,?ROBERTJ. CAMPOS$and WILLIAMA. SPENCER~ Baylor College of Medicine and Texas Institute for Rehabilitation

and Research, Houston, Texas

(Received in final form 15 May 1974)

HYPERCALCEMIA in conjunction with hypercalciuria due to prolonged immobilization is an unusual occurrence. Since the original description by Albright [I], only 11 cases of immobilization hypercalcemia, including the three described here, have been documented [2-4]. Among these patients, two (1 male and 1 female), had Paget’s disease; both were 59 yr old. Seven others (6 males and 1 female), were between 9 and 15 yr old. All nine patients had been immobilized 1 to 3 months for various bone fractures. The patients described in this presentation were between 17 and 18 yr old, were paralyzed by cervical spinal cord injury and were immobilized from 5 to 16 months. Each of the 12 subjects already had an elevated rate of bone turnover prior to immobilization, each had hypercalcemic episodes when they developed a drastic reduction in renal function and in each case, the condition was confused with hyperparathyroidism. Decreased renal function is often a complication noticed after the onset of paralysis. When it occurs during the post-onset period of increased bone resorption, the fractional excretion of calcium may be significantly increased, aggravating the renal condition. If total calcium excretion becomes excessively reduced, hypercalcemia may develop. The immediate treatment for hypercalcemia should aim at reducing bone resorption and calcium intestinal absorption until improved renal function can be obtained. In one quadriplegic patient, a short term treatment with anabolic steroids reduced the hypercalcemia in a few days; his renal function improved and there was no recurrence. In another patient the hypercalcemia was immediately reduced after removal of bladder and urethral calculi. And in the third patient who had chronic pyelonephritis, treatment with anabolic steroids was not successful in reducing the hypercalcemia because of the extreme renal insufficiency; this patient ultimately died of renal failure. Serum parathyroid hormone and calcitonin evaluated in two patients were within the normal ranges. *Departments of Rehabilitation and Physiology. tDepartments of Medicine, Physical Medicine and Rehabilitation. *Departments of Rehabilitation and Neurology. §Department of Rehabilitation. Supported by grants NSO8042-03 from the Neurological Disease and Stroke Division of National Institutes of Health and SRS-P56813-6/10 from the Social and Rehabilitation Service. 81

82

JACQUELINE CLAUS-WALKER et

al.

METHOD

Patients admitted to Texas Institute for Rehabilitation and Research for quadriplegia due to cervical spinal cord injury undergo a series of laboratory tests during their initial hospitalization, which lasts from 3 months to a year, and during readmission for follow-up examinations or for complications. These currently include determinations at 2-week intervals of serum (s) and urinary (u) electrolytes (Na, K), total calcium (Ca” and Gas) and phosphorus (P” and P”); beta-glucuronidase/creatinine ratio, which gives a good index of tubular function [5]; creatinine clearance; and blood urea nitrogen. Every other month alkaline phosphatase is determined. In recent years, patients admitted within a few weeks after onset of paralysis have had daily evaluations of urinary calcium and hydroxyproline and monthly evaluations of several hormones which influence calcium metabolism. In the Clinical Laboratory, Ca is measured by atomic absorption; Na and K by flame photometry; creatinine in an autoanalyzer; alkaline phosphatase by the method of Bessey et al. [6]; P by the method of Fiske and Subbarrow [7] and betaglucuronidase by the method of Talalay [g]. In the Neuroendocrine Laboratory, hydroxyproline (OHP) is measured by the method of Kivirikko et al. [9]; serum thyroxine (T4) by a protein binding assay (Tetrasorb+M 125, Abbott Laboratories). The radioimmunoassays for serum calcitonin (CT) were carried out at M. D. Anderson Hospital by Drs. Stratton Hill and Naguib Samaan [lo], and for low and high molecular weight parathyroid hormones (PTH) by Drs. Murphy Scurry and William Deiss at the University of Texas Medical Branch in Galveston, Texas. One serum PTH was measured in the Department of Endocrine Research at the Mayo Clinic by Dr. Claude Arnaud. Crystallographic analysis of DC’s calculi was performed by Dr. D. Griffith in the Urolithiasis Laboratory, St. Luke’s Hospital, Houston, Texas and chemical analysis in this laboratory. The results of the laboratory tests are routinely stored in the computer memory for future reference. For this investigation blood and urine chemistries from 429 patients who had sustained physiologically complete cervical spinal cord transections were retrieved from the computer files of the studies conducted at TIRR from 1959 to the present. Information related to calcium metabolism had been recorded for 115 patients. RESULTS

Episodes of hypercalcemia were detected in three patients. Patient FB

FB was admitted for the first time to TIRR for decubitus ulcers and acute respiratory and renal insufficiency. He was 17 yr old and had been paralyzed 14 weeks earlier in a diving accident, sustaining a physiologically complete spinal cord transection at the 4th cervical vertebral level. He was completely immobilized prior to his admission at TIRR; his Ca” was 14.4 mg% before his transfer. Further laboratory results on this patient are shown in Table 1. Urinary aldosterone and 17-hydroxycorticosteroids were low on admission (aldosterone, 0.65 pg/day; 170HCS, 0.96 mg/day). Serum alkaline phosphatase was normal in both measurements made (1.6 and 1.0 Sigma units). Serum T4 was normal (7.7 pg”/o). measurements of CT and PTH were not

Hypercalcemia

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83

available. During his hospitalization FB was given sulfanilamide and various antibiotics for treatment of multiple decubitus ulcers and Pseudomonas urinary and pulmonary infections. At admission he was treated with 100 mg hydrochlorothiazide administered for two consecutive days each week for 8 weeks and 5 mg a day of norethandrolone for 6 weeks (Table 1). The patient’s pyelonephritis became chronic; he developed bilateral stag-horn calculi, general osteoporosis, and autonomic dysreflexia. He was discharged 9 months after his admission and died 6 months later of renal insufficiency. TABLE 1. DATA ON PATIENTFB

FB, No. 19712; Date of onset: 7.27.69; Age at onset: 18; Sex: Male Creatinine clearance PS* (ml/ min) (mg%)

Date 1969,12-16 12-30 1970,1-13 2-14 2-15 4-29

69 94 43 33 33 68

Date 1969,12-13 12-16 12-30 1970,1-13 2-14 2-15

3.35 4.18 3.81 3.81

Gas (mg%) 14.23 12.83 14.0 15.03 12.0 13.03

KS (mEs/l)

2.3 2.2 2.0 3.6

PU (mgl day) 1084 1084

BGlucuronidase Alk. phos. BUN creatinine ratio 11 (Sig. U.)§ (mg %)

Cau (mgl day)

P, g (AF/ day)?

291 216 387 331 269

3.31 5.67 2.35

Urine (S.G.)

$I$

9

1.0

13 10

10.5 9.0 27.9 5.4 9.2

Ca% (FE)

14.1 17.4 8.7 7.1 5.7 12.8

19.2 46.0

1.83

Aldosterone 170HCS (mg/day) lI @g/day) 0.96

.

Ca, g (AF/ day)

2.05 1.25 4.46 4.63 4.70

Serum thyroxine (ug %)

0.65

1.015

1.006

7.7

Treatment and medication

Date

1969’ 1970,1-3 -;II;olone

2-15

K+mEq 20 9

Hydrochloro] thiazide, 1 IOOmg 20 Mon. and Tues. discont. discont.

1 Na+mEq:

9

> Pmg: 310 discont.

discont.

Normal ranges : *Ps, Gas, KS, electrolytes in serum; Ps, 2.5-4 mg%; Gas, 9-l 1 mg%; KS, 3-5.5 mEq/l. Pu, Cau, electrolytes in urine; Pu, 780-980 mg/day; Cau, 100-300 mg/day. tAF=amount filtered, Gas or Ps (mg/liter) xcreatinine clearance (liter per min x 1440 min. Normal ranges: Ca, 10.4-14.3 g per day; P, 3.56-7.84 g per day. $FE=Fractional excretion, or (Cau/AF) x 100, expressed as a per cent of amount filtered. Normal range: Ca2+, 0.70-2.38 per cent; P, 12-22 per cent. $Alkaline phosphatase: 0.81-2.3 Sigma units. IjRatio normal range x 500: 2.6-14.5 (x=7.9) (ref. [5]). 7170HCS, l-7 mg/day; aldosterone, l-20 ug/day; T4, 5.4-14.5 ug/day. **December 16 was a Tuesday.

JACQUELINE CLAUS-WALKERet

84

al.

Patient DR

DR was admitted to TIRR for decubitus ulcers and acute respiratory and renal insufficiency. He was 18 yr old and had been paralyzed for 21 weeks by a fall from a tree. He sustained a physiologically complete spinal cord transection at the 5th cervical vertebral level. He was completely immobilized prior to his admission to TIRR; his Ca” was 14.5 mg% prior to his transfer. Further laboratory results on this patient are shown on Table 2. Urinary aldosterone 3 weeks after admission was elevated (17.7 pg/day), and 17-hydroxycorticosteroids were low (0.37 mg/day). Serum alkaline phosphatase was normal on four different occasions. Laboratory values of CT and PTH were normal (Table 2). Since the Ca” values were 12.6 and 12.8 mg% at approximately the time when PTH was measured, 14 and 24 @Eq/ml may be inappropriately high. Urinary OHP was elevated until 7 months after onset. During his hospitalization DR was given sulfanilamide and various antibiotics for treatment of the multiple decubitus ulcers and urinary and pulmonary infections. Prior to admission he was treated for hypercalcemia by intravenous fluid with 100 mg furosemide. He was given more diuretics off and on for 12 more days (Table 2). Oral supplements of K were started a week after admission, and continued for 3 months. Two months after admission the patient was given 5 mg norethandrolone and l/2 grain thyroid tablets daily for 7 days; his Ca” returned rapidly to normal. This treatment was repeated twice at lo-day intervals. DR had a cystolithopaxy 11 months post onset. His Ca” was still high, but Ca” was normal; increased uricemia and uricosuria were detected so continuous allopurinol treatment was prescribed. At a recent check-up, 18 months post onset, both Ca” and Ca” were normal but the uricosuria was still augmented. TABLE 2. DATA ON PATIENTDR No. 21367; Date of onset: 6.12.71; Age at onset: 18; Sex: Male

Clearance

(ml/ Date 1971,l l-20 11-29 12-13 1972, l-6 l-10 l-15 1-21 l-23 l-25 1-29 24 2-5 2-8 2-11 2-15 2-18 2-22 2-29 3-28 5-23 1973, l-24

min) 40 62 54 25 35 45 47 58 42 46 68 64 63 76 71 71 66 79 89 90 86

Urine OHP*

Pu

Ca*

(mg/ day)

(mgl day)

$wJ

P? g (A$

660 836 520 217 542 397 902 905 601 601 781 867 232 712 644 951 1022

443 401 419 303 128 226 172 234 84 114 421 198 261 273 333 409 445

7.28 3.66 2.87 1.67 2.35 3.28 2.73 2.32 2.29 2.39 3.75 3.69 3.72 4.34 3.90 3.97 3.84

Ps (mg%)

Gas (mg/0

4.61 4.09 4.31 5.39 4.65 5.05 4.06 4.27 3.78 3.59 3.84 4.00 4.09 3.97 3.81 3.87 4.03

12.63 12.22 12.63 13.03 11.83 12.03 12.83 10.82 10.42 10.62 9.22 9.22 8.02 9.82 10.22 9.82 9.62

62

11.22 11.62 9.42 9.22

Oral phosphates discontinued 784 431 3.78 517 273 271 505 78

3.31 3.81 4.68 4.68

72 83

80

Ca, g !$ 9.1 22.9 15.5 11.2 23.1 12.1 32.8 39.2 26.3 25.3 20.8 23.6 6.3 16.4 16.6 24.0 26.7 20.8

Ca% (FE)

z*: 910 8.5 7.3 10.7 10.4 10.0 9.1

2.23 3.67 4.26 6.45 2.15 2.91 1.98 3.96 1.34 1.87 4.66 2.33 3.58 2.54 3.18 4.07 4.87

12.7 14.9 12.2 11.4

3.37 1.83 2.21 0.68

19.9 10.9 9.8 4.7 5.9 7.8 8.7 5.9

Hypercalcemia TABLE

in Quadriplegia

85

2-continued BGlucAlk. uroniphos. dase (Sig. BUN creatinine Urine u.) (mg%) ratio (S.G.)

Date 1971,11-19 11-29 1972,12-7 12-13 1-6 l-20 2-3 3-28 5-23 6-27 1973, l-24

1.8 1.6

19 6

11.2

Aldo17OHCS sterone (ug/ day)

PTHt ulE;/

1.010 8

7.7 5.4 2.9

Uric acid Blotd Urine (mg LJ (mg/day)

1.007

7.2 14

1.5 1.7

CT* (n${

0.37

1.65

17.7 24

1.011

6.0

a 12 13

1.4

665 2300

9.2 9.0 6.0

1.016

510 1856 1314 2928

Treatment and medication for hypercalcemia

Date 1971,11-19 Ii-20 11-27 11-31 1972,12-l 12-2 12-3 12-4 12-8 12-18 12-29 1973,1-5 1-17 1-21 1-28 2-7 2-17 2-27 3-9 5-23 7-1

Furosemide IV (dose unknown) discont. Hydrochlorothiazide, 100 mg discont. Furosemide IV, 100 mg x 8 same40mgx19mg2+ 16mEqIV i discont.

K+mEq, 40 49

69 78 69 200 38

Norethandrolone,

5 mg/

Norethandrolone,

5 mg/

Norethandrolone,

5 mg/

Thyroid, l/2 g/ day Thyroid, l/2 g/ day discont. Thyroid, l/2 g/ day discont.

discont.

Na+mEq 9

Pmg

18 29

I discont. 38

619.6 991.4 1301.2 991.4 3098.0 1301.2

discont.

discont.

309.8

Allopurinol from 5.23.72 Cystoscopy and cystolithopaxy

Serum potassium was low on 12-13 (1.1) and normal thereafter when DR was given KS supplements. *Urine hydroxyproline normal range, 25-50 mg/day. TPTH normal range, O-46 ulEq/ml (Dr. M. T. Scurry, U.T.M.B.). *CT normal range, O-2 ng/ml. See Table 1 for other normal ranges.

Patient DC

DC was 15 yr old when he was paralyzed by a wrestling injury. He had had a laminectomy and a cervical fusion between the 4th and 6th cervical vertebrae. Five days later he had a tracheostomy, was placed on an artificial respirator and was admitted to TIRR. The physiological level of the cord transection was at the first cervical vertebral level. During a year of hospitalization he had perforated stomach ulcers, peritonitis requiring a laparotomy, tracheal stenosis requiring several dilations, and recurrent pulmonary infections. He had recurrent activation of chronic urinary

86

JACQUELINE CLAUS-WALKERet al.

infections with fever and developed automonic dysreflexia, deep-vein thrombosis and anemia. He received several blood transfusions. His food and fluid intake were low. Because of his early complications and of the high level of his injury, DC’s wheelchair training was always limited to approximately 1 hr a day at 60” and he was intolerant to verticalization after the first month at TIRR. I-Ie was discharged 13 months after his admission to TIRR, able to sit an hour daily at 60” in a wheelchair. He was using an external urinary catheter and a respirator at home. At the time of his first admission, CaS, P”, and alkaline phosphatase were within normal ranges and no further studies were carried out (Table 3). TABLE3. DATA ON PATIENTDC No. 21395; Date of onset: 12-1-71; Age at onset: 15; Sex: Male

Date 1971,12-7 1973,4-16 4-18 4-20 4-22

Clearance (ml/ Ps min) (mg%) 124 25 24 33 37

Date 1971,12-7 1973, 4-16 4-18 4-20 4-22 4-23 5 -2 1973, 4-19

4.30 3.69 3.59 2.79 2.88

Gas (mg%) 8.82 13.03 13.63 12.83 12.63

Ku Pu (mEq/l)(mg%) 4.7 3.2

BGlucuroniAlk. dase BUN creatinine phos. (Sig.U.) (mg %) ratio 2.3

21 18 14 20 15

94 204 52 44

Urine (S.G.)

Ca(mg/ day)

(!Z/ day)

146 176 493 505

1.33 1.24 1.30 1.55

PTH (plEq/ ml)

(ii/ day)

Cay (FE;

4.7 4.7 6.1 6.7

3.12 3.74 8.09 7.51

70.6 82.0 39.5 28.7

CT (nglml)

16.7 43.4

Uric acid Blood Urine (mg%) (mg/day) 8.2 9.5 11.8

27 665

1.012 38* 1st

1.20

Treatment and medication for hypercalcemia Cystoscopy and cystolithopaxy

*The normal PTH range was ‘less than 46 ylEq/ml’ in the last evaluation. tData from Dr. Claude Arnaud, Mayo Clinic.

Four months later DC was readmitted to TIRR for reevaluation and was found to have multiple bladder stones. His food and fluid intake were good at that time and his general condition was much improved. At readmission DC was found to have 13.03 mg% Ca”, 9.5 mg% uric acid in blood (normal 2.5-7 mg), and 27 mg/day uric acid in urine (normal, 250-750 mg) (Table 3). Three days later he had a cystoscopy and a cystolithopaxy. The calculi were composed of 40-41 per cent calcium apatite and calcium oxalate as was expected from his history of urinary infection. Immediately after surgery DC’s Ca” fell from 13.6 mg% to 12.6 mgq/,; urinary uric acid increased from 27 mg to 665 mg per day and remained elevated in the blood. Twelve days after surgery the calcemia was still 12.6 mg%. Eighteen days after surgery the patient was sufficiently improved to go home, with no medication other

Hypercalcemia

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87

than guanethidine sulfate for dysreflexia, antibiotics and analgesics, to wait for the results of the hormone evaluation in blood samples taken on the day of his discharge. His serum CT was 1.20 ng/ml and PTH was slightly elevated 4 days after surgery (38 plEq/ml, CaS, 12.6 mg%) but returned to the normal range 9 days later (18 ulEq/ml). No further treatment for hypercalcemia has been planned other than care of the urinary tract.

DISCUSSION

At the onset of quadriplegia, paraplegia and paralytic poliomyelitis, patients undergo a period of increased bone turnover [ll-141, leading to increased excretion of fecal and urinary calcium and hydroxyproline, and eventually to osteoporosis [13-151. In paralysis due to spinal cord injury, 6 months to a year after onset bone resorption decreases and calciuria and hydroprolinuria rapidly drop to abnormally low values. The initial period of hypercalciuria is more prolonged in patients who do not undergo early rehabilitation exercises, in quadriplegics with high lesions and in poliomyelitic patients [12-161. Bone resorption occurs in hemiplegic patients [17], and similar but small changes in calcium balance are observed during recumbency reaching a maximum after 6 weeks [ 1g-261. Healing of bone fractures produces activation of bone turnover, temporary hypercalciuria and increased serum ionized Ca2+ [l 1, 22, 23, 271. Hypercalcemia is seldom observed in paralyzed patients [28] and in subjects immobilized for bone fractures or for experimental purposes. Fractional excretion (FE) of calcium or phosphorus can be calculated when creatinine clearance, serum and urine calcium and phosphorus are obtained on the same day. These data were available, and FE for calcium was calculated on the recumbent healthy subjects studied by Hantman et al. [29], on patients with bone fractures studied by Hyman et al. [29] and by Lawrence et al. [3], and on our patients: calcium FE was augmented in every subject. Increased calcium FE may be caused in part by an increase in ionized Ca during immobilization [22, 23,291 and in part by the modulation of hormonal secretion. This is suggested by the experiment of Hantman et al. [29] which also demonstrated that the hypercalciuria of recumbency is increased during administration of calcitonin. If Hantman’s data are used to calculate the fractional excretion of calcium in his experimental subjects, the renal effect of calcitonin seems more obvious: bed rest alone increased FE from 0.92 to 1.14 per cent, 0.74 to 1.18 per cent, 1.18 to 1.71 per cent, 0.91 to 1.32 per cent, 1.25 to 2.23 per cent, 0.82 to 1.21 per cent; bed rest and calcitonin increases were 1.25 to 2.54 per cent and 0.082 to 1.48 per cent. This indicates that physiological increases of calcitonin may be partly responsible for increasing calciuria during recumbency in order to keep calcium blood level constant. High exogenous doses of calcitonin may result in excessive FE and formation of calcium tubular casts [29, 301. Calcitonin levels of less than 0.6 ng/ml were found in 31 sera from 14 quadriplegic patients at TIRR : one patient had 4 ng/ml4 weeks after onset of quadriplegia, at the peak of calciuria when Ca FE increased from 0.87 to 2.25 per cent. The hypercalcemic patients DC and DR had respectively 1.20 and 1.65 ng/ml corresponding with periods of very high Ca FE (7.51 and 4.26 per cent). These calcitonin values are higher than those obtained in 13 out of 14 nonhypercalcemic quadriplegic patients (unpublished data).

88

JACQUELINE CLAUS-WALKER et al.

Over an unknown threshold of calcium released in the circulation, the fractional excretion of Ca may increase sufficiently for tubular fluid to become oversaturated with calcium salts which may precipitate and form tubular casts; renal function is impaired; the excretion of Ca” diminishes and hypercalcemia occurs. This is observed during Vitamin D intoxication. Such mechanisms have been discussed by Albright [l] and Hyman [2]. On the other hand, reduced renal function per se may be the origin of the hypercalcemia because the amount of filtered calcium is so reduced that it is not compensated for by the increase in Ca fractional excretion. However, the rarity of hypercalcemia in these immobilized patients is due to the efficiency of the complex homeostatic control of blood calcium by Vitamin D and multiple hormones. The three patients described here had low levels of serum K, even when they were not treated with diuretics; hypokalemia was also observed in the patients of Hyman and Lawrence [2, 31. The highest Ca” was observed when Ca FE was maximal in patients FB and DR but not in patient DC, where calculi caused the renal insufficiency. However, in this patient Ca FE was 8.09 per cent the day following cystolithopaxy. The fractional excretion of P was usually high in these patients suggesting that the PTH secretion was augmented ; however, this was contradicted by the normal values found using the ‘hypercalcemia discrimination index’ described by Transbol [32]. This index takes into account Ca”, CaU, P”, and creatinine clearance and may be very useful when direct measurements of PTH are not available. These results suggest a new approach for the treatment of hypercalcemia of immobilization. As soon as hypercalcemia is diagnosed, the patient should have reduced intake of calcium and Vitamin D [27, 33, 34, 351. He should be given divided doses of oral steroids for a few days, preferably norethandrolone or prednisone, to reduce intestinal calcium absorption, and depress the effects of endogenous Vitamin D [35, 361; further treatment should aim toward decreasing calcium losses from bones. This was achieved in patient DR by treatment with anabolic steroids. The results obtained by us on the quadriplegic patient DR, and elsewhere on patients with bone fractures, indicate that such treatment, together with ambulation when feasible, will help overcome’ hypercalcemia complications until the patients recover normal renal function. SUMMARY

Episodes of unusual hypercalcemia have been described in three men, 15, 17, and 18 yr old, who had sustained physiologically complete transections of the spinal cord at the first, fourth, and fifth vertebral levels. The patients with injuries at C4 and C5 had been completely immobilized for 14 and 21 weeks when they developed hypercalcemia. The patient with the Cl injury had never been able to remain more than 1 hr in a wheelchair during the 16 months preceding the hypercalcemia episode. All three patients were in the post-onset period of increased bone resorption and at an age when bone turnover is increased. They had hypercalciuria when they developed a drastic reduction in renal and subsequently hypercalcemia. In the C5 patient short term treatments with anabolic steroids reduced the calcemia; his renal function improved and he has had no recurrence. In the Cl patient calcemia was reduced after removal of bladder and urethral calculi. In the C4 patient, treatment

Hypercalcemia

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89

with anabolic steroids was not successful in reducing the calcemia because of irreversible renal insufficiency. In two patients the levels of serum parathyroid hormone and calcitonin were evaluated. PTH was in the normal range and CT in the high normal range. REFERENCES

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