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Immobilization hypercalcemia treatment with pamidronate disodium after spinal cord injury
998
Immobilization Hypercalcemia Treatment With Pamidronate Disodium After Spinal Cord Injury Teresa L. Massagli, MD, Diana D. Cardenas, MD ABSTRACT. Massagli TL, Cardenas DD. Immobilization hypercalcemia treatment with pamidronate disodium after spinal cord injury. Arch Phys Med Rehabil 1999;80:998-1000.
Objective: To review the use of pamidronate to treat immobilization hypercalcemia after acute spinal cord injury (SCI) in 9 cases. Design: Retrospective case series. Setting: Two inpatient rehabilitation programs, one pediatric and one adult, in the Northwest Regional Spinal Cord Injury System. Patients: Patients with acute SCI who developed immobilization hypercalcemia that was treated with pamidronate. Results: Nine patients (7 men, 2 women), ages 15 to 41yrs, with SCI (8 tetraplegia, I paraplegia) were treated using pamidronate between 1994 and 1998. A single dose of 60mg of pamidronate resolved the hypercalcemia or its symptoms in 7 (78%) patients within days. One patient required a second dose (90rag) and one patient required three additional doses (the fourth at 90mg) to achieve resolution of the hypercalcemia or symptoms. Side effects were mild and included drug-related fever in one patient and transient asymptomatic hypocalcemia in four patients. Conclusion: Pamidronate was effective in treating immobilization hypercalcemia caused by SCI. Its advantages include its effectiveness, the duration of treatment, ease of administration, and elimination of the need for long-term intravenous saline or daily medications. © •999 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation MMOBILIZATION hypercalcemia is a complication that occur after acute spinal cord injury (SCI). ImmobilizaItioncan after SCI or other diseases triggers an increase in bone resorption and depressed parathyroid hormone that lasts weeks to months/,2 The calcium released from the bone resorption is excreted in the urine. Hypercalciuria develops within the first week after injury and continues for 6 months or longer, until the new steady state level of bone mineral density is reached. 3 Hypercalcemia results when the accelerated bone resorption exceeds the capacity of the kidneys to filter calcium. Hypercalcemia is seen most often in children, adolescents, and young adults, perhaps because of a higher rate of bone turnover as a
From the Department of Rehabilitation Medicine (Drs. Massagli, Cardenas) and Department of Pediatrics (Dr. Massagli), University of Washington; the Departments of Rehabilitation Medicine and Pediatrics, Children's Hospital and Regional Medical Center (Dr. Massagli), and the Department of Rehabilitation Medicine, University of Washington Medical Center (Dr. Cardenas), Seattle, WA. Submitted for publication October 7, 1998. Accepted in revised form March 20, 1999. No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the authors or upon any organization with which the authors are associated. Reprints are not available. © 1999 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation 0003-9993/99/8009-524053.00/0
Arch Phys Med Rehabil Vol 80, September 1999
result of growth. 4 It has been reported in 24% of children and young adults with SCI. 5 Hypercalcemia has its onset 2 weeks to 6 months after SCI, but most commonly 4 to 8 weeks after. 6,7 Its clinical manifestations can include fatigue, constipation, anorexia, nausea, vomiting, lethargy, polydipsia, polyuria, and intravascular volume depletion/ For patients without SCI, the most effective treatment for immobilization hypercalcemia is active weight-bearing. 9 Treatment regimens after SCI have included enhancing excretion of calcium via intravenous saline (0.9%), furosemide, and glucocorticoids, and reducing resorption via calcitonin, etidronate, and pamidronate. Intravenous saline can be inconvenient for long-term treatment of patients in an active rehabilitation program. Calcitonin may temporarily reduce serum calcium levels, but tachyphylaxis often develops within several days to 2 weeks. 4,8 The addition of etidronate to calcitonin has been used to reduce the serum calcium concentration in patients with 4610 Recently, pamidronate was immobilization hypercalcemia.,, reported to be helpful in normalizing the level of serum calcium in two patients with incomplete paraplegia who had failed treatment with calcitonin.ll Pamidronate disodium (aminohydroxypropylidene diphosphonate disodium) is a newer bisphosphonate approved for treatment of hypercalcemia of malignancy. It acts by inhibiting osteoclast-mediated resorption and by reducing osteoclast viability. It is administered as a single intravenous dose of 30 to 90mg over 4 to 24 hours, and it rapidly decreases the level of serum calcium within 3 days after administration. Serum calcium decreases to a nadir within 7 days and the effect may last several weeks or longer. Additional doses can be repeated if needed. 12It has been found effective in the treatment of cancer-related hypercalcemia in adults and children 13,14and in immobilization hypercalcemia in adults and children with SCI and other diseases. ~,15 We report our experience using pamidronate to treat hypercalcemia of immobilization following SCI. This study adds to the two cases of persons with incomplete paraplegia treated by Kedlaya's group. 11 Our cases included patients with tetraplegia as well as paraplegia. Some of our cases required multiple doses of pamidronate to resolve the hypercalcemia. We also describe the spectrum of observed side effects.
METHODS This was a retrospective study of all patients with immobilization hypercalcemia after SCI treated at two hospitals in the Northwest Regional Spinal Cord Injury System. The cases were identified by review of pharmacy records of prescription of pamidronate, or by recall of the investigators. Hospital records were screened for patient demographic data, symptoms and timing of onset of hypercalcemia, laboratory data, therapeutic interventions for the hypercalcemia, and side effects of pamidronate.
RESULTS We treated immobilization hypercalcemia with pamidronate in 9 patients (7 men, 2 women) between 1994 and 1998. Their ages, gender, and level of SCI are shown in table 1. Six of the 9
PAMIDRONATE TREATMENT OF IMMOBILIZATION HYPERCALCEMIA, Massagli
999
Table 1: Characteristics of Patients and Changes in Calcium After Pamidronate
Case
SCI Level
Age Sex
Onset of Hypercalcemia: DaysAfter SCI
Symptoms
1
C1,ASIAA
22
M
2
C2, A S I A A
18
F
3 4 5
C5, ASIA A C5, ASIAA C6, A S l A A
21 28 19
M M M
6
C6, A S l A A
41
F
7
C6, ASIA B
23
M
8
Left C4, right C7, ASIA D T12, ASIAC
15
M
Saline (57-59, 69), furosemide (69), etidronate (57139), calcitonin (101-154) 54 (asymptomatic Nausea, abdominal Saline (104-130), until day 104) discomfort furosemide (113130) 116 Nausea, anorexia -64 Nausea, dry heaves -60 Nausea, abdominal -discomfort 23 Nausea Saline (23-25), etidronate (25-72) 73 Malaise, vomiting Saline (73), etidronate (82-173, for heterotopic ossification) Irritability -23
16
M
26
9
57
Treatments Before Pamidronate (Days After SCI)
Nausea
Fatigue, nausea, irritability, anorexia
patients had American Spinal Injury Association (ASIA) A tetraplegia, one had ASIA B tetraplegia, one had ASIA D tetraplegia, and only one patient had paraplegia, ASIA C. Our patients were primarily teens or young adults (mean age, 22yrs; range, 15 to 41yrs). In most cases, the etiology of hypercalcemia was presumed to be immobilization, with no further workup done. Case 2 was confirmed to have a low parathyroid level of <9pg/mL (normal, 10 to 65pg/mL) and an elevated urinary calcium level of 508mg/24 hours (normal, 30 to 150mg/24 hours). Case 6, who was older than the usual age range for immobilization hypercalcemia after SCI, had mild preexisting renal insufficiency caused by lithium toxicity, with a creatinine clearance of 58mL/mirdl.73m 2 (normal, 80 to 125mL/ mirdl.73m2). The renal insufficiency was the most likely explanation for development of immobilization hypercalcemia after SCI in a person of this age. The patients had typical symptoms of hypercalcemia and the onset ranged from 3 to 16 weeks after injury (table 1). In 8 patients, ionized calcium levels were measured. In the other patient, serum calcium levels were measured and corrected for hypoalbuminemia. 8 The ionized calcium levels at the time of treatment ranged from 1.29 to 1.53mmol/L (normal, 1.16 to 1.27), and the corrected serum calcium was 12.7mg/dL (normal, 8.7 to 10.7). Pamidronate was the initial treatment used for 6 patients (cases 3, 4, 5, 7, 8, 9), and two of these patients received simultaneous hydration with intravenous saline (cases 7, 9). Cases 1, 2, and 6 received other medications before the use of pamidronate, including furosemide, etidronate, or intranasal calcitonin. The timing of these interventions is reported in table 1. One patient, case 7, was also treated with etidronate for heterotopic ossification, beginning 9 days after the first use of pamidronate and extending for a 13-week course. None of the other cases received any other medications that would interact with calcium metabolism. All 9 patients received an initial dose of 60rag of pamidro-
Saline (26-28)
Calcium Nadir After Pamidronate Day After SCl Calcium (Days After Pamidronate Before Pamidronate Administered Pamidronate to Nadir) 139 147 (90mg)
1.32mmol/L 1.32mmol/L (8) 1.32mmol/L 1.20mmol/L (7)
130
1.53mmol/L
118 67 60
1.31mmol/L 1.13mmol/L (15) 1.29mmol/L 1.18mmol/L (8) 1.33mmol/L 1.24mmol/L (10)
72
1.43mmol/L 1.34mmol/L (13)
73 87 91 98 (90mg) 23
1.35mmol/L 1.21mmol/L (9) 1.35mmol/L 1.29mmol/L (4) 1.29mmol/L 1.39mmol/L (6) 1.39mmol/L 1.32mmol/L (8) 1.38mmol/L 1.00mmol/L (7)
27
12.7mg/dL
1.11mmol/L (6)
7.6mg/dL (7)
hate, and this was sufficient to treat the hypercalcemia in 7 patients. Cases 4 and 9 were the only patients for whom daily calcium levels were available and both showed normalization within 2 days. Two patients (cases 1, 7) required additional doses to resolve the hypercalcemia or its symptoms. In cases 6 and 7, the ionized calcium did not completely normalize, but the patients became and remained asymptomatic. Table 1 describes the typical changes in calcium before and after use of pamidronate. The nadir for most patients was between 6 and 8 days, but for case 3 the nadir did not occur until 15 days. Because of the retrospective nature of the study, intervening data were not available for cases 5 and 6 before days 10 and 13 respectively. One patient (case 9) experienced transient drug-related fever on the second and third days after treatment. In four patients (cases 2, 3, 8, 9), the serum or ionized calcium level decreased into the hypocalcemic range after treatment, but the patients were asymptomatic. Three patients (cases 1, 4, 9) also had transient asymptomatic hypophosphatemia. DISCUSSION The initial treatment of immobilization hypercalcemia should include hydration with normal saline to expand intracellular volume and to immediately increase renal clearance of calcium. A variety of medications can be considered simultaneously with hydration. Furosemide can be added to protect against volume overload and to inhibit calcium reabsorption by the kidney. Although not specifically reported for patients with SCI, the combination of saline and furosemide decreases calcium concentrations by 2 to 3mg/dL in cancer-related hypercalcemia. It is most effective for mild to moderate hypercalcemia (10.4 to 12mg/dL), but is insufficient for severe hypercalcemia. ~°,1z13 Hypercalcemia after SCI may not reach the life-threatening values seen in cancer-related hypercalcemia, but the duration of the problem makes use of intravenous saline inconvenient for Arch Phys Med Rehabil Vol 80, September 1999
1000
PAMIDRONATE TREATMENT OF IMMOBILIZATION HYPERCALCEMIA, Massagli
patients and therapists. It can be cumbersome to manage intravenous equipment during therapy sessions, and fluid administration can disrupt catheterization schedules. Although prednisone can also enhance urinary calcium excretion 13 and has been used to treat immobilization hypercalcemia after SCI, the hypercalcemia recurs after discontinuation of prednisone. 7 Inhibitors of bone resorption have been added to hydration in the treatment of hypercalcemia. Calcitonin acts by inhibiting osteoclastic bone resorption and increasing renal excretion of calcium. Calcitonin is administered subcutaneously or intramuscularly and may cause nausea, abdominal pain, flushing, or systemic allergic reaction. 8 The intranasal form of calcitonin is currently indicated only for treatment of postmenopausal osteoporosis, although we did try it in case 1. Calcitonin has a rapid onset of action, within a few hours, but its use is limited by tachyphylaxis, usually within days. 4,8,13 Bisphosphonates also act by inhibiting osteoclastic activity. Etidronate disodium and pamidronate disodium are currently available in the US for treatment of hypercalcemia. Etidronate can be administered intravenously or orally and has been demonstrated to be effective in the treatment of cancer-related hypercalcemia. 13 The adverse effects of etidronate can include renal insufficiency, elevation of the serum phosphorous concentration, hypocalcemia, transient fever, rash, and nausea. The combination of calcitonin and etidronate has been used in patients with SCI to treat hypercalcemia and eliminate the need for intravenous lines, hydration, and an indwelling urinary catheter. Calcitonin was used for 3 to 7 days until the calcium level normalized and concurrent therapy with etidronate was continued for several months with good success. 6,1° Two of our subjects received etidronate (cases 6, 7), and one received calcitonin with etidronate (case 1), with less favorable results than noted in previous studies. In comparative studies in patients with cancer-related hypercalcemia, pamidronate was more effective in reducing hypercalcemia than etidronate. 12,13,16 We found pamidronate to be effective in reducing hypercalcemia in three patients who received prior or concomitant therapy with etidronate. The action of pamidronate on osteoclast viability may account for its greater efficacy and longer duration of action. Pamidronate is poorly absorbed after oral administration. It accumulates selectively in the skeleton, liver, and spleen and is eliminated unmetabolized in the urine. In contrast to etidronate, pamidronate does not have any detrimental effect on bone growth or mineralization. 12 Adverse effects can include transient fever in 20% of patients, occurring within 3 days of administration, as well as malaise, myalgia, transient leukopenia, and lymphopenia. The self-limited pyrexia, leukopenia, and lymphopenia occur only on initial exposure to pamidronate. Although serum calcium levels frequently decrease below normal, clinically significant hypocalcemia is rare. 12 Transient hypophosphatemia occurs in 10% to 30% of patients, is usually asymptomatic, and results from decreased phosphate mobilization from bone. 12,16 In patients with cancer-related hypercalcemia, mild increases in serum creatinine levels have been reported after both pamidronate and etidronate. ~6 In patients with underlying renal failure, pamidronate use did not worsen renal function. ~7 We agree with Kedlaya's initial report H that pamidronate adds a new regimen for treatment of immobilization hypercalcemia after SCI and has some distinct advantages over other options. A reasonable approach is to restore hydration (and enhance renal excretion) with saline and administer pamidronate at the same time. When the pamidronate takes effect 2 to 3 days later, the intravenous fluids can be discontinued if the patient is well hydrated. Furosemide or other loop diuretics Arch Phys Med Rehabil Vol 80, September 1999
should not be used until volume repletion is achieved and may not be needed unless fluid overload is a risk. The duration of effect of pamidronate can be several weeks, and repeat doses can be administered as needed. Further research may help to clarify why some patients have complete resolution of hypercalcemia while others require repeated doses before normalization is maintained. CONCLUSION We believe the effectiveness, duration of treatment, and ease of administration of pamidronate appear promising for use in patients with immobilization hypercalcemia after SCI. The use of pamidronate to treat immobilization hypercalcemia should result in less interruption to rehabilitation. Activities, including transfers, mobility, and bladder management, are easier to perform when patients do not need intravenous catheters and indwelling urinary drainage to handle the large volume of fluid excreted. Our patients had an excellent response to treatment of immobilization hypercalcemia using pamidronate with few complications. In 78% of our patients, only one treatment was needed. Only one patient had transient pyrexia lasting 48 hours. The patients with transient hypophosphatemia or hypocalcemia were asymptomatic. References
1. Stewart AF, Adler M, Byers CM, Segre GV, Broadus AE. Calcium homeostasis in immobilization: an example of resorptive hypercalciuria. N Engl J Med 1982;306:1136-40. 2. Gallacher SJ, Ralston SH, Dryburgh FJ, Logue FC, Allam BE Boyce FEet al. hnmobilization related hypercalcemia--apossible novel mechanism and response to pamidronate. Postgrad Med J 1990;66:918-22. 3. Naftchi NE, Viau AT, Sell GH, Lowman EW. Mineral metabolism in spinal cord injury. Arch Phys Med Rehabil 1980;61:139-42. 4. Latham BB, Osterman J, Lin T, Nankin HR. Immobilization hypercalcemia in an adult patient with pancreatitis and sepsis: case report. J South Carolina Med Assoc 1992;88:570-2. 5. Tori JA, Hill LL. Hypercalcemia in children with spinal cord injury. Arch Phys Med Rehabil 1978;59:443-7. 6. Merli GJ, McElwain GE, Adler AG, Martin JH, Roberts JD, Schnall B, et al. Immobilizationhypercalcemia in acute spinal cord injury treated with etidronate. Arch Intern Med 1984; 144:1286-8. 7. Maynard FM, Imal K. Immobilization hypercalcernia in spinal cord injury. Arch Phys Med Rehabil 1977;58:16-24. 8. Nussbaum SR. Pathophysiology and management of severe hypercalcemia. Endocrinol Metab Clin North Am 1993;22:343-62. 9. van Zuiden L, Anquist KA, Schachar N, Kastelen N. Immobilization hypercalcemia. Can J Surg 1982;25:646-49. 10. Meythaler JM, Tuel SM, Cross LL. Successful treatment of immobilization hypercalcemia using calcitonin and etidronate. Arch Phys Med Rehabil 1993;74:316-9. 11. Kedlaya D, Brandstater ME, Lee JK. Immobilization hypercalcemia in incomplete paraplegia: successful treatment with pamidrohate. Arch Phys Med Rehabil 1998;79:222-5. 12. Fitton A, McTavish D. Pamidronate: a review of its pharmacological properties and therapeutic efficacy in resorptive bone disease. Drugs 1991;41:289-318. 13. Chisholm MA, Mulloy AL, Taylor AT. Acute management of cancer-related hypercalcemia. Ann Pharmacother 1996;30:507-13. 14. Young G, Shende A. Use of pamidxonate in the management of acute cancer-related hypercalcemia in children. Med Pediatr Oncol 1998;30:117-2l. 15. Profumo RJ, Reese JC, Foy TM, Garibaldi LR, Kane RE. Severe immobilization induced hypercalcemia in a child after liver transplantation successfully treated with pamidronate. Transplantation 1994;57:301-3. 16. Gucalp R, Ritch R Wiernik PH, Sarma PR, Keller A, Richman SP, et al. Comparative study of pamidronate disodium and etidronate disodium in the treatment of cancer-related hypercalcemia. J Clin Oncol 1992;10:134-42. 17. Machado LE, Flombaum CD. Safety of pamidronate in patients with renal failure and hypercalcemia. Clin Nephrol 1996;45:175-9.
Immobilization Hypercalcemia Treatment With Pamidronate Disodium After Spinal Cord Injury Teresa L. Massagli, MD, Diana D. Cardenas, MD ABSTRACT. Massagli TL, Cardenas DD. Immobilization hypercalcemia treatment with pamidronate disodium after spinal cord injury. Arch Phys Med Rehabil 1999;80:998-1000.
Objective: To review the use of pamidronate to treat immobilization hypercalcemia after acute spinal cord injury (SCI) in 9 cases. Design: Retrospective case series. Setting: Two inpatient rehabilitation programs, one pediatric and one adult, in the Northwest Regional Spinal Cord Injury System. Patients: Patients with acute SCI who developed immobilization hypercalcemia that was treated with pamidronate. Results: Nine patients (7 men, 2 women), ages 15 to 41yrs, with SCI (8 tetraplegia, I paraplegia) were treated using pamidronate between 1994 and 1998. A single dose of 60mg of pamidronate resolved the hypercalcemia or its symptoms in 7 (78%) patients within days. One patient required a second dose (90rag) and one patient required three additional doses (the fourth at 90mg) to achieve resolution of the hypercalcemia or symptoms. Side effects were mild and included drug-related fever in one patient and transient asymptomatic hypocalcemia in four patients. Conclusion: Pamidronate was effective in treating immobilization hypercalcemia caused by SCI. Its advantages include its effectiveness, the duration of treatment, ease of administration, and elimination of the need for long-term intravenous saline or daily medications. © •999 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation MMOBILIZATION hypercalcemia is a complication that occur after acute spinal cord injury (SCI). ImmobilizaItioncan after SCI or other diseases triggers an increase in bone resorption and depressed parathyroid hormone that lasts weeks to months/,2 The calcium released from the bone resorption is excreted in the urine. Hypercalciuria develops within the first week after injury and continues for 6 months or longer, until the new steady state level of bone mineral density is reached. 3 Hypercalcemia results when the accelerated bone resorption exceeds the capacity of the kidneys to filter calcium. Hypercalcemia is seen most often in children, adolescents, and young adults, perhaps because of a higher rate of bone turnover as a
From the Department of Rehabilitation Medicine (Drs. Massagli, Cardenas) and Department of Pediatrics (Dr. Massagli), University of Washington; the Departments of Rehabilitation Medicine and Pediatrics, Children's Hospital and Regional Medical Center (Dr. Massagli), and the Department of Rehabilitation Medicine, University of Washington Medical Center (Dr. Cardenas), Seattle, WA. Submitted for publication October 7, 1998. Accepted in revised form March 20, 1999. No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the authors or upon any organization with which the authors are associated. Reprints are not available. © 1999 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation 0003-9993/99/8009-524053.00/0
Arch Phys Med Rehabil Vol 80, September 1999
result of growth. 4 It has been reported in 24% of children and young adults with SCI. 5 Hypercalcemia has its onset 2 weeks to 6 months after SCI, but most commonly 4 to 8 weeks after. 6,7 Its clinical manifestations can include fatigue, constipation, anorexia, nausea, vomiting, lethargy, polydipsia, polyuria, and intravascular volume depletion/ For patients without SCI, the most effective treatment for immobilization hypercalcemia is active weight-bearing. 9 Treatment regimens after SCI have included enhancing excretion of calcium via intravenous saline (0.9%), furosemide, and glucocorticoids, and reducing resorption via calcitonin, etidronate, and pamidronate. Intravenous saline can be inconvenient for long-term treatment of patients in an active rehabilitation program. Calcitonin may temporarily reduce serum calcium levels, but tachyphylaxis often develops within several days to 2 weeks. 4,8 The addition of etidronate to calcitonin has been used to reduce the serum calcium concentration in patients with 4610 Recently, pamidronate was immobilization hypercalcemia.,, reported to be helpful in normalizing the level of serum calcium in two patients with incomplete paraplegia who had failed treatment with calcitonin.ll Pamidronate disodium (aminohydroxypropylidene diphosphonate disodium) is a newer bisphosphonate approved for treatment of hypercalcemia of malignancy. It acts by inhibiting osteoclast-mediated resorption and by reducing osteoclast viability. It is administered as a single intravenous dose of 30 to 90mg over 4 to 24 hours, and it rapidly decreases the level of serum calcium within 3 days after administration. Serum calcium decreases to a nadir within 7 days and the effect may last several weeks or longer. Additional doses can be repeated if needed. 12It has been found effective in the treatment of cancer-related hypercalcemia in adults and children 13,14and in immobilization hypercalcemia in adults and children with SCI and other diseases. ~,15 We report our experience using pamidronate to treat hypercalcemia of immobilization following SCI. This study adds to the two cases of persons with incomplete paraplegia treated by Kedlaya's group. 11 Our cases included patients with tetraplegia as well as paraplegia. Some of our cases required multiple doses of pamidronate to resolve the hypercalcemia. We also describe the spectrum of observed side effects.
METHODS This was a retrospective study of all patients with immobilization hypercalcemia after SCI treated at two hospitals in the Northwest Regional Spinal Cord Injury System. The cases were identified by review of pharmacy records of prescription of pamidronate, or by recall of the investigators. Hospital records were screened for patient demographic data, symptoms and timing of onset of hypercalcemia, laboratory data, therapeutic interventions for the hypercalcemia, and side effects of pamidronate.
RESULTS We treated immobilization hypercalcemia with pamidronate in 9 patients (7 men, 2 women) between 1994 and 1998. Their ages, gender, and level of SCI are shown in table 1. Six of the 9
PAMIDRONATE TREATMENT OF IMMOBILIZATION HYPERCALCEMIA, Massagli
999
Table 1: Characteristics of Patients and Changes in Calcium After Pamidronate
Case
SCI Level
Age Sex
Onset of Hypercalcemia: DaysAfter SCI
Symptoms
1
C1,ASIAA
22
M
2
C2, A S I A A
18
F
3 4 5
C5, ASIA A C5, ASIAA C6, A S l A A
21 28 19
M M M
6
C6, A S l A A
41
F
7
C6, ASIA B
23
M
8
Left C4, right C7, ASIA D T12, ASIAC
15
M
Saline (57-59, 69), furosemide (69), etidronate (57139), calcitonin (101-154) 54 (asymptomatic Nausea, abdominal Saline (104-130), until day 104) discomfort furosemide (113130) 116 Nausea, anorexia -64 Nausea, dry heaves -60 Nausea, abdominal -discomfort 23 Nausea Saline (23-25), etidronate (25-72) 73 Malaise, vomiting Saline (73), etidronate (82-173, for heterotopic ossification) Irritability -23
16
M
26
9
57
Treatments Before Pamidronate (Days After SCI)
Nausea
Fatigue, nausea, irritability, anorexia
patients had American Spinal Injury Association (ASIA) A tetraplegia, one had ASIA B tetraplegia, one had ASIA D tetraplegia, and only one patient had paraplegia, ASIA C. Our patients were primarily teens or young adults (mean age, 22yrs; range, 15 to 41yrs). In most cases, the etiology of hypercalcemia was presumed to be immobilization, with no further workup done. Case 2 was confirmed to have a low parathyroid level of <9pg/mL (normal, 10 to 65pg/mL) and an elevated urinary calcium level of 508mg/24 hours (normal, 30 to 150mg/24 hours). Case 6, who was older than the usual age range for immobilization hypercalcemia after SCI, had mild preexisting renal insufficiency caused by lithium toxicity, with a creatinine clearance of 58mL/mirdl.73m 2 (normal, 80 to 125mL/ mirdl.73m2). The renal insufficiency was the most likely explanation for development of immobilization hypercalcemia after SCI in a person of this age. The patients had typical symptoms of hypercalcemia and the onset ranged from 3 to 16 weeks after injury (table 1). In 8 patients, ionized calcium levels were measured. In the other patient, serum calcium levels were measured and corrected for hypoalbuminemia. 8 The ionized calcium levels at the time of treatment ranged from 1.29 to 1.53mmol/L (normal, 1.16 to 1.27), and the corrected serum calcium was 12.7mg/dL (normal, 8.7 to 10.7). Pamidronate was the initial treatment used for 6 patients (cases 3, 4, 5, 7, 8, 9), and two of these patients received simultaneous hydration with intravenous saline (cases 7, 9). Cases 1, 2, and 6 received other medications before the use of pamidronate, including furosemide, etidronate, or intranasal calcitonin. The timing of these interventions is reported in table 1. One patient, case 7, was also treated with etidronate for heterotopic ossification, beginning 9 days after the first use of pamidronate and extending for a 13-week course. None of the other cases received any other medications that would interact with calcium metabolism. All 9 patients received an initial dose of 60rag of pamidro-
Saline (26-28)
Calcium Nadir After Pamidronate Day After SCl Calcium (Days After Pamidronate Before Pamidronate Administered Pamidronate to Nadir) 139 147 (90mg)
1.32mmol/L 1.32mmol/L (8) 1.32mmol/L 1.20mmol/L (7)
130
1.53mmol/L
118 67 60
1.31mmol/L 1.13mmol/L (15) 1.29mmol/L 1.18mmol/L (8) 1.33mmol/L 1.24mmol/L (10)
72
1.43mmol/L 1.34mmol/L (13)
73 87 91 98 (90mg) 23
1.35mmol/L 1.21mmol/L (9) 1.35mmol/L 1.29mmol/L (4) 1.29mmol/L 1.39mmol/L (6) 1.39mmol/L 1.32mmol/L (8) 1.38mmol/L 1.00mmol/L (7)
27
12.7mg/dL
1.11mmol/L (6)
7.6mg/dL (7)
hate, and this was sufficient to treat the hypercalcemia in 7 patients. Cases 4 and 9 were the only patients for whom daily calcium levels were available and both showed normalization within 2 days. Two patients (cases 1, 7) required additional doses to resolve the hypercalcemia or its symptoms. In cases 6 and 7, the ionized calcium did not completely normalize, but the patients became and remained asymptomatic. Table 1 describes the typical changes in calcium before and after use of pamidronate. The nadir for most patients was between 6 and 8 days, but for case 3 the nadir did not occur until 15 days. Because of the retrospective nature of the study, intervening data were not available for cases 5 and 6 before days 10 and 13 respectively. One patient (case 9) experienced transient drug-related fever on the second and third days after treatment. In four patients (cases 2, 3, 8, 9), the serum or ionized calcium level decreased into the hypocalcemic range after treatment, but the patients were asymptomatic. Three patients (cases 1, 4, 9) also had transient asymptomatic hypophosphatemia. DISCUSSION The initial treatment of immobilization hypercalcemia should include hydration with normal saline to expand intracellular volume and to immediately increase renal clearance of calcium. A variety of medications can be considered simultaneously with hydration. Furosemide can be added to protect against volume overload and to inhibit calcium reabsorption by the kidney. Although not specifically reported for patients with SCI, the combination of saline and furosemide decreases calcium concentrations by 2 to 3mg/dL in cancer-related hypercalcemia. It is most effective for mild to moderate hypercalcemia (10.4 to 12mg/dL), but is insufficient for severe hypercalcemia. ~°,1z13 Hypercalcemia after SCI may not reach the life-threatening values seen in cancer-related hypercalcemia, but the duration of the problem makes use of intravenous saline inconvenient for Arch Phys Med Rehabil Vol 80, September 1999
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PAMIDRONATE TREATMENT OF IMMOBILIZATION HYPERCALCEMIA, Massagli
patients and therapists. It can be cumbersome to manage intravenous equipment during therapy sessions, and fluid administration can disrupt catheterization schedules. Although prednisone can also enhance urinary calcium excretion 13 and has been used to treat immobilization hypercalcemia after SCI, the hypercalcemia recurs after discontinuation of prednisone. 7 Inhibitors of bone resorption have been added to hydration in the treatment of hypercalcemia. Calcitonin acts by inhibiting osteoclastic bone resorption and increasing renal excretion of calcium. Calcitonin is administered subcutaneously or intramuscularly and may cause nausea, abdominal pain, flushing, or systemic allergic reaction. 8 The intranasal form of calcitonin is currently indicated only for treatment of postmenopausal osteoporosis, although we did try it in case 1. Calcitonin has a rapid onset of action, within a few hours, but its use is limited by tachyphylaxis, usually within days. 4,8,13 Bisphosphonates also act by inhibiting osteoclastic activity. Etidronate disodium and pamidronate disodium are currently available in the US for treatment of hypercalcemia. Etidronate can be administered intravenously or orally and has been demonstrated to be effective in the treatment of cancer-related hypercalcemia. 13 The adverse effects of etidronate can include renal insufficiency, elevation of the serum phosphorous concentration, hypocalcemia, transient fever, rash, and nausea. The combination of calcitonin and etidronate has been used in patients with SCI to treat hypercalcemia and eliminate the need for intravenous lines, hydration, and an indwelling urinary catheter. Calcitonin was used for 3 to 7 days until the calcium level normalized and concurrent therapy with etidronate was continued for several months with good success. 6,1° Two of our subjects received etidronate (cases 6, 7), and one received calcitonin with etidronate (case 1), with less favorable results than noted in previous studies. In comparative studies in patients with cancer-related hypercalcemia, pamidronate was more effective in reducing hypercalcemia than etidronate. 12,13,16 We found pamidronate to be effective in reducing hypercalcemia in three patients who received prior or concomitant therapy with etidronate. The action of pamidronate on osteoclast viability may account for its greater efficacy and longer duration of action. Pamidronate is poorly absorbed after oral administration. It accumulates selectively in the skeleton, liver, and spleen and is eliminated unmetabolized in the urine. In contrast to etidronate, pamidronate does not have any detrimental effect on bone growth or mineralization. 12 Adverse effects can include transient fever in 20% of patients, occurring within 3 days of administration, as well as malaise, myalgia, transient leukopenia, and lymphopenia. The self-limited pyrexia, leukopenia, and lymphopenia occur only on initial exposure to pamidronate. Although serum calcium levels frequently decrease below normal, clinically significant hypocalcemia is rare. 12 Transient hypophosphatemia occurs in 10% to 30% of patients, is usually asymptomatic, and results from decreased phosphate mobilization from bone. 12,16 In patients with cancer-related hypercalcemia, mild increases in serum creatinine levels have been reported after both pamidronate and etidronate. ~6 In patients with underlying renal failure, pamidronate use did not worsen renal function. ~7 We agree with Kedlaya's initial report H that pamidronate adds a new regimen for treatment of immobilization hypercalcemia after SCI and has some distinct advantages over other options. A reasonable approach is to restore hydration (and enhance renal excretion) with saline and administer pamidronate at the same time. When the pamidronate takes effect 2 to 3 days later, the intravenous fluids can be discontinued if the patient is well hydrated. Furosemide or other loop diuretics Arch Phys Med Rehabil Vol 80, September 1999
should not be used until volume repletion is achieved and may not be needed unless fluid overload is a risk. The duration of effect of pamidronate can be several weeks, and repeat doses can be administered as needed. Further research may help to clarify why some patients have complete resolution of hypercalcemia while others require repeated doses before normalization is maintained. CONCLUSION We believe the effectiveness, duration of treatment, and ease of administration of pamidronate appear promising for use in patients with immobilization hypercalcemia after SCI. The use of pamidronate to treat immobilization hypercalcemia should result in less interruption to rehabilitation. Activities, including transfers, mobility, and bladder management, are easier to perform when patients do not need intravenous catheters and indwelling urinary drainage to handle the large volume of fluid excreted. Our patients had an excellent response to treatment of immobilization hypercalcemia using pamidronate with few complications. In 78% of our patients, only one treatment was needed. Only one patient had transient pyrexia lasting 48 hours. The patients with transient hypophosphatemia or hypocalcemia were asymptomatic. References
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