From the EM Model:
1.0 Signs, Symptoms, and Presentations.
As the population ages and an increasing number of patients undergo aggressive chemotherapy, radiation therapy, and bone marrow transplantation, an increasing number of emergency department visits will be for patients with cancer-related problems. Some complications represent an immediate threat to the patient’s life or functional capacity. Some are treatable in ways that are lifesaving or may improve quality of life in a significant way.
A 57-year-old man with a history of squamous cell carcinoma of the lung is brought in by his wife and eldest daughter because he has become unresponsive. He has been increasingly fatigued over the past 2 weeks but is now stuporous. Apart from some abdominal pain last week, he seems to have been pain-free. His wife reports that he has been chronically constipated and has been essentially bed-confined for several days. On examination he does not answer questions and seems oriented to name only.
Hypercalcemia occurs frequently in patients with advanced malignancy; it has been reported in 10% to 30% of patients with cancer at some time during their disease.1,2 The rate of rise of serum calcium concentration and the degree of hypercalcemia often determine symptoms and urgency of therapy.3 Patients with chronic hypercalcemia could be minimally symptomatic with levels of 15 mg/dL, while patients with acute hypercalcemia might present with coma with levels as low as 12 mg/dL. Acute hypercalcemia presents with central nervous system (CNS) effects ranging from mental status changes such as lethargy, paranoia, confusion, depression, and somnolence, to coma. Chronic hypercalcemia can present with constipation, polyuria, polydipsia, anorexia, nausea, memory loss, or a shortened QT interval on ECG.
Multiple factors may cause hypercalcemia of malignancy: elaboration of a parathyroid-hormone-related protein; local bone destruction; and tumor producing vitamin D-like substances.2
The most common malignancies associated with hypercalcemia are multiple myeloma, lung cancer, and breast cancer.1,4 These patients may have other electrolyte abnormalities caused by hypokalemia or dehydration. Serum phosphorus, albumin, and alkaline phosphatase should be measured as well. In patients with hypoalbuminemia, total serum calcium concentration can be normal while serum ionized calcium is elevated. The measured total serum calcium should be added to 0.8x(4.0-[albumin]) to correct for hypoalbuminemia.4 A serum calcium level above 14 mg/dL generally constitutes a medical emergency requiring treatment even if the patient appears minimally symptomatic.
What therapies are available in the emergency setting to treat hypercalcemia?
Therapy usually is initiated with isotonic saline intravenously. This restores blood volume and increases urinary calcium excretion. The aim is to maintain urine output in adults at 100 to 150 mL/hour. If the patient is fluid overloaded initially, a loop diuretic such as furosemide, which inhibits passive resorption of sodium, may be given. Patients should be monitored for hypomagnesemia, hypokalemia, and hypovolemia if a loop diuretic is given. Medications such as thiazide diuretics, which increase serum calcium, should be avoided.
Bisphosphonates inhibit calcium release by interfering with osteoclast-mediated bone resorption.5 Their maximum effect occurs in 2 to 4 days, and they are usually given with saline as above and possibly calcitonin.2,6 Pamidronate, 60 to 90 mg IV over several hours, or zoledronic acid, 4 mg IV over at least 15 minutes, are recommended doses.2 These medications can cause impaired renal function, hypophosphatemia, and osteonecrosis of the jaw.7
Calcitonin increases renal calcium excretion and decreases bone resorption. In intramuscular or subcutaneous doses of 4 IU/kg, salmon calcitonin works rapidly to lower serum calcium by 1 to 2 mg/dL within 4 to 6 hours.8 Glucocorticoids such as hydrocortisone, 100 mg IV every 6 hours, can be useful if the hypercalcemia is related to elevated levels of vitamin D, as in Hodgkin disease and some other lymphomas. Treatment of the underlying malignancy can control the hypercalcemia. As treatments of last resort, hemodialysis and peritoneal dialysis are effective therapies for hypercalcemia.9,10
Syndrome of Inappropriate Antidiuretic Hormone
In patients with cancer, the syndrome of inappropriate antidiuretic hormone (SIADH) is a paraneoplastic syndrome resulting from the secretion of arginine vasopressin (also known as antidiuretic hormone [ADH]). The increased production of ADH results in a characteristic constellation of chemical abnormalities including hypo-osmolality, hyponatremia, and an inappropriately elevated urine osmolality, generally above 100 mOsm/kg. Urine sodium is usually above 40 mEq/liter. Potassium levels are typically unaffected, and acid-base balance should be normal unless there are confounding factors.11,12
SIADH can result from many causes such as stroke, hemorrhage, infection, or other CNS disorders that can enhance ADH release. When due to ectopic production of ADH by a tumor, the cause is most often small cell carcinoma of the lung (and can occur in up to 10% of small cell carcinoma lung patients). However, other cancers of the head and neck, pancreas, and duodenum can be responsible.13,14
The increase in ADH is usually the result of secretion of vasopressin by certain tumors, resulting in increased water resorption in the collecting ducts of the kidneys and an increased loss of sodium in the urine. Some drugs can enhance ADH release or effect, notably the chemotherapy drugs vincristine and cyclophosphamide.15 Recent chemotherapeutic agents should be reviewed, along with a search for CNS disease or pulmonary disease, especially pneumonia, asthma, atelectasis, and pneumothorax.16 There should not be other reasons for normovolemic hyponatremia such as diuretic therapy, preexisting renal disease, adrenal insufficiency, or hypothyroidism.
The clinical findings of SIADH are primarily due to hyponatremia. In some cases, the patient will be asymptomatic. Patients could complain of fatigue, emesis, myalgias, and poor appetite. The extent of symptoms depends upon the rate of development of the hyponatremia and level of the serum sodium. As sodium levels fall below 100 mEq/L, patients can develop altered mental status, seizures, psychosis, lethargy, or coma.
What are the treatment options for SIADH?
Treatment of SIADH depends on the severity of symptoms and the acuity of onset of the hyponatremia. Mild degrees of hyponatremia may not necessitate any immediate treatment. Mild fluid restriction until followup may be appropriate. The underlying malignancy should be treated. In cases unresponsive to fluid restriction, therapy with demeclocycline may be started to induce a reversible nephrogenic diabetes insipidus (DI) to counteract the influence of the excess vasopressin. If the SIADH is due to chemotherapeutic agents, the patient’s therapeutic regimen might need to be altered.
In those patients with more severe degrees of hyponatremia or those with significant CNS symptoms related to their hyponatremia, normal saline can be initiated, or for those with seizures and altered mental status, 3% hypertonic saline (300 to 500 mL at a time over 3 to 4 hours) may be administered followed by furosemide to control intravascular volume.17 It is desirable to control the rate of correction of serum sodium by no more than 0.5 to 1 mEq/L/hour in order to prevent CNS disorders such as central pontine myelinolysis. These patients will require admission to an ICU.
Tumor Lysis Syndrome
Tumor lysis syndrome is an oncologic emergency caused by a massive destruction of cancer cells with ensuing release of nucleic acids, potassium, and phosphate into the circulation. Breakdown of the nucleic acids into uric acid leads to hyperuricemia. The precipitation of uric acid into the renal tubules can lead to renal failure. Tumor lysis syndrome most commonly occurs in cancer types with a high proliferative rate, large tumor burden, or those particularly sensitive to cytotoxic therapy. These include acute lymphoblastic leukemia and Burkitt or other non-Hodgkin lymphomas, but other tumor types have been implicated.
Specific laboratory abnormalities have been proposed in 2004 to define tumor lysis syndrome.18 These are an elevated uric acid, above 8 mg/dL; a serum potassium of more than 6 mmol/L or a 25% increase from baseline; serum phosphate elevated above 6.5 mg/dL in children or above 4.5 mg/dL in adults; or a depressed serum calcium, lower than 7 mg/dL or a 25% decrease from baseline. Serum lactate dehydrogenase is typically elevated.19
Clinical tumor lysis syndrome includes increased serum creatinine, cardiac dysrhythmia or sudden death, or a seizure. Rapid lysis of tumor cells can be associated with a large tumor burden, with cytotoxic chemotherapy, or radiation therapy in the setting of a malignancy with a high proliferative rate.
Hyperuricemia is a result of the breakdown of purine nucleic acids and must be addressed. Historically, the xanthine oxidase inhibitor allopurinol has been employed to lower the peak uric acid level and to prevent uric acid nephropathy.20 Allopurinol treatment leads to the accumulation of hypoxanthine and xanthine. Because xanthine is less soluble than uric acid, it can precipitate in the renal tubules. Urinary alkalinization increases the solubility of uric acid but not of xanthine. This therapy for tumor lysis syndrome has the potential to form xanthine crystals resulting in obstruction of renal tubules.18
Clinical manifestations of tumor lysis syndrome include nausea, vomiting, diarrhea, lethargy, anorexia, seizures, tetany, cramps, syncope, and sudden death. Urinalysis can show urate crystals. An ECG should be performed in patients with serious electrolyte abnormalities.
What is the appropriate treatment for tumor lysis syndrome?
Treatment includes aggressive intravenous hydration at approximately 2 to 3 liters/m2 per day to keep urine output at 80 to 100 mL/m2 per hour. Potassium should be withheld from hydration fluids initially because of the risk of hyperkalemia; calcium should be withheld because of the risk of calcium phosphate precipitation. Urinary alkalinization has the potential disadvantage of promoting calcium phosphate deposition in the kidney and elsewhere.21
The usual allopurinol dose in adults to address hyperuricemia is 100 mg/m2 every 8 hours, initiated 24 to 48 hours before chemotherapy and continued for up to 1 week.21 An alternative to allopurinol is rasburicase, a recombinant urate oxidase, which catalyzes the degradation of uric acid and rapidly lowers serum uric acid levels. It is effective in preventing and treating hyperuricemia and in treating tumor lysis syndrome.22 It may be given at a dose of 0.15 to 0.2 mg/kg in 50 mL of isotonic saline infused over 30 minutes once daily for 5 to 7 days but is FDA-approved only for pediatric patients. Serum levels of calcium, phosphate, uric acid, potassium, creatinine, and lactate dehydrogenase should be monitored.
Hyperphosphatemia can be treated with aluminum hydroxide, a phosphate binder, and restriction of phosphate intake. Dialysis can be necessary to treat persistent hyperphosphatemia, hypocalcemia, or low urine output. The best management is prevention via intravenous hydration and with hypouricemic agents.21
In the case of the 57-year-old man who is unresponsive, an intravenous line is established and a normal saline solution is infused. Because of his fatigue and constipation in the face of known lung cancer, a diagnosis of hypercalcemia is suspected, and serum electrolytes are drawn. His serum calcium level is measured at 15.2 mg/dL (3.8 mmol/L), and isotonic saline is started at 250 mL/hour. He is treated with intravenous furosemide and, after consultation with the oncologist on call, he is given 4 mg of zoledronic acid intravenously, as well as salmon calcitonin, 4 IU/kg intramuscularly every 12 hours. He becomes alert, and his serum calcium declines to 11.5 mg/dL 36 hours later. He is at baseline mental status 18 hours after admission.
Cancer remains the second leading cause of death in the United States. With an aging population, it is inevitable that the number of patients with acute illness and disability from malignancy will increase. The accurate diagnosis and treatment of metabolic emergencies in cancer patients can potentially forestall disability and enhance quality of life.
The management of tumor lysis syndrome centers on establishment of hydration and control of elevated uric acid and serum potassium.
The mainstays of emergency management of hypercalcemia from malignancy are hydration and the use of furosemide and bisphosphonates.
- Failure to aggressively investigate weakness and change in mental status in patients with established malignancy.
- Inadequate hydration or inadequate use of hypouricemic agents in a patient with leukemia or lymphoma who is on chemotherapy.
- Body JJ. Hypercalcemia of malignancy. Semin Nephrol. 2004;24:48-54.
- Stewart AF. Clinical practice associated with cancer. N Engl J Med. 2005;352:373-379.
- Bilezikian JP. Drug therapy: management of acute hypercalcemia. N Engl J Med. 1992;326:1196-1203.
- Halfdanarson TR, Hogan WJ, Moynihan TJ. Oncologic emergencies: diagnosis and treatment. Mayo Clin Proc. 2006;81(6):835-848.
- Rizzoli R, Thiébaud D, Bundred N, et al. Serum parathyroid hormone-related protein levels and response to bisphosphonate treatment of hypercalcemia of malignancy. J Clin Endocrinol Metab. 1999;84:3545-3550.
- Carano A, Teitelbaum SL, Konsek JD, et al. Bisphosphonates directly inhibit the bone resorption activity of isolated avian osteoclasts in vitro. J Clin Invest. 1990;85:456-461.
- Tanvetyanon T, Stiff PJ. Management of the adverse effects associated with intravenous bisphosphonates. Ann Oncol. 2006;17:897-907.
- Vaughn CB, Vaitkevicius VK. The effects of calcitonin in hypercalcemia in patients with malignancy. Cancer. 1974;34:1268-1271.
- Bockman R. The effects of gallium nitrate on bone resorption. Semin Oncol. 2003;30:5-12.
- Koo WS, Jeon DS, Ahn SJ, et al. Calcium-free hemodialysis for the management of hypercalcemia. Nephron. 1996;72:424-428.
- Rose BD, Post TW. Clinical Physiology of Acid-Base and Electrolyte Disorders. 5th ed. McGraw-Hill Companies: New York, NY; 2001:707-711.
- Ellison DH, Berl T. The syndrome of inappropriate diuresis. N Engl J Med. 2007;356:2064-2072.
- Johnson BE, Chute JP, Rushin J, et al. A prospective study of patients with lung cancer and hyponatremia of malignancy. Am J Respir Crit Care Med. 1997;156:1669-1678.
- Ferlito A, Rinaldo A, Devaney KO. Syndrome of inappropriate antidiuretic syndrome associated with head and neck cancers: review of the literature. Ann Otol Rhinol Laryngol. 1997;106:878-883.
- Bressler RB, Huston DP. Water intoxication following moderate-dose intravenous cyclophosphamids. Arch Intern Med. 1985;145:548-549.
- Anderson RJ. Hospital-associated hyponatremia. Kidney Int. 1986;29:1237-1247.
- Markman M. Common complications and emergencies associated with cancer and its therapy. Cleve Clin J Med. 1994;12:105-114.
- Cairo MS, Bishop M. Tumor lysis syndrome: new therapeutic strategies and classification. Br J Haematol. 2004;127:3-11.
- Montesinos P, Lorenzo I, Martin G, et al. Tumor lysis syndrome in patients with acute myeloid leukemia: identification of risk factors and development of a predictive model. Haematologica. 2008;93:67-74.
- Hande KR, Garrow GC. Acute tumor lysis syndrome in patients with high-grade non-Hodgkin’s lymphoma. Am J Med. 1993;94:133-139.
- Coiffier B, Altman A, Pui CH, et al. Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol. 2008;26:2767-2778.
- Hummel M, Reiter S, Adam K, et al. Effective treatment and prophylaxis of hyperuricemia and impaired renal function in tumor lysis syndrome with low doses of rasburicase. Eur J Haematol. 2008;80:331-336.
Contributors and Disclosures
Contributors: Dr. Jonathan M. Glauser wrote “Metabolic and Infectious Emergencies in Cancer Patients.” Dr. Glauser is vice chair of the Department of Emergency Medicine at the Cleveland Clinic Foundation and faculty member in the MetroHealth Case Western Reserve Emergency Medicine Residency Program in Cleveland, Ohio.
Dr. Robert C. Solomon is Medical Editor of ACEP News and editor of the “Focus On … Critical Decisions” series, core faculty in the emergency medicine residency at Allegheny General Hospital, Pittsburgh, Pennsylvania, and assistant professor in the Department of Emergency Medicine at Temple University School of Medicine, Philadelphia. Mary Anne Mitchell is an ACEP staff member who reviews and manages the ACEP “Focus On … Critical Decisions” series.
In accordance with the Accreditation Council for Continuing Medical Education (ACCME) Standards and American College of Emergency Physicians policy, all individuals in control of content must disclose to the program audience the existence of significant financial interests in or relationships with manufacturers of commercial products that might have a direct interest in the subject matter.
Dr. Glauser, Dr. Solomon, and Ms. Mitchell have disclosed that they have no significant relationships with or financial interests in any commercial companies that pertain to this article. There is no commercial support for this activity.
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