eMedicine Specialties > Pediatrics: General Medicine > Oncology

Tumor Lysis Syndrome

Alan K Ikeda, MD, Assistant Professor, Department of Pediatrics, Division of Hematology and Oncology, David Geffen School of Medicine at UCLA; Assistant Director of Pediatric Blood and Marrow Transplantation, Mattel Children's Hospital
Kathleen Sakamoto, MD, Professor, Department of Pediatrics, Division of Hematology-Oncology and Pathology and Laboratory Medicine, Mattel Children's Hospital, David Geffen School of Medicine, University of California at Los Angeles; Koyamangalath Krishnan, MD, FRCP, FACP, Dishner Endowed Chair of Excellence in Medicine, Professor of Medicine and Chief of Hematology-Oncology, Program Director, Hematology-Oncology Fellowship, James H Quillen College of Medicine at East Tennessee State University; Amit P Sarnaik, MD, Staff Physician, Department of Pediatrics, Wayne State University and Children's Hospital of Michigan

Updated: Sep 26, 2008

Introduction

Background

Tumor lysis syndrome (TLS) is a very serious and sometimes life-threatening complication of cancer therapy. It can be defined as a constellation of metabolic abnormalities that results from spontaneous or treatment-related tumor necrosis. The metabolic abnormalities observed in patients with tumor lysis syndrome include hyperkalemia, hyperuricemia, and hyperphosphatemia with secondary hypocalcemia. These can lead to acute renal failure (ARF). The main principles of tumor lysis syndrome are the identification of high-risk patients, initiation of preventive therapy, and early recognition and intervention of its complications.

Pathophysiology

Tumor lysis syndrome can be precipitated before the initiation of therapy and usually lasts as long as 3 days after the start of chemotherapy, especially with tumors that have a high growth fraction and high sensitivity to chemotherapy. Burkitt lymphoma and T-cell acute lymphoblastic leukemia are most frequently associated with this complication.

Tumor lysis syndrome has also been observed in association with solid tumors, such as hepatoblastoma and stage IV neuroblastoma. From a non-oncologic perspective, intraoperative cardiac arrest secondary to tumor lysis syndrome has been reported after a preoperative splenic artery embolization.¹ Although no tumor was present, the patient was noted to have a clinical presentation similar to tumor lysis syndrome, which included hyperkalemia and hyperphosphatemia with ARF and cardiac arrhythmia. No source for the hyperkalemia was identified other than tissue lysis. 

In 1980, Cohen et al identified risk factors that predispose patients to metabolic derangements, such as bulky abdominal disease, elevated pretreatment uric acid level, elevated lactate dehydrogenase level, and poor urine output.² Lysis of tumor cells results in rapid release of potassium, purine nucleic acids, and phosphorus, which leads to hyperkalemia, hyperuricemia, and hyperphosphatemia with secondary hypocalcemia. These metabolic abnormalities can subsequently lead to ARF. These complications may result in multiple organ failure and death.

The kidney is the primary organ involved in the clearance of uric acid, phosphorus, and potassium. Uric acid (pKa = 5.4) is soluble at physiologic pH, but can precipitate in the acidic environment of renal tubules. Hemoconcentration and decreased tubular flow rate within the renal system also contributes to the precipitation of uric acid. Precipitation of uric acid crystals within the collecting ducts and ureters can cause an obstructive uropathy.

The phosphorus content of the lymphoblasts is 3-4 times the content of normal lymphocytes. When these cells lyse as a result of therapy or spontaneous apoptosis, the serum phosphorous rises. The elevated phosphorous can spurn nephrocalcinosis from calcium phosphate crystal precipitation. This occurs in the renal tubules and microvasculature as the in vivo calcium-phosphorus solubility product exceeds 60-70 because of hyperphosphatemia and may be worsened with iatrogenic alkalinization. Symptomatic hypocalcemia may result from hyperphosphatemia.

Frequency

International

Incidence is unknown. Prevalence varies among different malignancies; bulky, aggressive, and treatment-sensitive tumors are associated with higher frequencies of tumor lysis syndrome. In studies of frequency in patients with intermediate-grade or high-grade non-Hodgkin lymphomas, laboratory evidence of tumor lysis syndrome (42%) occurred much more frequently than the symptomatic clinical syndrome (6%).³ In children with acute leukemia receiving induction chemotherapy, silent laboratory evidence of tumor lysis syndrome occurred in 70% of cases, but clinically significant tumor lysis syndrome occurred in only 3%. As advances are made in cancer treatment and more aggressive regimens become in favor, the incidence of tumor lysis syndrome may increase and the syndrome may emerge in a broader spectrum of malignancies.

Mortality/Morbidity

• ARF: Renal tubule precipitation of uric acid, calcium phosphate, or hypoxanthine causes ARF. This often is oliguric (<400 mL/d) in nature, leading to volume overload and complications of hypertension and pulmonary edema. High BUN levels due to increased protein catabolism and renal impairment can be severe enough to result in pericarditis, platelet dysfunction, and defective cellular immunity. Renal dysfunction can be severe enough to require dialysis, but with prompt supportive measures it usually is reversible.
• Cardiac arrhythmia: Hyperkalemia can lead to ECG changes and life-threatening cardiac arrhythmia, including asystole. Severe potassium elevation can cause ECG alterations such as peaked T waves, flattened P waves, prolonged PR interval, widened QRS complexes, deep S wave, and sine waves. Hypocalcemia can lead to QT interval lengthening, which predisposes patients to ventricular arrhythmia.
• Metabolic acidosis: ARF and liberation of large amounts of endogenous intracellular acids from cellular catabolism result in acidemia. This acidemia causes a decrease in serum bicarbonate concentration and a high anion gap acidosis. Acidemic states can worsen the many electrolyte imbalances already present in tumor lysis syndrome; intracellular uptake of potassium is hindered, uric acid solubility is decreased, and extracellular shift of phosphate is promoted. Calcium phosphate solubility, however, improves in acidic conditions. The myriad of metabolic disorders must be assessed and rapidly treated. Proper fluid management, alkalinization of the urine, correction of acidosis, and attention to infections are the mainstays of therapy.

Race

No race predilection is noted.

Sex

No sex predilection is noted.

Age

Although tumor lysis syndrome occurs in all age groups, advanced age is associated with more frequent underlying impaired renal function, which may, in turn, predispose patients to clinically significant tumor lysis syndrome secondary to decreased ability to dispose of tumor lysis byproducts.

Clinical

History

Pertinent historic information in tumor lysis syndrome (TLS) should include the following:

• Time of onset of symptoms of malignancy
• Abdominal pain and distension
• Urinary symptoms, such as dysuria, oliguria, flank pain, and hematuria
• Occurrence of any symptoms of hypocalcemia, such as anorexia, vomiting, cramps, seizures, spasms, altered mental status, and tetany
• Symptoms of hyperkalemia, such as weakness and paralysis

Physical

Symptoms reflect the severity of underlying metabolic abnormalities.

• Hyperkalemia can cause paresthesia, weakness, and fatal cardiac arrhythmias.
• Uremia can manifest as fatigue, weakness, malaise, nausea, vomiting, anorexia, metallic taste, hiccups, neuromuscular irritability, difficulty concentrating, pruritus, restless legs, and ecchymoses. As uremia progresses, paresthesia and evidence of pericarditis may develop, as well as signs of drug toxicity for administered medications eliminated by the kidney. Features of volume overload, such as dyspnea, pulmonary rales, edema, and hypertension, may develop.
• Elevated uric acid levels may present with lethargy, nausea, and vomiting. Rapidly increasing uric acid levels may lead to arthralgia and renal colic.
• Patients with hypocalcemia may present with carpopedal spasms, tetany with positive Chvostek and Trousseau signs, seizures, anxiety, bronchospasm, and cardiac arrest in extreme cases. Deposition of calcium phosphate in various tissues may be responsible for pruritus, gangrenous changes of the skin, iritis, and arthritis.

Causes

• Tumor lysis syndrome occurs most often in patients with acute leukemia with high WBC counts and in those with high-grade lymphomas in response to aggressive treatment. Tumor lysis syndrome may also occur in other hematologic malignancies and in various solid tumors. It has been reported to occur spontaneously, prior to any form of therapy.
• Those at highest risk have bulky, rapidly proliferating tumors that are sensitive to treatment. An elevated pretreatment lactate dehydrogenase (LDH) level, which correlates with high tumor volume, is a strong indicator for developing clinically significant complications of therapy. Presence of renal insufficiency prior to therapy is also correlated with an increased likelihood of tumor lysis syndrome.

Differential Diagnoses

Other Problems to Be Considered

Patients with cancer are at increased risk of renal failure from etiologies other than tumor lysis syndrome (TLS). Prerenal causes include volume depletion from anorexia, vomiting, diarrhea, and bleeding. Pelvic or retroperitoneal masses can lead to kidney failure from postrenal urinary tract obstruction. Renal parenchymal diseases include tumor infiltration, myeloma kidney, drug nephrotoxicity from chemotherapeutic agents or antibiotics, radiocontrast nephropathy, vasculitis, and cryoglobulinemic glomerulonephritis. The combination of volume depletion, hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia strongly support the diagnosis of tumor lysis syndrome as opposed to other causes.

Workup

Laboratory Studies

In patients with tumor lysis syndrome (TLS), a sample of blood obtained by a wide-bore needle or, preferably, an indwelling cannula should be used to obtain a biochemical profile of the patient for biochemical monitoring, which includes serum sodium, potassium, chloride, and bicarbonate.

• Blood chemistry
  • Most patients have laboratory derangements in lactate dehydrogenase (LDH), potassium, phosphate, calcium, uric acid, and abnormal renal functions 1-3 days following the initiation of chemotherapy.
  • Hyperkalemia is often the first life-threatening abnormality.
  • High-risk patients should have laboratory monitoring (BUN, creatinine, phosphate, uric acid, LDH, and calcium levels) prior to therapy and for 48-72 hours after treatment induction. Follow measurements at least twice daily or more often if evidence of tumor lysis syndrome develops.
• Urine pH
  • Urine alkalinization prevents renal precipitation of uric acid, but may increase the risks for nephrocalcinosis.
  • If alkaline diuresis is used, regular determinations of urine pH levels should guide the extent of therapy.

Imaging Studies

• Radiography of the chest is useful to determine the presence of a large tumor (eg, mediastinal mass).
• Perform ultrasonography or CT scanning of the abdomen and retroperitoneum immediately if mass lesions in the abdomen or renal failure are present. Intravenous contrast may be contraindicated in a patient with renal insufficiency.

Other Tests

• Because increased urine flow rates help to inhibit crystal deposition in renal tubules, close monitoring of urine output is necessary to assess adequacy of hydration. Monitoring urine output for signs of oliguric renal failure is also necessary.
• Frequent cardiac assessment (ECG or continuous cardiac monitoring) is necessary to monitor electrocardiographic changes, which may herald a lethal arrhythmia caused by potassium and calcium disturbances.

Histologic Findings

• Pathologic studies demonstrate deposits of uric acid within the distal renal tubule lumina, causing intrarenal hydronephrosis.
• Uric acid crystals can also be seen within tubular epithelial cells and the medullary microcirculation.
• Uric acid precipitates may also occur in the renal pelvis and ureters, leading to hydronephrosis and acute renal failure (ARF) from extrarenal sources.

Treatment

Medical Care

• Overview
  • Tumor lysis syndrome (TLS) management requires initiation of preventive measures in high-risk patients prior to cancer treatment as well as prompt initiation of supportive care for patients who develop acute tumor lysis syndrome during treatment.
  • Patients with evidence of pretreatment acute tumor lysis syndrome should be immediately started on tumor lysis syndrome treatment. Although the correction of all parameters prior to the initiation of chemotherapy is preferable, treatment of the malignancy may be needed sooner. Identify high-risk patients before treatment by assessing the extent of tumor burden, histopathologic findings, and renal function.
• Surveillance
  • Severe manifestations of tumor lysis syndrome can be prevented only through meticulous laboratory monitoring and careful clinical observation. Necessary cardiac studies include baseline ECG with follow-up studies or continuous cardiac monitoring during treatment.
  • Appropriate renal surveillance and fluid status determinations require baseline and daily weights, regular vital sign checks, and frequent measurements of both fluid intake and urine output.
  • High-risk patients and those with evidence of tumor lysis syndrome should have at least thrice-daily laboratory monitoring of BUN, creatinine, uric acid, potassium, calcium, and phosphate levels. Monitoring should continue for the first 48-72 hours after chemotherapy initiation.
• Control of hyperuricemia
  • Allopurinol is a competitive inhibitor of xanthine oxidase and is given to reduce the conversion of nucleic acid byproducts to uric acid in order to prevent urate nephropathy and subsequent oliguric renal failure.
    • It is usually administered orally at 600 mg/d for prophylaxis and at 600-900 mg/d (maximum of 500 mg/m²/d) for treatment of tumor lysis syndrome.
    • Patients unable to take oral medications can be given intravenous allopurinol. The inhibition of uric acid synthesis promotes an increase of xanthine in both plasma and the renal system.
    • Although reported to be rare, xanthine has the capacity to precipitate in the renal tubules. Other adverse effects include mild-to-severe rash, xanthine stone-induced urolithiasis, acute interstitial nephritis, pneumopathy, fever, and eosinophilia.
    • Dose reduction is necessary in renal insufficiency. Dose reduction is also necessary if concomitantly administered with mercaptopurine, 6-thioguanine, or azathioprine because allopurinol interferes with the metabolism of these agents.
  • Rasburicase (recombinant urate oxidase) is a newer therapy that can be used when the uric acid levels cannot be sufficiently lowered by standard approaches. It has been shown to be both safe and effective in pediatric patients, as well as adults.
    • Rasburicase has emerged as the preferred choice for treatment of hyperuricemia in tumor lysis syndrome.
    • Rasburicase has a more rapid onset of action than allopurinol. Some urate oxidase is absent in primates; urate oxidase catalyses the conversion of poorly soluble uric acid to soluble allantoin. By converting uric acid to water-soluble metabolites, it effectively decreases plasma and urinary uric acid levels.
    • Unlike allopurinol, uricase does not increase excretion of xanthine and other purine metabolites; therefore, it does not increase tubule crystallization of these compounds.
    • Methemoglobinemia has been reported.⁴ Hemolytic anemia and methemoglobinemia may be adverse effects caused by the oxidative stress produced by hydrogen peroxide, which is a by product of the breakdown of urate to allantoin. 
• Hydration
  • Volume depletion is a major risk factor for tumor lysis syndrome and must be vigorously corrected. Aggressive intravenous hydration not only helps correct electrolyte disturbances by diluting extracellular fluid but also increases intravascular volume. Increased volume enhances renal blood flow, glomerular filtration rate, and urine volume to decrease the concentration of solutes in the distal nephron and medullary microcirculation.
  • Ideally, intravenous hydration in high-risk patients should begin 24-48 hours prior to initiation of cancer therapy and continue for 48-72 hours after completion of chemotherapy.
  • Continuous intravenous infusion rates as high as 4-5 L/d (or 3 L/m²/d) yielding urine volumes of at least 3 L/d should be given unless the patient's cardiovascular status indicates impending volume overload.
• Urinary alkalinization
  • Use of isotonic sodium bicarbonate solutions intravenously to promote alkaline diuresis has the potential benefits of solubilizing, and thus minimizing, intratubular precipitation of uric acid. The goal is to increase urinary pH levels to 7 to maximize uric acid solubility in renal tubules and vessels.
  • Drawbacks to systemic alkaline therapy include magnification of clinical hypocalcemia by shifting ionized calcium to its nonionized form. Increased likelihood of calcium phosphate precipitation in renal tubules is an additional drawback. For these reasons, routine urine alkalinization is controversial and, if used, must include close monitoring of urinary pH, serum bicarbonate, and uric acid levels to both guide therapy and avoid overzealous alkalinization. Consider titrating sodium bicarbonate intravenous fluid solutions to keep the urine pH level at 7-8.
  • If urinary alkalinization is not achieved with exogenous bicarbonate solutions despite increasing serum bicarbonate levels, intravenous acetazolamide at doses of 250-500 mg/d (5 mg/kg/d) may be added to decrease proximal tubule bicarbonate reabsorption, thereby increasing urinary pH level.
• Control of electrolyte disturbances
  • Aggressively treat and monitor hyperkalemia. Immediately restrict dietary potassium and remove potassium from intravenous fluids. Acute treatment modalities include intravenous infusion of glucose plus insulin to promote redistribution of potassium from the extracellular to intracellular space, and intravenous calcium gluconate as cardioprotection for potassium levels greater than 6.5 mmol/L or for those with ECG alterations. Intravenous hydration with alkaline fluid as described above can also increase intracellular uptake of potassium. Potassium-wasting diuretics may be used with caution because they may worsen renal precipitation in patients with volume contraction. Long-term therapy (eg, oral potassium-exchange resins) should be given immediately because of the transient effectiveness of acute treatment modalities. If these measures fail to control serum potassium, dialysis should be promptly initiated.
  • Hyperphosphatemia is managed with oral phosphate binders and the same solution of glucose plus insulin used for control of hyperkalemia. Hyperphosphatemia may lead to hypocalcemia, which usually resolves as phosphate levels are corrected. In some cases, depressed serum 1,25-dihydroxycholecalciferol levels contribute to hypocalcemia, and administration of calcitriol may correct calcium levels. Such therapy, however, should not be undertaken until serum phosphate levels have normalized to avoid metastatic calcium phosphate calcifications. As a rule, do not correct hypocalcemia unless evidence of neuromuscular irritability is observed, as indicated by a positive Chvostek or Trousseau sign.
  • Use of furosemide or mannitol for osmotic diuresis has not proven to be beneficial as front-line therapy. In fact, these modalities may contribute to uric acid or calcium phosphate precipitation in renal tubules in a volume-contracted patient. Instead, diuretics should be reserved for well-hydrated patients with insufficient diuresis, and furosemide alone should be considered for the normovolemic patient with hyperkalemia or for the patient with evidence of fluid overload.
  • If the previously mentioned methods fail, consider early initiation of dialysis. Dialysis avoids irreversible renal failure and other life-threatening complications. Indications for dialysis include persistent hyperkalemia or hyperphosphatemia despite treatment, volume overload, uremia, symptomatic hypocalcemia, and hyperuricemia.
  • Hemodialysis is preferred over peritoneal dialysis because of better phosphate and uric acid clearance rates. Continuous hemofiltration also has been used and is effective in correcting electrolyte abnormalities and fluid overload.
  • Because hyperkalemia can recur after dialysis is initiated and because of the high phosphate burden in some patients with tumor lysis syndrome, electrolyte levels must be frequently monitored and dialysis must be repeated as needed.

Surgical Care

• Patients with tumor lysis syndrome may need surgical intervention for central venous line placement or the placement of a dialysis catheter in cases of extreme hyperkalemia or renal failure.

Consultations

• Patients with cancer who have acute manifestations of tumor lysis syndrome or those at high risk should be treated by personnel who are experienced with tumor lysis syndrome complications and treatment. An oncology unit or ICU with readily available continuous cardiac monitoring and hemodialysis capabilities is preferable.
• If basic supportive care measures are ineffective in controlling electrolyte disturbances or renal function, nephrology and critical care consultants should be accessible to assist in further management.
• Laboratory turnover time must be rapid so that metabolic derangements can be addressed before life-threatening problems arise.

Diet

• Dietary restrictions highly depend on the status of the individual patient. However, patients who are not restricted to a nothing by mouth diet could theoretically benefit from restricting intake of foods that contain high levels of potassium, phosphorus, or uric acid.

Medication

Management of tumor lysis syndrome (TLS), other than hydration and alkalinization, necessitates the use of drugs to correct metabolic disturbances. Use of medications must be instituted before the start of chemotherapy; the goal is to achieve optimal metabolic stability.

An alternative to allopurinol for decreasing uric acid load is rasburicase (urate oxidase), which controls hyperuricemia by converting uric acid to water-soluble allantoin.^5,6,7,8 This drug is widely used in Europe and was approved by the Food and Drug Administration (FDA) in the United States.

Xanthine oxidase inhibitors

Allopurinol is used to inhibit xanthine oxidase, thereby reducing uric acid. The intravenous form (Aloprim) may be used for patients unable to tolerate oral administration.

Caution is necessary because of the high uric acid concentration in the urine. In 1986, Andreoli and associates explained some cases of renal failure on the basis of effects of allopurinol in altering purine excretion.⁹ In the presence of allopurinol, the excretion of uric acid, xanthine, and hypoxanthine increases several hundred folds, enough to exceed their solubility limit in the renal tubules even at a urinary pH level of 7. Also, at a urinary pH level higher than 7.5, crystallization of hypoxanthine may occur, which necessitates withdrawal of bicarbonate from intravenous fluids.

Allopurinol (Aloprim, Zyloprim)

Inhibits xanthine oxidase, the enzyme that synthesizes uric acid from hypoxanthine and xanthine, thus decreasing production and excretion of uric acid and increasing the levels of more soluble xanthine and hypoxanthine. Reduces the synthesis of uric acid without disrupting the biosynthesis of vital purines.

Dosing

Adult

Oral prophylaxis: 200-600 mg/d PO
Oral treatment: 600-900 mg/d PO; not to exceed 500 mg/m²/d
If unable to take PO: 200-400 mg/m²/d IV; not to exceed 600 mg/d

Pediatric

300-500 mg/m²/d PO divided q8h
200 mg/m²/d IV

Interactions

Alcohol decreases effects; incidence of rash increased when used concurrently with ampicillin and amoxicillin; large amounts of vitamin C acidify urine and may cause kidney stone formation; allopurinol inhibits metabolism of azathioprine and mercaptopurine; increases serum theophylline level

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Diffuse, erythematous, maculopapular rash; not for use in asymptomatic hyperuricemia; reduce dose in renal insufficiency; monitor liver function and perform CBC counts before initiating therapy and periodically thereafter

Uric acid oxidizers

These agents metabolize uric acid to a soluble form, thus preventing acute renal failure (ARF).

Rasburicase (Elitek)

Recombinant form of the enzyme urate oxidase that oxidizes uric acid to allantoin. Used in management and prophylaxis of severe hyperuricemia associated with treatment of malignancy. Hyperuricemia causes a precipitant in kidneys, which leads to acute renal failure. Unlike uric acid, allantoin is soluble and easily excreted by kidneys.

Dosing

Adult

0.15-0.2 mg/kg/d IV infused over 30 min for 5-7 d

Pediatric

Administer as in adults

Interactions

None reported

Contraindications

Documented hypersensitivity; G-6-PD deficiency

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May cause hemolytic anemia secondary to hydrogen peroxide produced during uric acid oxidation; may cause methemoglobinemia; other adverse effects include fever, nausea, and vomiting; children <2 y may experience more vomiting, diarrhea, fever, and rash; avoid shaking or vortexing during product reconstitution; highly antigenic, multiple administration may produce allergic reaction, anaphylaxis, or death; produces false low uric acid levels, accurate levels obtained by collecting blood into prechilled, heparin containing tubes kept at 4 º C and centrifuged at that temperature, maintain resultant plasma at 4 º C and analyze within 4 h of collection; do not administer as IV bolus

Minerals

Calcium is used to treat arrhythmias due to hyperkalemia or hypocalcemia. Frank or impending renal failure requires additional therapeutic measures. Hyperkalemia is the most common life-threatening emergency. Chemotherapy may have to be discontinued temporarily. The entire potassium intake should be immediately discontinued. The use of calcium does not lower serum potassium levels. It is primarily used to protect the myocardium from the deleterious effects of hyperkalemia (ie, arrhythmias) by antagonizing the membrane actions of potassium.

Calcium

Administer IV calcium gluconate or calcium chloride to stabilize myocardial conduction in a patient with cardiac arrhythmias. Also moderates nerve and muscle performance by regulating action potential excitation threshold. IV calcium indicated in all cases of severe hyperkalemia (ie, >6 mEq/L), especially when accompanied by ECG changes. Calcium chloride contains about 3 times more elemental calcium than an equal volume of calcium gluconate. Therefore, when hyperkalemia is accompanied by hemodynamic compromise, calcium chloride is preferred over calcium gluconate.
Administration of calcium should be accompanied by the use of other therapies that actually help lower the serum levels of potassium. Other calcium salts (eg, glubionate, gluceptate) have even less elemental calcium than calcium gluconate and are not generally recommended for the therapy of hyperkalemia.

Calcium chloride 1 g = 270 mg (13.5 mEq) of elemental calcium.

Calcium gluconate 1 g = 90 mg (4.5 mEq) of elemental calcium.

Dosing

Adult

Calcium chloride 10% IV solution:
Hyperkalemia: 2-4 mg/kg slow IV q6-8h prn
Hypocalcemia: 0.5-1 g (7-14 mEq) slow IV; may repeat q1-3d prn

Pediatric

Calcium gluconate: 50 mg/kg slow IV q6-8h prn
Calcium chloride: 10-30 mg/kg slow IV q6-8h prn

Interactions

Coadministration with digoxin may cause arrhythmias; coadministration with thiazides may induce hypercalcemia; may antagonize effects of calcium channel blockers, atenolol, and sodium polystyrene sulfonate; do not administer with bicarbonate because precipitation in the IV tubing or catheter may occur

Contraindications

Ventricular fibrillation not associated with hyperkalemia; digitalis toxicity; hypercalcemia; renal insufficiency; cardiac disease

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Administer slowly (not to exceed 0.5-1 mL/min) to avoid extravasation; hypercalcemia may occur in renal failure

Intracellular potassium transporters

Sodium bicarbonate, insulin, and glucose cause a transcellular shift of potassium into muscle cells, thereby lowering (temporarily) serum levels of potassium.

Sodium bicarbonate

Intracellularly shifts potassium. May be considered in the treatment of hyperkalemia, even in the absence of metabolic acidosis.

Dosing

Adult

1 mEq/kg IV; can be administered as a continuous IV infusion by mixing 50-100 mEq/L of IV solution

Pediatric

Administer as in adults

Interactions

Urinary alkalinization induced by increased sodium bicarbonate concentrations may cause decreased levels of lithium, tetracyclines, chlorpropamide, methotrexate, and salicylates; increases levels of amphetamines, pseudoephedrine, flecainide, anorexiants, mecamylamine, ephedrine, quinidine, and quinine; do not admix calcium and sodium bicarbonate (precipitant forms)

Contraindications

Alkalosis; hypernatremia; hypocalcemia; severe pulmonary edema; unknown abdominal pain

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Sodium bicarbonate should only be used to treat documented hyperkalemia; can cause alkalosis, decreased plasma potassium, hypocalcemia, and hypernatremia; caution in electrolyte imbalances (eg, CHF, cirrhosis, edema, corticosteroid use, renal failure); when administering, avoid extravasation because tissue necrosis can occur

Insulin and dextrose, IV (Novolin, Humulin, Lente Iletin)

Induces intracellular flux of potassium. Presence of insulin results in the intracellular movement of glucose, followed by entry of potassium into muscle cells. Effect is almost immediate, but temporary, and should therefore be followed by therapy that actually enhances potassium clearance (eg, sodium polystyrene sulfonate).

Dosing

Adult

10 U IV and 50 mL dextrose 50% IV bolus or 500 mL dextrose 10% over 1 h; may be administered prn or by continuous IV infusion

Pediatric

1 U/kg of regular insulin with 2 mL/kg IV bolus of dextrose 25%; may be administered prn or as a continuous IV infusion

Interactions

Medications that may decrease hypoglycemic effects of insulin include acetazolamide, AIDS antivirals, asparaginase, phenytoin, nicotine, isoniazid, diltiazem, diuretics, corticosteroids, thiazide diuretics, thyroid estrogens, ethacrynic acid, calcitonin, PO contraceptives, diazoxide, dobutamine, phenothiazines, cyclophosphamide, dextrothyroxine, lithium carbonate, epinephrine, morphine sulfate, and niacin; medications that may increase hypoglycemic effects of insulin include calcium, ACE inhibitors, alcohol, tetracyclines, beta-blockers, lithium carbonate, anabolic steroids, pyridoxine, salicylates, MAOIs, mebendazole, sulfonamides, phenylbutazone, chloroquine, clofibrate, fenfluramine, guanethidine, octreotide, pentamidine, and sulfinpyrazone

Contraindications

Documented hypersensitivity; hypoglycemia

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Hyperthyroidism may increase renal clearance of insulin, necessitating more insulin to treat hyperkalemia; hypothyroidism may delay insulin turnover, requiring less insulin to treat hyperkalemia; monitor glucose carefully; dose adjustments of insulin may be necessary in patients diagnosed with renal and hepatic dysfunction

Exchange resins

Sodium polystyrene sulfonate is an exchange resin that can be used to treat mild-to-moderate hyperkalemia. Each mEq of potassium is exchanged for 1 mEq of sodium.

Sodium polystyrene sulfonate (Kayexalate)

Exchanges sodium for potassium and binds it in the gut, primarily in the large intestine and decreases total-body potassium. Onset of action after PO administration is 2-12 h and is longer when administered rectally. Used in the second stage of therapy to reduce total-body potassium.

Dosing

Adult

25-50 g PO/PR q6h prn; mix in 25-50 mL of sorbitol

Pediatric

1 g/kg PO q6h prn; mix with 50% sorbitol

Interactions

Systemic alkalosis may occur if administered concurrently with magnesium hydroxide, aluminum carbonate or similar antacids, and laxatives

Contraindications

Documented hypersensitivity; hypernatremia

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution when administering to patients who can be adversely affected by a small increase in sodium loads (eg, severe hypertension, severe congestive heart failure, marked edema); constipation with the possibility of fecal impaction may occur; constipation should be treated with 10-20 mL of 70% sorbitol q2h or prn to produce at least 1-2 watery stools daily

Phosphate Binder

These agents are used to treat hyperphosphatemia.

Aluminum hydroxide (AlternaGEL, Alu-Cap, Amphojel, Dialume)

Has been shown to be an effective phosphate binder. However, aluminum salts are not first-line because of their potential for toxicity.

Dosing

Adult

2 cap or tab or 10 mL of regular susp PO (in water or fruit juice) as often as q2h, as many as 12 times/d

Pediatric

50-150 mg/kg/d PO divided q4-6h, titrate to maintain serum phosphorus levels within reference range

Interactions

Decreases effects of tetracyclines, ranitidine, ketoconazole, benzodiazepines, penicillamine, phenothiazines, digoxin, indomethacin, and isoniazid; corticosteroids decrease effects of aluminum in hyperphosphatemia

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Use is controversial, onset of action is slow, and response is erratic; caution in recent massive upper GI hemorrhage; renal failure may cause aluminum toxicity

Sevelamer hydrochloride (Renagel)

Polymeric phosphate binder for PO administration. Does not contain aluminum and, thus, aluminum intoxication is not a concern.

Dosing

Adult

2-4 cap PO pc; adjust based on serum phosphorus concentrations to lower serum phosphorus to <6 mg/dL.
>6 mg/dL and <7.5 mg/dL 2 caps PO tid
>7.5 mg/dL and <9 mg/dL 3 caps PO tid
>9 mg/dL 4 caps PO tid
not to exceed 30 caps/d

Pediatric

Not established. In one study, the most commonly used dosing was 400 mg (1 cap) PO bid in patients aged 2.7-17.9 years old.

Interactions

May reduce absorption of drugs co-administered with sevelamer

Contraindications

Documented hypersensitivity; bowel obstruction, hypophosphatemia

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in patients with dysphagia, severe GI motility disorders, or swallowing disorders; can cause hypophosphatemia in patients with low or normal serum phosphate levels; when changes in absorption of oral medications may have clinical consequences (eg, antiseizure or antiarrhythmic drugs), medications should be taken 1 h before or 3 h after a dose of sevelamer

Follow-up

Further Inpatient Care

• Please refer to Medical Care.

Inpatient & Outpatient Medications

• Please refer to Medical Care.

Deterrence/Prevention

• Patients without laboratory evidence of tumor lysis syndrome (TLS) who remain at high risk should have prophylactic measures begun 24-48 hours prior to initiation of cytotoxic therapy. Prophylactic measures include liberal intravenous fluid administration, allopurinol, and urinary alkalinization. Close monitoring of fluid status and blood chemistry is important and should continue until 48-72 hours after chemotherapy initiation. Please refer to the previous section on Medical Care for more information.

Complications

• Potential complications include uremia and oliguric renal failure due to tubule precipitation of uric acid, calcium phosphate, or hypoxanthine.
• Severe electrolyte disturbances, such as hyperkalemia and hypocalcemia, predispose patients to cardiac arrhythmia and seizures.
• Iatrogenic complications, such as pulmonary edema from overly vigorous hydration or metabolic alkalosis from excess exogenous administration of bicarbonate, also can occur and are life threatening if not immediately addressed.

Prognosis

• Early recognition of signs and symptoms of patients at risk for tumor lysis syndrome, including identification of abnormal clinical and laboratory values, can lead to successful prevention of the otherwise life-threatening complications of tumor lysis syndrome.

References

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Keywords

tumor lysis syndrome, TLS, acute tumor lysis syndrome, ATLS, hyperkalemia, hyperuricemia, hyperphosphatemia, hypocalcemia, acute renal failure, ARF, Burkitt lymphoma, T-cell acute lymphoblastic leukemia, hepatoblastoma, neuroblastoma, obstructive uropathy, pericarditis, uremia, renal colic, arthralgia, arthritis, hypertension

Contributor Information and Disclosures

Author

Alan K Ikeda, MD, Assistant Professor, Department of Pediatrics, Division of Hematology and Oncology, David Geffen School of Medicine at UCLA; Assistant Director of Pediatric Blood and Marrow Transplantation, Mattel Children's Hospital
Alan K Ikeda, MD is a member of the following medical societies: American Academy of Pediatrics, American Society for Blood and Marrow Transplantation, and American Society of Pediatric Hematology/Oncology
Disclosure: emedicine Honoraria author

Coauthor(s)

Kathleen Sakamoto, MD, Professor, Department of Pediatrics, Division of Hematology-Oncology and Pathology and Laboratory Medicine, Mattel Children's Hospital, David Geffen School of Medicine, University of California at Los Angeles
Kathleen Sakamoto, MD is a member of the following medical societies: American Society of Hematology, American Society of Pediatric Hematology/Oncology, New York Academy of Sciences, Society for Pediatric Research, and Western Society for Pediatric Research
Disclosure: Nothing to disclose.

Koyamangalath Krishnan, MD, FRCP, FACP, Dishner Endowed Chair of Excellence in Medicine, Professor of Medicine and Chief of Hematology-Oncology, Program Director, Hematology-Oncology Fellowship, James H Quillen College of Medicine at East Tennessee State University
Koyamangalath Krishnan, MD, FRCP, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, American Society of Hematology, and Royal College of Physicians
Disclosure: Nothing to disclose.

Amit P Sarnaik, MD, Staff Physician, Department of Pediatrics, Wayne State University and Children's Hospital of Michigan
Amit P Sarnaik, MD is a member of the following medical societies: American Academy of Pediatrics
Disclosure: Nothing to disclose.

Medical Editor

Stephan A Grupp, MD, PhD, Director, Stem Cell Biology Program, Department of Pediatrics, Division of Oncology, Children's Hospital of Philadelphia; Associate Professor of Pediatrics, University of Pennsylvania
Stephan A Grupp, MD, PhD is a member of the following medical societies: American Association for Cancer Research, American Society for Blood and Marrow Transplantation, American Society of Hematology, American Society of Pediatric Hematology/Oncology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

Steven K Bergstrom, MD, Assistant to the Chairman, Department of Pediatrics, Division of Hematology-Oncology, Kaiser Permanente Medical Center of Oakland
Steven K Bergstrom, MD is a member of the following medical societies: Alpha Omega Alpha, American Society of Clinical Oncology, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Children's Oncology Group, and International Society for Experimental Hematology
Disclosure: Nothing to disclose.

CME Editor

Helen SL Chan, MBBS, FRCP(C), FAAP, Senior Scientist, Research Institute; Professor, Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Canada
Helen SL Chan, MBBS, FRCP(C), FAAP is a member of the following medical societies: American Academy of Pediatrics, American Association for Cancer Research, American Society of Hematology, and Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

Chief Editor

Max J Coppes, MD, PhD, MBA, Executive Director, Center for Cancer and Blood Disorders, Children's National Medical Center, Washington, DC; Professor of Medicine, Oncology, and Pediatrics, Georgetown University
Max J Coppes, MD, PhD, MBA is a member of the following medical societies: American Association for Cancer Research, American Society of Pediatric Hematology/Oncology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

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