AUTHOR INFORMATION

Section 1 of 10

Authored by Alan K Ikeda, MD, Clinical Fellow, Department of Pediatrics, Division of Hematology and Oncology, Mattel Children's Hospital, David Geffen School of Medicine at UCLA

Coauthored by 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

Alan K Ikeda, MD, is a member of the following medical societies: American Academy of Pediatrics, and American Society for Blood and Marrow Transplantation

Edited by Stephan A Grupp, MD, PhD, Director, Stem Cell Biology Program, Children's Hospital of Philadelphia; Assistant Professor, Department of Pediatrics, Division of Oncology, University of Pennsylvania; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Steven K Bergstrom, MD, Assistant to the Chairman, Department of Pediatrics, Division of Hematology-Oncology, Kaiser Permanente Medical Center of Oakland, CA; 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; and Max J Coppes, MD, PhD, MBA, Executive Director, Center for Cancer and Blood Disorders, Children's National Medical Center

Author's Email:	Alan K Ikeda, MD
Editor's Email:	Stephan A Grupp, MD, PhD

eMedicine Journal, September 12 2006, VOLUME 7, Number 9

INTRODUCTION

Section 2 of 10

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 resulting from spontaneous or treatment-related tumor necrosis or fulminant apoptosis. 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 TLS are the identification of high-risk patients, initiation of preventive therapy, and early recognition and intervention of its complications.

Pathophysiology: Tumor lysis syndrome (TLS) can be precipitated before the initiation of therapy and usually lasts up to 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.

TLS has also been observed in association with solid tumors, such as hepatoblastoma and stage IV neuroblastoma. 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. 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 acute renal failure (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:

• Internationally: Incidence is unknown. Prevalence varies among different malignancies; bulky, aggressive, and treatment-sensitive tumors are associated with higher frequencies of TLS. In studies of frequency in patients with intermediate-grade or high-grade non-Hodgkin lymphomas, laboratory evidence of TLS (42%) occurred much more frequently than the symptomatic clinical syndrome (6%). In children with acute leukemia receiving induction chemotherapy, silent laboratory evidence of TLS occurred in 70% of cases, but clinically significant TLS occurred in only 3%. As advances are made in cancer treatment and more aggressive regimens become in favor, the incidence of TLS may increase and the syndrome 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 blood urea nitrogen (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 TLS; 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 treated rapidly. Proper fluid management, alkalinization of the urine, correction of acidosis, and attention to infections are the mainstays of therapy.

Race: No race predilection exists.

Sex: No sex predilection exists.

Age: Although TLS 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 TLS secondary to decreased ability to dispose of tumor lysis byproducts.

CLINICAL

Section 3 of 10

History: Pertinent historic information 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:

• TLS occurs most often in patients with acute leukemia with high WBC counts and in those with high-grade lymphomas in response to aggressive treatment. TLS may also occur in other hematologic malignancies and in a variety of 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 also is correlated with an increased likelihood of TLS.

DIFFERENTIALS

Section 4 of 10

Other Problems to be Considered:

Patients with cancer are at increased risk of renal failure from etiologies other than 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 TLS over other causes.

WORKUP

Section 5 of 10

Lab Studies:

• A sample of blood collected 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 LDH, potassium, phosphate, calcium, uric acid, and abnormal renal functions, occurring 1-3 days following the initiation of chemotherapy.
  
  
  
  • Hyperkalemia often is the first life-threatening abnormality.
  
  
  
  • High-risk patients should have laboratory monitoring (BUN, creatinine, phosphate, uric acid, LDH, and calcium) prior to therapy and for 48-72 hours after treatment induction. Follow measurements at least twice daily or more often if evidence of TLS develops.
  
  
  
• Urine pH


• • Urine alkalinization prevents renal precipitation of uric acid, but may increase the risks for nephrocalcinosis.
  
  
  
  • If alkaline diuresis is employed, regular determinations of urine pH 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 computed tomography 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.

TREATMENT

Section 6 of 10

Medical Care:

• Overview
  • 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 TLS during treatment.

  • Patients with evidence of pretreatment acute TLS should be started immediately on TLS treatment. Although it is preferable that all parameters are corrected prior to the initiation of chemotherapy, 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 TLS 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 TLS should have at least thrice-daily laboratory monitoring of BUN, creatinine, uric acid, potassium, calcium, phosphate. 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 given orally as 600 mg/d for prophylaxis and 600-900 mg/d (up to a maximum of 500 mg/m²/d) for treatment of TLS. 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. Xanthine, although reported to be rare, 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 given concomitantly 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 lowered sufficiently by standard approaches. It has been shown to be both safe and effective in pediatrics, as well as adults. Rasburicase has emerged as the preferred choice for treatment of hyperuricemia in TLS. 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. It is administered by intramuscular injection or intravenous infusion at dosages ranging from 50-100 U/kg/d. It is contraindicated in G-6-PD deficiency and pregnancy.



• Hydration
  • Volume depletion is a major risk factor for TLS and must be corrected vigorously. Aggressive intravenous hydration not only helps correct electrolyte disturbances by diluting extracellular fluid, but it 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, IV 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 IV 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 to 7.0 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 it is employed it 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 between 7.0 and 8.0.

  • 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.



• 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 already described also can increase intracellular uptake of potassium. Potassium-wasting diuretics may be employed with caution since these may worsen renal precipitation in the volume-contracted patient. Long-term therapy such as 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 initiated promptly.

  • 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 exists, 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 will avoid 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 TLS, electrolyte levels must be monitored frequently and dialysis 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:

• Hospital setting: Cancer patients with acute manifestations of TLS or those at high risk should be treated by personnel who are experienced with TLS 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.
  
  
  

MEDICATION

Section 7 of 10

Management of tumor lysis syndrome, 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. This drug is used widely in Europe and was recently approved by the Food and Drug Administration (FDA) in the United States.

Drug Category: Xanthine oxidase inhibitors -- Allopurinol is used to inhibit xanthine oxidase, thereby reducing uric acid. The IV form (Aloprim) may be used for patients unable to tolerate PO 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. 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 of 7. Also, at a urinary pH higher than 7.5, crystallization of hypoxanthine may occur, which necessitates withdrawal of bicarbonate from IV fluids.

Drug Name	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.
Adult Dose	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 Dose	300-500 mg/m2/d PO divided q8h 200 mg/m2/d IV
Contraindications	Documented hypersensitivity
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
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Diffuse, erythematous, maculopapular rash; not for use in asymptomatic hyperuricemia; reduce dose in renal insufficiency; monitor liver function and perform CBCs before initiating therapy and periodically thereafter

Drug Category: Uric acid oxidizers -- These agents metabolize uric acid to a soluble form, thus preventing acute renal failure.

Drug Name	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.
Adult Dose	0.15-0.2 mg/kg/d IV infused over 30 min for 5-7 d
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; G-6-PD deficiency
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
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; do not administer as IV bolus

Drug Category: 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 discontinued immediately. 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.

Drug Name	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.
Adult Dose	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 Dose	Calcium gluconate: 50 mg/kg slow IV q6-8h prn Calcium chloride: 10-30 mg/kg slow IV q6-8h prn
Contraindications	Ventricular fibrillation not associated with hyperkalemia; digitalis toxicity; hypercalcemia; renal insufficiency; cardiac disease
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
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Administer slowly (not to exceed 0.5-1 mL/min) to avoid extravasation; hypercalcemia may occur in renal failure

Drug Category: Intracellular potassium transporters -- Sodium bicarbonate, insulin, and glucose cause a transcellular shift of potassium into muscle cells, thereby lowering (temporarily) serum levels of potassium.

Drug Name	Sodium bicarbonate -- Shifts potassium intracellularly. May be considered in the treatment of hyperkalemia, even in the absence of metabolic acidosis.
Adult Dose	1 mEq/kg IV; can be administered as a continuous IV infusion by mixing 50-100 mEq/L of IV solution
Pediatric Dose	Administer as in adults
Contraindications	Alkalosis; hypernatremia; hypocalcemia; severe pulmonary edema; unknown abdominal pain
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)
Pregnancy	C - Safety for use during pregnancy has not been established.
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

Drug Name	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).
Adult Dose	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 Dose	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
Contraindications	Documented hypersensitivity; hypoglycemia
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
Pregnancy	B - Usually safe but benefits must outweigh the risks.
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

Drug Category: 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.

Drug Name	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.
Adult Dose	25-50 g PO/PR q6h prn; mix in 25-50 mL of sorbitol
Pediatric Dose	1 g/kg PO q6h prn; mix with 50% sorbitol
Contraindications	Documented hypersensitivity; hypernatremia
Interactions	Systemic alkalosis may occur if administered concurrently with magnesium hydroxide, aluminum carbonate or similar antacids, and laxatives
Pregnancy	C - Safety for use during pregnancy has not been established.
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

Drug Category: Phosphate-binding agents -- These agents are used to treat hyperphosphatemia.

Drug Name	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.
Adult Dose	2 cap or tab or 10 mL of regular susp PO (in water or fruit juice) as often as q2h, up to 12 times/d
Pediatric Dose	50-150 mg/kg/d PO divided q4-6h, titrate to maintain serum phosphorus levels within reference range
Contraindications	Documented hypersensitivity
Interactions	Decreases effects of tetracyclines, ranitidine, ketoconazole, benzodiazepines, penicillamine, phenothiazines, digoxin, indomethacin, and isoniazid; corticosteroids decrease effects of aluminum in hyperphosphatemia
Pregnancy	B - Usually safe but benefits must outweigh the risks.
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

FOLLOW-UP

Section 8 of 10

Further Inpatient Care:

• Please refer to Medical Care.

In/Out Patient Meds:

• Please refer to Medical Care.

Deterrence/Prevention:

• Patients without laboratory evidence of 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.

TEST QUESTIONS

Section 9 of 10

CME Question 1: Which of the following is the best way to manage an 11-year-old patient with Burkitt lymphoma who has developed tumor lysis syndrome and has laboratory values of 120 mg/dL BUN, 11.2 mg/dL creatinine, 22 mg/dL uric acid, 11 mg/dL calcium, and 7.5 mEq/L potassium?

A: Start IV hydration at 3 times maintenance.
B: Institute hemodialysis.
C: Administer allopurinol.
D: Provide radiation therapy.
E: Administer diuretics.

The correct answer is B: This patient is in acute renal failure and meets the criteria to start hemodialysis. IV fluids may need to be restricted at this point. Allopurinol cannot reverse the severe metabolic abnormalities the patient is facing. Radiation therapy has no role, and diuretics serve no purpose at this point.

CME Question 2: A physician is taking care of a patient with tumor lysis syndrome with laboratory values of 15 mg/dL uric acid, 10 mg/dL BUN, 1 mg/dL creatinine, 9.5 mg/dL calcium, 4.5 mEq/L potassium, and 4.2 mg/dL phosphorus. He has been started on 2 times maintenance IV rate allopurinol and sodium bicarbonate infusion. His urine pH is 5.2. What is the next step for the physician?

A: Administer tris-hydroxymethyl-amino-methane (THAM).
B: Intubate and hyperventilate the patient to produce respiratory alkalosis.
C: Administer bicarbonate bolus and increase the rate of continuous bicarbonate infusion.
D: Start the patient on PO calcium carbonate.
E: Start peritoneal dialysis.

The correct answer is C: The patient is in need of optimum alkalinization of urine to achieve efficient excretion of uric acid. A urine pH of 7.5 is the goal and should be achieved by administering IV bicarbonate bolus and increasing the bicarbonate load in the infusion. THAM is not necessary because hypercarbia is not a concern in a stable ventilating patient. Intubation is not indicated. PO calcium carbonate has no role in alkalinizing urine acutely. The patient does not meet any criterion of renal failure and, therefore, does not need dialysis.

Pearl Question 1 (T/F): The triad of metabolic disturbances in tumor lysis syndrome involves hyperuricemia, hyperkalemia, and hyperphosphatemia with hypocalcemia and renal failure as secondary complications.

The correct answer is True: Tumor lysis syndrome involves spontaneous or chemotherapy-induced cell lysis, leading to increased levels of potassium and phosphorus. The increased cellular turnover as well as lysis contributes to hyperuricemia. Increased levels of phosphates lead to hypocalcemia to maintain the calcium-phosphorus product of 60-70. Acute renal failure may develop in a patient because of urate nephropathy or obstructive nephropathy due to bulky abdominal disease or dehydration.

Pearl Question 2 (T/F): Tumor lysis syndrome is frequently encountered in T-cell lymphoblastic leukemia.

The correct answer is True: Tumors with high growth fraction and tumors that are exquisitely sensitive to chemotherapy, such as T-cell acute lymphoblastic leukemia (ALL) and Burkitt lymphoma, are more likely to lead to tumor lysis syndrome.

Pearl Question 3 (T/F): In tumor lysis syndrome, alkalinization to obtain a urinary pH of 10.0 is necessary.

The correct answer is False: Alkalinization is necessary in tumor lysis syndrome. A goal urine pH between 7.0 and 8.0 promotes efficient excretion of uric acid without the increased risk for calcium-phosphate precipitation. Overalkalinization can also lead to hypocalcemia and its complications, as well as leading to crystallization of hypoxanthine, which results from inhibition of xanthine oxidase by allopurinol in the renal tubules, exacerbating the renal failure.

Pearl Question 4 (T/F): Allopurinol reduces uric acid load by converting it to more water-soluble allantoin.

The correct answer is False: Allopurinol acts as competitive inhibitor of xanthine oxidase that catalyzes the conversion of xanthine and hypoxanthine to uric acid, thereby reducing the levels of uric acid and facilitating excretion of more soluble xanthine and hypoxanthine. Urate oxidase converts uric acid to more the water-soluble allantoin.

BIBLIOGRAPHY

Section 10 of 10

• Andreoli SP, Clark JH, McGuire WA: Purine excretion during tumor lysis in children with acute lymphocytic leukemia receiving allopurinol: relationship to acute renal failure. J Pediatr 1986 Aug; 109(2): 292-8[Medline].
• Arramide K, Toto RD: Tumor lysis syndrome. Semin Nephrol 1993 May; 13(3): 273-80.
• Arrowsmith ER, Greer JP, Macon WR: Complications of hematopoietic neoplasms. Wintrobe's Clinical Hematology 1999; 2052-5.
• Bessmertny O, Robtaille LM, Cairo MS: Rasburicase: a new approach for preventing and/or treating tunor lysis syndrome. Curr Pharm Des 2005 Jan; 11(32): 4177-85[Medline].
• Bishop MR, Coccia PF: Tumor lysis syndrome. Abeloff, ed. Clinical Oncology 2000; 750-3.
• Cohen LF, Balow JE, Magrath IT: Acute tumor lysis syndrome. A review of 37 patients with Burkitt's lymphoma. Am J Med 1980 Apr; 68(4): 486-91[Medline].
• Davidson MB, Thakkar S, Hix JK: Pathophysiology, clinical consequences, and treatment of tumor lysis syndrome. The American Journal of Medicine 2004; 116: 546-54.
• Ezzone SA: Tumor lysis syndrome. Semin Oncol Nurs 1999 Aug; 15(3): 202-8[Medline].
• Fildes RD, Springate JE, Feld LG: Acute renal failure. II. Management of suspected and established disease. J Pediatr 1986 Oct; 109(4): 567-71[Medline].
• Fleming DR, Doukas MA: Acute tumor lysis syndrome in hematologic malignancies. Leuk Lymphoma 1992 Nov; 8(4-5): 315-8.
• Flombaum CD: Metabolic emergencies in the cancer patient. Semin Oncol 2000 Jun; 27(3): 322-34.
• Goldman SC: Rasburicase: potential role in managing tumor lysis in patients with hematological malignancies. Expert Rev Anticancer Ther 2003 Aug; 3(4): 429-33[Medline].
• Hande KR, Garrow GC: Acute tumor lysis syndrome in patients with high-grade non-Hodgkin's lymphoma. Am J Med 1993 Feb; 94(2): 133-9.
• Holland P, Holland NH: Prevention and management of acute hyperuricemia in childhood leukemia. J Pediatr 1968 Mar; 72(3): 358-66[Medline].
• Jeha S, Pui CH: Recombinant urate oxidase (rasburicase) in the prophylaxis and treatment of tumor lysis syndrome. Contrib Nephrol 2005 Jan; 147: 69-79[Medline].
• Jones DP, Mahmoud H, Chesney RW: Tumor lysis syndrome: pathogenesis and management. Pediatr Nephrol 1995 Apr; 9(2): 206-12.
• Kalemkerian GP, Darwish B, Varterasian ML: Tumor lysis syndrome in small cell carcinoma and other solid tumors. ;. Am J Med 1997 Nov; 103(5): 363-7.
• Kelly KM, Lange B: Oncologic emergencies. Pediatr Clin North Am 1997 Aug; 44(4): 809-30[Medline].
• Klinenberg JR, Kippen I, Bluestone R: Hyperuricemic nephropathy: pathologic features and factors influencing urate deposition. Nephron 1975; 14(1): 88-98.
• Lange B, O'Neill JA, Goldwein JW: Oncologic Emergencies. In: Pizzo PA, Poplack DG, eds. Principles and Practice of Pediatric Oncology. 3rd ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 1997: 1041-43.
• Lorigan PC, Woodings PL, Morgenstern GR: Tumour lysis syndrome, case report and review of the literature. Ann Oncol 1996 Aug; 7(6): 631-6.
• Rohaly-Davis J, Johnston K: Hematologic emergencies in the intensive care unit. Crit Care Nurs Q 1996 Feb; 18(4): 35-43.
• Schlisky RL: Renal and metabolic toxicities of cancer treatment. 1982.
• Stapleton FB, Linshaw MA, Hassanein K: Uric acid excretion in normal children. J Pediatr 1978 Jun; 92(6): 911-4[Medline].
• Yim BT, Sims-McCallum RP, Chong PH: Rasburicase for the treatment and prevention of hyperuricemia. Ann Pharmacother 2003 Jul-Aug; 37(7-8): 1047-54.
• Zusman J, Brown DM, Nesbit ME: Hyperphosphatemia, hyperphosphaturia and hypocalcemia in acute lymphoblastic leukemia. N Engl J Med 1973 Dec 20; 289(25): 1335-40[Medline].

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