eMedicine Specialties > Oncology > Special Topics in Oncology

Tumor Lysis Syndrome

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
Ahmad Hammad, MD, Clinical Assistant Professor, Department of Internal Medicine, Division of Hematology/Oncology, East Tennessee State University, James H Quillen Veterans Affairs Medical Center

Updated: Mar 11, 2009

Introduction

Background

Tumor lysis syndrome (TLS) refers to the constellation of metabolic disturbances that may be seen after initiation of cancer treatment.^1,2,3 Tumor lysis syndrome usually occurs in patients with bulky, rapidly proliferating, and treatment-responsive tumors.⁴ Tumor lysis syndrome is typically associated with acute leukemias and high-grade non-Hodgkin lymphomas,⁵ such as Burkitt lymphoma.^6,7 Tumor lysis syndrome has also been reported with other hematologic malignancies and solid tumors.^8,9

A potentially lethal complication of anticancer treatment,¹⁰ tumor lysis syndrome occurs when large numbers of neoplastic cells are killed rapidly, leading to release of intracellular ions and metabolic byproducts into the systemic circulation. Clinically, the syndrome is characterized by rapid development of hyperuricemia,¹¹ hyperkalemia, hyperphosphatemia, hypocalcemia, and acute renal failure (ARF).¹² The main principles of tumor lysis syndrome management are (1) identification of high-risk patients with initiation of preventive therapy and (2) early recognition of metabolic and renal complications with prompt supportive care, including hemodialysis.

Pathophysiology

Rapid tumor cell turnover results in release of intracellular contents into the circulation. This release can inundate renal elimination and cellular buffering mechanisms, which lead to numerous metabolic derangements. Clinically significant tumor lysis syndrome can occur spontaneously, but it is most often seen 48-72 hours after initiation of cancer treatment. Hyperkalemia is often the earliest laboratory manifestation. Hyperkalemia and hyperphosphatemia result directly from rapid cell lysis. Nucleic acid purines, which are also released by cell breakdown, are ultimately metabolized to uric acid by hepatic xanthine oxidase. This conversion leads to hyperuricemia. Hypocalcemia is a consequence of acute hyperphosphatemia with subsequent precipitation of calcium phosphate in soft tissues. In acute renal failure, decreased calcitriol levels also cause hypocalcemia.

Uric acid is the terminal catabolic product of purine metabolism in humans; it is a weak acid with pKa of approximately 5.4, is soluble in plasma, and is freely filtered at the renal glomeruli. However, uric acid is less soluble in renal tubular and collecting duct fluid due to normally acidic media, thus increasing the possibility of uric acid crystal formation in case of hyperuricemia.

The kidney is the primary organ involved in clearance of uric acid, potassium, and phosphate. Preexisting volume depletion or renal dysfunction predisposes patients to worsening metabolic derangements and acute renal failure. Acute renal failure is often oliguric and can be multifactorial in etiology; uric acid nephropathy is the major cause of acute renal failure. Its development is due to mechanical obstruction by uric acid crystals in the renal tubules. With a pKA of 5.6, uric acid precipitation is enhanced by high acidity and high concentration in the renal tubular fluid, becoming less soluble as renal tubule pH decreases. Renal medullary hemoconcentration and decreased tubular flow rate also contribute to crystallization.

Another cause of acute renal failure is acute nephrocalcinosis from calcium phosphate crystal precipitation, which may occur in other tissues. This occurs in the setting of hyperphosphatemia and is exacerbated by overzealous iatrogenic alkalinization, because calcium phosphate, unlike uric acid, becomes less soluble at an alkaline pH. Precipitation of xanthine, which is even less soluble in urine than uric acid, or other purine metabolites whose urinary excretion is increased by use of allopurinol are other causes of acute renal failure.

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%). 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% of cases. As advances are made in cancer treatment and as high-dose regimens become more commonplace, tumor lysis syndrome incidence may increase and the syndrome emerge in a broader spectrum of malignancies.

Mortality/Morbidity

• Acute renal failure: Renal tubule precipitation of uric acid, calcium phosphate, or hypoxanthine causes acute renal failure. This is often 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 is usually 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: Acute renal failure 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 treated rapidly. Proper fluid management, alkalinization of the urine, correction of acidosis, and attention to infections are the mainstays of therapy.

Race

No racial predilection exists.

Sex

No sex predilection exists.

Age

Although tumor lysis syndrome occurs in all age groups, advanced age leading to impaired renal function may predispose patients to clinically significant tumor lysis syndrome owing to decreased ability to dispose of tumor lysis byproducts.

Clinical

History

A constellation of clinical symptoms, such as nausea, vomiting, lethargy, edema, fluid overload, congestive heart failure, cardiac dysrhythmias, seizures, muscle cramps, tetany, syncope, and sudden death may develop prior to initiation of chemotherapy or more commonly within 72 hours after administration of cytotoxic therapy.

Physical

• Symptoms reflect the severity of underlying metabolic abnormalities.
• Hyperkalemia can cause paresthesia and weakness. Severe hypocalcemia can also lead to paresthesia and tetany with positive Chvostek and Trousseau signs, anxiety, carpal and pedal spasms, and bronchospasm.
• 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.
• Rapidly increasing uric acid levels may lead to arthralgia and renal colic.

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 a variety of solid tumors. It has occasionally occurred spontaneously, prior to any form of therapy.¹³
• 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 prognostic 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.
• Reports exist of tumor lysis syndrome associated with the administration of radiation therapy,¹⁴ corticosteroids, hormonal agents, biologic response modifiers, and monoclonal antibodies. Agents reported to cause tumor lysis syndrome include paclitaxel, fludarabine, etoposide, thalidomide,¹⁵ bortezomib,¹⁶ zoledronic acid,¹⁷ and hydroxyurea.
• Tumor lysis syndrome is not limited to systemic administration of agents; it can occur with intrathecal administration of chemotherapy and with chemo-embolization.
• Rare clinical situations in which tumor lysis syndrome has been observed include pregnancy and fever. Patients under general anesthesia have also experienced tumor lysis syndrome.

Differential Diagnoses

Acute Renal Failure

Other Problems to Be Considered

Patients with cancer are at increased risk of renal failure from etiologies other than tumor lysis syndrome.¹⁸ 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 over other causes.

Workup

Laboratory Studies

• Blood chemistry
  • Most patients have laboratory derangements in potassium, phosphate, calcium, and uric acid, and abnormal renal functions, occurring 1-3 days following chemotherapy initiation.
  • Hyperkalemia is often 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 tumor lysis syndrome develops.
• Urine pH
  • If hyperuricemia develops, urine alkalinization prevents renal precipitation of uric acid.
  • If alkaline diuresis is employed, regular determinations of urine pH should guide the extent of therapy.

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 from extrarenal sources.

Treatment

Medical Care

The identification of patients at risk for the development of tumor lysis syndrome is the most important aspect of management, as prophylactic measures may be initiated before the initiation of therapy. Most of the complications can be readily managed when they are recognized early; however, delay in recognition and initiation of treatment of tumor lysis syndrome can be life-threatening. 

Guidelines for management of pediatric and adult tumor lysis syndrome have recently been published.¹⁹ Tumor lysis syndrome management^20,21 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 started immediately on tumor lysis syndrome treatment, withholding cancer therapy if possible until all parameters are corrected. Identify high-risk patients before treatment by assessing the extent of tumor burden, histopathologic findings, and renal function. 

Conservative management and prevention of tumor lysis syndrome are similar and are discussed together.

• Hospital setting
• Cancer patients with 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.²²
• 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.
• 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.
• Patients at high risk and those with evidence of tumor lysis syndrome should have at least thrice-daily laboratory monitoring of BUN, creatinine, uric acid, potassium, calcium, phosphate, and LDH. Monitoring should continue for the first 48-72 hours after chemotherapy initiation.
• Control of hyperuricemia²³
• Allopurinol is a xanthine oxidase inhibitor 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 tumor lysis syndrome. Patients unable to take oral medications can be given intravenous allopurinol. 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, since 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.²⁴ Rasburicase is useful in cases of hyperuricemia. Humans do not express urate oxidase; 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 glucose-6-phosphate dehydrogenase (G-6-PD) deficiency and pregnancy.
• In G-6-PD deficiency, as rasburicase breaks down uric acid and accelerates catabolism of its precursors xanthine and hypoxanthine, excess hydrogen peroxide accumulates from G-6-PD deficiency, placing patients at risk for both hemolytic anemia and methemoglobinemias.²⁵ Some authorities recommend screening for G-6-PD deficiency prior to administration of the drug.
• Studies are underway to establish safety and efficacy in those populations at highest risk for developing tumor lysis syndrome. It is approved by the U.S. Food and Drug Administration (FDA) for the prevention and treatment of hyperuricemia and tumor lysis syndrome in pediatric patients with leukemia, lymphoma, or solid organ malignancy receiving chemotherapy. It is also indicated in treatment of adults in countries like Australia, Canada, and in parts of Europe.
• Since humans do not express urate oxidase, rasburicase can potentially elicit an immune response.
• Hydration
• Volume depletion is a major risk factor for tumor lysis syndrome 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, 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 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 withdrawing sodium bicarbonate from intravenous fluid solutions once serum bicarbonate levels reach 30 mEq/L, urinary pH exceeds 7.5, or serum uric acid levels have normalized.
• 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.
• Diuretics
• 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.
• 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.
• 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 can also 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.
• Dialysis
• If the previously mentioned methods fail, consider early initiation of dialysis. Dialysis prevents 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 monitored frequently and dialysis repeated as needed.

Consultations

• If initial supportive care measures fail to control electrolyte disturbances or renal failure, nephrology and critical care consultations are important for assistance in further management.
• Should dialysis become necessary, consultation with a surgeon to place an appropriate vascular access device is required.

Medication

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Uricosurics

These agents control hyperuricemia and attempt to prevent urate nephropathy and subsequent oliguric renal failure.

Allopurinol (Zyloprim)

Inhibits xanthine oxidase, the enzyme that synthesizes uric acid from hypoxanthine. Reduces synthesis of uric acid without disrupting biosynthesis of vital purines. Response measured by serum uric acid levels assessed at 48 h after initiation of therapy; dosage adjustments made prn.

Dosing

Adult

600-800 mg/d PO, not to exceed 800 mg/d; alternatively, 200-400 mg/m²/d IV; not to exceed 600 mg/d

Pediatric

<6 years: 150 mg/d PO divided bid/tid, not to exceed 800 mg/d
6-10 years: 300 mg/d PO
IV: 200 mg/m²/d
>10 years: Administer as in adults

Interactions

Alcohol decreases effects; ampicillin and amoxicillin increase incidence of skin rash; large amounts of vitamin C acidify urine and may cause kidney stone formation; inhibits metabolism of azathioprine and mercaptopurine (reduce dose of mercaptopurine or azathioprine to one third to one fourth the dose necessary to avoid toxicity); prolongs half-life of warfarin (monitor PT time); uricosuric agents increase urinary excretion of uric acid; thiazides may increase toxicity (monitor renal function if taken concomitantly); may increase half-life of chlorpropamide, increasing risk for hypoglycemia; may increase cyclosporine levels (adjust dose of cyclosporine when coadministered)

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

Not for use in asymptomatic hyperuricemia; reduce dose in renal insufficiency; monitor liver function and perform complete blood counts before initiating therapy and periodically thereafter; potential increased risk for formation of xanthine calculi (slightly alkaline urine and sufficient fluid intake to yield urine output of at least 2 L/d recommended)

Rasburicase (Elitek)

A recombinant form (derived from Saccharomyces cerevisiae -synthesized, Aspergillus flavus) of the enzyme urate oxidase, which oxidizes uric acid to allantoin. Indicated for treatment and prophylaxis of severe hyperuricemia associated with the treatment of malignancy. Hyperuricemia causes a precipitant in the kidneys, which leads to ARF. Unlike uric acid, allantoin is soluble and easily excreted by the kidneys. Elimination half-life is 18 h.

Dosing

Adult

0.15-0.2 mg/kg/d IV infused over 30 min for 5 d; dilute in 50 mL 0.9% NaCl

Pediatric

Administer as in adults

Interactions

None reported

Contraindications

Documented hypersensitivity; G-6-PD deficiency; pregnancy

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, or 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°C and centrifuged at that temperature, maintain resultant plasma at 4°C and analyze within 4 h of collection

Alkalinizing agents

These agents may prevent the crystallization of uric acid.

Acetazolamide (Diamox)

Carbonic anhydrase inhibitor. May be added to decrease proximal tubule bicarbonate reabsorption, thereby increasing urinary pH.

Dosing

Adult

250-500 mg/d IV (5 mg/kg/d)

Pediatric

Not established

Interactions

Can decrease therapeutic levels of lithium and alter excretion of drugs (eg, amphetamines, quinidine, phenobarbital, salicylates) by alkalinizing urine

Contraindications

Documented hypersensitivity; hepatic disease; severe renal disease; adrenocortical insufficiency; severe pulmonary obstruction

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

Patients with impaired hepatic function may go into coma; may cause substantial increase in blood glucose in some diabetic patients

Sodium bicarbonate (Neut)

Used IV to alkalinize urine. Promotes alkaline diuresis with potential benefits of solubilizing, and thus minimizing, intratubular precipitation of uric acid. Goal is to increase urinary pH to 7 to maximize uric acid solubility in renal tubules and vessels. Routine urine alkalinization is controversial, and if employed must include close monitoring of urinary pH, serum bicarbonate, and uric acid levels. Consider withdrawing sodium bicarbonate from IVF solutions once serum bicarbonate levels reach 30 mEq/L, urinary pH >7.5, or serum uric acid levels have normalized.

Dosing

Adult

1 ampule (44 mEq) of sodium bicarbonate is added to 1 L of 0.45% isotonic saline and infused at 100 cc/h IV

Pediatric

1.9 mEq/kg IV q1-2h prn

Interactions

Urinary alkalinization, induced by increased sodium bicarbonate concentrations, may decrease levels of lithium, tetracyclines, chlorpropamide, methotrexate, and salicylates; increases levels of amphetamines, pseudoephedrine, flecainide, anorexiants, mecamylamine, ephedrine, quinidine, and quinine

Contraindications

Documented hypersensitivity; alkalosis; hypernatremia; hypocalcemia; severe pulmonary edema; abdominal pain of unknown cause

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

Can cause alkalosis, decreased plasma potassium, hypocalcemia and hypernatremia; caution in electrolyte imbalances (eg, patients with CHF, cirrhosis, edema, corticosteroid use, renal failure); when administering, avoid extravasation since can cause tissue necrosis

Electrolytes

These agents are used to prevent and treat hyperkalemia and restore electrolyte balance.

Dextrose (D-glucose) plus insulin

Promotes redistribution of potassium from extracellular to intracellular space. Stimulates cellular uptake of potassium within 20-30 min. Glucose should be administered along with insulin to prevent hypoglycemia. Monitor blood sugar levels frequently.

Dosing

Adult

Suggested dosing:
10 U IV and 50 mL D50W bolus or 500 mL D10W over 1 h

Pediatric

Not established

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, oral 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, increasing need for insulin to treat hyperkalemia; hypothyroidism may delay insulin turnover, decreasing need for insulin to treat hyperkalemia; monitor glucose carefully; dose adjustments of insulin may be necessary in patients diagnosed with renal or hepatic dysfunction

Calcium gluconate (Kalcinate)

Used for cardioprotection for potassium levels >6.5 mmol/L or for patients with ECG alterations. Moderates nerve and muscle performance, and facilitates normal cardiac function.

Dosing

Adult

100-300 mg elemental calcium IV diluted in 150 mL D5W over 10 min; initial rate of infusion should be 0.3-2 mg of elemental calcium/kg/h

Pediatric

2 mg/kg of elemental calcium IV (about 20 mg/kg of calcium gluconate 10%)

Interactions

May decrease effects of tetracyclines, atenolol, salicylates, iron salts, and fluoroquinolones; antagonizes effects of verapamil; large intakes of dietary fiber may decrease absorption and levels

Contraindications

Documented hypersensitivity; renal calculi; hypercalcemia; hypophosphatemia; renal or cardiac disease; digitalis toxicity

Precautions

Pregnancy

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

Precautions

Caution in digitalized patients, respiratory failure, acidosis, or severe hyperphosphatemia

Diuretics

These agents should be reserved for well-hydrated patients with insufficient diuresis.

Furosemide (Lasix)

Increases excretion of water by interfering with chloride-binding cotransport system that in turn inhibits sodium and chloride reabsorption in ascending loop of Henle and distal renal tubule. Not proven to be beneficial as front-line therapy in TLS. May contribute to uric acid or calcium phosphate precipitation in renal tubules in volume-contracted patients.

Dosing

Adult

20-80 mg/d PO/IV/IM

Pediatric

1-2 mg/kg/dose PO; not to exceed 6 mg/kg/dose; do not administer more frequently than q6h
1 mg/kg IV/IM slowly under close supervision; not to exceed 6 mg/kg

Interactions

Metformin decreases concentrations; interferes with hypoglycemic effect of antidiabetic agents and antagonizes muscle-relaxing effect of tubocurarine; aminoglycosides increase auditory toxicity—hearing loss of varying degrees may occur; may increase anticoagulant activity of warfarin; may increase plasma lithium levels and toxicity

Contraindications

Documented hypersensitivity; hepatic coma; anuria; severe electrolyte depletion

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

Perform frequent serum electrolyte, CO₂, glucose, creatinine, uric acid, calcium, and BUN determinations during first few months of therapy and periodically thereafter

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 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 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.
• Iatrogenic complications, such as pulmonary edema from overly vigorous hydration or metabolic alkalosis from excess exogenous administration of bicarbonate, can also occur and are life threatening if not immediately addressed.

References

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Keywords

tumor lysis syndrome, TLS, acute tumor lysis syndrome, ATLS, hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, acute renal failure, ARF, malignancy-associated hyperuricemia, acute leukemia, non-Hodgkin lymphoma, Burkitt lymphoma, Burkitt's lymphoma, malignancy, anticancer treatment, cancer treatment, acute hyperphosphatemia, cardiac arrhythmia, metabolic acidosis, rapid tumor cell turnover, metabolic derangements, rapid cell lysis

Contributor Information and Disclosures

Author

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.

Coauthor(s)

Ahmad Hammad, MD, Clinical Assistant Professor, Department of Internal Medicine, Division of Hematology/Oncology, East Tennessee State University, James H Quillen Veterans Affairs Medical Center
Disclosure: Nothing to disclose.

Medical Editor

Philip Schulman, MD, Chief, Medical Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center; Clinical Professor, Department of Medicine, New York University School of Medicine
Philip Schulman, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, American Society of Hematology, and Medical Society of the State of New York
Disclosure: celgene Honoraria Speaking and teaching; Amgen Honoraria Speaking and teaching; genetech/idec Honoraria Speaking and teaching

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

CME Editor

Rajalaxmi McKenna, MD, FACP, Consulting Staff, Department of Medicine, Southwest Medical Consultants, SC, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Jules E Harris, MD, Clinical Professor of Medicine, Division of Hematology/Medical Oncology, Department of Internal Medicine, University of Arizona College of Medicine at Tucson; Consulting Staff, Arizona Cancer Center
Jules E Harris, MD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Association of Immunologists, American Society of Hematology, and Central Society for Clinical Research
Disclosure: GlobeImmune Salary Consulting; Amplimed Consulting fee Consulting

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