Pathophysiology: Tumor lysis syndrome can be precipitated before the initiation of therapy or up to 5 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 most frequently are associated with this complication. It also has been seen in association with solid tumors like hepatoblastoma and stage IV neuroblastoma. 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, uric acids (from nucleic acids), and phosphorus leading to hyperkalemia, hyperuricemia, hyperphosphatemia with secondary hypocalcemia. These can subsequently lead to renal failure. These complications may result in multiple organ failure and death. The kidneys primarily excrete uric acid, phosphorus, and potassium. Uric acid (pKa = 5.4)is soluble at physiologic pH, but can precipitate in an acidic environment of renal tubules leading to crystallization in collecting ducts and the ureters, causing obstructive uropathy. Calcium phosphate is precipitated in the renal tubules and microvasculature as the in vivo calcium-phosphorus solubility product exceeds 60-70 due to hyperphosphatemia. It is important to note that the phosphorus content of the lymphoblasts is 3 -4 times the content of normal lymphocytes. Symptomatic hypocalcemia may result from hyperphosphatemia. Hyperkalemia results from release of intracellular potassium and is aggravated further by renal failure and metabolic acidosis.

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, 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: Special attention should be given to the following:

• Blood pressure and cardiac rhythm

• Hyperuricemia may be responsible for myriad of abnormal physical findings.

• Lethargy, nausea, and vomiting manifest at uric acid levels of 10-15 mg/dL.

• Signs of frank renal failure, such as hypertension and altered sensorium, present at uric acid levels in the excess of 20 mg/dL

• Hypocalcemia may manifest as carpopedal spasms, tetany, seizures, 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.

• Hyperkalemia can cause fatal ventricular arrhythmias.

• Patients with malignancy may be at risk of tumor lysis if they have the following findings:

• Signs of massive tumor

• Superior vena caval obstruction

• Tracheal obstruction

• Pleural effusion

• Ascites

• Palpable kidneys

• Cerebral edema

Other Problems to be Considered:

Pseudohyperkalemia may result from lysis of cells occurring during collection, clotting or storage of blood samples. This problem is more likely when the leukocyte count exceeds 50,000/mm³, the platelet count exceeds 1,000,000/mm³, or if blood is collected through narrow bore needles or by capillary sampling.

Lab Studies:

• Order several laboratory studies immediately.

• Complete blood count (CBC) will help determine leukocyte and platelet counts.

• A sample of blood collected by a wide bore needle or, preferably, an indwelling cannula should be used to get a biochemical profile of the patient for biochemical monitoring, which includes serum sodium, potassium, chloride, and bicarbonate. The presence of indwelling cannula could be dangerous in presence of large mediastinal tumor bulk.

• Blood urea nitrogen (BUN) and creatinine as markers of renal function

• Obtain calcium, ionized calcium, magnesium and phosphorus levels to determine the extent of hypocalcemia and hyperphosphatemia.
  Coincident hypomagnesemia needs to be treated.

• Serum uric acid level should be obtained to determine the extent of hyperuricemia.

• Urinalysis will help the clinician determine urine pH and visualize abnormalities, such as uric acid crystals.

• Serum albumin may need to be determined to differentiate between true and pseudohypocalcemia.
  A decrease in serum albumin by 10 gm/L lowers serum calcium by 0.2 mmol/L. However, serum albumin does not affect the levels of ionized calcium.

Imaging Studies:

• Radiograph and computed tomography of chest is useful to determine the extent and local invasion of the lesion.

• Perform ultrasonography or computed tomography of 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:

• ECG monitoring of patient is strongly recommended.

• Serum potassium level >7 mEq/L is associated with ECG changes, such as tall, peaked T waves and QRS widening.

• ECG also helps in differentiating true hyperkalemia from pseudohyperkalemia when no electrocardiographic changes are present.

• Hypocalcemia may manifest as prolonged QT interval on ECG.

Procedures:

• Endotracheal intubation may be required in a patient with mental status changes or in uncontrolled symptoms of severe metabolic disturbances, such as seizures and cardiac arrhythmias.

• Urinary catheter placement in patients with renal failure may be necessary for exact quantification of urine output.

• Central venous catheter placement may be necessary for accurate monitoring of central venous pressure in a patient with renal failure and hemodynamic instability.

• Patient with severe renal failure will require access for hemodialysis or a peritoneal dialysis catheter.

Medical Care: Identification of patients at risk and initiation of preventive interventions are the focus of medical and nursing management.

• Ongoing monitoring is necessary to promote early response to changes in patient condition and minimize adverse events. This requires frequent blood sampling in the initial period of clinical instability or potential instability. Testing at 4-8 hour intervals may be required in a patient at high risk for tumor lysis syndrome.
  Additionally, careful monitoring of the patient’s intake and output, weight and blood pressure must be done at close intervals.

• Metabolic stability must be achieved even before treatment proceeds.

• Prevention of renal failure entails hydration, alkalinization, and metabolic correction using medications.

• Hydration is the most critical factor. Patients should receive 2-3 times maintenance fluid volume as 5% dextrose in 0.2% NaCl. This should be monitored to maintain a urine output of at least 3 mL/kg/h for children younger than 9 years and approximately 90 mL/m²/h in older children. With adequate fluids, diuresis may be assisted with furosemide or mannitol. Avoid adding potassium to intravenous fluids.

• Sodium bicarbonate of 75-100 mEq/L (100-125 mEq/m²)should be added to IV fluids to achieve urinary pH of 7-7.5 and urine specific gravity of 1.010 to enable efficient excretion of uric acid in soluble form.

• Vigorous alkalinization is no longer required after allopurinol has been started and the uric acid level is back to normal to decrease the potential problems with hypocalcemia and hyperphosphatemia.

Surgical Care: Patients with tumor lysis syndrome may need surgical intervention in the form of dialysis catheter placement in cases of extreme hyperkalemia or renal failure.

Consultations: Effective management of patients with tumor lysis syndrome requires a team approach on part of medical and nursing staff.

• Treat patients with tumor lysis syndrome in an intensive care unit with active participation of the oncologist, intensivist, nephrologist, and general surgeon.

Management of tumor lysis syndrome, apart from hydration and alkalinization, necessitates use of drugs to correct metabolic disturbances. Use of medications must be instituted before the start of chemotherapy; the aim is to achieve optimal metabolic stability.

An alternative to allopurinol for decreasing uric acid load is urate oxidase, which controls hyperuricemia by converting uric acid to water-soluble allantoin. This drug is used widely in Europe and was recently FDA-approved 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 oral administration.
Caution is necessary because of the high uric acid concentration in the urine. Andreoli and associates explained some cases of renal failure on the basis of effects of allopurinol in altering purine excretion. In 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 intravenous fluids.

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

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 used primarily to protect the myocardium from the deleterious effects of hyperkalemia (ie, arrhythmias) by antagonizing the membrane actions of potassium.

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 Category: Exchange resin -- 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 Category: Phosphate binding agents -- Used to treat hyperphosphatemia.

Further Inpatient Care:

• The majority of patients with acute renal failure can be managed conservatively, but consider peritoneal or hemodialysis if conservative management fails.

• Dialysis may be indicated if the following apply. The decision to initiate dialysis is usually not based on a single lab abnormality, but on the constellation of findings and the likelihood of further clinical deterioration. Each of the lab findings below is much more worrisome in the setting of oliguria or anuria.

• Uncontrolled hyperkalemia (generally serum potassium >7 mEq/L)

• Worsening hyperuricemia (serum uric acid >10 mg/dL and increasing; elevated uric acid in the absence of other abnormalities usually does not require dialysis)

• Symptomatic hypocalcemia

• Serum phosphorus (>10 mg/dL or persistent symptomatic hypocalcemia)

• Uncontrolled hypertension and hypervolemia

• Significant elevation of serum creatinine and blood urea nitrogen in the setting of other metabolic abnormalities or decreasing urine output. Elevation of these parameters of renal function in the absence of other abnormalities is usually not used as an indication to start dialysis.

• Hemodialysis is preferred over peritoneal dialysis because it corrects metabolic disturbances very rapidly. Peritoneal dialysis clears uric acid with only 10% efficiency of hemodialysis and also is contraindicated in abdominal tumors. Chemotherapy can be reinstated with the initiation of dialysis. Dialysis usually is required for 4-11 days, until the patient's own kidney function has recovered.

• Many centers employ modalities, such as leukopheresis, exchange transfusion, or low dose steroids, to reduce the metabolic consequences of massive tumor lysis, which occurs often in a setting of a high leukocyte count. None of the above methods have been subjected to any controlled analysis. However more and more North American protocols are using steroids and allowed for registration after 48 hours of steroid therapy. Leukopheresis is often considered at leukocyte counts of greater than 100,000/mm³ in patients with AML or greater than 400,000 in patients with ALL, and may be more successful at correcting leukostasis than preventing tumor lysis syndrome.

Transfer:

• Manage patients with complicated tumor lysis syndrome in an intensive care setting. Once hemodynamically stable, patients can be transferred to regular floor with rigorous monitoring.

Complications:

• Tumor lysis syndrome can be complicated by several problems that may be severe and life threatening in a patient who has the potential to attain full remission. Therefore, it is of paramount importance to evaluate high-risk patients frequently by clinical assessment and biochemical monitoring.

• The metabolic disturbances encountered during tumor lysis syndrome may be responsible for CNS complications, such as seizures.

• Cardiac complications, such as ventricular arrhythmias leading to multiple organ failure and death, may result from hyperkalemia.

• The course of tumor lysis syndrome may be complicated by acute renal failure, as described above.

• Vigorous prophylactic management, anticipation, and the prompt treatment of detected metabolic problem are essential for the optimal management of high-risk patients.