A. Tumor lysis syndrome
1. Overview
a. Acute tumor lysis syndrome is a consequence of the rapid release of intracellular metabolites (uric acid, potassium, and phosphorus) in quantities that exceed the excretory capacity of the kidneys.
b. Renal failure and hypocalcemia are common complications.
2. Etiology
a. Tumor lysis syndrome is seen in tumors that have a high growth fraction and that are exquisitely sensitive to chemotherapy.
b. Burkitt lymphoma and T-cell leukemia-lymphoma syndrome and/or hyperleukocytosis are the most common causes. Evidence for the onset of tumor lysis can be found before beginning therapy, because of sponta-eous tumor degradation, and also from 1 to 5 days after the initiation of treatment.
3. Evaluation
a. Perform repeated physical examinations.
b. Measure urine output, blood pressure, and weight 1-3 times daily.
c. Monitor serum creatinine, uric acid, calcium, sodium, phosphate, and potassium every 8 hours until the risk period is over.
d. If the patient remains oliguric, imaging studies of the kidney may be useful to rule out obstructive uropathy.
4. Prevention
a. Urine output should be maintained at >5 mL/kg/h before initiating chemotherapy and at >3 mL/kg/h once chemotherapy is begun, and verified every 2 to 4 hours. If urine output falls, institute corrective measures promptly (more fluids and/or diuretics).
b. Assure adequate hydration by replacing calculated deficits: intravenous (IV) fluids at 3000 mL/m2/day; may need to increase fluids further to maintain urine output.
c. Diuresis with furosemide (Lasix) (0.5-1 mg/kg) or mannitol (circulating fluid volume must be adequate: 5-15 g/m2 as 2596 solution over 5-10 minutes repeated every
6 hours as necessary to achieve desired urine volume).
5. Management
a. Hyperuricemia (>8 mg/dL)
An elevated uric acid results from nucleic acid breakdown. Urates can precipitate in the acid environment of the kidney, causing renal failure.
i. Allopurinol 300 mg/m2/day divided t.i.d.
ii. Alkalinization of urine pH from >6.5 to <7.5 with NaHC03 120 mEq/m2/day IV will increase the solubility of urates; pH >7.5 is associated with a precipitation of hypoxanthine as well as calcium phosphate crystals. Alkalinization should be discontinued once uric acid is controlled and/or if phosphorus is elevated.
b. Hyperphosphatemia (>6.5 mg/dL)
Lymphoblasts have four times the content of phosphate of normal lymphocytes. When the calcium phosphate product exceeds 60, calcium phosphate precipitates in microvasculature and renal tubules, which can lead to renal failure.
i. Low-phosphate diet
ii. Aluminum hydroxide 150 mg/kg/day divided q4-6h
iii. urine output >3 mL/kg/h
c. Hyperkalemia (>6.0 mEq/L)
Potassium can be elevated because of tumor lysis or secondary to renal failure. Hyperkalemia leads to ventricular arrhythmias and death.
i. Do not administer intravenous potassium until the
tumor lysis is controlled.
ii. Sodium polystyrene sulfonate (Kayexalate) removes 1 mEq potassium/L/g resin over 24 hours; give as 1 g/kg PO q6h with sorbitol 50-150 mL. This is not an emergency intervention. The duration of action depends on the rate of endogenous potassium release.
iii. Administering calcium is the fastest means of reversing the cardiac effects of hyperkalemia. The onset of action is within minutes, but the duration of action is only about a 1/2 hour. Administer for life-threatening arrhythmias as calcium chloride 10 mg/kg IV. (Do not administer in the same line as sodium bicarbonate.)
iv. Sodium bicarbonate at 1-2 mEq/kg IV will drive potassium into the cell. For every increase in 0.1 pH unit, potassium decreases about 1 mEq/L. The onset of action is in 1/2 hour; the duration of activity is several hours.
v. Administering insulin and glucose will also move excess potassium into the cell. Glucose is administered continuously at 0.5 g/kg/h with insulin 0.1 U/kg/h. Monitor serum glucose closely and adjust infusion rates appropriately. In an emergency, glucose alone can facilitate potassium entry into the cell (1 mL/kg of 5056 dextrose in a central line). Onset is in 20-30 minutes; the duration of activity is several hours.
d. Hypocalcemia (ionized calcium <1.5 mEq/L) Hypocalcemia occurs secondary to hyperphosphatemia as a compensatory mechanism to maintain the calcium phosphate product at 60. i. For symptomatic hypocalcemia, administer 10 mg/kg of elemental CaCl in a drip over several minutes. ii. Discontinue administration when symptoms resolve. e. Dialysis Indications include fluid overload with congestive heart failure, anuria, symptomatic hypocalcemia with hyperphosphatemia, hyperkalemia with QRS interval widening which generally occurs with potassium >6, and elevated creatinine with poor urine output.
f. Institute hyperleukocytosis interventions if appropriate.
B. Hypercalcemia
1. Overview
a. Hypercalcemia, a paraneoplastic syndrome, although rarer in children than in adults, has been reported in patients with leukemias, lymphomas, rhabdomyosarcoma, neuroblastoma, Ewing sarcoma, Wilms tumor, and rhabdoid tumors of the kidney.
b. Mechanisms postulated to be the cause for the hypercalcemia are the following.
i. Production by the tumor of a parathyroid hormone-related protein
ii. Production by the tumor of bone-resorbing substances (Iymphotoxin and tumor necrosis factor)
iii. Elevation of 1,25 dihydroxyvitamin D
iv. Production of parathyroid hormone
c. All the above cause excess release of calcium from bone into the blood. This results in polyuria, dehydration leading to diminished glomerular filtration with increased renal absorption of calcium, worsening the hypercalcemia.
2. Evaluation
a. The normal value of calcium corrected for albumin is 9-11 mg/dL (4.5-5.5 mEq/L). Mild hypercalcemia can be defined as 12-14 mg/dL (6-7 mEq/L) and severe hypercalcemia is >15 mg/dL (7.5 mEq/L). Add 0.8 mg/dL of calcium for every gram per liter reduction of serum albumen.
b. Non-protein-bound ionized calcium (normal = 1.00-1.31 mmol/L) is of greater physiologic importance and does not need correction for serum protein.
Management
a. Mild hypercalcemia
i. Administer intravenous hydration with normal saline (3000 mL/m2/day) and encourage oral intake. High fluid volume promotes the excretion of calcium, and saline interferes with the reabsorption of calcium in the proximal tubule of the kidney.
ii. Furosemide 1-2 mg/kg IV t.i.d. or q.i.d. blocks the
reabsorption of calcium in the ascending loop of
Henle.
iii. Monitor electrolytes frequently.
iv. Maintain exercise and movement.
b. Severe hypercalcemia
i. Increase intravenous hydration to 6000 mL/m2/day and continue furosemide as above.
ii. Administer biphosphonates such as pamidronate 60 mg IV over 4 hours once for children over 50 kg. May repeat in 7 days as necessary The dosage for smaller children has not been established. Action results in an inhibition of bone resorbtion.
iii. For lymphoproliferative disorders, steroids (prednisone 2 mg/kg/day or its equivalent) may decrease serum calcium over several days of use.
iv. Calcitonin, gallium nitrate, indomethacin, and mithramycin have all been used with some success but should be tried only if the above fails.
v. Oral or intravenous phosphates seem to have more toxicity than benefit. They decrease bone resorption and can increase extraosseous bone formation, possibly leading to increased renal toxicity. If they are used, monitor carefully, vi. For patients refractory or resistant to other methods of treatment, dialysis, either peritoneal or hemodialysis, can be used.
C. Syndrome of inappropriate antidiuretic hormone
1. Overview
Antidiuretic hormone (ADH or arginine vasopressin) causes the resorption of free water at the renal collecting duct; thus, it is an important mechanism in regulating the volume and osmolality of extracellular fluid.
a. ADH is released from the pituitary gland when osmoreceptors in the hypothalamus detect increased osmolality of the serum.
b. Secretion of ADH also occurs when volume receptors in the left atrium, carotid sinus, and aortic arch detect decreased effective circulating volume.
c. Volume depletion stimulates the secretion of ADH regardless of serum osmolality.
2. Etiology
The syndrome of inappropriate antidiuretic hormone (SIADH) exists when the release of ADH occurs in the absence of increased serum osmolality or volume depletion and is not suppressed by further volume depletion. It may occur with the following.
a. Malignancies (e.g., leukemia, lymphoma, Ewing sarcoma, and brain tumor)
b. Drugs (e.g., vincristine, vinblastine, barbiturates, and opiates)
Cyclophosphamide produces a SIADH-Iike syndrome by acting directly at the kidney tubule to enhance the absorption of free water.
c. Head trauma
d. Infection of the central nervous system (CNS) or lungs
e. Pain and/or stress
f. Surgery
3. Evaluation
a. The urine is maximally dilute with a relatively high urinary sodium (>20 mEq/L) despite hyponatremia and low serum osmolality.
b. Volume depletion, nephrotic syndrome, adrenal insufficiency, hypothyroidism, and congestive heart failure are absent.
4. Management
a. Treatment of the underlying disorder
b. Mild disease
i. Fluid restriction, equaling urine output
ii. Normal maintenance of Na+ intake
c. Severe hyponatremia (120-125 mEq/L) without life- threatening symptoms
i. Furosemide 1 mg/k promotes a free water diuresis.
ii. Replace urine loss milliliter for milliliter with normal saline.
iii. Demeclocycline 6.6-13.2 mg/kg divided into 2-4 doses (maximum 600-1200/day) inhibits the action of ADH on renal tubules by interfering with the formation and action of cyclic adenosine monophosphate.
d. Life-threatening neurologic symptoms (convulsions and stupor)
i. Furosemide 1 mg/kg promotes a free water diuresis.
ii. To correct sodium to 120 mEq/L, give 200 mL/m2 of 1.5% NaCl in 6-8 hours, and then more slowly to normal over 24-72 hours.
iii. It is important to avoid a rapid correction of serum sodium. Hypertonic sodium causes a sodium diuresis and may exacerbate the loss of sodium. Neurologic deterioration and death have occurred with too-rapid correction of serum Na+.
Hypokalemia
1. Overview
a. Normal serum potassium is 3.5-5.5 mEq/L; electrocardiogram (ECG) changes are seen at <2.5 mEq/L.
b. The principal effects are on cardiac rhythm, with symptoms occurring most commonly when the cause is acute.
c. Patients may develop ileus or muscle weakness.
2. Etiology
a. Renal wasting secondary to drugs is the usual etiology in pediatric cancer patients.
b. Commonly administered agents associated with tubular potassium loss include amphotericin B, antipseudo-monal penicillins, aminoglycosides, ifosfamide, cisplatin, loop diuretics, and glucocorticoids.
3. Evaluation
a. A semiquantitative assessment of potassium needs per day determines the potassium content of the patient’s spot urine and the 24-hour urine output.
b. Serum magnesium must be assessed, as potassium
cannot be conserved without adequate magnesium.
4. Management
a. Oral therapy is indicated for chronic hypokalemia.
b. Intravenous replacement is indicated for an acute decrease (particularly <2.5 mEq/L) or if the patient cannot take an oral supplement. c. The potassium infusion rate should not exceed 0.5 mEq/kg/h. d. Potassium concentrations of 100 mEq/L are acceptable in a central line. Concentrations > 40 mEq/L administered via peripheral vein are irritating or painful and can cause phlebitis.
e. ECG monitoring throughout IV potassium replacement is essential.
f. Potassium-sparing diuretics such as amiloride or
aldactone may help conserve potassium.
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