Rasburicase Rasburicase, recombinant urate oxidase, converts

2005 ; Patel et al. 2012 . An economic analysis by Annemans et al. 2003 b reported that rasbu- ricase is highly cost effective in the pediatric cohort, but the analysis was based on preventing treating HU and LTLS rather than clinically sig- nifi cant endpoints. Another economic compari- son specifi cally in pediatric patients showed no difference in total cost or length of stay between those treated with allopurinol and rasburicase although the number of days in critical care was signifi cantly reduced in the rasburicase cohort Eaddy et al. 2010 . Consensus guidelines rec- ommend rasburicase in those with “high-risk disease,” defi ned as AML with WBC ≥ 100 × 10 9 L, ALL with LDH ≥2× ULN or WBC ≥100 × 10 9 L, BL with LDH ≥2× ULN or advanced stage i.e., IIIIV, other NHL with advanced stage and LDH ≥2× ULN, and any patient with LTLS Cairo et al. 2010 . Tosi et al. 2008 defi ne high risk as those with renal impairment, obstructive uropathy, hyperurice- mia uric acid 8 mgdL, bulky disease, high- grade lymphoma, T cell ALL or LDH 2× ULN. Although some of these patients will ben- efi t from the addition of rasburicase, many of these subpopulations likely do not need rasburi- case in all cases, such as ALL with solely LDH ≥ 2× ULN or WBC ≥100 × 10 9 L, AML with WBC ≥100 × 10 9 L, all T cell ALL, all LDH ≥ 2× ULN, and those with LTLS but without HU Table 3.3 Tosi et al. 2008 ; Agrawal and Feusner 2011 .

3.4.2 Hyperkalemia

Potassium, the most abundant intracellular cation, is released into the circulation when cells lyse. The rate of release of potassium from malignant cells can exceed the excretory capa- city of the kidney resulting in hyperkalemia. Dehydration, renal insuffi ciency and inadvertent iatrogenic administration of potassium are fac- tors that can exacerbate the degree of hyperkale- mia observed in TLS. Hyperkalemia can be acutely life threatening by precipitating cardiac arrhythmias and therefore is a medical emergency that warrants prompt intervention. Treatment of hyperkalemia involves three main mechanisms: 1 stabilization of the resting membrane poten- tial of cardiac myocytes, 2 transmembrane shifting of potassium from the extracellular to the intracellular compartment, and 3 enhanced excretion of potassium. Care should be taken to eliminate parenterally administered forms of potassium e.g., intravenous fl uids should not contain potassium. Enterally consumed sources of potassium should be minimized. Administration of calcium gluconate helps stabilize the resting membrane potential of the myocardium. Calcium gluconate should be given to any patient with a serum potassium level 7.0 mEqL or any patient with evidence of an arrhythmia Coiffi er et al. 2008 . Calcium gluco- nate has an onset of action within minutes with a duration of effect of about 30 min. Due to the short half-life, the dose may need to be repeated until more defi nitive measures to reduce the potassium have been initiated. The translocation of potassium from the extracellular compartment to the intracellular compartment is an effective, albeit, temporary management strategy. Drugs that can be used to shift potassium into the intracellular compartment include the combina- tion of insulin and glucose, β-agonists such as albuterol, and sodium bicarbonate. The combi- nation of insulin and glucose shifts potassium into cells within 10–20 min, has a duration of effect that lasts 2–3 h and can lower serum potassium by 0.5–1.5 mEqL Gennari 2002 . Continuous inhalation of albuterol is equally effective compared to insulin and glucose with a similar duration of effect; however the onset of action is slightly longer at 20–30 min Gennari 2002 . Sodium bicarbonate can be used to shift potassium intracellularly when an acido- sis is present but is felt to be somewhat less effective than insulin and glucose or albuterol Gennari 2002 . The defi nitive treatment of hyperkalemia involves enhancing the excretion of potassium in order to lower body levels. Ion-exchange resins such as sodium polystyrene sulfonate Kayexalate® administered orally along with the laxative sorbitol bind to potassium in the colon and enhance excretion of potassium in the stool. The onset of action of sodium polystyrene sulfonate is delayed and can take up to 4–6 h, necessitating the administration of more tempo- rizing measures in the interim Gennari 2002 . Potassium-wasting loop diuretics such as furose- mide can be used to enhance renal excretion of potassium. Furosemide should be used with caution in patients with renal insuffi ciency i.e., estimated GFR 35 mLmin1.73 m 2 using the Schwartz formula and should be avoided in patients with hypovolemia Schwartz et al. 1987 . Dialysis should be considered in the patient with hyperkalemia not improving with the above therapies, at risk for continued signifi - cant cell lysis or with oliguriaanuria. See Table 3.3 for a summary of recommendations, dosing and grading.

3.4.3 Hyperphosphatemia

The backbone of DNA is abundantly rich in phos- phate and tumor cells have been noted to have sig- nifi cantly increased phosphate concentrations Traut 1994 . Therefore, actively dividing malig- nant cells are a risk for hyperphosphatemia with rapid cell lysis. Hyperphosphatemia in and of itself rarely leads to clinical symptoms; however, signifi cant complications can arise if calcium phosphate precipitates in the kidneys leading to nephrocalcinosis and AKI. The treatment of hyperphosphatemia includes hyperhydration, limiting enteral intake of phos- phate, utilization of phosphate binders, and, when severe, initiation of dialysis. Phosphate binders used in the treatment of TLS include alu- minum hydroxide, sevelamer and calcium car- bonate Abdullah et al. 2008 . Prolonged use of aluminum hydroxide beyond 1–2 days has been cautioned against in order to avoid the potential for aluminum toxicity Coiffi er et al. 2008 . Patients with hyperphosphatemia should not receive urinary alkalinization as described. Calcium carbonate should be utilized with cau- tion due to the potential for calcium phosphate precipitation. See Table 3.3 for a summary of rec- ommendations, dosing and grading.

3.4.4 Hypocalcemia

In order to maintain a steady level of calcium rela- tive to phosphorus i.e., calcium-phosphate prod- uct, calcium and phosphate have an inverse homeostatic relationship. Therefore the hypocal- cemia seen in TLS is a direct consequence of hyperphosphatemia. Clinical symptoms of hypo- calcemia include neuromuscular irritability e.g., muscle cramps, tetany, carpopedal spasms, sei- zure and cardiac arrhythmias, and can range in severity from relatively minor to potentially life- threatening Diercks et al. 2004 . Accurate mea- surement of serum calcium levels is dependent upon albumin levels. When the patient is hypoal- buminemic, an ionized calcium level should be measured to confi rm the degree of hypocalcemia. No intervention is needed for the patient with asymptomatic hypocalcemia. For patients who are symptomatic, calcium gluconate may be administered. The lowest dose required to allevi- ate symptoms should be given in order to mini- mize the risk for calcium phosphate precipitation. The risk for precipitation is not insignifi cant and can be estimated by calculating the calcium- phosphate product serum calcium multiplied by serum phosphate. Risk for nephrocalcinosis increases as the calcium-phosphate product increasingly exceeds 60 mg 2 dL 2 Howard et al. 2011 . See Table 3.3 for a summary of recom- mendations, dosing and grading.

3.5 Renal Interventions

No clear evidence-based guidelines exist as to when dialysis should be implemented for TLS. Coiffi er et al. 2008 suggest renal consul- tation in patients with decreased urine output and in those with persistent hyperphosphatemia or hypocalcemia. Tosi et al. 2008 suggest renal replacement therapy in those with persistent hyperkalemia, severe metabolic acidosis, volume overload not respon ding to diuresis, and uremic symptoms such as pericarditis and encephalopa- thy. The need for dialysis with hyperuricemia is unlikely other than in settings without access to