Allopurinol Allopurinol inhibits xanthine oxidase, an enzyme

3.4.1.3 Rasburicase Rasburicase, recombinant urate oxidase, converts

uric acid into allantoin, a fi ve to ten times more soluble compound, in an extremely effective manner. Due to this fact, many studies have shown that rasburicase is effi cacious in correct- ing HU in pediatric and adult patients Pui et al. 2001 ; Patte et al. 2002 ; Bosly et al. 2003 ; Coiffi er et al. 2003 ; Jeha et al. 2005 ; Pession et al. 2005 ; Shin et al. 2006 ; Kikuchi et al. 2009 . Follow-up studies comparing effi cacy of rasburicase and allopurinol naturally show that rasburicase is much more effective in rapidly and dramatically reducing the uric acid level although such studies fail to incorporate a clinically relevant endpoint Goldman et al. 2001 ; Cortes et al. 2010 . Many of these studies were supported by the pharma- ceutical maker of rasburicase, including grant support, providing the drug, logistic support, edi- torial support, and data management, and some study authors had a fi nancial stake in the pharma- ceutical company Goldman et al. 2001 ; Pui et al. 2001 ; Patte et al. 2002 ; Bosly et al. 2003 ; Coiffi er et al. 2003 ; Jeha et al. 2005 ; Shin et al. 2006 ; Kikuchi et al. 2009 ; Cortes et al. 2010 . Early studies also utilized higher doses of rasburicase i.e., 0.15–0.2 mgkgday and for a longer dura- tion up to 7 days based on the recommendation of the manufacturer and what was approved by the United States Food and Drug Administration [FDA], rather than what is more rational based on the mechanism of the drug and underlying dis- ease process Pui et al. 2001 ; Patte et al. 2002 ; Bosly et al. 2003 ; Coiffi er et al. 2003 ; Jeha et al. 2005 ; Pession et al. 2005 ; Shin et al. 2006 ; Kikuchi et al. 2009 . Rasburicase doses as low as 0.017 mgkg as a single dose have subsequently been found effec- tive; many studies have shown that abbreviated rasburicase schedules are suffi cient Hummel et al. 2003 ; Lee et al. 2003 ; Liu et al. 2005 ; Ho et al. 2006 ; Hutcherson et al. 2006 ; McDonnell et al. 2006 ; Trifi lio et al. 2006 ; Reeves and Bestul 2008 ; Campara et al. 2009 ; Giraldez and Puto 2010 ; Vadhan-Raj et al. 2012 . Hummel et al. 2007 were able to utilize a low-dosing schedule resulting in an average decrease in uric acid lev- els by 83 while utilizing a median total dose of rasburicase of 0.049 mgkg, resulting in a cost reduction of 96.8 based on manufacturer dos- ing recommendations. Adult patients with initial average hyperuricemia of 13.1 mgdL were able to achieve uric acid 8.0 mgdL with an average single rasburicase dose of 0.032 mgkg Hummel et al. 2007 . Knoebel et al. 2011 similarly showed that most adult patients could be effec- tively treated with a single 0.05 mgkg dose. Yet, recent consensus guidelines still recommend a range of 1–7 days of rasburicase at a dose of 0.1–0.2 mgkgdose Coiffi er et al. 2008 ; Tosi et al. 2008 ; Pession et al. 2011 . Although gener- ally safe, rasburicase must be avoided in patients with glucose-6-phosphate dehydrogenase G6PD defi ciency and methemoglobinemia, and hemolytic anemia has been reported in childhood ALL Bauters et al. 2011 . Even though HU is a factor in LTLS, data are less clear that rasburicase is more effective in the prevention of CTLS than allopurinol. In their analysis of BFM data, Wössmann et al. 2003 compared LTLS and anuria risk in pediatric ALL and stage IIIIV BL patients with LDH ≥500 UL treated with either allopurinol or rasburicase; they found that although ALL patients treated with rasburicase had a trend toward decreased LTLS, it was not clinically signifi cant although there was a signifi cant decrease in the incidence of anuria. LTLS or anuria risk in children with BL was not signifi cantly different between rasbu- ricase and allopurinol Wössmann et al. 2003 . Despite decreasing uric acid levels, Ahn et al. 2011 noted no statistical difference in LTLS, CTLS or need for renal dialysis with rasburicase compared with allopurinol. A Cochrane review of rasburicase for the prevention and treatment of TLS in children with cancer similarly showed signifi cant reduction in uric acid levels, but the relevant analyzed studies failed to show that this equated to a signifi cant reduction in clinically signifi cant endpoints, specifi cally renal failure and mortality Cheuk et al. 2010 . Rasburicase remains an extremely expensive drug 535 per 1.5 mg vial compared to allopu- rinol and therefore it is vital to appropriately select patients that would benefi t from rasburi- case through the prevention of CTLS Goldman 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