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  • Caused by rapid & massive tumor cell lysis and release of intracellular contents (potassium, phosphate and nucleic acids) into the bloodstream that overwhelms the kidney’s ability to excrete those productsCan occur at presentation or more commonly after initiation of chemo for high grade lymphomas (e.g., Burkitt’s) and leukemiaCan also be precipitated by radiation, steroid or antibody therapyRisk of renal failure and life-threatening electrolyte disturbances is caused by the breakdown of nucleic acids -> uric acid, which can precipitate in the renal tubulesHyperphostatemia with deposition of calcium phosphate in the renal tubules can also cause renal failure

    1. 1. Tumor Lysis Syndrome Caused by rapid & massive tumor cell lysis and release of intracellularcontents (potassium, phosphate and nucleic acids) into thebloodstream that overwhelms the kidney’s ability to excrete thoseproducts Can occur at presentation or more commonly after initiation of chemofor high grade lymphomas (e.g., Burkitt’s) and leukemia Can also be precipitated by radiation, steroid or antibody therapy Risk of renal failure and life-threatening electrolyte disturbances iscaused by the breakdown of nucleic acids -> uric acid, which canprecipitate in the renal tubules Hyperphostatemia with deposition of calcium phosphate in the renaltubules can also cause renal failure
    2. 2. Common Tumors Associated withTLS ALL 63% Non-Hodgkin’s Lymphoma 18% AML 11% Solid Tumors 5% - Neuroblastoma; Medulloblastoma;germ cell tumors; sarcoma
    3. 3. Risk Factors Patients with highly proliferative tumors and/or hightumor burden (>10cm diameter; WBC>50,000) Pretreatment LDH > 2x upper limit of normal Pre-existing renal insufficiency Tumor with high sensitivity to treatment
    4. 4. Cairo Bishop Grading System Laboratory TLS requires 2 or more abnormal serumvalues be present 3 days before or 7 days afterinstituting chemotherapy in the setting of adequatehydration and use of a hypouricemic agent Adopted by COG
    5. 5. Cairo Bishop Grading System Laboratory tumor lysis syndrome:Uric acid ≥8 mg/dL (≥476 mol/L) or 25% increase frombaselinePotassium ≥6.0 mEq/L (≥6 mmol/L) or 25% increasefrom baselinePhosphorus ≥6.5 mg/dL (≥2.1 mmol/L) or 25%increase from baselineCalcium ≤7 mg/dL (≤1.75 mmol/L) or 25% decreasefrom baseline
    6. 6. Clinical TLS Clinical TLS constitutes laboratory TLS plus at leastone of the following: serum Creatinine > 1.5 x ULN cardiac arrythmia/sudden death seizure
    7. 7. Clinical TLSGrade 0† Grade I Grade II Grade III Grade IV Grade VLTLS No Yes Yes Yes Yes YesCreatinine‡ ≤1.5 × ULN 1.5 × ULN>1.5–3.0 ×ULN>3.0–6.0 ×ULN>6 × ULN Death§Cardiacarrhythmia‡ NoneInterventionnot neededNonurgentinterventionneededSymptomaticandincompletelycontrolledmedically orcontrolled witha deviceLife-threatening(eg, arrhythmiaassociatedwith CHF,hypotension,or shock)Death§Seizures‡ None NoneOne brief,generalizedseizure,seizurescontrolled withanticonvulsantdrugs, orinfrequentmotor seizuresSeizures withimpairedconsciousness, poorlycontrolledseizures,generalizedseizuresdespitemedicalinterventionsStatusepilepticusDeath§
    8. 8. Clinical Manifestations of TLS Nausea/Vomiting, diarrhea, anoxeria Hyperkalemia weakness, dysrhythmias Hyperphosphatemia hypocalcemia, renal failure Hypocalcemia muscle cramps, tetany, mental statuschanges, seizures Hyperuricemia “uric acid nephropathy” =oliguria, renal failure
    9. 9. Hyperuricemia
    10. 10. Hyperuricemia
    11. 11. Hyperphosphatemia Malignant cells contain higher concentration ofphosphorus Hyperphosphatemia causes hypocalcemia(precipitation in renal tubules/heart is increased whenphos*ca product > 60 mg/dL) More common cause of renal failure since the use ofAllopurinol and UO
    12. 12. Prevention - Monitoring Follow laboratory parameters (UA, phosphate,potassium, calcium, creatinine, LDH) closely, starting4-6 hours after initiation of chemo & then every 6hours therafter Monitor UOP/Intake; monitor for seizures/cardiacarrthymias Monitor for 24-72 hours after intiation of chemo
    13. 13. Prevention - Hydration Hydration to produce high urine output Fluid intake = 2-3 L/m2/day (or 200 ml/kg/day forpatients <10kg) enhances uric acid excretion, phosphateexcretion Goal UOP of 80-100 ml/m2 per hour (or 4-6 ml/kg/hr ifpatient < 10kg) Use isotonic fluid: D5 1/4 NS or NS if hyponatremic Do not add calcium or potassium Monitor for fluid overload in patients with underlyingcardiac dysfunction or renal insufficiency
    14. 14. Prevention - Urinary Alkalinization Urine alkalinization - add NaHCO3 to IVF Uric acid more soluble at urine pH = 7.0 vs 5.0 Goal of urine specific gravity 1.015 and pH 7.0-7.5 Caution -- hypoxanthine and Ca-PO4 stones possible ifurine pH >7.5 Fallen out of favor as no demonstrated advantage; maybe appropriate for patients with underlying metabolicacidosis
    15. 15. Prevention - Hypouricemic Agents Allopurinol – a hypoxanthine analog that inhibits XOproducing more hypoxanthine and xanthine which aremore soluble in acidic urine; takes 2-3 days to beeffective Urate Oxidase/Rasburicase – breaks down uric acid toallantoin which is more soluble in urine; acts withinseveral hours UO has significantly reduced the need for rescuedialysis therapy for TLS
    16. 16. Prevention - Allopurinol Decrease production ofuric acid allopurinol inhibitsxanthine oxidase 300 mg/m2/daydivided tid PO/IV Dose reduction inrenal insufficiency Long-time standardRxXanthine HypoxanthinexanthineoxidaseUric acidAllopurinol
    17. 17. Prevention - Urate Oxidase Present in othermammalian species Catalyzes conversion ofuric acid to allantoin Allantoin more soluble,easily excreted bykidneys Urine alkalinizationunnecessary if used Recombinant urate oxidase(rasburicase) moreeffective than allopurinolin prevention andtreatment ofhyperuricemia Goldman SC et al. A randomizedcomparison between rasburicase andallopurinol in children with lymphoma orleukemia at high risk for tumor lysis.Blood. 2001;97:2998-3003. Contraindicated withG6PD deficiency, asthma
    18. 18. Treatment of Established TLS Hyperphosphatemia
    19. 19. Hyperkalemia Moderate and Asymptomatic (K>6.0): remove all K from IVF; ECGmonitoring. May give Sodium Polystyrene sulfonate (1 gram/kg) every4-6 hours until normalized Severe and/or symptomatic (K>7.0; loss of p waves, widened QRS,peaked T waves): Ca Gluconate (50-100 mg/kg) slow IVP IV Insulin (0.1 unit/kg) and D25 (0.5 gram/kg = 2 ml/kg) over 30minutes. Monitor blood glucose level. If acidotic, may give NaHCO3 1-2 meq/kg over 5-10 minutes Albuterol inhaled Dialysis
    20. 20. Hypocalcemia No treatment needed if asymptomatic Administer Calcium Gluconate with ECG monitoring(50-100 mg/kg) if symptomatic, however, If the patient is hyperphosphatemic, then correctbefore giving Ca unless clinically unstable
    21. 21. Dialysis for Tumor Lysis Syndrome Indications oliguria hyperkalemia azotemia hyperphosphatemia refractory hyperuricemia Hemodialysis or continuous veno-venoushemofiltration with dialysis most effective
    22. 22. Hyperleukocytosis5%-20% of children withnew Dx of leukemia haveWBC count >100,000/mm3These patients at risk ofsevere complicationsfrom hyperviscosity ofblood
    23. 23. Hyperleukocytosis - Complications Blasts interact with endothelium to form aggregates,thrombi in microcirculation Most problems in CNS and pulmonary circulation Complications more common with AML than ALL myeloblasts and monoblasts larger, less deformable,“stickier”
    24. 24. Pulmonary LeukostasisPulmonary arteriolewith leukostaticthrombus in patientwith AML andhyperleukocytosis
    25. 25. Pulmonary Leukostasis Sx: dyspnea, tachypnea,hypoxemia, acidosis, corpulmonale CXR: diffuse interstitialinfiltrates
    26. 26. CNS Leukostasis Headache, mental statuschanges, seizures, coma inspectrum of symptoms High risk of intracranialhemorrhage, especiallywith AML andthrombocytopenia
    27. 27. Therapy for Hyperleukocytosis Decrease blood viscosity (directly related tomorbidity) Hydration AVOID use of diuretics AVOID PRBC transfusion (Hb goal <10gm/dL forviscosity) Transfuse platelets to keep >20,000/mm3 and treatcoagulopathy (common with AML) to decrease risk ofintracranial hemorrhage
    28. 28. Therapy for Hyperleukocytosis Initiation of chemotherapy Urine alkalinization?, hydration, etc., as with tumorlysis syndrome Consider leukapheresis or exchange transfusion Supportive care - mechanical ventilation,hemodynamic support, etc.