12.3 Oncologic Emergencies: Tumor Lysis Syndrome & Supportive Care

12.3 Oncologic Emergencies: Tumor Lysis Syndrome & Supportive Care

Oncologic emergencies in pediatric hematology and oncology arise directly from tumor mass effects or from the rapid, massive lysis of malignant cells following initiation of cytotoxic chemotherapy. The sudden release of intracellular electrolytes, nucleic acids, and cellular metabolites overwhelms homeostatic clearance mechanisms, producing profound metabolic derangements, multiorgan failure, and early mortality.

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Tumor Lysis Syndrome (TLS): Pathophysiology & Risk Factors

Tumor lysis syndrome (TLS) is characterized by the rapid breakdown of malignant cells that release large quantities of potassium, phosphorus, and nucleic acids into the systemic circulation:

• Potassium: The primary intracellular cation (intracellular concentration ~140–150 mmol/L). Massive release overwhelms renal excretory capacity, producing life-threatening hyperkalemia within hours.
• Phosphorus: Malignant lymphoblasts contain up to four times more intracellular organic phosphorus than normal mature lymphocytes. Rapid cell death dumps massive inorganic phosphate loads into plasma (hyperphosphatemia), which complexes with circulating calcium to precipitate insoluble calcium phosphate ($Ca_3(PO_4)_2$) crystals into renal collecting tubules and microvasculature, inducing acute nephrocalcinosis and secondary hypocalcemia.
• Purine Nucleic Acids: Catabolized sequentially into hypoxanthine, then to xanthine, and finally to uric acid by the hepatic enzyme xanthine oxidase. Uric acid has low water solubility at normal physiological urinary pH ($pK_a \approx 5.4\text{--}5.7$). When filtered in massive amounts, it precipitates as needle-shaped monosodium urate crystals within the acidic lumen of the distal tubules and collecting ducts, producing obstructive uropathy, inflammation, and oliguric acute kidney injury.

Purine Catabolic Cascade & Drug Interventions in TLS:

         Purine Nucleic Acids (Adenine, Guanine)
                          │
                          ▼
                     Hypoxanthine
                          │
                          │  ◄── [Allopurinol Inhibits Xanthine Oxidase]
                          ▼
                       Xanthine
                          │
                          │  ◄── [Allopurinol Inhibits Xanthine Oxidase]
                          ▼
                      Uric Acid (Poor Aqueous Solubility; Precipitates in Renal Tubules)
                          │
                          │  ◄── [Rasburicase Catalyzes Degradation]
                          ▼
           Allantoin + Hydrogen Peroxide (H2O2) + CO2
  (5–10x More Soluble in Water; Easily Excreted in Urine)

Malignancy Risk Stratification

• High Risk: Burkitt lymphoma/leukemia, lymphoblastic lymphoma, T-cell ALL, B-cell ALL with hyperleukocytosis ($WBC \ge 100,000/\text{mcL}$), AML with $WBC \ge 50,000/\text{mcL}$, and bulky tumors with baseline serum lactate dehydrogenase (LDH) $>2\times$ upper limit of normal.
• Intermediate Risk: B-ALL with WBC 50,000 to 100,000/mcL, AML with WBC 10,000 to 50,000/mcL, early-stage Burkitt lymphoma, and high-grade solid tumors (e.g., metastatic neuroblastoma, rhabdomyosarcoma) with extensive metastasis.
• Low Risk: Indolent lymphomas, low-grade leukemias, and non-metastatic solid tumors.

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Diagnostic Classification: Cairo-Bishop Definition

The standardized Cairo-Bishop Definition divides TLS into Laboratory TLS (LTLS) and Clinical TLS (CTLS). Criteria must manifest within 3 days prior to or up to 7 days after the initiation of antineoplastic chemotherapy.

1. Laboratory TLS (LTLS)

Diagnosis requires two or more of the following metabolic abnormalities occurring concurrently within the 3-day pre-chemo to 7-day post-chemo window:

2. Clinical TLS (CTLS)

Diagnosis requires the presence of Laboratory TLS (LTLS) PLUS at least one of the following clinical toxicities not attributable to other causes:

• Renal Dysfunction: Serum creatinine $\ge 1.5\times$ upper limit of normal for age, or oliguria ($<0.5\text{ mL/kg/hour}$ for $\ge 6$ hours).
• Cardiac Arrhythmias: Life-threatening ventricular arrhythmias, heart block, or sudden cardiac arrest secondary to severe hyperkalemia or hypocalcemia.
• Neuromuscular Seizures: Tetany, severe neuromuscular irritability, carpopedal spasm, altered mental status, or generalized tonic-clonic seizures secondary to severe hypocalcemia.

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TLS Prevention & Management Protocols

Management Algorithm for Tumor Lysis Syndrome:

           [High-Risk Pediatric Malignancy Identified]
                                │
                                ▼
  Aggressive Intravenous Hyperhydration (2,000–3,000 mL/m2/day without added K+/Ca2+)
  Target Urine Output: ≥100 mL/m2/hr (≥2–4 mL/kg/hr in infants <10 kg)
                                │
          ┌─────────────────────┴─────────────────────┐
          ▼                                           ▼
  [Hyperphosphatemia Present?]               [G6PD Deficiency Screen]
  • NO Urinary Alkalinization                • Negative: Rasburicase 0.1–0.2 mg/kg
  • Alkaline pH (≥7.0) precipitates           (Degrades existing uric acid)
    Calcium Phosphate (Ca x P > 60)          • Positive: Allopurinol 300–400 mg/m2/day
  • Nephrocalcinosis & Renal Failure          (Avoid Rasburicase -> Hemolysis/MetHb)

1. Aggressive Intravenous Hyperhydration

• Fluid Volume: Administer 2,000 to 3,000 mL/m$^2$/day (or 150 to 200 mL/kg/day for infants $<10\text{ kg}$), roughly $1.5$ to $2$ times maintenance.
• Fluid Composition: $D_5$ 0.2% NaCl or $D_5$ 0.45% NaCl. STRICTLY EXCLUDE all potassium, calcium, and phosphate from intravenous hydration fluids.
• Urine Output Benchmark: Target a continuous urine output of $\ge 100\text{ mL/m}^2/\text{hour}$ (or $\ge 2.0\text{ to } 4.0\text{ mL/kg/hour}$ in infants and young children). If urine output is inadequate despite adequate intravascular volume repletion, administer a loop diuretic (furosemide 0.5 to 1.0 mg/kg IV) to promote tubular flow, provided obstructive uropathy and hypovolemia are ruled out.

2. The Urinary Alkalinization Controversy: Why It Is Contraindicated

Historically, intravenous sodium bicarbonate was added to hydration fluids to alkalinize urine ($pH \ge 7.0\text{--}7.5$), increasing the solubility of free uric acid. However, contemporary pediatric oncology guidelines strongly advise against urinary alkalinization, particularly when hyperphosphatemia is present, for several reasons:

1. Calcium Phosphate Precipitation: In an alkaline milieu ($pH \ge 7.0$), phosphate ionizes into dibasic phosphate ($HPO_4^{2-}$), which binds circulating calcium with high affinity. When the calcium-phosphorus solubility product exceeds $60\text{ mg}^2/\text{dL}^2$ ($[\text{Calcium}] \times [\text{Phosphate}] > 60$), calcium phosphate precipitates into renal tubules, myocardium, and cardiac conduction tissue, accelerating acute renal failure and causing fatal arrhythmias.
2. Exacerbation of Hypocalcemic Symptoms: Alkalinization increases the negative charge on serum albumin, promoting competitive binding of ionized calcium to albumin. This sharply reduces the physiologically active ionized calcium fraction, precipitating severe tetany, laryngospasm, and seizures.
3. Xanthine Precipitation: In patients receiving allopurinol, urinary alkalinization actually decreases the solubility of xanthine and hypoxanthine, promoting xanthine nephropathy.
4. Rasburicase Superiority: The availability of rasburicase rapidly clears uric acid without requiring an alkaline urine pH.

[!CAUTION] BCPPS Board Rule: Do NOT add sodium bicarbonate to hydration fluids in patients with hyperphosphatemia or those receiving rasburicase. Maintain neutral urine pH with aggressive hydration alone.

3. Hypouricemic Pharmacotherapy: Allopurinol vs. Rasburicase

Rasburicase Black Box Warnings & Laboratory Sample Handling

• G6PD Deficiency Black Box Warning: Rasburicase oxidizes uric acid to allantoin, generating stoichiometric quantities of hydrogen peroxide ($H_2O_2$). In erythrocytes with normal glucose-6-phosphate dehydrogenase (G6PD) activity, $H_2O_2$ is neutralized by reduced glutathione (GSH) generated via NADPH. In patients with inherited G6PD deficiency, erythrocytes cannot produce NADPH; unbuffered $H_2O_2$ oxidizes hemoglobin iron ($Fe^{2+} \rightarrow Fe^{3+}$), producing life-threatening methemoglobinemia and inducing massive oxidative membrane damage that precipitates acute intravascular hemolysis. Screen high-risk ethnic groups (African, Mediterranean, Middle Eastern, Southeast Asian descent) prior to administration when feasible. If severe hemolysis or methemoglobinemia occurs, discontinue rasburicase immediately and administer supportive care. Note that methylene blue is ineffective for rasburicase-induced methemoglobinemia in G6PD-deficient patients because its mechanism depends on NADPH generated by G6PD; use ascorbic acid or exchange transfusion instead.
• Critical Laboratory Handling Mandate: Rasburicase remains enzymatically active ex vivo in drawn blood samples at room temperature. If blood is allowed to sit at room temperature, rasburicase will continue to rapidly degrade all uric acid in the tube, resulting in falsely low or undetectable laboratory uric acid measurements that mask severe in vivo hyperuricemia.

[!IMPORTANT] Blood Sample Handling for Uric Acid in Rasburicase-Treated Patients:

1. Draw blood into pre-chilled heparinized tubes (green-top tubes placed on ice before venipuncture).
2. Immediately immerse the tube in an ice-water slurry (wet ice).
3. Transport on ice directly to the clinical laboratory.
4. Centrifuge and assay the plasma within 4 hours of collection.

4. Management of Life-Threatening Hyperkalemia & Hyperphosphatemia

• Acute Hyperkalemia ($K^+ > 6.0\text{--}6.5\text{ mmol/L}$ or ECG Changes):
  • Myocardial Membrane Stabilization: Calcium gluconate 10% at 50 to 100 mg/kg IV (0.5 to 1.0 mL/kg) infused over 5 to 10 minutes with continuous cardiac monitoring. Restores normal myocardial membrane threshold potential to prevent ventricular fibrillation. Does NOT lower serum potassium.
  • Intracellular Potassium Shifting:
    • Regular Insulin: 0.1 units/kg IV combined with Dextrose 25% 2.0 mL/kg IV (0.5 g/kg) over 30 minutes.
    • Nebulized Albuterol: 2.5 mg (weight $<20\text{ kg}$) or 5.0 mg (weight $\ge 20\text{ kg}$) via nebulizer over 15 minutes.
    • Sodium Bicarbonate: 1 to 2 mEq/kg IV over 10 minutes if metabolic acidosis is present.
  • Potassium Removal: Loop diuretics (furosemide 1 mg/kg IV); potassium-binding resins (Sodium Zirconium Cyclosilicate [Lokelma] 5–10 g orally TID or Patiromer); emergent Continuous Renal Replacement Therapy (CRRT) or Hemodialysis if medical therapy fails.
• Hyperphosphatemia ($>6.5\text{ mg/dL}$) & Hypocalcemia Management:
  • Treat hyperphosphatemia with hyperhydration and non-calcium oral phosphate binders (Sevelamer carbonate 50–100 mg/kg/dose orally TID with meals).
  • Hypocalcemia Warning: Do NOT treat asymptomatic hypocalcemia! Administering intravenous calcium in a patient with severe hyperphosphatemia sharply increases the $[\text{Calcium}] \times [\text{Phosphate}]$ product, precipitating widespread metastatic calcification in renal tubules, coronary vessels, and lung parenchyma. Administer IV calcium gluconate ONLY for symptomatic hypocalcemia manifested by tetany, seizures, or severe QTc prolongation.

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Pediatric Febrile Neutropenia (FN)

Febrile neutropenia is a medical emergency that carries high mortality in pediatric oncology due to impaired inflammatory responses and rapid progression to septic shock.

• Clinical Definitions:
  • Fever: A single oral or tympanic temperature measurement of $\ge 38.3^\circ\text{C}$ ($101.0^\circ\text{F}$), OR a sustained temperature of $\ge 38.0^\circ\text{C}$ ($100.4^\circ\text{F}$) over a 1-hour duration.
  • Neutropenia: An Absolute Neutrophil Count (ANC) $< 500/\text{mcL}$, OR an ANC $< 1,000/\text{mcL}$ with an anticipated decline to $< 500/\text{mcL}$ within 48 hours.

$\text{ANC Calculation (cells/mcL)} = \text{Total WBC (cells/mcL)} \times \left( \frac{\%\text{ Segmented Neutrophils} + \%\text{ Band Neutrophils}}{100} \right)$

• The 60-Minute "Door-to-Needle" Benchmark: Broad-spectrum intravenous antimicrobials must be administered within 60 minutes of triage arrival.
• First-Line Empiric Antimicrobial Monotherapy:
  • Cefepime: 50 mg/kg IV every 8 hours (maximum single dose 2,000 mg).
  • Piperacillin-Tazobactam: 80 to 100 mg/kg (piperacillin component) IV every 6 to 8 hours (maximum 4,000 mg/dose).
  • Meropenem: 20 mg/kg IV every 8 hours (maximum 1,000 mg/dose; preferred for penicillin anaphylaxis or ESBL history).
• When to Add Vancomycin (15 mg/kg IV every 6 to 8 hours): Do NOT routinely add empiric vancomycin to initial monotherapy. Vancomycin is reserved for:
  • Hemodynamic instability or septic shock
  • Suspected central catheter-associated bloodstream infection (erythema, purulence at exit site)
  • Clinically obvious skin or soft tissue infection
  • Known colonization with Methicillin-Resistant S. aureus (MRSA)
  • Severe mucositis in patients receiving high-dose cytarabine

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Supportive Care Prophylaxis Regimens

1. Pneumocystis jirovecii Pneumonia (PCP / PJP) Prophylaxis

Prolonged T-cell suppression and high-dose corticosteroid therapy place pediatric leukemia and lymphoma patients at extreme risk for life-threatening interstitial pneumonia caused by Pneumocystis jirovecii.

• First-Line Regimen: Trimethoprim-Sulfamethoxazole (TMP-SMX): Dosed at 5 mg/kg/day (based on the trimethoprim component) orally divided twice daily, administered on 2 or 3 consecutive days per week (e.g., Monday-Tuesday-Wednesday or Friday-Saturday-Sunday).
• Alternative Regimens (for Severe Sulfa Allergy / Documented G6PD Deficiency):
  • Dapsone: 2 mg/kg/day orally once daily (maximum 100 mg/day) OR 4 mg/kg once weekly (maximum 200 mg/week). Must screen for G6PD deficiency prior to initiation due to hemolytic risk.
  • Atovaquone (Mepron): Dosed at 30 to 45 mg/kg orally once daily with a high-fat meal (dosing: 30 mg/kg/day for ages 1–3 months and $>24$ months; 45 mg/kg/day for ages 4–24 months; maximum 1,500 mg/day).
  • Aerosolized Pentamidine: 300 mg once monthly via Respirgard II nebulizer for cooperative children $\ge 5$ years of age.

2. Chemotherapy-Induced Nausea & Vomiting (CINV)

Pediatric guidelines from the Pediatric Oncology Group of Ontario (POGO) and ASCO/MASCC stratify CINV regimens based on the emetogenic potential of the chemotherapy protocol:

• Highly Emetogenic Chemotherapy (HEC) (e.g., cisplatin, cyclophosphamide $\ge 1,000\text{ mg/m}^2$, high-dose cytarabine, dacarbazine): Requires an aggressive 3-Drug Prophylactic Regimen administered prior to antineoplastic infusion:
  1. 5-HT3 Receptor Antagonist: Ondansetron 0.15 mg/kg IV every 8 hours (maximum 16 mg/dose) OR Granisetron 10 to 40 mcg/kg IV once daily (maximum 1,000 mcg/dose).
  2. Dexamethasone: 2 to 4 mg/m$^2$ orally or IV every 12 hours (Note: Omit dexamethasone if the chemotherapy protocol already incorporates therapeutic corticosteroids, as in ALL induction).
  3. Neurokinin-1 (NK1) Receptor Antagonist:
     • Aprepitant (Oral): Approved down to 6 months of age; weight-tiered dosing for patients $\ge 6$ months: Body weight $<30\text{ kg}$: Day 1: 3.0 mg/kg (max 125 mg); Days 2 and 3: 2.0 mg/kg (max 80 mg); Body weight $\ge 30\text{ kg}$: Day 1: 125 mg; Days 2 and 3: 80 mg.
     • Fosaprepitant (IV Prodrug): 4.0 mg/kg IV (maximum 150 mg) infused over 30 minutes as a single dose on Day 1.

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Practice Pearls & BCPPS Exam Traps

• Exam Trap 1: Never administer rasburicase to a patient with known or suspected G6PD deficiency. The resulting hydrogen peroxide surge triggers irreversible methemoglobinemia and massive intravascular hemolysis that cannot be treated with methylene blue.
• Exam Trap 2: Do not interpret a post-rasburicase uric acid level of $<0.5\text{ mg/dL}$ as therapeutic success if the blood specimen was left sitting on the nursing station counter at room temperature. The report reflects ex vivo destruction of uric acid in the tube rather than true intravascular status.
• Exam Trap 3: Never add sodium bicarbonate to IV hydration fluids when serum phosphorus is elevated. Alkalinizing the urine in the face of hyperphosphatemia precipitates catastrophic calcium phosphate crystal nephropathy ($Ca \times P > 60$), directly causing oliguric renal failure.
• Board Rule: For pediatric febrile neutropenia, never delay the first dose of broad-spectrum antibiotics to await blood culture results, central line placement, or chest radiographs. The institutional "door-to-needle" time must be under 60 minutes.