CONTENTS

• Prevention of TLS:
  • [1] Risk stratification
  • [2] Monitoring and prophylaxis
• Diagnosis and management of established TLS:
  • Signs & symptoms
  • Diagnosis
  • Treatment
• Clinically relevant physiology
• Podcast
• Questions & discussion
• Pitfalls

---

risk stratification for the development of TLS

(back to contents)

---

general risk factors for tumor lysis syndrome

• Initial induction therapy.
• Bulk of disease, e.g.:
  • Baseline LDH >1,500 IU/L.
  • WBC count >50,000/uL.
  • Bulky disease with >10 cm diameter.
  • Infiltration of the marrow, spleen, and/or liver.
• Potential for cell lysis:
  • Use of novel and more potent therapies (e.g., biological treatments).
  • Highly chemosensitive tumor.
• Smouldering tumor lysis syndrome:
  • Pretreatment hyperuricemia (uric acid >7.5 mg/dL or >446 uM).
  • Pretreatment hyperkalemia.
  • Pretreatment hyperphosphatemia.
• Cardiorenal insufficiency:
  • Baseline renal dysfunction.
  • Older age.
  • Concurrent use of nephrotoxins.
  • Kidney infiltration by the tumor.
  • Obstructive uropathy from the tumor.
  • Inability to tolerate hyperhydration (>3,000 ml/m2/day). (32850076, 37579533)

malignancies with high risk for tumor lysis syndrome

• Beyond the above risk factors, the tumor type and burden may predict the risk of tumor lysis syndrome (table below).  Low-risk is defined as <1%; intermediate risk is defined as 1-5%, and high risk is defined as >5%. (37579533)
• Tumor lysis syndrome is rare with most cancers (especially solid tumors). Therefore, don't assume that any renal failure or electrolyte abnormality following chemotherapy is tumor lysis syndrome.

---

monitoring and prophylaxis for TLS

(back to contents)

---

monitoring for TLS

• TLS generally occurs 12-72 hours after chemotherapy initiation. (37579533)
• TLS labs (full electrolytes including Ca/Mg/Phos plus uric acid and lactate dehydrogenase) should be monitored:
  • Low risk: monitor daily.
  • Intermediate risk: monitor q12hr.
  • High risk: monitor q6hr.
  • (Established diagnosis of TLS: monitor q4hr.)
• Consider screening for G6PD deficiency, in case rasburicase is needed.

renal protection

• Avoid any nephrotoxic medications (full list here: 📖).
• Avoid hypotension/malperfusion of kidneys.

hydration

• Consensus guidelines suggest:
  • IV hydration for intermediate and high-risk patients with the administration of 2-3 L/m2/day (~175 ml/hr) beginning the day prior to therapy and until the end of the day following treatment completion. (37579533)
  • Target a urine output of >80-100 ml/m2/hour. (37579533)
• 🛑 Be careful about placing the patient on a high rate of crystalloid if the patient isn't mobilizing infused fluid.
  • Ideally, patient will mobilize excess fluid in the urine, to achieve a net even fluid balance.
  • For patients with low urine output, diuretics may be considered to achieve adequate urine output. (37579533) Loop diuretics seem to be preferred, given their ability to reduce phosphate and potassium. (35190110)  Scheduled oral torsemide might be a gentle approach to promote ongoing urine output. 📖 Thiazide diuretics may increase serum uric acid, so these are not ideal.
  • If the patient is retaining fluid (e.g., due to cardiac or renal dysfunction), then reduce or stop the fluid infusion.
• Balanced crystalloids are reasonable for most patients (e.g., lactated Ringers).
  • Acidic pH may encourage crystallization of uric acid, so historically urinary alkalinization has been used. More recent evidence indicated that urinary alkalinization isn't beneficial, so this has been abandoned.
  • For most patients, balanced crystalloid is a reasonable choice (e.g., LR or Plasmalyte). For patients with significant acidosis due to non anion-gap metabolic acidosis or uremia, isotonic bicarbonate could be considered with a goal of bringing the serum bicarbonate level to a normal level (more on pH-guided resuscitation here).

purine nucleotide metabolism manipulation

• [1] Allopurinol or febuxostat for all patients: 
  • Allopurinol may be started 2-3 days before chemotherapy. The usual dose of allopurinol is 300 mg PO BID, with lower doses in renal dysfunction.
  • Febuxostat is another xanthine oxidase inhibitor that may be used for patients allergic to allopurinol. (32850076)
• [2] Rasburicase doses PRN to knock down the uric acid:
  • Prophylactic rasburicase may be used. (18509186) This is expensive, but it is the most effective medication for protecting against purine metabolites.
  • Rasburicase should be utilized in patients whose baseline uric acid level is already elevated (e.g., >7.5 mg/dL).

---

clinical signs & symptoms

(back to contents)

---

symptoms / signs are due to electrolyte abnormalities

• Hyperkalemia (usually first abnormality to emerge):
  • Arrhythmias
• Hypocalcemia:
  • Paresthesias, muscle spasms/tetany.
  • Seizures.
  • Delirium.
• Uric acid:
  • Oliguric renal failure.
  • Gout (joint pain).

---

diagnosis

(back to contents)

---

pre-test probability for TLS

• [1] Timing:
  • TLS generally occurs 12-72 hours after chemotherapy initiation. (37579533)
  • TLS can also occur spontaneously, or after radiation therapy.
• [2] Risk factors for TLS are discussed above. ⚡️

Cairo definition of tumor lysis syndrome

• Laboratory definition: Malignancy plus at least two of the following abnormalities (generally within a week of chemotherapy initiation):
  • Phosphate >4.5 mg/dL (>1.45 mM).
  • K >6 mEq/L.
  • Calcium <7 mg/dL (<1.75 mM).
  • Uric acid >8 mg/dL (>476 uM).
• Clinical definition
  • (1) Laboratory definition plus:
  • (2) At least one of the following:
    • Acute kidney injury (Cr >1.5 times baseline).
    • Cardiac arrhythmia.
    • Sudden death.
    • Seizure.
• Technically, the definition may also be met based on changes in electrolytes over time (e.g. 25% increase in potassium, 25% increase in phosphate). However, in practice such changes are usually not considered. (25876990).

differential diagnosis

• Pseudohyperkalemia may occur among patients with very high WBC or platelet count.
  • Suspect this in patients with elevated potassium, but normal ECG.
  • May diagnose this either by:
    • (a) Sending STAT potassium to the lab on ice using a heparinized tube.
    • (b) Measuring potassium at the bedside with a point-of-care monitor.
• Other sources of tissue necrosis may cause a similar pattern of electrolyte abnormalities
  • Rhabdomyolysis.
  • Hemolysis.
  • Acute hepatic necrosis.
  • Crush injury.
• ⚠️ Renal failure of any etiology may cause electrolyte abnormalities similar to those seen in TLS (e.g., hyperkalemia, hyperphosphatemia, hyperuricemia).
  • Be careful about attributing any AKI to TLS, without excluding alternative etiologies. (38471470)

---

treatment

(back to contents)

---

---

basics

monitoring

• TLS labs (full electrolytes including Ca/Mg/Phos plus uric acid and lactate dehydrogenase) should be monitored q4hr among patients with established TLS. (37579533)

renal protection

• Discontinue nephrotoxins as able (list: 📖).
• Avoid hypotension/malperfusion of kidneys.

avoidance of hyperkalemia & hyperphosphatemia

• Transition to renal diet (limit K, Phos intake).
• Discontinue PRN potassium orders (hold potassium unless K<3.0 mM).
• Consider short-term use of an oral phosphate binder. Sevelamer 💊 800-1600 mg TID with meals may be best choice here (using a higher dose if the phosphate level is already elevated >7.5 mg/dL or >2.4 mM)

---

uric acid management: rasburicase 

rasburicase

• General: Rasburicase metabolized uric acid into a harmless byproduct (allantoin). It is effective at getting rid of uric acid within hours.
• Rasburicase is indicated for patients with tumor lysis syndrome and a uric acid level of >8 mg/dL (>476 uM), especially patients with acute renal failure.
• Contraindications: G6PD deficiency.
• Risks are rare:
  • Anaphylaxis.
  • Methemoglobinemia.
  • Hemolysis (if patient has G6PD deficiency).
• Dose:
  • Conventional dosing: 0.2 mg/kg daily for up to 5 days (this will work great, but it's probably a higher dose than is necessary).
  • Reduced dosing strategy: Give 3 mg (fixed dose), repeat if uric acid level remains elevated 12 hours later. (29320954) However, doses of 4.5-6 mg may be considered for patients with very high uric acid levels (>15 mg/dL) or weight >100 kg. (37579533)
  • The half-life of rasburicase is ~20 hours. Rasburicase may be re-dosed daily, depending on uric acid levels.
• 💡After rasburicase administration, uric acid measurement may be artificially low, due to degradation of uric acid in the blood collection tube. To prevent this, uric acid levels must be obtained on ice and sent directly to the lab. Make sure to order the uric acid level properly:

allopurinol is potentially harmful

• Allopurinol reduces the uric acid level, but increases the level of xanthine production. This is a problem for a few reasons:
  • Xanthine can precipitate in the kidneys, causing acute kidney injury (xanthine nephropathy).
  • Xanthine levels can't be measured clinically – so we cannot know whether this is happening.
• For most patients, it's better to allow purine nucleotides to be metabolized into uric acid, which can then be treated with rasburicase.
  • Allopurinol use may impair the efficacy of rasburicase, so the two drugs shouldn't be used together. (25876990)
• Allopurinol could be considered in patients who cannot receive rasburicase (due to allergy or G6PD deficiency).

---

adequate hydration +/- diuretic

fluid selection

• Alkalinizing the urine may reduce the risk of uric acid precipitation, but an alkaline urine will promote precipitation of calcium-phosphate and xanthine. The uric acid level can generally be controlled with rasburicase, so it's best to avoid urine alkalinization.
• For most patients, a balanced crystalloid is optimal (lactated Ringers or Plasmalyte). In patients with marked acidosis (due to NAGMA or uremic acidosis), isotonic bicarbonate is probably preferable – but it should be used cautiously with a goal of elevating the bicarbonate to the low-normal range (e.g., ~20-24 mM).

step 1: achieve euvolemia

• The first and most important step is to establish euvolemia. If the patient is clinically hypovolemic, administer crystalloid to achieve euvolemia.

step 2: challenge with generous IV fluid

• Once the patient is euvolemic, provide a generous amount of IV fluid (e.g., ~150-200 ml/hr, or 2-3 L/m2/day). (37579533)
• Fluid selection is discussed above. In general, lactated ringers is usually a reasonable choice.

step 3: follow fluid balance (inputs/outputs)

• Target a urine output of 80-100 ml/m2/hour. (37579533)
• If the patient establishes a net even fluid balance (i.e., the patient is excreting most of the administered fluid), then continue with ongoing fluid administration.
• If patient doesn't excrete most of the fluid you're administering, consider judicious administration of diuretic:
  • Loop diuretics may be preferred, given their ability to reduce phosphate and potassium. (35190110)  Scheduled oral torsemide might be a gentle approach to promote ongoing urine output. 📖
  • Thiazide diuretics may increase serum uric acid. However in a patient being treated actively with rasburicase, this probably doesn't matter. Indapamide might be considered to promote renal excretion of potassium and phosphate. (3277416)
  • Be careful to replace urinary losses and avoid hypovolemia.
• The goal is for patient to have a high urine output while being euvolemic. If the patient has poor urine output (despite diuretic use), then stop fluid administration.

---

hyperkalemia management

• Hyperkalemia is generally the most life-threatening abnormality.
• Management of hyperkalemia is explored in detail within the hyperkalemia chapter: 📖
• Some modifications should be considered in TLS:
  • Utilization of high fluid infusion rates with diuretics to promote a high urine output is often utilized for therapy of TLS (as discussed above). This may promote potassium excretion by the kidneys.
  • Overall there is a lower threshold for initiation of dialysis (discussed below).
  • Avoid acetazolamide (urinary alkalinization could theoretically promote calcium-phosphate precipitation within renal tubules).
  • Bicarbonate therapy should be used a bit more cautiously than usual. Excessive bicarbonate and metabolic alkalosis may encourage calcium-phosphate precipitation in kidneys.
  • Sodium zirconium cyclosilicate may be utilized for mild-moderate hyperkalemia, but shouldn't be expected to be rapidly effective for severe hyperkalemia. (37579533)
  • IV calcium may be used if needed, but it should be avoided in borderline situations (because calcium may promote the precipitation of calcium-phosphate).

---

dialysis

💡 In general, there is a low threshold for dialysis, because this will resolve numerous problems encountered in tumor lysis syndrome. Continuous renal replacement therapy is often ideal to promote ongoing removal of tumor lysis byproducts. (35190110)

indications for dialysis in the context of established TLS include:

• Refractory volume overload, and/or severe oliguria/anuria.
• Refractory hyperkalemia.
• Uremia.
• Calcium-phosphate product >70 mg2/dL2.
• Symptomatic hypocalcemia.

---

ignore hypocalcemia if possible

• Do not treat asymptomatic hypocalcemia (calcium may precipitate with phosphate).
• Symptomatic hypocalcemia may be treated with the lowest dose of calcium possible as a temporizing measure.
• The ideal treatment for hypocalcemia is arguably dialysis (with a goal of removing phosphate).
  • Hypocalcemia here is really a secondary problem due to hyperphosphatemia, so giving calcium doesn't really fix this.

---

clinically relevant physiology

(back to contents)

---

purine metabolism

• Lysis of tumor cells releases purine nucleotides, which are metabolized as shown above.
• Uric acid and Xanthine are both potentially nephrotoxic, due to precipitation in the renal tubules. Uric acid has a greater tendency to precipitate and to cause renal damage.
• Allopurinol is a medication which inhibits xanthine oxidase.
  • i) This will reduce the production of uric acid (which is potentially beneficial).
  • ii) This may cause the accumulation of xanthine (which is potentially dangerous, but not as bad as uric acid).
• Rasburicase is the most effective approach to manage purine nucleotide toxicity. It converts uric acid into allantoin, which is harmless. Treatment with rasburicase has the advantage over allopurinol of not leading to accumulation of Xanthine.
• Only Rasburicase can act on uric acid which has already been generated (allopurinol can prevent generation of additional uric acid, but doesn't affect pre-existing uric acid).

vicious cycle of tumor lysis syndrome

• Tumor lysis may lead to a spiral of progressive renal dysfunction as follows:
  • (1) This begins with tumor cells releasing phosphate, potassium, and uric acid.
  • (2) Renal failure occurs due to the precipitation of uric acid and calcium phosphate in the kidneys.
  • (3) Renal failure then inhibits the excretion of potassium and uric acid, which causes further elevation of potassium and uric acid levels with worsening of tumor lysis syndrome.
• Early dialysis may be needed to break this cycle (more on this below).

the primary problem is now calcium-phosphate

• Tissue damage in tumor lysis syndrome results largely from the precipitation of two substances: uric acid and calcium-phosphate.
• Historically, uric acid was a major concern. This is currently less of an issue because it's relatively easily treated with rasburicase.
• Calcium-phosphate precipitation is becoming the predominant problem:
  • The calcium-phosphate product is the calcium concentration (in mg/dL) multiplied by the phosphate concentration (in mg/dL).
  • When the calcium-phosphate product rises >60-70, there is a risk of systemic precipitation of calcium phosphate (calciphylaxis).

one minute video to illustrate this better:

---

podcast

(back to contents)

---

Follow us on iTunes

---

questions & discussion

(back to contents)

---

To keep this page small and fast, questions & discussion about this post can be found on another page here.

• Don't “correct” hypocalcemia unless mandatory, as this may cause calcium-phosphate precipitation.
• Consult nephrology and consider dialysis early.
• Consider the possibility of tumor lysis syndrome in any cancer patient with hyperkalemia or renal failure.
• Don't forget to discontinue allopurinol in patients with established tumor lysis syndrome who are being treated with rasburicase.

Guide to emoji hyperlinks

• = Link to online calculator.
• = Link to Medscape monograph about a drug.
• = Link to IBCC section about a drug.
• = Link to IBCC section covering that topic.
• = Link to FOAMed site with related information.
• = Link to supplemental media.