Written by: Kevin Dyer, MD (NUEM PGY-2) Edited by: Carrie Pinchbeck, MD (NUEM 2017 Graduate) Expert Commentary by: Colin McCloskey, MD
What is Tumor Lysis Syndrome?
Acute tumor lysis syndrome (TLS) refers to the constellation of metabolic disturbances that result from ongoing cell death in a rapidly growing tumor (1). TLS is most commonly seen within days after initiation of chemotherapy, but can also occur spontaneously when there is a rapidly proliferating malignancy or large tumor burden. The most common types of cancer causing TLS are Non-Hodgkins Lymphoma and acute leukemias, particularly those with white blood cell counts >100k (2,3). TLS is the result of the destruction of a large number of cells with subsequent release of intracellular potassium, phosphorous, and nucleic acids resulting in hyperkalemia, hyperphosphatemia, secondary hypocalcemia, and hyperuricemia.
What are the laboratory hallmarks of this condition?
Potassium >6.0 meq/L or a 25% increase from baseline
Phosphorous >4.5 mg/dL or a 25% increase from baseline
Calcium <7 mg/dL or a 25% decrease from baseline
Uric acid >8 mg/dL or a 25% increase from baseline
What is clinical TLS and why should the Emergency Physician worry about these patients?
Clinical TLS is defined as:
The presence of laboratory markers consistent with tumor lysis syndrome PLUS
Acute Kidney Injury
OR
Symptoms associated with metabolic derangements. For example, tetany, paresthesias, or seizures from hypocalcemia, or cardiac dysrhythmias from hyperkalemia or hypocalcemia (3,4).
Figure 1 (5)
Hyperkalemia induced cardiac arrhythmias are the most lethal complication of TLS. Other causes of morbidity and mortality result from the deposition of calcium-phosphate, xanthine crystals, and uric acid crystals in the renal parenchyma causing acute renal failure and worsening hyperkalemia (Figure 1).
What are my management priorities for these patients in the emergency department?
Early recognition of electrolyte derangements and kidney injury is key!
Aggressive IV hydration is the single most important therapy and is the cornerstone of treatment (3). Increasing urine output and facilitating excretion of uric acid and phosphorus is the goal of IV hydration (6).
Patients may require 4-5 L/day of hydration unless there is concern for impending volume overload (1).
Hyperkalemia induced cardiac arrhythmias are the most lethal complication of TLS. Management in the patient with TLS is very similar to management of hyperkalemia from other causes, but with some very important caveats. The first line agents are still dextrose with insulin and beta-2 agonists. Administration of calcium should be reserved for patients with EKG changes as the administered calcium can lead to further formation of calcium-phosphate crystals and worsening renal function. Use of diuretics should be reserved for patients with volume overload. Dialysis is indicated for patients with refractory hyperkalemia (3,7).
Hyperphosphatemia can be treated with the use of oral phosphate binders such as aluminum hydroxide or calcium carbonate, however there is currently a lack of studies showing their efficacy (2-4).
Symptomatic hypocalcemia should be corrected with the lowest dose required for symptom relief. Correction of the hyperphosphatemia will correct hypocalcemia (2,4).
Hyperuricemia is the result of purine nucleotide catabolism (Figure 2). The tubular precipitation of urate crystals leads to oliguric renal failure and worsening hyperkalemia. There are a couple of options for treating hyperuricemia:
Figure 2 (8)
Allopurinol is a xanthine oxidase inhibitor that decreases the formation of uric acid stones and can be given to prevent urate nephropathy and renal failure. However, allopurinol has limitations. It has no effect on preexisting uric acid, so levels are not reduced until after 48 hours of treatment, which is problematic for patients with significant hyperuricemia. Another downside is the potential xanthine crystal formation and uropathy.
Rasburicase is a newer therapy which works by converting poorly soluble uric acid to water soluble allantoin, which is easily excreted in the urine. Rasburicase can lower uric acid levels in hours and does not increase xanthine formation. Rasburicase should not be combined with allopurinol and should be avoided in patients with G6PD deficiency (9).
Any patient with severe or refractory electrolyte derangements, volume overload, acidosis, or uremia should be treated with hemodialysis (3,4).
Take Home Points:
Have a high suspicion for TLS in patients with rapidly proliferating tumors and those who have recently started chemotherapy.
Laboratory markers of TLS include hyperkalemia, hyperphosphatemia, hypocalcemia, and hyperuricemia.
Aggressive hydration is the cornerstone of management.
Hemodialysis is a potentially life-saving measure that should be initiated in any patient refractory to medical therapy.
Expert Commentary
This is a solid review on tumor lysis syndrome (TLS). The major pitfall I’ve observed is the lack of inclusion of TLS in the differential diagnosis for oncology patients presenting with new acute kidney injury. These patients can be overlooked as simply volume depleted (which they usually are given the emetic effects of cancer/chemotherapy) leading to a prerenal AKI, with early closure preventing the true diagnosis of TLS. Hence, in any oncology patient presenting with new AKI, or any of the aforementioned metabolic abnormalities, TLS labs should be sent.
Furthermore, the other area of uncertainty for emergency physicians is when to initiate treatment, and with what agent. A few pearls gleaned from the British Journal of Hematology Guidelines (2015)(10):
Fluid Management
Volume resuscitation is paramount, and should be with a crystalloid without additional potassium included (ie, normal saline instead of ringers lactate)
Have a urine output goal, 100 mL/hr for adults
Use loop diuretics with caution, as they can promote tubular uric acid deposition and may be minimally effective in the presence of urate nephropathy
Hyperuricemia
Allopurinol is useful for prophylaxis, but given that it takes ~48 hours for optimal uric acid reduction and does not break down already formed uric acid, it should not be considered in the emergency department for acute TLS.
Any patient with confirmed TLS and new AKI should receive rasburicase, generally dosed at 0.2 mg/kg/day as a 30 minute infusion. This can be repeated as clinically necessary for up to 5 days.
Contraindications to rasburicase are allergy and G6PD deficiency
Hyperphosphatemia/Hypocalcemia
Adequate hydration is first intervention for hyperphosphatemia. Hypocalcemia will resolve as hyperphosphatemia resolves. If recalcitrant to this, renal dialysis should be considered
Asymptomatic hypocalcemia should not be treated, as it can worsen calcium phosphate precipitation and further kidney injury. Symptomatic hypocalcemia (arrhythmia, tetany, seizures) should be treated.
Hyperkalemia
Manage similarly as with other causes of hyperkalemia.
Calcium as necessary for cardiac myocyte stabilization.
Renal dialysis as necessary
Renal Dialysis
Employ for classic indications: volume overload, electrolyte derangements as above
Reduced need in rasburicase era.
May require continuous renal replacement therapy instead of intermittent dialysis given concern for potential rebound hyperkalemia and hyperphosphatemia.
Involve your nephrologist early
The last consideration is that the rates of TLS are relatively unknown in this new era of targeted molecular therapies for both hematologic and solid malignancies (11). As these new agents gain more experience/post-marketing surveillance data, the prevalence of TLS may increase in novel oncologic populations.
Colin McCloskey, MD
Emergency Medicine/Critical Care Fellow, Department of Emergency Medicine, Department of Anesthesia, University of Michigan Medicine
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How to cite this post
[Peer-Reviewed, Web Publication] Dyer K, Pinchbeck C (2017, Aug 29). Tumor Lysis Syndrome. [NUEM Blog. Expert Commentary By McCloskey C]. Retrieved from http://www.nuemblog.com/blog/tls
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