Abeloff's Clinical Oncology, 4th Edition

Part II – Problems Common to Cancer and its Therapy

Section D – Metabolic and Paraneoplastic Syndromes

Chapter 50 – Tumor Lysis Syndrome

Jessica Hochberg,Mitchell S. Cairo,
Peter F. Coccia

SUMMARY OF KEY POINTS

Incidence and Epidemiology

  

   

The exact incidence of tumor lysis syndrome is unknown; incidence in high-grade non-Hodgkin's lymphoma is approximately 40%.

  

   

Tumor lysis syndrome is most commonly associated with acute lymphocytic leukemia and “high-grade” non-Hodgkin's lymphoma; however, it has been observed in a variety of hematologic and solid malignancies.

  

   

Tumor lysis syndrome has been observed with the administration of chemotherapy, corticosteroids, radiation, hormonal agents, and biologic response modifiers. Tumor lysis syndrome can rarely occur spontaneously before the initiation of therapy.

Etiology

  

   

Tumor lysis syndrome results from the spontaneous release of intracellular ions and metabolites from malignant cells before or after the initiation of cytotoxic therapy.

  

   

The body's inability to handle the increased concentrations of ions and metabolites results in the characteristic metabolic abnormalities associated with tumor lysis syndrome, including hyperuricemia, hyperphosphatemia, hyperkalemia, hypocalcemia, and/or uremia.

  

   

The metabolic disturbances associated with tumor lysis syndrome can lead to life-threatening complications including arrhythmias, acute renal failure, and sudden death.

Evaluation of the Patient

  

   

Patients with tumors with a high proliferative rate and sensitivity to cytotoxic therapy, large tumor masses, pre-existing renal insufficiency, and high serum lactate dehydrogenase levels are at highest risk for the development of tumor lysis syndrome.

Management and Treatment

  

   

Recognition of patients at risk for the development of tumor lysis syndrome is the most important management issue.

  

   

Establishing central venous access and administration of intravenous fluids and allopurinol or rasburicase should begin before the initiation of tumor therapy.

  

   

Alkalinization of urine with sodium bicarbonate or acetazolamide is not recommended.

  

   

Prompt initiation of hemodialysis may aid in the reversal of severe complications associated with renal failure and metabolic abnormalities.

INTRODUCTION

Tumor lysis syndrome (TLS) describes the metabolic derangements that occur from rapid tumor breakdown associated with the initiation of cytotoxic therapy of malignancy in both children and adults. The syndrome is characterized by a tetrad of abnormalities including hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia; it should be considered an oncologic emergency. [1] [2] [3] [4] [5] The abrupt release of intracellular ions, nucleic acids, proteins, and their metabolites results from the rapid destruction of malignant cells and the release of their intracellular contents into the extracellular space after the initiation of therapy. Cell lysis can overwhelm the body's normal homeostatic mechanisms and cause severe metabolic disturbances that require immediate clinical intervention ( Fig. 50-1 ).

 
 

Figure 50-1  Schematic of the metabolic abnormalities associated with the development of tumor lysis syndrome and the clinical complications stemming from these metabolic derangements.

 

 

TLS has been primarily observed in patients with acute lymphocytic leukemia and high-grade non-Hodgkin's lymphomas, in particular Burkitt's lymphoma. However, TLS has also been recognized in a variety of other malignancies, both hematologic and solid. These malignancies share the characteristics of a high proliferative rate and a relative sensitivity to cytotoxic therapy. [6] [7] [8] [9] [10] [11] [12] [13] [14]Other hematologic malignancies associated with TLS include acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and low-grade and intermediate-grade non-Hodgkin's lymphomas. TLS has also been reported to occur in a number of solid tumors such as breast cancer, ovarian and testicular cancer, neuroblastoma, and small cell carcinoma of the lung. [15] [16] [17] [18] [19] [20] [21] [22] [23] [24]

The overall incidence of TLS is not well established and has only been closely studied in high-grade non-Hodgkin's lymphomas.[25] In a retrospective study of 102 patients with high-grade non-Hodgkin's lymphoma, the incidence of TLS was reported to be 42% as determined by serial laboratory testing. The incidence of clinically significant TLS was only 6% in the same group of patients. Part of the difficulty in obtaining the true incidence of TLS is that there is no unifying definition or grading system. Recent proposals define TLS by both laboratory (LTLS) and clinical (CTLS) criteria and use these criteria to develop a grading system (Tables 50-1 through 50-3 [1] [2] [3]). [1] [2] [5]


Table 50-1   -- Cairo-Bishop Definition of Laboratory Tumor Lysis Syndrome

Uric acid

≥8.0 mg/dL or 25% increase from baseline

Potassium

≥6.0 mEq/L or 25% increase from baseline

Phosphorous

≥6.5 mg/dL (children)

 

≥4.5 mg/dL (adults) or 25% increase from baseline

Calcium

≤7.0 mg/dL or 25% decrease from baseline

Modified from Hande and Garrow (1993). (This research was originally published in Cairo MS, Bishop M: Tumour lysis syndrome: New therapeutic strategies and classification. Br J Haematol 2004;127:3–11. © Blackwell Publishing Ltd.)

Laboratory tumor lysis syndrome (LTLS) is defined as either a 25% change or level above or below normal, as defined above, for any two or more serum values of uric acid, potassium, phosphate, and calcium within 3 days before or 7 days after the initiation of chemotherapy. This assessment assumes that a patient has or will receive adequate hydration and a hypouricemic agents(s).

 

 

 

 


Table 50-2   -- Cairo-Bishop Definition of Clinical Tumor Lysis Syndrome

  

1.   

Renal failure (creatinine[*]: ≥1.5 ULN[†] [age >12 yr or age adjusted])

  

2.   

Cardiac arrhythmia/sudden death[*]

  

3.   

Seizure[*]

Modified from Hande and Garrow (1993).; (This research was originally published in Cairo MS, Bishop M: Tumour lysis syndrome: New therapeutic strategies and classification. Br J Haematol 2004;127:3–11. © Blackwell Publishing Ltd.)

Clinical tumor lysis syndrome (CTLS) assumes the laboratory evidence of metabolic changes and significant clinical toxicity that requires clinical intervention. CTLS is defined as the presence of laboratory tumor lysis syndrome (LTLS) and any one or more of the above-mentioned criteria.

 

*

Not directly or probably attributable to a therapeutic agent (e.g., rise in creatinine after amphotericin administration).

Patients will be considered to have elevated creatinine if their serum creatinine is 1.5 times greater than the institutional upper limit of normal (ULN) below age/gender defined ULN. If not specified by an institution, age/sex ULN creatinine may be defined as: >1 <12 years, both male and female, 61.6 mol/L; ≥12 <16 years, both male and female, 88 μmol/L; ≥16 years, female, 105.6 μmol/L; ≥16 years, male, 114.4 μmol/L.

 

 


Table 50-3   -- Cairo-Bishop Grading System for Tumor Lysis Syndrome

 

Grade 0[*]

Grade I

Grade II

Grade III

Grade IV

Grade V

LTLS

-

+

+

+

+

+

Creatinine[†][‡]

≤1.5 × ULN

1.5 × ULN

>1.5–3.0 × ULN

>3.0–6.0 × ULN

>6.0 ULN

Death[§]

Cardiac arrhythmia[‡]

None

Intervention not indicated

Non-urgent medical intervention indicated

Symptomatic and incompletely controlled medically or controlled with device (e.g. defibrillator)

Life-threatening (e.g. arrhythmia associated with CHF, hypotension, syncope, shock)

Death[§]

Seizure[‡]

None

One brief generalized seizure; seizure(s) well controlled by anti-convulsants or infrequent focal motor seizures not interfering with ADL

Seizure in which consciousness is altered; poorly controlled seizure disorder; with breakthrough generalized seizures despite medical intervention

Seizures of any kind which are prolonged, repetitive or difficult to control (e.g. status epilepticus, intractable epilepsy)

Death[§]

(This research was originally published in Cairo MS, Bishop M: Tumour lysis syndrome: New therapeutic strategies and classification. Br J Haematol 2004;127:3–11. © Blackwell Publishing Ltd.)

Clinical tumor lysis syndrome (CTLS) requires one or more clinical manifestations along with criteria for laboratory tumor lysis syndrome (LTLS). Maximal CTLS manifestation (renal, cardiac, neuro) defines the grade.

 

*

No LTLS.

Patients will be considered to have elevated creatinine if their serum creatinine is 1.5 times greater than the institutional upper limit of normal (ULN) below age/gender defined ULN. If not specified by an institution, age/sex ULN creatinine may be defined as: >1 <12 years, both male and female, 61.6 μmol/L; ≥12 <16 years, both male and female, 88 μmol/L; ≥16 years, female, 105.6 μmol/L; ≥16 years, male, 114.4 μmol/L.

Not directly or probably attributable to a therapeutic agent (e.g. rise in creatinine after amphotericin administration).

§

Attributive probably or definitely to CTLS.

 

 

The development of TLS is not limited to the administration of chemotherapy alone. Reports of TLS have been associated with the administration of radiation therapy, corticosteroids, hormonal agents, biologic response modifiers, monoclonal antibodies, and more recently, the low-molecular-weight inhibitor, imatinib mesylate, better known as Gleevec. [15] [20] [24] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] TLS is not limited to systemic administration of agents; it has been observed with intrathecal administration of chemotherapy and with chemo-embolization. It is extremely important clinically to note that TLS can occur spontaneously, before the initiation of any intervention. The identification of patients at risk for the development of TLS is the most important aspect of management, so that prophylactic measures can be initiated before the initiation of therapy. Most of the complications can be readily managed when they are recognized early; however, delay in recognition and initiation of treatment of TLS can be life-threatening. In addition, a recent cost analysis looking at acute renal failure, length of stay, and total cost demonstrated that those patients who went on to develop acute renal failure requiring dialysis had up to two to three times the length of stay and more than five times the cost. [42] [43]

PATHOPHYSIOLOGY

The majority of agents that are used in the treatment of malignancies are dependent on the proliferative rate of malignant cells for their activity. In tumors with a high proliferative rate, a relatively large mass, and a high sensitivity to cytotoxic agents, the initiation of therapy often results in the rapid release of intracellular anions, cations, and the metabolic products of proteins and nucleic acids into the bloodstream. The increased concentrations of uric acid, calcium, phosphates, potassium, and urea can overwhelm the body's natural mechanisms to process and excrete these materials and result in the clinical spectrum associated with TLS.

Hyperuricemia and its associated complications are the most frequently recognized manifestations of TLS, and more importantly, predispose to many of the other clinical derangements. Hyperuricemia results from rapid release and catabolism of intracellular nucleic acids. Purine nucleic acids are catabolized to hypoxanthine, then xanthine, and finally to uric acid by xanthine oxidase. In humans, who lack urate oxidase, uric acid is the final endpoint of purine catabolism ( Fig. 50-2 ). Uric acid clearance is renal, and in normal circumstances approximately 500 mg of uric acid are excreted through the kidneys each day. Uric acid has a pKa of 5.4 to 5.7 and is poorly soluble in water. At normal concentrations and at physiologic blood pH, more than 99% of uric acid is in the ionized form.[44] The concentration of uric acid has been noted to be elevated in patients with acute leukemias and lymphomas before the initiation of therapy.[45] The high concentrations of uric acid increase the risk for urate crystal precipitation in the renal collecting ducts and distal tubules, which are sites of urinary acidification. [46] [47] General clinical manifestations of hyperuricemia include nausea, vomiting, diarrhea, and anorexia. Uric acid crystal precipitation within renal tubules results in a decline in glomerular filtration and the subsequent development of acute renal failure. The risk of acute renal failure caused by uric acid precipitation may be increased by dehydration, which is often present at the time of diagnosis; ureteral obstruction by tumor; a history of renal insufficiency; and the possible need for nephrotoxic antibiotics, such as aminoglycosides, in patients with active infections. If the hyperuricemia results in acute obstructive uropathy, other clinical manifestations may include hematuria, flank pain, hypertension, azotemia, acidosis, edema, oliguria, anuria, lethargy, and somnolence.

 
 

Figure 50-2  Mechanism of action: rasburicase and allopurinol. Depicted is the pathway of purine catabolism. Rasburicase is a recombinant form of urate oxidase, an enzyme that converts uric acid to allantoin. Allopurinol in comparison acts by inhibiting the endogenous enzyme xanthine oxidase, thereby inhibiting formation of uric acid. *A normal endpoint of purine metabolism in humans.  (This research was originally published in Goldman SC, Holcenberg JS, Finklestein JZ, et al: A randomized comparison between rasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor lysis. Blood 2001;97:2998–3003. © The American Society of Hematology.)

 

 

 

Hyperphosphatemia results from the rapid release of intracellular phosphates from malignant cells, which may contain as much as four times the amount of organic and inorganic phosphates as normal cells.[1] [2] [3] [4] [5] [25] Initially, the kidneys are able to respond to the increased concentration of phosphorus from tumor lysis by increased urinary excretion and decreased tubular absorption of phosphorus. Eventually, however, the tubular transport mechanism becomes saturated and is unable to maintain normal serum phosphorus concentrations. The development of hyperphosphatemia may be further exacerbated by acute renal insufficiency associated with uric acid precipitation, resulting in obstructive uropathy or other complications of tumor therapy. Hyperphosphatemia can lead to the development of acute renal failure after precipitation with calcium in renal tubules during TLS. Hyperphosphatemia may be associated with nausea, vomiting, diarrhea, lethargy, and seizures. More importantly, hyperphosphatemia may result in tissue precipitation of calcium-phosphate crystals, resulting in hypocalcemia, metastatic calcification, intrarenal calcification, nephrocalcinosis, nephrolithiasis, and additional acute obstructive uropathy. The serum concentration of calcium rapidly decreases as precipitation with phosphate occurs. Hypocalcemia is one of the most serious clinical manifestations of TLS and has been associated with the development of severe muscle cramping, tetany, and cardiac arrhythmias. In addition to the kidneys, other tissues such as muscle may be sites of precipitation of calcium and phosphorus.[8]

Hyperkalemia may also be a life-threatening consequence of TLS. [8] [37] [48] Hyperkalemia results from the kidneys’ inability to clear the massive load of intracellular potassium released by lysed tumor cells. General clinical manifestations of hyperkalemia may include nausea, anorexia, vomiting, and diarrhea. More specific complications include neuromuscular and cardiac abnormalities. Neuromuscular signs and symptoms may include muscle weakness, cramps, paresthesias, and possible paralysis. Cardiac manifestations may include asystole, ventricular tachycardia or fibrillation, syncope, and possible sudden death. [1] [2] [3] [4] [5] [25]

Increases in blood urea nitrogen and creatinine levels occur as a result of renal impairment associated with acute uric acid crystal nephropathy, calcium-phosphate crystals and nephrocalcinosis, or a combination of both, leading to an acute obstructive uropathy syndrome. A correlation with the pretreatment serum lactate dehydrogenase (LDH) concentration and the development of azotemia has been reported, and the blood urea nitrogen level will generally rise in parallel with the rise in the serum phosphorus concentration. Acute clinical manifestations may include uremia resulting in nausea, vomiting, and lethargy; oliguria or anuria leading to fluid retention; edema, hypertension, congestive heart failure, metabolic disturbances, and exacerbations of hyperphosphatemia and/or hyperkalemia (see previous discussion); flank or back pain; hematuria; and severe acidosis. Extreme elevations in blood urea nitrogen concentrations can result in a platelet function defect, cellular immunodeficiency, and inflammatory pericarditis. [49] [50] Furthermore, acute obstructive uropathy may precipitate acute renal failure (anuria), confusion, somnolence, seizures, and/or coma.

TREATMENT

The management of TLS can be classified into preventative and immediate treatments. The ability to prevent TLS is highly dependent on the immediate recognition of patients at risk for its development (Table 50-4 ). Patients at high risk include those with tumors with a high proliferative rate, large tumor masses including elevated leukocyte counts, extensive adenopathy and splenomegaly, pre-existing renal insufficiency, and elevated levels of phosphorus, uric acid, or both before the initiation of therapy ( Table 50-5 ). The elevation of the serum LDH level before the initiation of therapy has also been associated with the recognition of patients at risk for TLS. [1] [2] [4] Cytotoxic therapy should be delayed in patients at high risk for development of TLS until prophylactic measures can be initiated. Unfortunately, a delay in therapy is not possible for many patients because of the aggressive nature of their underlying malignancy. In this clinical situation, a decision must be made regarding the relative risks in the delay of tumor therapy versus the risk of development or exacerbation of TLS and its associated complications including acute renal failure. [51] [52] Regardless of time constraints, the patient should have reliable venous access and be treated in an intensive care or oncology special care unit with personnel who are trained and familiar with the complications associated with TLS. The unit should have, at a minimum, the capability of continuous cardiac monitoring and preferably the capacity for hemodialysis.


Table 50-4   -- Risk for Tumor Lysis Syndrome by Tumor Type

Burkitt's lymphoma

Frequent cases

Lymphoblastic lymphoma

 

Acute leukemia

 

Large cell lymphoma

 

Low-grade lymphoma treated with chemotherapy, radiotherapy or steroids

Recognized complication but few occurrences

Breast carcinoma treated with chemotherapy or hormonal therapy

 

Small cell lung carcinoma

 

Seminoma

 

Neuroblastoma

 

Low-grade lymphoma treated with interferon

Case reports only

Merkel's cell carcinoma

 

Medulloblastoma

 

Adenocarcinoma of the gastrointestinal tract

 

 

 


Table 50-5   -- Initial Management of Patients at Risk for Tumor Lysis Syndrome

  

1.   

Identification of the patient at risk (see Table 50-4 ).

  

2.   

Admit to intensive care or hematology/oncology unit.

  

3.   

Alert dialysis team of existence of patient and potential emergent need of assisted renal support.

  

4.   

Establish adequate venous access.

  

5.   

Perform baseline electrocardiogram and continuous cardiac monitoring.

  

6.   

Determine baseline and serial WBC, serum LDH, uric acid, Na+, K+, creatinine, BUN, phosphorous, and Ca++ levels. Repeat every 4–6 hours.

  

7.   

Provide intravenous hydration with hypotonic or isotonic saline solution at 2500 to 3000 mL/m2/24 hours.

  

8.   

Given allopurinol, 300 mg/m2/day orally, or rasburicase, 0.20 mg/kg/day intravenously, over 30 minutes for up to 3 days.

 

 

The patient's vital signs, weight, urinary output, and fluid intake must be carefully monitored. Serum creatinine, blood urea nitrogen, sodium, potassium, calcium, phosphorus, LDH, and uric acid concentrations should be determined before therapy and every 4 to 6 hours for the first 48 to 72 hours after the initiation of tumor therapy. The LDH concentration serves as an excellent marker for tumor proliferation and response to therapy. Patients should have a baseline electrocardiogram and continuous cardiac monitoring until the completion of treatment. Ideally, all patients should receive intravenous hydration 24 to 48 hours before the initiation of tumor therapy. [4] [53]Intravenous hydration, preferably with a hypotonic or isotonic saline solution at 2500 to 3000 mL/m2/24 hr, should ideally begin 24 to 48 hours before the initiation of therapy and continue for 48 to 72 hours after completion of chemotherapy. Care must be taken to prevent severe hyponatremia, especially when hypocalcemia is present, because the risk of seizures is increased. A hypotonic saline solution should be used when the urinary sodium concentration is less than 150 mEq/L, to reduce the risk of uric acid supersaturation. The rate and amount of fluid is dependent on each patient's cardiovascular function. Administration of mannitol may be considered if sufficient diuresis cannot be achieved with intravenous hydration alone. A test dose of 200 to 500 mg/kg may be given intravenously and discontinued if an appropriate increase in urine output is not observed. Careful attention must be given to the administration of both intravenous fluids and mannitol to avoid fluid overload and the potential for congestive heart failure.

In addition, it is necessary to administer a hypouricemic agent, either allopurinol or rasburicase, before the initiation of therapy. Allopurinol is a potent inhibitor of xanthine oxidase and blocks the conversion of hypoxanthine and xanthine to uric acid.[47] Whereas hypoxanthine is more soluble than uric acid is at physiologic pH, xanthine is less soluble than uric acid. This may result in the formation of xanthine crystals in the kidney and lead to obstructive uropathy. Although allopurinol prevents new uric acid formation, it does not reduce the amount of uric acid already present. Thus allopurinol requires administration for 2 to 3 days before the serum uric acid concentration begins to fall and therefore needs to be initiated 2 to 3 days before the initiation of cytotoxic therapy. Allopurinol is generally given at a dose of at least 300 mg/m2/day.[54] Allopurinol is known to interfere with the degradation of 6-mercaptopurine, 6-thioguanine, and azathioprine through inhibition of the P450 pathway; thus, the dose of allopurinol should be reduced 50% to 75% in patients receiving these chemotherapeutic agents. Allopurinol should be used with caution in patients with underlying renal insufficiency, because it can cause a syndrome consisting of rash, hepatitis, eosinophilia, and worsening renal function. A previous limitation of allopurinol has been the requirement for administration by the oral route. For some critically ill patients or young infants who may be unable to tolerate oral medications during the prevention or treatment of TLS, there is an intravenous preparation of allopurinol available. [53] [55]Previously, urine alkalinization was recommended to increase uric acid solubility and promote uric acid excretion in patients treated with allopurinol. However, alkalinization is not currently recommended because of the risk of decreasing ionized calcium concentrations, decreasing phosphate excretion, and increasing serum phosphate concentrations.

An alternative to inhibiting uric acid formation by competitively inhibiting xanthine oxidase is to promote the catabolism of uric acid to allantoin by uric acid oxidase. Allantoin is 5 to 10 times more soluble in the urine than uric acid. Urate oxidase is an endogenous enzyme commonly found in many mammalian species but not in humans. Urate oxidase, extracted from Aspergillus flavus, has been demonstrated to rapidly and significantly reduce uric acid levels in patients at high risk for TLS. Recently, the gene encoding urate oxidase was identified and expressed in yeast to yield large quantities of the pure recombinant form of urate oxidase (rasburicase). [54] [56] [57] [58] [59] [60] [61] [62] [63] In a multicenter trial, 52 pediatric patients with hematologic malignancy at high risk for TLS were randomly assigned to receive allopurinol or rasburicase. Uric acid levels significantly decreased by 85% with rasburicase as compared with 12% with allopurinol within 4 hours of drug administration ( Fig. 50-3 ).[64] Pui and colleagues administered rasburicase IV at doses up to 0.2 mg/kg in 131 pediatric patients with newly diagnosed leukemia or lymphoma. They found a rapid drop in uric acid levels from 9.7 to 1 mg/dL within 4 hours of treatment in patients with hyperuricemia and further reductions to 0.5 mg/dL within 24 hours after rasburicase administration. Serum phosphorus and creatinine concentrations also decreased significantly within 1 to 3 days.[65] The same investigators went on to review data on 173 children and 72 adults with malignancy who were treated with rasburicase. All patients had a dramatic decrease in uric acid concentration with median post-treatment concentrations of 0.5 to 0.7 mg/dL. There were very few adverse reactions after administration, and all of these were mild, making this an excellent therapeutic option. [66] [67] Coiffier and associates investigated the safety and efficacy of rasburicase in 100 adult patients with non-Hodgkin's lymphoma over a 1-year period. Of these patients, 66% had elevated LDH levels and 11% were hyperuricemic with concentrations higher than 7.56 mg/dL. Rasburicase was given to all subjects and uric acid levels then measured at 4 hours. All of the patients responded to rasburicase with normalization of uric acid, and none exhibited increased creatinine levels or required dialysis.[56]

 
 

Figure 50-3  Mean (± SE) plasma uric acid concentrations over time for all patients. Squares denote patients who received rasburicase (n = 27) and stars allopurinol (n = 25). The 24-hour post levels reflect 24 hours after the last dose of study drug. Patients who received rasburicase demonstrated more rapid decline and maintained lower plasma uric acid levels throughout the study period. The area under the serial plasma uric acid concentration curve (AUC) through the first 96 hours of therapy was significantly less for patients receiving rasburicase (P < 0.0001).  (This research was originally published in Goldman SC, Holcenberg JS, Finklestein JZ et al: A randomized comparison between rasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor lysis. Blood 2001;97:2998–3003. © The American Society of Hematology.)

 

 

 

Attempts should be made to correct fluid overload, dehydration, and electrolyte and acid-base abnormalities, and to establish adequate urinary output before the initiation of therapy. Hyperkalemia should be treated expediently with standard measures such as the administration of sodium polystyrene sulfonate, a potassium-binding resin, at a dose of 15 to 60 g/day given orally or rectally. There should be little hesitation about initiating hemodialysis to correct this electrolyte abnormality. Aluminum hydroxide, given orally or through a nasogastric tube at a dose of 15 mL (50–150 mg/kg/24 hr) every 4 to 6 hours, should be used to treat hyperphosphatemia. The degree of tumor lysis declines after the first 48 to 72 hours of treatment, and a decline in the serum LDH level serves as an excellent marker for a decrease in tumor lysis. However, close monitoring of the patient should continue until treatment is completed. [1] [2] [54] Treatment of asymptomatic hypocalcemia is generally not recommended. In patients with symptomatic hypocalcemia, intravenous calcium gluconate (50–100 mg/kg per dose) may be administered to correct the clinical symptoms; however, this may increase the risk of calcium and phosphorus deposition and acute obstructive uropathy.

For patients who have acute renal failure, significant uremia, or severe electrolyte abnormalities associated with TLS, the general consensus is that hemodialysis should be initiated as soon as possible. Continuous hemofiltration has been used to correct fluid overload and electrolyte abnormalities associated with TLS in children.[68] The failure to promptly initiate hemodialysis for acute renal failure may turn a potentially reversible clinical situation into an irreversible one ( Table 50-6 ).


Table 50-6   -- Approach to the Management and Treatment of Tumor Lysis Syndrome

 

Decreased Urinary Output (< 50 mL/h)

Hyperkalemia

Uremia

Hypocalcemia

Hyperuricemia

Hyperphosphatemia

Primary intervention

Mannitol challenge

K+ binding resin

Diuretic

Cautious replacement

Allopurinol or rasburicase

Aluminum hydroxide (200–500 mg/kg)

Clinical manifestation

Renal insufficiency or fluid overload

Arrhythmia

Pericarditis or platelet dysfunction

Arrhythmia or tetany

Renal insufficiency

Renal insufficiency

Secondary intervention

Hemodialysis

Treat arrhythmia

Hemodialysis

Treat arrhythmia

Hemodialysis

Hemodialysis

 

 

CONCLUSIONS

Successful management and treatment of TLS is highly dependent on the prompt identification of clinical and laboratory characteristics, signs, and symptoms of patients at risk. Establishment of vascular access and the initiation of prophylactic measures, especially hydration and administration of allopurinol or rasburicase, are vital. The early recognition and treatment of metabolic abnormalities usually prevents the severe and life-threatening complications associated with TLS.

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