1. Barre, Stephanie PharmD
  2. McElwee, Jessica PharmD
  3. Calhoun, Chara PharmD, BCPS
  4. Weant, Kyle A. PharmD, BCPS, BCCCP, FCCP
  5. Maldonado, Andy PharmD, BCOP
  6. Bell, Carolyn M. PharmD, BCCCP


Patients with hematological malignancies, both treated and untreated, or solid tumors undergoing treatment are at risk of life-threatening complications, which may present in the emergency department (ED). Such emergencies are diverse in etiology and often require prompt treatment. Traditional complications, such as febrile neutropenia, have had recent guideline updates, which incorporate new evidence and a new validated risk stratification tool. In addition, newer approaches to treatment, such as chimeric antigen receptor (CAR) T-cell therapy, are becoming more widely available and have unique associated toxicities. This review discusses the management of the following hematological and oncological emergencies likely to be encountered in the ED: febrile neutropenia, CAR T-cell toxicities, differentiation syndrome, tumor lysis syndrome, hypercalcemia of malignancy, and hyponatremia.


Article Content

ONCOLOGICAL EMERGENCIES include a variety of disorders, due to both the malignancy- and treatment-associated toxicities, which require prompt medical attention. Although complications often occur with chemotherapy, patients are subject to such emergencies throughout the course of their malignancy. The intent of this review is to discuss the pathophysiology, presentation/diagnosis, and treatment of the following oncological emergencies most likely to be encountered in the emergency department (ED): febrile neutropenia, chimeric antigen receptor (CAR) T-cell therapy toxicities, differentiation syndrome, tumor lysis syndrome (TLS), hypercalcemia of malignancy (HCM), and hyponatremia. Although this review focuses on the initial emergent treatment, it would be beneficial to consult the hematology and oncology service at your institution to assist with management of this patient population.



Febrile neutropenia is one of the most common complications encountered in patients with malignancy. It is defined as a temperature of 38.3 [degrees]C (101 [degrees]F) or higher, or 38 [degrees]C (100.4 [degrees]F) and higher if sustained for 1 hr with a current absolute neutrophil count (ANC) of less than 500 cells/mm3 or an ANC of less than 500 cells/mm3 expected within 48 hr. Profound neutropenia refers to an ANC of less than 100 cells/mm3 and is associated with a higher risk of severe infection when anticipated to continue for more than 7 days (Freifeld et al., 2011). Documented infection is reported to occur in about 30% of patients with febrile neutropenia, and bacteremia accounts for 10%-25% of febrile neutropenia infections (Freifeld et al., 2011). Patients can experience myelosuppression as a direct effect of their primary malignancy (i.e., leukemia, lymphoma, or multiple myeloma) or as a consequence of recent chemotherapy. The nadir neutrophil count is often seen around 5-10 days after receiving chemotherapy (Brock & Cruz-Carreras, 2020). Cytotoxic agents can compromise the entire alimentary tract, including oral cavity and gastrointestinal tract, which can inadvertently cause a mucosal barrier injury. The mucosal damage, in combination with minimal host defense mechanisms, allows bacteria to translocate, leading to local infection or bacteremia (Southwick, 2020; van der Velden, Herbers, Netea, & Blijlevens, 2014). Another common source of bacteremia is the use of indwelling central venous catheters (CVCs). Other potential sources of infection include skin and soft tissue, respiratory, genitourinary, cardiovascular, and central nervous systems (Southwick, 2020).


The majority of initial infections in febrile neutropenia are caused by bacteria. The most common gram-positive blood isolates include coagulase-negative staphylococci, Staphylococcus aureus, viridans group streptococci, and Enterococcus species. However, drug-resistant gram-negative pathogens are increasingly the causative organisms, such as Escherichia coli and other Enterobacteriaceae, as well as Pseudomonas species (Cattaneo et al., 2008). Fungal infections are more likely to occur after a week of empirical antibiotics (Freifeld et al., 2011).



One of the major challenges in recognizing febrile neutropenia is the lack of typical infectious signs/symptoms due to the inability to produce an inflammatory response. Therefore, fever is frequently the only sign of infection and, consequently, has the potential to go unrecognized. For example, a chest radiograph may not demonstrate an infiltrate developing due to the lack of neutrophil production. Skin and soft-tissue infections (SSTIs) may not be accompanied by erythema, warmth, pain, and/or induration (Cantwell & Perkins, 2018). Obtaining a thorough history, including cancer origin, chemotherapy regimen, and last cycle, is essential. The National Comprehensive Cancer Network (NCCN) Guidelines for Hematopoietic Growth Factors categorizes common chemotherapy regimens based on risk of febrile neutropenia, with high risk occurring in more than 20% of cases (Becker et al., 2020). Examples of such regimens include RICE (rituximab, ifosfamide, carboplatin, and etoposide) for non-Hodgkin's lymphoma or FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin) for pancreatic cancer.


The American Society of Clinical Oncology (ASCO) and Infectious Diseases Society of America (IDSA) guidelines focus on risk assessment to determine which patients are at highest risk of serious complications in an effort to treat more appropriately. One common scoring system utilized is the Multinational Association for Supportive Care in Cancer (MASCC) Risk-Index Score, which categorizes patients' risk of complications/death. The scoring components are shown in Table 1. An MASCC score of 21 or greater correlates to a low risk, whereas a score of less than 21 identifies high-risk patients. There are, however, limitations of this screening tool and up to 13% of patients may be misclassified as at low risk (Carmona-Bayonas et al., 2011; Coyne et al., 2017). In 2015, the Clinical Index of Stable Febrile Neutropenia (CISNE) was validated to assess the risk of complications in patients who received chemotherapy for solid tumors and appear clinically stable (Carmona-Bayonas et al., 2015). The scoring system components are displayed in Table 2. The 2018 ASCO/IDSA guideline on outpatient management of febrile neutropenia incorporates Talcott's groups, another risk stratification tool, with the CISNE and MASCC scores to assist in determining empirical antibiotics, medication route (intravenous vs. oral), treatment location (inpatient vs. outpatient), and duration (Freifeld et al., 2011; Taplitz et al., 2018).

Table 1 - Click to enlarge in new windowTable 1. The MASCC Risk-Index Score
Table 2 - Click to enlarge in new windowTable 2. The Clinical Index of Stable Febrile Neutropenia

The ASCO/IDSA guidelines recommend the initial diagnostic approach and evaluation include the following: complete blood cell count with leukocyte differential count, complete metabolic panel, and serum lactate concentration (Taplitz et al., 2018). Guidelines recommend obtaining two or more sets of blood cultures from different sites, including a CVC, if applicable and cultures from other sources as clinically indicated. Because many patients have central venous access, such as ports or peripherally inserted central catheters, it is important to ensure only appropriately trained individuals access these catheters.



Before selecting antimicrobial therapy, it is important to identify which patients are appropriate for inpatient, compared with outpatient, treatment using risk stratification (Taplitz et al., 2018). Patients with most of the following factors are classified as at low risk: outpatient at time of fever, no acute comorbid illness, expected duration of profound neutropenia less than 7 days, no hepatic or renal insufficiency, and an MASCC score of greater than 21 or a CISNE score of less than 3 (Baden et al., 2020). For those with low risk of complications, outpatient treatment with oral antibiotics may be appropriate. However, any patient with colonization or suspected methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), or Stenotrophomonas maltophilia should be considered for inpatient treatment (Taplitz et al., 2018).


For patients appropriate for outpatient treatment, the first dose of antibiotics is recommended to be given in the ED after cultures are obtained and the patient should be observed for at least 4 hr thereafter. Empirical treatment with a fluoroquinolone, such as ciprofloxacin or levofloxacin, plus amoxicillin/clavulanate is recommended. Clindamycin can be used as an alternative to amoxicillin/clavulanate in patients with a true penicillin allergy (Taplitz et al., 2018). Fluoroquinolones as monotherapy are not recommended for empirical treatment despite studies demonstrating similar efficacy in low-risk patients, likely due to increasing resistance (Kern et al., 2013; Taplitz et al., 2018). Antibiotic dosing recommendations are shown in Table 3. Patients treated outpatient who return with ongoing signs or symptoms after 2-3 days of treatment should be considered for inpatient therapy. The treatment duration should be based on site of infection and organism, if known, or until resolution of neutropenia (Freifeld et al., 2011).

Table 3 - Click to enlarge in new windowTable 3. Antibiotic dosing guide

Patients are considered at high risk if any of the following factors are present: MASCC score is less than 21 or CISNE score of 3 or greater, inpatient at time of fever occurrence, allogeneic hematopoietic stem cell transplantation, anticipated profound neutropenia for at least 7 days, hepatic or renal insufficiency, uncontrolled or progressive cancer, pneumonia or complex infections at presentation, use of alemtuzumab, and mucositis Grade 3 or 4 (Baden et al., 2020). In addition, any patient who has significant medical comorbidities or is clinically unstable, with features such as hypotension, hypoxemia, or altered mental status, is considered at high risk. Such patients are candidates for inpatient treatment with intravenous antibiotics. Intravenous antibiotics should be administered within 1 hr of initial presentation of fever (Taplitz et al., 2018).


Inpatient antimicrobial recommendations are adopted from the 2010 update to the IDSA guidelines, which recommend standard treatment with an antipseudomonal [beta]-lactam such as cefepime, piperacillin/tazobactam, or a carbapenem (excluding ertapenem). Additional gram-positive coverage with vancomycin or other anti-MRSA agent is not recommended as part of the standard regimen; however, it can be considered for patients with suspected CVC-related infections, SSTIs, pneumonia, hemodynamic instability, or risk factors for resistant organisms. Risk factors are defined as a previous infection or colonization with a resistant gram-positive organism and treatment in a facility with high rates of endemicity (Freifeld et al., 2011; Taplitz et al., 2018).


For patients with a history of MRSA infection, consideration should be given to adding vancomycin, linezolid, or daptomycin based on the suspected source of infection. For those with previous VRE isolates, the addition of linezolid or daptomycin is indicated. If there is a history of an extended-spectrum [beta]-lactamase-producing organism, empirical initiation of a carbapenem is warranted. Other empirical antimicrobial therapy is generally not necessary. Antiviral therapy is not indicated unless the patient has documented evidence of an acute viral illness. Antifungal therapy should be considered in patients who are persistently febrile despite at least 4 days of antibiotic therapy and are expected to be neutropenic for more than 7 days (Freifeld et al., 2011).



CAR T-cell therapy is a novel immunotherapy that has yielded impressive outcomes for hematological malignancies. It is created directly from the patient's own blood. After leukapheresis, the patient's T cells are genetically engineered to express CARs to recognize specific antigen tumor cells. Before reinfusion, the patient undergoes lymphodepleting chemotherapy to allow space for CAR T-cell expansion (Frey & Porter, 2019). There are three current U.S. Food and Drug Administration (FDA)-approved agents available, all of which target CD19 (Kite Pharma, Inc., 2020; Novartis Pharmaceutical Corporation, 2018). Tisagenlecleucel (Kymriah), the first approved CAR T-cell therapy, has FDA indications for adult patients with relapsed or refractory large B-cell lymphoma or B-cell acute lymphoblastic leukemia (ALL) (Novartis Pharmaceutical Corporation, 2018). Axicabtagene ciloleucel (Yescarta) has an FDA indication for relapsed or refractory large B-cell lymphoma (Kite Pharma, Inc., 2020). Brexucabtagene autoleucel (Tecartus) was recently FDA-approved for relapsed or refractory mantle cell lymphoma (Kite Pharma, Inc., 2020). CAR T-cell therapy is currently being investigated with additional malignancies, including multiple myeloma. Despite successes, CAR T-cell therapy is not without risks and can cause several serious side effects that have warranted black box warnings including cytokine release syndrome (CRS) and neurotoxicity, for which the management of each is discussed further. When administered as an outpatient, patients should remain within the proximity of the certified facility for at least 4 weeks and report to the ED for CAR T-cell-associated toxicities (Kite Pharma, Inc., 2020; Novartis Pharmaceutical Corporation, 2018).


Cytokine Release Syndrome

CRS is the most common toxicity of CAR T-cell therapy. It occurred in 58%-93% of patients in clinical trials, and up to 47% were reported at a Grade 3 level of severity, requiring vasopressor administration and/or high-flow nasal cannula placement (Maude et al., 2018; Neelapu et al., 2017; Schuster et al., 2019). CRS is defined as a heightened response due to immune system activation from CAR T-cell expansion, causing elevations in cytokines (e.g., interleukin [IL]-6, IL-10, IL-2) and inflammatory markers, such as C-reactive protein and ferritin (Shimabukuro-Vornhagen et al., 2018). Although CRS has been largely linked to CAR T-cell therapy, it can occur following administration of other medications such as blinatumomab (Blincyto), a bispecific T-cell engager monoclonal antibody used in the treatment of B-cell ALL (Frey & Porter, 2019).



The presentation is highly nonspecific as many patients exhibit mild to moderate symptoms including fever, hypotension, rigors, and malaise. CRS may also present with severe symptoms including hypotension requiring vasopressor support, capillary release syndrome, hypoxia, and organ failure such as acute kidney injury or acute liver failure (Lee et al., 2019). Fever may not always be present, as it may be masked by an antipyretic, anti-cytokine therapy, or corticosteroids (Frey & Porter, 2019). Most CRS cases present within 14 days of CAR T-cell infusion. Because of the high risk of CRS, CAR T-cell products are limited to availability through a Risk Evaluation and Mitigation Strategy (REMS) program, which mandates that the certified health care facility have two patient-specific doses of tocilizumab (Actemra), an IL-6 receptor antagonist, on hand for treatment of toxicities related to CAR T-cell therapy and all relevant staff members involved in prescribing, dispensing, and administering CAR T-cell therapy must be trained (Kite Pharma, Inc., 2020; Novartis Pharmaceutical Corporation, 2018).



Treatment of CRS, which is dependent on grade, has been challenging to standardize due to variations in grading scales between clinical trials and institutions. Recently, the American Society of Blood and Marrow Transplantation (ASBMT) released formalized grading scales for CRS and neurotoxicity to allow for a more consistent approach to management, although practice still may differ between institutions (Lee et al., 2019). Patients experiencing Grade 2-4 CRS will warrant prompt pharmacological intervention with tocilizumab with or without high-dose corticosteroids. Full ASMBT assessment criteria and management recommendations are described in Table 4 (Lee et al., 2019). Tocilizumab was investigated and approved for CRS after the discovery that serum IL-6 was elevated in patients with CRS (Shimabukuro-Vornhage et al., 2018). It exerts its effect through IL-6 inhibition, with minimal impact on T-cell function, making it an effective treatment option (Maude, Barrett, Teachey, & Grupp, 2014). For adults, tocilizumab should be dosed at 8 mg/kg of actual body weight (maximum dose of 800 mg) and given by intravenous infusion over 1 hr (Genentech, Inc., 2010). Tocilizumab dosing can be repeated every 8 hr as needed, for a maximum of three doses per 24-hr period, and a maximum of four total doses (Genentech, Inc., 2010). Once diluted, tociluzimab is stable for 24 hr, should be protected from light, and not be infused concomitantly in the same intravenous line as other medications (Genentech, Inc., 2010). The most common adverse reactions include upper respiratory tract infections, hypertension, hypersensitivity reactions, headache, and liver dysfunction (Genentech, Inc., 2010). Essential laboratory monitoring includes neutrophils, platelets, lipids, and liver function tests (Genentech, Inc., 2010). Although package labeling does suggest dose modifications for serious laboratory abnormalities, these adjustments are not applicable when used for CRS (Genentech, Inc., 2010). Corticosteroids are typically reserved for tocilizumab refractory cases because they have been found to suppress T cells, potentially interfering with CAR T-cell activity (Lee et al., 2019). However, recent literature suggests that corticosteroids do not impact efficacy and kinetics of CAR T cells, as there was no difference in complete remission found in those who received corticosteroids as first-line treatment compared with those who did not (Liu et al., 2020). Corticosteroid use remains controversial, and many institutions will only allow administration following direct approval from a hematologist. Other agents, such as siltuximab, are currently being evaluated for patients refractory to the aforementioned therapies (Leyfman, 2018).

Table 4 - Click to enlarge in new windowTable 4. ASBMT cytokine release syndrome grading and management

Neurologic Toxicity

Neurotoxicity is another potentially serious adverse effect that can occur in up to 64% of patients (Kite Pharma, Inc., 2020). The exact mechanism of neurotoxicity in CAR T-cell patients has not been elucidated; however, it is thought to be due to systemic inflammation and cytokine production that causes endothelial activation, coagulopathy, and blood-brain barrier disruption (Frey & Porter, 2019). It can be a separate entity from CRS or occur concomitantly.



Immune effector cell-associated neurotoxicity syndrome (ICANS) can present as a tremor, speech difficulty, and/or delirium in more mild stages; however, it can potentially cause agitation, seizures, and, in rare cases, cerebral edema (Frey & Porter, 2019). Because of the high incidence of neurotoxicity, patients should be counseled to avoid driving or operating dangerous machinery for at least 8 weeks following CAR T-cell infusion (Kite Pharma, Inc., 2020; Novartis Pharmaceutical Corporation, 2018). Medications including prochlorperazine and haloperidol that may lower the seizure threshold should be avoided. Often, inpatient providers will initiate a nonsedating, prophylactic antiepileptic medication such as levetiracetam. The earliest characteristic feature of neurotoxicity is often deficits in expressive speech, including naming of objects, and may quickly progress to global aphagia (Frey & Porter, 2019). Usually, it has a later onset than CRS, with a median onset of 4-6 days compared with 2-3 days for CRS (Kite Pharma, Inc., 2020; Novartis Pharmaceutical Corporation, 2018).



Both tocilizumab and high-dose steroids are appropriate for patients with CRS and neurotoxicity concurrently (Kite Pharma, Inc., 2020; Novartis Pharmaceutical Corporation, 2018). However, tocilizumab should not be given to patients without concomitant CRS because tocilizumab does not effectively penetrate the blood-brain barrier and thus is not effective for neurotoxicity (Genentech, Inc., 2010). Tables 5 and 6 provide further guidance on grading and management of neurotoxicity.

Table 5 - Click to enlarge in new windowTable 5. ASBMT-based grading for ICANS
Table 6 - Click to enlarge in new windowTable 6. Treatment example for ICANS


Differentiation syndrome can be a life-threatening oncological emergency. It is associated with rapid proliferation and differentiation of myeloid cells and has historically been identified in patients receiving all-trans retinoic acid (ATRA) and/or arsenic trioxide (ATO) for the treatment of acute promyelocytic leukemia (APL). Yet, this syndrome has been identified with the use of more recently FDA-approved therapies for the management of newly diagnosed and relapsed acute myelogenous leukemia (AML). These newer agents include the isocitrate dehydrogenase inhibitors, ivosidenib (Tibsovo) and enasidenib (IDHIFA), and the kinase inhibitor, gilteritinib (Xospata).



The features of differentiation syndrome may include rapid weight gain (5 kg or more), dyspnea, hypoxia, peripheral edema, unexplained fever, hypotension, acute renal or hepatic failure, and pulmonary infiltrates on chest radiograph or pleural/pericardial effusion. If left uncontrolled, multiorgan failure may ensue (Stahl & Tallman, 2019). The incidence of differentiation syndrome ranges anywhere from 2% to 48% in patients with APL and from 3% to 25% in patients with AML (Astellas Pharma Inc., 2019; Fathi et al., 2018; Norsworthy et al., 2020; Pollyea et al., 2019; Roboz et al., 2020; Stahl & Tallman, 2019). The timing can also vary on the basis of the agents being used. In patients receiving ATRA and/or ATO, it has a bimodal distribution and can be seen most commonly during the first and third weeks of treatment (Stahl & Tallman, 2019). For patients receiving gilteritinib or ivosidenib, it can occur as early as 1 day and up to 3 months after the start of treatment and in patients receiving enasidenib, it may occur as early as 1 day and up to 5 months after the start of treatment (Astellas Pharma Inc., 2019; Fathi et al., 2018; Norsworthy et al., 2020; Roboz et al., 2020).



Management generally consists of the use of corticosteroids combined with increased hemodynamic monitoring. Dexamethasone 10 mg intravenously every 12 hr (or an equivalent dose of an oral or intravenous corticosteroid) should be initiated as soon as differentiation syndrome is suspected. The dose may be increased to 10 mg intravenously every 6 hr if there is no clinical improvement noted in 24 hr. The corticosteroid is usually continued for a minimum of 3 days or until symptoms resolve. For patients receiving ATRA and/or ATO, the medication is held in severe cases of differentiation syndrome (those patients exhibiting severe organ dysfunction) or for patients requiring admission to the intensive care unit (Sanz & Montesinos, 2014). The newer agents all have long half-lives ranging from 4 to 8 days, so discontinuation of the agent does not usually lead to quick improvement of differentiation syndrome symptoms and may do away with any gains made in controlling the disease (Agios Pharmaceuticals, Inc., 2019; Astellas Pharma Inc., 2019; Celgene Corporation, 2019). It is recommended to interrupt therapy if severe signs/symptoms persist for more than 48 hr after the initiation of corticosteroids, and in the case of enasidenib, for any severe pulmonary symptoms requiring intubation or ventilator support (Celgene Corporation, 2019).



TLS is characterized by the breakdown of malignant cells and rapid release of intracellular contents into the blood. This causes metabolic abnormalities such as hyperuricemia, hyperkalemia, hyperphosphatemia, uremia, and hypocalcemia, which can lead to acute renal failure, cardiac dysrhythmias, and sudden death (Jones et al., 2015). TLS may present with one or more of the following: vomiting, diarrhea, anorexia, lethargy, edema, fluid overload, hematuria, congestive heart failure, seizure, muscle cramps, tetany, and syncope (Will & Tholouli, 2011).


TLS occurs most commonly 12-72 hr postchemotherapy but can occur before chemotherapy is initiated in patients with high disease burden (Davidson et al., 2004; Ribiero & Pui, 2003). Risk of TLS depends on factors such as tumor type, tumor/disease burden, baseline renal function, baseline uric acid, and response to chemotherapy. It is more common in patients with leukemia, lymphoma, and solid tumors with high proliferative rates and/or rapid response to chemotherapy. Incidence is also higher with bulky diseases (tumor greater than 10 cm), lactate dehydrogenase elevation more than two times the upper limit of normal (ULN), and a white blood cell count greater than 25,000 cells/mm3. Patients with preexisting renal failure and those with a baseline uric acid level greater than 7.5 mg/dl are also at an increased risk.



Patients can have either laboratory TLS, defined as metabolic abnormalities only, or clinical TLS, defined as laboratory abnormalities with associated clinical symptoms (Jones et al., 2015). Laboratory TLS is defined as two or more of the following within 3 days before or 7 days after initiation of treatment: uric acid 8 mg/dl or more or 25% increase from baseline, potassium of 6 mg/L or more or 25% increase from baseline, phosphorus 6.5 mg/dl or more or 25% increase from baseline, or calcium less than 7 mg/dl or 25% decrease from baseline. Clinical TLS is defined as laboratory TLS plus one or more of the following: serum creatinine 1.5 times or more the ULN, cardiac arrhythmias/sudden death, and/or seizures (Cairo & Bishop, 2004).


Prophylactic measures such as intravenous fluid administration and allopurinol play a key role in preventing TLS. All patients who receive chemotherapy should have a risk assessment for TLS and receive appropriate pro-phylaxis (Jones et al., 2015). Unfortunately, many patients presenting to the ED have not had a risk assessment and are not on prophylaxis because they have aggressive malignancy and spontaneous TLS before initiating chemotherapy (Galardy et al., 2013).



TLS management includes treatment of each metabolic abnormality, including hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia.



Aggressive hydration and diuresis are a mainstay of both the prevention and treatment of TLS. Hydration and increased urine output help excrete uric acid and phosphorus, therefore preventing uric acid crystallization and calcium phosphate deposits in the renal tubules (Coiffier, Altman, Pui, Younes, & Cairo, 2008). Fluids should be used to maintain a urine output of 100 ml/m2/hr (Coiffier et al., 2008; Jones et al., 2015).


Allopurinol is a xanthine oxidase inhibitor, which reduces the production of uric acid (Casper Pharma LLC, 2018). Although allopurinol has demonstrated efficacy in preventing hyperuricemia, it does not break down uric acid that is already formed (de Bont & Pieters, 2004). The effects of allopurinol are not seen for 24-72 hr and therefore it is considered an option for prophylaxis but is not the drug of choice in the acute treatment of TLS (Coiffier et al., 2008; Jones et al., 2015).


Rasburicase is a recombinant urate oxidase that metabolizes uric acid to allantoin, a more soluble compound (Pui, 2002; Sanofi-aventis, 2019). Therefore, rasburicase can break down uric acid deposits and reduce uric acid levels (Goldman et al., 2001; Jeha et al., 2005). Rasburicase should be given if a patient has hyperuricemia with laboratory or clinical TLS unless there are contraindications. Rasburicase is contraindicated in patients with glucose-6-phosphate dehydrogenase deficiency and women who are pregnant or breastfeeding (Sanofi-aventis, 2019). The recommended dose of rasburicase is 0.15-0.2 mg/kg once daily over 30 min for 5 days (Sanofi-aventis, 2019). Lower doses of 0.05-0.2 mg/kg once have been used successfully in clinical trials and were not inferior to higher or multiple daily doses (Hutcherson, Gammon, Bhatt, & Faneuf, 2006, McBride et al., 2013, McDonnell et al., 2006; Reeves & Bestul, 2008; Trifilio et al., 2006). In practice, doses are typically rounded to 3-6 mg. Available data suggest that one dose of rasburicase 6 mg is sufficient to lower uric acid and creatinine levels in adult patients with TLS (Feng et al., 2013; Yu et al., 2017). Furthermore, the NCCN Guidelines on Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma support the use of a fixed, single dose of rasburicase 3-6 mg, with repeat dosing individualized on the basis of response (Wierda et al., 2020). Administer as an infusion over 30 min in a dedicated intravenous line or flush with 0.9% sodium chloride prior to and after infusion. Uric acid levels should be monitored to guide the need for repeat rasburicase dose(s) and duration of therapy (Coiffier et al., 2008; Jones et al., 2015). In practice, uric acid concentrations are often monitored every 8 hr during initial treatment. Of note, rasburicase causes breakdown of uric acid in blood samples at room temperature. To limit interference with accurate measurements, blood samples for monitoring uric acid levels should be placed on ice until the assay is run and testing should be completed within 4 hr of collection (Coiffier et al., 2008).



Hyperkalemia should be verified with repeat sampling to rule out hemolysis as the cause (Coiffier et al., 2008). Patients should be monitored with electrocardiogram (ECG). For asymptomatic patients, consider administering sodium polystyrene sulfonate 1 g/kg orally or rectally (rectal route not recommended in patients who are neutropenic and/or thrombocytopenic). For symptomatic patients with ECG abnormalities consistent with hyperkalemia, consideration should be given to administering 1 g of calcium gluconate, 5 units of regular insulin intravenously, 25 g of intravenous dextrose, and sodium bicarbonate 50 mEq intravenous push. Calcium and sodium bicarbonate should not be administered via the same line without flushing between administrations. Life-threatening hyperkalemia may require dialysis (Coiffier et al., 2008).



The treatment of acute hyperphosphatemia is primarily focused on adequate hydration. Phosphorus binders such as aluminum hydroxide, sevelamer hydroxide, and lanthanum carbonate can be utilized to prevent further absorption of phosphorus (Coiffier et al., 2008). Aluminum hydroxide, if used, should be limited to 1-2 days to prevent toxicity. Severe hyperphosphatemia may require renal replacement therapy (Coiffier et al., 2008).



Hypocalcemia should only be treated if the patient is symptomatic (Cario & Bishop, 2004). Treatment with calcium can lead to precipitation of a calcium phosphate product that can deposit in the kidneys. Symptomatic patients with cardiac arrhythmias, seizures, or tetany should be given calcium gluconate intravenous push over 5 min and have ECG monitoring in place (Cario & Bishop, 2004).



As nearly 30% of patients with a malignancy will develop hypercalcemia, it is one of the most common causes of hypercalcemia in patients presenting to the ED (Klemencic & Perkins, 2019). Calcium homeostasis is mediated by the actions of parathyroid hormone (PTH), vitamin D metabolites, and calcitonin on the gastrointestinal tract, kidneys, and bones. Increased serum calcium occurs through multiple mechanisms including the following: intestinal absorption occurs with increased 1,25-dihydroxyvitamin D3 (calcitriol), reabsorption in the kidney via PTH and calcitriol, and, finally, decreased kidney excretion with PTH. Both PTH and calcitriol mediate increased bone resorption, whereas calcitonin inhibits bone resorption (Maier & Levine, 2013).



Patient presentations may range from asymptomatic to the following symptoms alone or in combination: nausea, vomiting, anorexia, lethargy, weakness, hyporeflexia, confusion, and bone pain (Dellay & Groth, 2016). These symptoms correspond with the rate of serum calcium increase and not necessarily the level. Supratherapeutic calcium levels can act as an osmotic diuretic causing polyuria and polydipsia resulting in volume depletion (Klemencic & Perkins, 2019). Cardiac abnormalities include prolonged PR interval and QRS, shortened QT, and ventricular dysrhythmias. Cardiac arrest may occur with calcium levels above 15 mg/dl (Maier & Levine, 2013).


Hypercalcemia is determined by total corrected serum calcium levels using the following calculation: measured calcium (mg/dl) + 0.8[4 - albumin (g/dl)]. The corrected calcium level can be classified as mild hypercalcemia, 10.5-11.9 mg/dl; moderate, 12-13.9 mg/dl; or severe, 14 mg/dl or higher (Goldner, 2016; Maier & Levine, 2013). Confirmation of calcium elevation is necessary as patients with hypoalbuminemia may actually have an elevated ionized calcium level due to reduced protein-bound calcium (Maier & Levine, 2013). Ionized serum calcium may be used to confirm hypercalcemia; however, it is greatly affected by pH levels. Patient evaluation should include an ECG to assess for potential cardiac abnormalities, and frequent neurological assessments may be necessary depending on presentation.



The degree of hypercalcemia and associated symptoms determines the treatment regimen. Asymptomatic patients with mild hypercalcemia may not require intervention, whereas moderate to severe hypercalcemia or the presence of renal or neurological symptoms warrants prompt treatment. The initial management of HCM in the ED includes intravenous fluid resuscitation, as dehydration is common. Often, 1-2 L of 0.9% sodium chloride, followed by a maintenance rate of 150-250 ml/hr, is a common starting regimen (Pi et al., 2016). However, it is important to avoid aggressive fluid resuscitation in patients with cardiac or renal insufficiency. The use of furosemide or other diuretics is no longer recommended as they have poor efficacy and may counteract attempts at fluid resuscitation (Goldner, 2016).


Bisphosphonate medications reduce osteoclast and increase osteoblast activity (Goldner, 2016). Bisphosphonate therapy is needed intravenously for calcium reduction in HCM, as oral therapy does not achieve concentrations necessary to reduce osteoclast activity (Zagzag, Hu, Fisher, & Perrier, 2018). However, these agents have limited utility in the acute management of this condition in the ED as the delayed onset of action occurs 1-3 days later and peak calcium reduction is observed after 4-7 days with an effect lasting up to 3 weeks (Zagzag et al., 2018). The two bisphosphonate regimens utilized for HCM are zoledronic acid 4 mg intravenously given over 15-30 min and pamidronate 60-90 mg intravenously administered over 2-6 hr, with zoledronic acid demonstrating greater efficacy in studies (Major et al., 2001; Pi et al., 2016).


It is prudent to ensure adequate volume resuscitation prior to bisphosphonate therapy because these agents may cause renal toxicity (Zagzag et al., 2018). Dose adjustments are required for renal dysfunction. To bridge the gap until the effects of bisphosphonates are present, calcitonin is a potential option to acutely reduce calcium levels, which is dosed 4-8 units per kilogram administered subcutaneously or intravenously every 8-12 hr (Pi et al., 2016). Intranasal calcitonin is not used for this indication. Calcitonin is expected to result in a mild calcium reduction of 1-2 mg/dl, but when used in conjunction with aggressive fluid resuscitation the synergistic calcium reduction may be sufficient to avoid severe toxicity from hypercalcemia (Maier & Levine, 2013). It is important to understand the aforementioned therapies only temporarily reduce serum calcium and the underlying cause, malignancy, must be addressed to prevent relapse following admission to the hospital.



One of the most common electrolyte disorders encountered in the ED is hyponatremia (Anderson, Chung, Kluge, & Schrier, 1985; Hawkins, 2003; Upadhyay, Jaber, & Madias, 2006). Hyponatremia can present within the context of hypervolemia, euvolemia, or hypovolemia. The etiology in those with malignancy can be multifactorial including gland dysfunction, paraneoplastic production of antidiuretic hormone (ADH), chemotherapy-induced dysfunction, and iatrogenic, secondary to the use of aggressive hydration as a part of chemotherapy regimens (Onitilo, Kio, & Doi, 2007). The most frequent cause of hyponatremia is the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and is associated with solid tumors, including a particularly high incidence among those with small cell lung cancer (Adrogue & Madias, 2000; Allan et al., 1990; Berghmans, Paesmans, & Body, 2000; Hansen, Sorensen, & Hansen, 2010; Lassen et al., 1995; Onitilo et al., 2007; Osterlind & Andersen, 1986). In patients with cancer receiving chemotherapy, such as vincristine and cyclophosphamide, the incidence of hyponatremia can be up to 47% (Liamis, Milionis, & Elisaf, 2008; Pi et al., 2016; Robertson, Bhoopalam, & Zelkowitz, 1973; Stuart, Cuaso, Miller, & Oski, 1975). At baseline, ADH is released from the posterior portion of the pituitary gland and allows for increased reabsorption of water in the kidney (Verbalis, Goldsmith, Greenberg, Schrier, & Sterns, 2007). An imbalance of this hormone can lead to an excess of total body water, without a corresponding rise in sodium, and result in hypervolemic hyponatremia. Hyponatremia can have a variety of presentations, ranging from asymptomatic to life-threatening. The most severe symptoms include confusion, hallucinations, seizures, coma, and death (Ellison & Berl, 2007).



When assessing hyponatremia, it is important to note the severity, duration, volume status of the patient, and presence of clinical symptoms (Berl, 1990; Decaux & Soupart, 2003). In patients who have severe hyponatremia (typically defined as a serum sodium less than 125 mmol/L) and associated symptoms that have developed within the previous 48 hr, rapid correction can be attempted with a target rise in serum sodium of 1-2 mmol/L/hr, usually with 3% sodium chloride or higher concentrations (Adrogue & Madias, 2000). Although limited data exist regarding the volume of 3% sodium chloride to administer in this setting, consensus recommendations suggest repeated 150-ml infusions every 20 min until symptoms abate (Spasovski et al., 2014). The total correction is generally recommended not to exceed 8-12 mmol/L over 24 hr and not more than 18-25 mmol/L over the first 48 hr (Adrogue & Madias, 2000; Janicic & Verbalis, 2003; Palmer, Gates, & Lader, 2003). However, if patients present with life-threatening symptoms (e.g., seizures), the correction of sodium should be done as rapidly as necessary to relieve the symptoms and thereafter reducing the correction rate (Decaux & Soupart, 2003). One of the primary concerns that exist with the overcorrection of hyponatremia is the occurrence of osmotic demyelination syndrome. This disorder encompasses myelinolysis of various regions of the brain including the pontine region and can lead to lethargy, dysarthria, quadriparesis, and pseudobulbar palsy (Laureno & Karp, 1997).


For the treatment of less acute presentations of unclear duration, particularly in the absence of clinical symptoms, the targeted correction rate is somewhat less clear, although general recommendations suggest an increase in serum sodium of 0.5-1 mmol/L/hr with a 24-hr limit of 8 mmol/L and a 48-hr limit of 18 mmol/L (Decaux & Soupart, 2003). Monitoring is critical in the treatment of all hyponatremia presentations and is recommended every 2-3 hr to prevent overcorrection. Fluid restriction also plays a key role in the treatment of hypervolemic hyponatremia, as well as the encouragement of adequate dietary protein and salt consumption (Schwartz, Bennett, Curelop, & Bartter, 1957). For euvolemic and hypervolemic hyponatremia, fluid restriction may be instituted between 500 and 1,000 ml per day (Adrogue & Madias, 2000; Onitilo et al., 2007). Although less common, patients presenting with hypovolemic hyponatremia should have their fluid status optimized, as well as increase their sodium concentration, with fluid replacement using 0.9% sodium chloride at approximately 0.5-1 ml/kg/hr (Verbalis et al., 2007).



Complications of malignancy and chemotherapy are frequently seen in the ED and often require emergent treatment. A fundamental understanding of the disease process and the appropriate acute management strategies in critical situations is important for all Emergency Medicine personnel. In addition, it is important to consult with the hematology and oncology service to ensure patients receive appropriate inpatient or outpatient management and follow-up.




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CAR T-cell therapy; differentiation syndrome; febrile neutropenia; hypercalcemia of malignancy; hyponatremia; tumor lysis syndrome