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CHAPTER 240: Emergency Complications of Malignancy 1513 Both agents had minimal use in emergency practice until a randomized clinical trial of the effect of tranexamic acid on mortality and vascular thrombotic events in 20,211 adult trauma victims was published in 2010. 82 This study found that tranexamic acid (1 gram IV over 10 minutes followed by 1 gram infused over 8 hours) reduced death due to bleeding and all-cause mortality, assessed at 4 weeks, with no observed increase in vascular thrombotic complications. 82 Mortality reduction was dependent on timing; efficacy was seen if administered within 3 hours, but not afterward. 83,84 Based on this study and additional analysis,85 the World Health Organization added tranexamic acid to its List of Essential Medications in 2011. There is ongoing debate about the role of tranexamic acid in trauma care, with questioning about its value in the modern trauma care systems found in heavily resourced counties as opposed to the resource-limited hospitals that treated the bulk of patients in the CRASH-2 study. COMPLICATIONS OF ANTIFIBRINOLYTIC AGENTS Both drugs have potential to cause vascular thrombosis, with reported rates that vary according to thrombus location and condition being treated. 100 The observed incidence of limb ischemia and myocardial infarction is low (<1%). 100 The incidence of deep vein thrombosis and pulmonary embolism is highest in patients with subarachnoid hemor rhage (2% and 3%, respectively). 100 In adult trauma, the observed inci dence of deep vein thrombosis or pulmonary embolism after treatment with IV tranexamic acid was not significantly increased compared to the control group (about 1% for each thrombotic event). REFERENCES The complete reference list is available online at www.TintinalliEM.com. Emergency Complications of Malignancy Patricia Brock Maria T. Cruz-Carreras INTRODUCTION The incidence of cancer is increasing as the general population ages and individual longevity grows. More patients with active malignancy are likely to come to the ED for care because of this increase, coupled with more intensive and varied treatments being applied in the outpatient setting. 1 Many conditions that prompt these patients to come to the ED will not be due to cancer. 2,3 Conversely, there are disorders often or uniquely related to malignancy that collectively are termed oncologic emergencies.4-7 These malignancy-related emergencies are broadly cate gorized as: (1) those due to local tumor effects, (2) those secondary to biochemical derangement, (3) those that are the result of hematologic derangement, and (4) those related to therapy (Table 240-1).  EMERGENCIES RELATED TO LOCAL TUMOR EFFECTS MALIGNANT AIRWAY OBSTRUCTION Malignancy-related airway compromise is usually an insidious pro cess that results from a mass originating in the oropharynx, neck, or superior mediastinum progressively obstructing airflow. 5,8 Acute com promise may occur with supervening infection, hemorrhage, or loss of CHAPTER protective mechanisms, such as muscle tone. Iatrogenic factors, such as radiation therapy, may create additional difficulties by producing local inflammation with tissue breakdown.

r mediastinum progressively obstructing airflow. 5,8 Acute com promise may occur with supervening infection, hemorrhage, or loss of CHAPTER protective mechanisms, such as muscle tone. Iatrogenic factors, such as radiation therapy, may create additional difficulties by producing local inflammation with tissue breakdown. It is helpful to classify airway impairment due to malignant tumor obstruction in two manners, as to location—from the lips and nares to the vocal cords ( upper airway) versus those from the vocal cords to the carina ( central airway)—and as to nature of the obstruction— endoluminal, extraluminal, or mixed. Almost regardless of the cause, airway obstruction usually presents with symptoms of shortness of breath and signs of tachypnea and stridor. The physical examination may show evidence of a mass in the pharynx, neck, or supraclavicular area. Patients with airway obstruction due to a malignant tumor are evaluated with a combination of plain radiographs, CT, and endoscopic visualization. 5,8 Direct laryngoscopy is discouraged because injudicious manipulation of the upper airway may convert a partial obstruction into a complete one by provoking bleeding or edema. Emergency management includes the administration of supplemental humidified oxygen and maintenance of the best airway possible through patient positioning. Heliox—typically a 50:50 mixture of helium and oxygen—may provide symptomatic improvement in upper airway obstruction due to cancer when combined with other therapy. 10 Highflow nasal oxygen administration can also bide time to definitive airway management. Mechanical intervention for critical airway obstruction from a tumor is rarely required in the ED. For patients with critical upper airway obstruction, emergency transtracheal jet ventilation or crico thyroidotomy could be lifesaving if the obstruction is above the vocal cords (see Chapter 30, “Surgical Airways”). However, the presence of an overlying tumor or swelling may render such procedures techni cally difficult. Alternatively, passage of the endotracheal tube beyond the area of obstruction is a consideration when the patient is progress ing to complete airway occlusion. 5,9 This is best done using awake fiberoptic intubation with a 5-0 or 6-0 endotracheal tube that is wire reinforced, if possible. Placement of such a tube can provide symptom atic relief and time until procedures with more sustained benefit can be performed. The various procedures to relieve malignancy-related airway obstruction include placement of an expanding stent at the stenotic site, neodymium-yttrium-aluminum-garnet laser photoradiation or argon plasma coagulation for vaporization of obstructing tissue, and mechanical tumor resection; these modalities are often combined. 11-13 Alternatively, variations of radiotherapy, such as endobronchial brachytherapy, photodynamic therapy, and external-beam radiation therapy, can be directed to the obstructing tumor, but the time for symptomatic response is longer than that of the mechanical approaches of laser photoradiation and stenting. TABLE 240-1 Emergency Complications of Malignancy Related to local tumor effects Malignant airway obstruction Bone metastases and pathologic fractures Malignant spinal cord compression Malignant pericardial effusion with tamponade Superior vena cava syndrome Related to biochemical derangement Hypercalcemia Hyponatremia due to inappropriate antidiuretic hormone secretion Adrenal insufficiency Tumor lysis syndrome Related to hematologic derangement Febrile neutropenia and infection Hyperviscosity syndrome Thromboembolism Related to therapy Chemotherapy-induced nausea and vomiting Chemotherapeutic drug extravasation Complications due to biologic therapy Tintinalli_Sec18_p1461-1522.indd 1513 8/2/19 8:37 PM

ncy Tumor lysis syndrome Related to hematologic derangement Febrile neutropenia and infection Hyperviscosity syndrome Thromboembolism Related to therapy Chemotherapy-induced nausea and vomiting Chemotherapeutic drug extravasation Complications due to biologic therapy Tintinalli_Sec18_p1461-1522.indd 1513 8/2/19 8:37 PM 1514 SECTION 18: Hematologic and Oncologic Disorders BONE METASTASES AND PATHOLOGIC FRACTURES Anatomic disruption of bone weakened by preexisting conditions is termed a pathologic fracture . Pathologic fractures due to malignancy most commonly affect the axial skeleton (calvarium included) and the proximal aspect of the limbs. Most pathologic fractures are due to metastases from solid tumors (e.g., breast, lung, prostate) that localize in areas of bones with high blood flow, identified as containing red marrow. 14 Most patients with pathologic fractures have a known malignancy. Patients with bone metastases usually present with local ized pain and a benign outward appearance of the involved area.15 Malignancy alters the normal radiographic appearance of bone, including loss of trabeculae with indistinct margins (osteolytic, or “moth eaten”), poorly demarcated areas of increased density (osteoblastic), and/or a periosteal reaction. Plain radiographs may identify only about half of metastatic bone lesions, and advanced imaging is often required for accurate detection. 16 CT with IV contrast, particularly when using reconstruction software, can visualize three-dimensional bone integ rity and soft tissue extension, whereas MRI best detects small tumors and delineates soft tissue and bone marrow involvement. A total-body radionuclide bone scan can be used as a screening tool to identify areas of increased bone activity that could represent additional metastatic spread. 16 However, areas of radionuclide localization on the bone scan are not specific for cancer, and additional imaging studies of these areas are necessary for confirmation. Treatment priorities are pain relief and restoration or salvage of function. 15 For acute pain or fracture, parenteral analgesics are recommended for rapid treatment. Patients with bone metastases often require long-acting oral opioids and other adjunctive medications for pain relief (see Chapter 38, “Chronic Pain”). Approximately 80% of painful bone metastases can be helped with palliative radiotherapy, although it may take several weeks after completion of a typical 5-day course of treatment to experience maximal benefit. 17 The majority of pathologic fractures require open surgical repair.18 MALIGNANT SPINAL CORD COMPRESSION Up to 20% of cancer patients will develop neoplastic involvement of the vertebral column, and 3% to 6% will develop spinal cord compression. 4,5,7,19 Most cases of malignant spinal cord compression are due to metastases to vertebral bodies from solid organ tumors, with the thoracic verte brae being the most common location for such metastases. Spinal cord compression occurs when these metastases enlarge, erode through the vertebral cortex into the spinal canal, and compress on the spinal cord. Less common causes of malignant spinal cord compression include local spread from paraspinal tumors through the intervertebral foramen or tumors (primary or metastatic) directly involving the spinal cord or meninges. Approximately 90% of patients with malignant spinal cord compres sion will have back pain (Table 240-2). 19 Such pain is often described as unrelenting, progressive, worse when supine, and located in the thoracic vertebral area. Approximately 80% of patients with malignant spinal cord compression have a prior diagnosis of cancer, so individuals with known cancer and back pain should undergo radiographic imaging.

e 240-2). 19 Such pain is often described as unrelenting, progressive, worse when supine, and located in the thoracic vertebral area. Approximately 80% of patients with malignant spinal cord compression have a prior diagnosis of cancer, so individuals with known cancer and back pain should undergo radiographic imaging. Other symptoms of malignant spinal cord compression may include muscular weakness, radicular pain, and bladder or bowel dysfunction. Weakness is most apparent in the proximal extremity musculature and may progress to complete paralysis. Sensory changes initially may be confined to a band of hyperesthesia around the trunk at the involved spinal level and that eventually becomes anesthetic distal to the level. Urinary retention (with overflow incontinence), fecal incontinence, and impotence are late manifestations. MRI preferably with contrast is the imaging modality of choice to localize the site, define the degree of cord compression, and identify additional vertebral lesions. The entire spinal column is imaged due to the potential for multiple level involvement. CT with or without myelography is used when MRI is contraindicated or inaccessible. Plain radi ography may identify an abnormality in approximately 80% of patients with painful vertebral metastases. However, plain radiographs are less useful in patients with suspected malignant spinal cord compression, because radiographic findings do not always correlate with the level of spinal cord compression, and causes of malignant spinal cord com pression other than vertebral body metastases will not produce visible changes in vertebral body radiographic appearance. Use opioid analgesics for initial pain control. Consider administration of corticosteroids in the ED, especially if there will be a delay in MRI or CT myelography. 4,5,7,19 Typically dexamethasone, 10 milligrams IV bolus, followed by 4 milligrams PO or IV every 6 hours, is used. Further treatment, with continued corticosteroids, radiation therapy, surgery, or a combination of modalities, will depend on the life expectancy of the patient, extent of disease, and degree of motor impairment. 20 Radiation therapy has been the typical treatment for patients with malignant spinal cord compression, and a beneficial response is seen in approximately 70% of those treated. 20,21 The overall prognosis for those treated with radiotherapy is highly dependent on pretreatment functional ability; approximately 90% of those who can walk at the time of diagnosis remain ambulatory after radiation treatment, about half of those who have motor function but cannot walk will recover ambulatory ability with radiotherapy, but few patients with complete paraplegia at the time of diagnosis will recover lower extremity motor function. 22 Select patients with malignant spinal cord compression may benefit from surgical tumor resection, including those with neurologic impairment (Table 240-2). 19,20 Because of the complex decision making from among the therapeutic options, specialists in oncology, radiotherapy, and spinal surgery should be consulted early. MALIGNANT PERICARDIAL EFFUSION WITH TAMPONADE Pericardial involvement, often with effusion, occurs in up to 35% of patients with all types of cancer, although the effusions are often small and remain undiagnosed. 4,5,7,23 Symptomatic pericardial effusions occur less frequently and usually result from lung or breast cancer. Other etiologies for pericardial effusions in patients with malignant disease include other tumor types (such as melanoma, leukemia, or lymphoma) and a complication of treatment (radiotherapy or chemotherapy).

,5,7,23 Symptomatic pericardial effusions occur less frequently and usually result from lung or breast cancer. Other etiologies for pericardial effusions in patients with malignant disease include other tumor types (such as melanoma, leukemia, or lymphoma) and a complication of treatment (radiotherapy or chemotherapy). TABLE 240-2 Malignant Spinal Cord Compression Suspect Patient with known cancer: especially lung, breast, prostate Thoracic location: 70% Progressive pain and worse when supine Motor weakness: proximal legs Sensory changes: initially radicular, later distal anesthesia Bladder or bowel dysfunction: late findings Imaging Plain radiographs: may detect vertebral body metastases but less sensitive and specific for malignant spinal cord compression MRI: modality of choice, preferably with contrast; image entire vertebral column CT myelography: used when MRI not available or accessible Corticosteroids Dexamethasone, 10 milligrams IV followed by 4 milligrams PO or IV every 6 h Consider starting in ED if imaging is delayed Radiotherapy Standard approach, beneficial in approximately 70% No specific radiotherapy regimen proven superior Prognosis highly dependent on pretreatment neurologic function Surgery Consider in highly selected cases, such as the following: Patient in good general condition and able to undergo extensive surgery Appropriate prognostic life expectancy Rapidly progressive symptoms Clinical worsening during radiotherapy Unstable vertebral column Tintinalli_Sec18_p1461-1522.indd 1514 8/2/19 8:37 PM

gery Consider in highly selected cases, such as the following: Patient in good general condition and able to undergo extensive surgery Appropriate prognostic life expectancy Rapidly progressive symptoms Clinical worsening during radiotherapy Unstable vertebral column Tintinalli_Sec18_p1461-1522.indd 1514 8/2/19 8:37 PM CHAPTER 240: Emergency Complications of Malignancy 1515 Symptoms and physical examination findings are a function of pericardial fluid accumulation rate and volume (see Chapter 55, “Cardiomyopathies and Pericardial Disease”). Large effusions can develop gradually and are surprisingly well tolerated. Symptoms of a pericardial effusion include dyspnea, orthopnea, chest pain, dysphagia, hoarseness, and hiccups. Physical findings include distant cardiac sounds, jugular venous distention, and a pulsus paradoxus. A sudden increase in fluid between the nondistensible pericardium and compressible heart creates a cardiac tamponade: the low-pressure right heart is unable to accept vena caval return or pump forward to the pulmonary arteries, and the left ventricle cannot fill or produce a sustainable ejection fraction. Signs and symptoms include accentuation of those noted with pericardial effusion with additional manifestations of circulatory shock. There is usually tachycardia, hypotension, and a narrowed pulse pressure. The ECG may demonstrate reduced voltage in the QRS complex throughout all leads, a reflection of the insulating characteristics of the effusion. Electrical alternans is a classic, although infrequent, finding with a large pericardial effusion. The cardiac silhouette on chest radiography may appear large, reflecting the gradually accumulated effusion in the stretched pericardial sac. Echocardiography is the diagnostic tool of choice, being noninvasive, portable, and highly accurate in trained hands. Echocardiography can not only detect the presence of a signifi cant pericardial effusion, but also assess cardiac function and identify physiologic changes associated with cardiac tamponade. Asymptomatic pericardial effusions do not require specific treatment. Patients with symptomatic effusions should undergo pericardiocentesis, ideally with echocardiographic guidance (see Chapter 34, “Pericardio centesis”). Most often, this procedure can await the arrival of the spe cialist and transport of the patient to the appropriate procedural area. If patients with cardiac tamponade require emergent pericardiocentesis in the ED, use bedside US to guide needle direction during the procedure. Malignant pericardial effusions are treated depending on the tumor type and overall patient condition. 23 Reduction in fluid production can be done by treating the tumor with appropriate systemic chemotherapy or radiotherapy. Intrapericardial chemotherapy may be useful in tumors sensitive to these agents. A pericardial window or partial pericardial resection can be done to prevent accumulation of fluid within the peri cardial space. A percutaneous indwelling intrapericardial catheter can also prevent accumulation of fluid, but with the risks associated with percutaneous devices. 24 Malignant pericardial effusion typically indicates the presence of advanced disease, and most patients die within 1 year after diagnosis. SUPERIOR VENA CAVA SYNDROME The term superior vena cava (SVC) syndrome describes the clinical effects of elevated venous pressure in the upper body that result from obstruction of venous blood flow through the SVC. 4,5,7,25,26 This syn drome is classically caused by external compression of the SVC by an extrinsic malignant mass. The most common tumors associated with malignant SVC syndrome are lung cancer in 70% and lymphoma in approximately 20%.

in the upper body that result from obstruction of venous blood flow through the SVC. 4,5,7,25,26 This syn drome is classically caused by external compression of the SVC by an extrinsic malignant mass. The most common tumors associated with malignant SVC syndrome are lung cancer in 70% and lymphoma in approximately 20%. Benign conditions and intravascular thrombosis (precipitated by indwelling vascular catheters or pacemaker leads) currently account for about one third of all SVC syndrome cases. SVC syndrome rarely constitutes an emergency; the vast majority of patients do not materially deteriorate during the initial 1 to 2 weeks after diag nosis. The exception is when neurologic abnormalities are present due to increased intracranial pressure. Symptom development correlates roughly with the severity of obstruction and the rate of narrowing. If compression occurs over weeks, col lateral vessels dilate to compensate for impaired flow through the SVC. Most patients will describe symptoms developing a few weeks before seeking medical attention. Clinical manifestations correlate with a jugular venous pressure of 20 to 40 mm Hg (2.7 to 5.4 kPa), as compared with a normal range of 2 to 8 mm Hg (0.3 to 1.0 kPa). The most com mon symptoms are facial swelling, dyspnea, cough, and arm swelling. 25,26 Less common symptoms include hoarse voice, syncope, headache, and dizziness. In rare but extreme cases, venous obstruction can lead to increased intracranial pressure that produces visual changes, dizziness, confusion, seizures, and obtundation. Physical examination findings may show swelling of the face and arm, sometimes with a violaceous hue or plethora, and distended neck and chest wall veins. The plain chest radiograph will usually show a mediastinal mass in cases of malignant SVC syndrome. CT of the chest with intravascular contrast is the recommended imaging modality to assess the patency of the SVC. 25,26 MRI is useful for patients who cannot receive IV contrast. Contrast venography is rarely needed, except in uncertain cases or as part of an intravascular interventional procedure. In patients with a known diagnosis of lung cancer, biopsy for pathologic confirmation of a malignancy is usually not required. For patients without a known intrathoracic cancer, tissue confirmation of a malignant cause is highly desirable before initiation of radiotherapy and required before initiation of chemotherapy. Initial management is with head elevation to decrease venous pres sure in the upper body and supplemental oxygen to reduce the work of breathing. Corticosteroids and loop diuretics are commonly used, but there is no evidence that they contribute to clinical improvement, with the exception that corticosteroids would be expected to be helpful when the cause of the obstruction is lymphoma. Radiation therapy is effective in reducing symptoms in approximately 75% of patients with SVC syndrome, reflecting the approximate inci dence of radiosensitive tumors producing this disorder. 26 Many patients will experience a reduction in symptoms within 3 days after the start of radiation treatment. Intravascular stents, with or without angioplasty, can be used to reduce obstruction to SVC flow. 26,27 These stents appear to produce a more rapid improvement in symptoms and signs compared with radiotherapy or chemotherapy, suggesting a preferential benefit in patients with severe manifestations who require urgent treatment. 26,27 Stent placement should also be considered for malignant causes that do not respond well to radiotherapy or chemotherapy (e.g., mesothelioma), for benign causes (e.g., fibrosing mediastinitis), or for intravascular thrombosis associated with an indwelling catheter.

vere manifestations who require urgent treatment. 26,27 Stent placement should also be considered for malignant causes that do not respond well to radiotherapy or chemotherapy (e.g., mesothelioma), for benign causes (e.g., fibrosing mediastinitis), or for intravascular thrombosis associated with an indwelling catheter. Chemotherapy is effective in producing symptomatic relief from SVC syndrome in approximately 80% of patients with lymphoma, 80% of patients with small-cell lung cancer, and 40% of patients with non– small-cell lung cancer. Patients with SVC syndrome due to intravascular thrombosis can be treated with catheter-directed fibrinolytics. 26 Removal of an inciting intravascular object, such as a central venous catheter, should be con sidered. Postfibrinolytic anticoagulation is generally recommended to prevent recurrence, although there is no firm supporting evidence. 26 For cancer patients with an indwelling central venous catheter, prophylactic low-molecular-weight heparin decreases the incidence of symptomatic catheter-related venous thromboembolism for up to 3 months, but its use must be balanced by the potential harms of anticoagulation. Recurrence of SVC syndrome is seen in approximately 20% of lung cancer patients treated with radiotherapy and/or chemotherapy and 10% treated with intravascular stents. 26 For patients with malignant SVC syndrome, survival is dependent on the causative cancer; with lung cancer, median survival is approximately 6 to 12 months.  EMERGENCIES RELATED TO BIOCHEMICAL DERANGEMENT HYPERCALCEMIA Hypercalcemia is seen in 5% to 30% of patients with advanced cancer at some time during their disease course. 29 Breast cancer, lung cancer, and multiple myeloma are the malignancies most commonly associated with hypercalcemia. The three primary mechanisms whereby malig nancy produces hypercalcemia are: (1) most commonly by production of a parathyroid hormone–related protein that is structurally similar to parathyroid hormone so that calcium is mobilized from bones and its renal reabsorption is increased; (2) by extensive local bone destruction associated with osteoclast-activating factors seen in lung and breast cancer and multiple myeloma; and (3) by production of vitamin D analogs, usually in lymphomas. Tintinalli_Sec18_p1461-1522.indd 1515 8/2/19 8:37 PM

mobilized from bones and its renal reabsorption is increased; (2) by extensive local bone destruction associated with osteoclast-activating factors seen in lung and breast cancer and multiple myeloma; and (3) by production of vitamin D analogs, usually in lymphomas. Tintinalli_Sec18_p1461-1522.indd 1515 8/2/19 8:37 PM 1516 SECTION 18: Hematologic and Oncologic Disorders Classic symptoms of hypercalcemia include lethargy, confusion, anorexia, and nausea (see Chapter 17, “Fluids and Electrolytes”). Because most patients with hypercalcemia due to malignancy have advanced cancer, symptoms of general debility due to tumor may be difficult to distinguish from those caused by hypercalcemia. Hypercal cemia reduces intestinal motility, so constipation is common, although that symptom can be produced by concomitant opioid therapy for pain. Hypercalcemia produces an osmotic diuresis, so some of the nonspecific symptoms can be due to relative hypovolemia. Clinical symptoms of hypercalcemia are most often correlated with the rate of rise in the serum calcium level, as opposed to the actual calcium level. There fore, slow increases in serum calcium may be relatively asymptomatic until reaching high levels. Hypercalcemia does not always require treatment, especially if the patient is asymptomatic and well hydrated and the total serum calcium is less than 14 milligrams/dL (3.5 mmol/L). The initial treatment of symptomatic hypercalcemia is with IV isotonic saline according to the patient’s initial volume status followed by a rate adjusted to the ability of the patient’s cardiovascular system to tolerate a volume load (Table 240-3). 6,7 IV saline will result in clinical improvement and a modest decrease in the plasma calcium over 24 to 48 hours, but rarely normalizes the level. Furosemide is useful in patients with heart failure or renal insufficiency to prevent volume overload from normal saline infusion, but has little additive effect to the use of IV saline alone in the treatment of hyper calcemia in patients with normal cardiac and renal function. Therefore, furosemide is not routinely recommended in the treatment of hypercalcemia due to malignancy. Because the initial priority is restoration of intravascular volume with IV saline, pharmacologic treatment of hypercalcemia is usually not initiated in the ED. 6,7 Bisphosphonates, such as pamidronate or zoledronic acid, are the recommended agents to treat malignancyassociated hypercalcemia. 6,7,29 Bisphosphonates are potent inhibitors of bone resorption and produce a sustained decrease in calcium 12 to 48 hours after administration, with the effect lasting for approximately 2 to 4 weeks. Bisphosphonates are given by slow IV infusion to prevent precipitation of bisphosphonate–calcium complexes in the kidney and subsequent renal failure. Other agents have a limited role in the treatment of malignancyinduced hypercalcemia. Calcitonin lowers plasma calcium within 2 to 4 hours, but it may cause a hypersensitivity response, and tachyphylaxis develops within 3 days, so the beneficial effect is short lived. Calcito nin is only used when prompt reduction of calcium levels is needed. Glucocorticoids, such as prednisone 60 milligrams PO daily, may be helpful with steroid-sensitive tumors, such as lymphomas and multiple myeloma. 6,7,29 Denosumab, a humanized monoclonal antibody that inhibits osteoclast activity and function, is approved for hypercalcemia refractory to bisphosphonate therapy. Hemodialysis can be used to treat hypercalcemia and is indicated for those with profound mental status changes or renal failure or those unable to tolerate a saline load.

, a humanized monoclonal antibody that inhibits osteoclast activity and function, is approved for hypercalcemia refractory to bisphosphonate therapy. Hemodialysis can be used to treat hypercalcemia and is indicated for those with profound mental status changes or renal failure or those unable to tolerate a saline load. HYPONATREMIA DUE TO INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION Inappropriate secretion of antidiuretic hormone is most commonly associated with bronchogenic cancer, but may be seen in other malignancies and can also occur from chemotherapy, opioids, carbamazepine, and selective serotonin reuptake inhibitors. 6,30,31 Regardless of the etiology, the syndrome of inappropriate antidiuretic hormone consists of hypo natremia, decreased serum osmolality, and less than maximally dilute urine, all in the presence of euvolemia, absence of diuretic therapy, and normal renal, adrenal, and thyroid function (see Chapter 17). Syndrome of inappropriate antidiuretic hormone secretion should be suspected if a patient with cancer presents with normovolemic hyponatremia. Signs and symptoms of hyponatremia are primarily neurologic and correlate with severity and with rapidity of development. Anorexia, nausea, and malaise are the earliest findings, followed by headache, confusion, obtundation, seizures, and coma. Seizures are usually generalized tonic-clonic in nature; focal seizures are uncommon from hyponatre mia, and their occurrence suggests focal CNS lesions. Life-threatening symptoms are almost invariably associated with sodium concentrations <110 mEq/L (<110 mmol/L). Water restriction is the mainstay of treatment in euvolemic asymptomatic patients. Patients with sodium levels >125 mEq/L (>125 mmol/L) are generally asymptomatic and can be managed with water restriction of 500 mL/d and close follow-up. More severe hyponatremia— serum sodium between 110 and 125 mEq/L with mild to moderate symptoms—may require furosemide 0.5 to 1.0 milligram/kg PO with concomitant IV normal saline to maintain euvolemia and effect a net free water clearance. For severe hyponatremia—serum sodium <110 mEq/L, usually with coma or repetitive or sustained seizures—infuse 3% hypertonic saline (510 mEq/L) 100 mL over 10 to 15 minutes. Then reassess patient and measure serum sodium. If symptoms have not resolved or the serum sodium has not increased by 5 mEq/L, one or two additional doses of 3% hypertonic saline may be necessary (see Chapter 17). ADRENAL INSUFFICIENCY Adrenal insufficiency associated with malignancy may be secondary to adrenal tissue replacement by metastases, but is more commonly due to abrupt physiologic stress in the face of chronic glucocorticoid therapy with pharmacologic adrenal suppression (see Chapter 230, “ Adrenal Insufficiency”). 32,33 The subsequent vasomotor collapse may be sudden and severe.32 Clues for acute adrenal insufficiency include mild hypo glycemia, hyponatremia, and hypotension refractory to volume loading and vasoconstrictor therapy.

ticoid therapy with pharmacologic adrenal suppression (see Chapter 230, “ Adrenal Insufficiency”). 32,33 The subsequent vasomotor collapse may be sudden and severe.32 Clues for acute adrenal insufficiency include mild hypo glycemia, hyponatremia, and hypotension refractory to volume loading and vasoconstrictor therapy. Obtain a serum cortisol level, institute IV rehydration with normal saline, and administer stress doses of steroids, such as hydrocortisone TABLE 240-3 Treatment of Cancer-Associated Hypercalcemia7 Intervention Dosage Comments Normal saline If hypovolemic: 1- to 2-L initial bolus over 1 h If euvolemic: 250–500 mL/h IV for 1 L, followed by 100–150 mL/h IV Adjust the infusion rate according to the patient’s cardiovascular status Furosemide 20–40 milligrams IV Use only for patients with volume overload after volume expansion Pamidronate 60–90 milligrams IV over 2–4 h Use with caution in renal insufficiency Onset of action may take days Zoledronic acid 4 milligrams IV over 15 min Use with caution in renal insufficiency Onset of action may take days Short infusion time is an advantage over pamidronate Calcitonin 4–8 IU/kg SC or IV every 12 h Rapid onset of action but short lived (about 3 d) Use when prompt reduction of calcium level is needed Glucocorticoids Prednisone 60 milligrams PO daily Hydrocortisone 100 milligrams IV every 6 h Used for hypercalcemia due to lymphomas and multiple myeloma Denosumab 120 milligrams (or 0.3 milligram/kg) SC weekly for 4 wk, then every 4 wk Used in hypercalcemia refractory to bisphosphonate therapy Can cause symptomatic hypocalcemia Tintinalli_Sec18_p1461-1522.indd 1516 8/2/19 8:37 PM

e 100 milligrams IV every 6 h Used for hypercalcemia due to lymphomas and multiple myeloma Denosumab 120 milligrams (or 0.3 milligram/kg) SC weekly for 4 wk, then every 4 wk Used in hypercalcemia refractory to bisphosphonate therapy Can cause symptomatic hypocalcemia Tintinalli_Sec18_p1461-1522.indd 1516 8/2/19 8:37 PM CHAPTER 240: Emergency Complications of Malignancy 1517 100 milligrams IV or dexamethasone 4 milligrams IV (see Chapter 230). The steroid-dependent patient will need increased doses of steroids during the acute illness, typically three times the daily maintenance dose of glucocorticoid. TUMOR LYSIS SYNDROME Tumor lysis syndrome is a metabolic crisis resulting from massive cytolysis and release of intracellular contents into the systemic circulation.6,7,34 Of particular concern are the individual ions (potassium, phosphate, calcium), nucleic acids (which metabolize to uric acid), and intracellular proteins. Tumor lysis syndrome most commonly occurs with treatment of hematologic malignancies because of rapid cell turnover and growth rates, bulky tumor mass, and high sensitivity to antineoplastic agents. Tumor lysis syndrome is uncommon with solid tumors or without prior therapy (“spontaneous tumor lysis syndrome”). The manifestations of tumor lysis syndrome can be categorized by clinical effects (acute kidney injury, seizure, cardiac dysrhythmia, or arrest) and laboratory abnormalities (hyperuricemia, hyperkalemia, hyperphosphatemia, or hypocalcemia). Renal failure is the strongest predictor of morbidity in tumor lysis syndrome and usually results from uric acid precipitation within the renal tubules. Phosphorus released from tumor cells may combine with calcium and precipitate in renal tubules and parenchyma as well. Hypovolemia may contribute to the renal impairment seen with tumor lysis syndrome. The release of intra cellular potassium can produce acute hyperkalemia and provoke or contribute to cardiac dysrhythmias or cardiac arrest. Because malignant cells can contain fourfold the amount of phosphorus as normal cells, the abrupt release of extensive phosphate into the circulation may produce a decrease in serum calcium. The resultant hypocalcemia may induce tetany and seizures and contribute to dysrhythmias. Recognize the potential for tumor lysis syndrome with treatment of hematologic malignancies. Prophylactic allopurinol and maintaining good hydration can reduce the risk of tumor lysis syndrome developing. Patients with established tumor lysis syndrome may experience sudden electrolyte changes and life-threatening complications, so admission to an intensive care unit with cardiac rhythm monitoring is indicated. Aggressive IV fluid administration to increase urinary excretion of the released intracellular solutes is the cornerstone for treatment of tumor lysis syndrome. 7,34 Increased urine flow will counteract the precipitation of urate and calcium phosphate crystals in the renal tubules. Hyperkalemia is the most immediate life-threatening element with tumor lysis syndrome because of induced cardiac dysrhythmias and cardiac arrest. 6,34 Treatment is identical to other causes of hyperkale mia: β-adrenergic agonists, sodium bicarbonate, and dextrose-insulin therapy (see Chapter 17). Avoid calcium administration unless there is cardiovascular instability (ventricular dysrhythmias or wide QRS complexes) or neuromuscular irritability (seizures) because supplemental calcium may cause metastatic precipitation of calcium phosphate. Hyperphosphatemia is managed with phosphate binders (limited effect) or by the administration of dextrose and insulin.

ardiovascular instability (ventricular dysrhythmias or wide QRS complexes) or neuromuscular irritability (seizures) because supplemental calcium may cause metastatic precipitation of calcium phosphate. Hyperphosphatemia is managed with phosphate binders (limited effect) or by the administration of dextrose and insulin. Hemodialysis can correct all biochemical abnormalities of tumor lysis syndrome, although a large phosphate burden may require repeat frequent and prolonged dialysis sessions or continuous renal replacement therapy. 6,34  EMERGENCIES RELATED TO HEMATOLOGIC DERANGEMENT FEBRILE NEUTROPENIA AND INFECTION Infections are a common source of morbidity and mortality in patients with malignancies. 35,36 A common feature associated with the increased risk of infection in these patients is the presence of impaired immunity, especially neutropenia. 35,36 For clinical decision making, neutropenia is defined as an absolute neutrophil count <1000/mm 3 (<1.0 × 10 9/L), severe neutropenia is defined as an absolute neutrophil count <500/mm3 (<0.5 × 109/L), and profound neutropenia is defined as an absolute neutrophil count <100/mm3 (<0.1 × 109/L). Fever is defined for the purposes of clinical decision making as a temperature of 38.3°C (100.9°F) on one occasion or 38.0°C (100.4°F) persisting >1 hour. Neutropenia in cancer patients is most commonly caused by chemo therapy, with the lowest neutrophil count typically seen 5 to 10 days after the last chemotherapeutic dose and recovery usually seen within 5 days afterward. 36-38 The risk of developing an infection primarily depends on the severity and duration of neutropenia. Comorbid conditions and other circumstances, such as indwelling devices, also contribute to the risk. 4,7,36,37 Fever is the most common finding seen with bacterial infections in the neutropenic patient. Common symptoms and signs that usually localize the infectious source are often absent or muted in the neutro penic patient because the lack of neutrophils impairs the inflammatory response and diminishes the occurrence of expected findings. 36 Thus, a pulmonary infection may have minimal cough, have no productive phlegm, and lack radiographic infiltrates. A kidney infection may not produce pyuria. Evaluation Perform a careful physical examination, with attention to three areas typically overlooked in routine examination: the oral cavity, the perianal area, and entry sites of intravascular catheters. Digital rectal examination is relatively contraindicated in neutrope nic patients—withhold until after initial antibiotic administration. Evaluate the entry sites of IV and tunneled catheters for evidence of infection. Clotted catheters represent a high risk of infection due to bacterial colonization, and central venous catheters may cause endocarditis. Because localizing signs and symptoms of a specific infection are often lacking, an evaluation for an occult infection is indicated. 36-39 Obtain two blood culture samples, with one from a central catheter, if present. A urinalysis, urine culture, and chest radiograph should be performed. Sputum, stool, and wound drainage Gram stain and culture should be obtained if productive cough, diarrhea, or wound drainage, respectively, are present. Assess serum electrolyte levels, renal function, and hepatic function. Assessment If an infectious source is found, therapy and disposition are guided by the presumed pathogens and the expected clinical course. If, after assessment, no localized infection can be found, the two major clinical decisions are: (1) Does this patient require hospitalization, and (2) should empiric antibiotics be started? To assist in addressing both these questions, consult with the patient’s oncologist.

pathogens and the expected clinical course. If, after assessment, no localized infection can be found, the two major clinical decisions are: (1) Does this patient require hospitalization, and (2) should empiric antibiotics be started? To assist in addressing both these questions, consult with the patient’s oncologist. Although hospitalization enhances the ability to reassess the patient and intervene early if a severe infection or clinical deterioration develops, hospitalization exposes the immunocompromised patient to hospital flora that is often drug resistant. Patients who appear well, have no abdominal pain, have no physical signs of infection, have a normal chest radiograph, and are expected to resolve their neutropenia within 7 days have a low risk of severe infection and can be considered for outpatient care. 36-38 High-risk febrile neutropenic patients for whom hospitalization is recommended are defined by one or more of the following features: profound neutropenia expected to last >7 days, comorbid medical conditions, acute liver or renal injury, or non–low-risk scores by the Multinational Association for Supportive Care in Cancer Risk Index or Clinical Index of Stable Febrile Neutropenia tool. 35,36,40-42 Treatment Empiric broad-spectrum antibiotics are used in febrile neutropenic patients when the benefits of early treatment are greater than the adverse side effects associated with such drugs. 36-39 Clinical evidence consistently supports the benefits of empiric antibiotics when the absolute neutrophil count is ≤500/mm 3 (<0.5 × 10 9/L). There is little convincing evidence for empiric antibiotics when the absolute neutro phil count is >1000/mm3 (>1.0 × 109/L). For neutrophil counts between 500 and 1000/mm3 (0.5 and 1.0 × 10 9/L), use other risk factors for bac terial infection to make the decision regarding empiric antibiotics.36-38 Administer the initial empiric antimicrobial therapy to cover the range of potential bacterial pathogens ( Table 240-4).36-38,43 No specific antibiotic regimen has proven consistently superior in clinical trials, and monotherapy with an appropriate broad-spectrum agent is as effective as dual-agent treatment in most circumstances. If there is no known colonization with multidrug-resistant bacteria or colonization with vancomycin-resistant enterococci, initial treatment should be with a Pseudomonas-active β-lactam. 37 Add vancomycin in the following Tintinalli_Sec18_p1461-1522.indd 1517 8/2/19 8:37 PM

s dual-agent treatment in most circumstances. If there is no known colonization with multidrug-resistant bacteria or colonization with vancomycin-resistant enterococci, initial treatment should be with a Pseudomonas-active β-lactam. 37 Add vancomycin in the following Tintinalli_Sec18_p1461-1522.indd 1517 8/2/19 8:37 PM 1518 SECTION 18: Hematologic and Oncologic Disorders situations: hemodynamic instability, catheter-related infection, skin or soft tissue infection, known colonization with resistant gram-positive organism, or severe mucositis when fluoroquinolone prophylaxis was recently used. 37 If there is a history of colonization with extended-spec trum β-lactamase–producing enterobacteria, initial treatment should be with imipenem or meropenem. The median duration of fever after initiation of empiric antibiotics is 2 days in low-risk patients and 5 to 7 days in high-risk patients. Therefore, continue initial empiric antibiotic therapy for 2 to 4 days before assess ing clinical response and making therapeutic adjustments. Adjustments may be made earlier if clinical deterioration occurs or culture results become available. Continue empiric antibiotics until the documented infection has clinically resolved and/or the patient has been afebrile for 2 days and the absolute neutrophil count is >500/mm 3 (>0.5 × 109/L).36-38 HYPERVISCOSITY SYNDROME Hyperviscosity syndrome is a pathologic condition in which blood is “thicker” than normal and its flow is impaired. 44 Blood viscosity depends on its plasma and cellular contents, and dehydration exacerbates hyperviscosity. Abnormal plasma contents that most commonly produce hyperviscosity are Waldenström’s macroglobulinemia and immunoglobulin A–producing myeloma. 44 Hyperproduction of any cell line can lead to hyperviscosity. Polycythemia (with a hematocrit >60%) and leukemia (with a WBC count >100,000/mm 3 [>100 × 109/L] or a leukocrit >10%) are often are associated with clinically significant hyperviscosity.45 Initial symptoms are vague and may include fatigue, abdominal pain, headache, blurry vision, or, most commonly, altered mental status. 44,46 Cutaneous or mucosal bleeding is common. Intravascular thrombosis may occur, with the creation of focal or unusual findings. Patients with hyperleukocytosis often report dyspnea and fever. Funduscopic findings include retinal venous engorgement appearing as linked sausages, along with exudates, hemorrhages, and papilledema. Laboratory findings suggesting hyperviscosity include rouleaux for mation (red cells stacked like coins) on a peripheral blood smear and being unable to perform chemical testing due to serum stasis in the laboratory analyzers. Laboratory testing of blood viscosity is usually done on plasma or serum, and specific analytic methodology varies. 46 A common approach is to report the viscosity of the sample as a ratio to that of water; normal plasma viscosity is 1.7 to 2.1 and normal serum viscosity is 1.4 to 1.8, compared with water. Symptomatic patients usu ally have a serum viscosity >4. 46 Laboratory measurement of plasma or serum viscosity will not identify hyperviscosity from polycythemia or leukemia. Initial therapy is intravascular volume repletion, early involvement of a hematologist, and emergency plasmapheresis or leukapheresis. 44-46 If coma is present and the diagnosis established, a temporizing mea sure can be a 2-unit (1000-mL) phlebotomy with concomitant volume replacement using 2 to 3 L of normal saline. Transfusion of red blood cells should be done with caution because such treatment may increase blood viscosity. Long-term management is appropriate chemotherapy. VENOUS THROMBOEMBOLISM Venous thromboembolism occurs with all tumor types and is the second leading proximate cause of death in cancer patients.

ormal saline. Transfusion of red blood cells should be done with caution because such treatment may increase blood viscosity. Long-term management is appropriate chemotherapy. VENOUS THROMBOEMBOLISM Venous thromboembolism occurs with all tumor types and is the second leading proximate cause of death in cancer patients. 47-49 Symptomatic deep venous thrombosis occurs in approximately 15% of all patients with cancer and up to 50% of those with advanced malignan cies. 47,48 Multiple factors contribute to an increased risk for venous thromboembolism. 49 The tumor may release procoagulant factors or inflammatory cytokines that directly activate the coagulation system. Large tumors may cause venous obstruction and promote thrombosis. Impaired production of proteins C and S and antithrombin can pro duce a hypercoagulable state. Surgery with attendant postoperative immobilization or long-term central venous catheterization can incite thrombosis. Chemotherapy or hormonal therapy for breast cancer increases the risk for thromboembolism. The angiogenesis inhibitors thalidomide, sunitinib, and bevacizumab are associated with signifi cant thrombotic risks. 47,48 Low-molecular-weight heparin is recommended as the initial treatment in cancer patients with venous thromboembolism, both deep venous thrombosis and pulmonary embolism. 50-53 Unfractionated heparin and fondaparinux are acceptable alternatives. 52,53 Con tinued treatment with low-molecular-weight heparin for at least 3 to 6 months is recommended because of better efficacy in preventing recurrent thromboembolic events compared to vitamin K antagonists. 51-54 Direct-acting oral anticoagulants are not recommended for treat ment of venous thromboembolism in patients receiving active treat ment for their cancer, but can be considered for use after the initial treatment with low-molecular-weight heparin of 10 days to 3 months in patients with stable cancer not receiving anticancer therapy. 53,55  EMERGENCIES RELATED TO THERAPY CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING Nausea and vomiting can be debilitating to an already compro mised patient. Most IV chemotherapeutic agents are emetogenic, so antiemetics are commonly administered on the day of therapy and for 2  to 4 days afterward based on the emetogenic potential of the agent. 56,57 Antiemetics used for chemotherapy-induced vomiting include neurokinin-1 receptor antagonists, serotonin receptor antagonists, and corticosteroids ( Table 240-5). 56-58 For refractory nausea and vomiting, benzodiazepines, dopamine receptor antagonists, or anti psychotic agents are added. 57,58 TABLE 240-4 Empiric Antibiotic Therapy in Febrile Neutropenia Situation Drug (Adult Dose) Comments Outpatient Ciprofloxacin 500 milligrams PO every 12 h Levofloxacin 750 milligrams PO daily plus Amoxicillin/clavulanate 500/125 milligrams PO every 8 h or 1000/62.5 milligrams PO twice daily Clindamycin 300 milligrams PO every 8 h For low-risk patients with daily assessments by a medical provider for the initial 3 d Monotherapy Piperacillin/tazobactam 4.5 grams IV every 6 h Cefepime 2 g IV every 8 h Ceftazidime 2 g IV every 8 h Imipenem/cilastatin 1 g IV every 8 h Meropenem 1 g IV every 8 h If no known colonization with multidrug-resistant bacteria or colonization with VRE, use piperacillin/ tazobactam, cefepime, or ceftazidime If known colonization with ESBL-E, use imipenem/ cilastatin or meropenem Dual therapy

h Ceftazidime 2 g IV every 8 h Imipenem/cilastatin 1 g IV every 8 h Meropenem 1 g IV every 8 h If no known colonization with multidrug-resistant bacteria or colonization with VRE, use piperacillin/ tazobactam, cefepime, or ceftazidime If known colonization with ESBL-E, use imipenem/ cilastatin or meropenem Dual therapy One of the monotherapy agents Increased risk of adverse effectsplus Vancomycin 1 gram IV every 12 hours Add if hemodynamic instability, catheter-related infection, cellulitis, or known colonization with MRSA Metronidazole 1 gram IV, followed by 500 milligrams IV every 6 h If abdominal symptoms are present Abbreviations: ESBL-E = expended-spectrum β-lactamase–producing enterobacteria; MRSA = methicillin-resistant Staphylococcus aureus; VRE = vancomycin-resistant enterococci. Tintinalli_Sec18_p1461-1522.indd 1518 8/2/19 8:37 PM

ronidazole 1 gram IV, followed by 500 milligrams IV every 6 h If abdominal symptoms are present Abbreviations: ESBL-E = expended-spectrum β-lactamase–producing enterobacteria; MRSA = methicillin-resistant Staphylococcus aureus; VRE = vancomycin-resistant enterococci. Tintinalli_Sec18_p1461-1522.indd 1518 8/2/19 8:37 PM CHAPTER 240: Emergency Complications of Malignancy 1519 Chemotherapy-induced vomiting can be anticipatory, acute, or delayed.58,59 Anticipatory vomiting is a conditioned reflex where vomit ing occurs prior to administration of the chemotherapeutic agent. Acute vomiting occurs during the first 24 hours with maximal intensity at 5 to 6 hours after administration. Delayed vomiting has maximal intensity 48 to 72 hours after administration and can last up to 7 days. For patients receiving highly emetogenic chemotherapy, the threedrug combination of a neurokinin-1 receptor antagonist (days 1 through 3 for aprepitant; day 1 only for fosaprepitant), a serotonin receptor antagonist (day 1 only), and dexamethasone (days 1 through 3 or 4) is recommended. For moderately emetogenic chemotherapy, the two-drug combination of palonosetron (day 1 only) and dexamethasone (days 1 through 3) is recommended. For low emetogenic agents, a single dose of dexamethasone 8 milligrams IV before chemotherapy is suggested. For delayed chemotherapy-induced vomiting, the neurokinin-1 receptor antagonists are recommended. EXTRAVASATION OF CHEMOTHERAPEUTIC AGENTS Most chemotherapeutic agents cause local tissue reaction when extravasated, but the agents associated with significant tissue damage are the vesicants primarily in the anthracycline, taxane, platin salt, and vinca alkaloid classes. 60-63 Clinical manifestations of chemotherapeutic drug extravasation include pain, erythema, and swelling, usually within hours of the infusion. Occasionally, clinical signs may be delayed if only a small amount of highly cytotoxic drug is extravasated. Serious injury produces blistering, induration, ulceration, and necrosis over a few days to weeks. If extravasation happens to occur through an active peripheral line, the infusion is stopped and aspiration through the line is attempted and continued while the catheter is removed. 62,63 Aspirate palpable cutane ous blebs containing the extravasated chemotherapeutic agent. Elevate and immobilize the affected limb. Cooling or warming is beneficial for some agents ( Table 240-6). Consult with the oncologist for treatment recommendations. Early referral to a plastic surgeon is suggested for anthracyclines and vinca alkaloids. Antidotes are available for some chemotherapy drugs (Table 240-6). 62,63 Dexrazoxane is used for anthracycline extravasation at a dose of 1000 milligrams/m 2 IV infused over 1 to 2 hours within 6 hours of the extravasation event, with additional doses of 1000 milligrams/m 2 at 48 hours and 500 milligrams/m2 at 72 hours.64 Dimethyl sulfoxide and hyaluronidase are used to enhance absorption of the extravasated agent. 62 Dimethyl sulfoxide is applied as a generous trickle of the 99% solution over the involved area without pressing or rubbing and then covered with dry pads. 62 Hyaluronidase is reconstituted with normal saline to a concentration of 150 units/mL and then injected in and around the extravasation area via multiple punctures. 62 Inject about 0.2 mL per puncture site with a typical total dose of 1 mL, but up to 10 mL may be required. There are limited data supporting the use of sodium thiosul fate for reversal of alkylating agent toxicity. 62 Intralesional injections of corticosteroids or bicarbonate are not effective.

ia multiple punctures. 62 Inject about 0.2 mL per puncture site with a typical total dose of 1 mL, but up to 10 mL may be required. There are limited data supporting the use of sodium thiosul fate for reversal of alkylating agent toxicity. 62 Intralesional injections of corticosteroids or bicarbonate are not effective. EMERGENCY COMPLICATIONS DUE TO BIOLOGIC THERAPY Targeted antineoplastic agents and immunotherapeutic drugs are increasingly used for cancer therapy, and many patients have experienced substantially improved outcomes. However, these biologic cancer agents are associated with toxicities, some of which can be potentially life threatening.  MONOCLONAL ANTIBODIES Monoclonal antibodies are proteins produced by immune cells that specifically recognize a cell target. In targeted cancer therapy, specially engineered humanized or chimeric antitumor monoclonal antibodies are designed to bind to T cells, activating them to target and kill cancer cells (Table 240-7). Common adverse effects associated with monoclonal antibodies are fevers, chills, pruritus, and muscle pain, which can be managed using antipyretics, antihistamines, adequate IV fluids, along with cardiopul monary monitoring and oxygen supplementation. A potentially serious TABLE 240-5 Antiemetic Agents for Chemotherapy-Induced Vomiting Class and Agent Adult Dose Comments Neurokinin-1 Receptor Antagonists Aprepitant 125 milligrams PO, followed by 80 milligrams PO on days 2 and 3 Half-lives: aprepitant = 9–13 h; fosaprepitant = 9–13 h; netupitant = 80 h; rolapitant = 169–183 h Common adverse effects: fatigue, neutropenia, abdominal pain, bradycardia, hypotension, headache, cough, decreased appetite, pruritus, and insomnia Fosaprepitant 150 milligrams IV Netupitant 300 milligrams plus palonosetron 0.5 milligram PO Rolapitant 180 milligrams PO Serotonin Receptor Antagonists Granisetron 1 milligram IV Common reactions: headache, abdominal pain Serious reactions: serotonin syndrome, QT interval prolongation Half-lives vary from 5 h for ondansetron, 9 h for granisetron, and 40 h for palonosetron Ondansetron 8 milligrams IV Palonosetron 0.25 milligram IV Tropisetron * 5 milligrams IV Ramosetron* 0.3 milligram IV Corticosteroids Dexamethasone 8–12 milligrams IV Mechanism unknown Benzodiazepines Lorazepam 1–2 milligrams IV Sedation, half-life 14 h Midazolam 1 milligram IV or 5 milligrams IM Sedation, half-life 2–3 h Dopamine Receptor Antagonists Metoclopramide 10 milligrams IV or IM Dose-related extrapyramidal side effects, half-life 5–6 h Prochlorperazine 5–10 milligrams IV or IM Extrapyramidal side effects, half-life 7 h Antipsychotics Olanzapine 10 milligrams PO or IM Not FDA approved for this indication, half-life 21–54 h Abbreviation: FDA = U.S. Food and Drug Administration. *Not available in the United States. TABLE 240-6 Antidotes for Selected Extravasated Chemotherapeutic Drugs Drug Antidotes Comments Anthracyclines (daunorubicin, doxorubicin, epirubicin, and idarubicin) Dry cooling Initially 1 h, then 15 min several times per day Hold during dexrazoxane infusion Dexrazoxane IV infusion within 6 h; repeat doses at 48 and 72 h Dimethyl sulfoxide Apply over involved area; repeat 4–6 times per day for ≥7 d Vinca alkaloids (vincristine and vinblastine) Dry warming Do not press or rub area Hyaluronidase Inject in and around extravasated area Mitomycin, cisplatin, mechlorethamine Dry cooling Initially 1 h, then 15 min several times per day Dimethyl sulfoxide Apply over involved area; repeat 4–6 times per day for ≥7 d Paclitaxel Hyaluronidase Inject in and around extravasated area Tintinalli_Sec18_p1461-1522.indd 1519 8/2/19 8:37 PM

around extravasated area Mitomycin, cisplatin, mechlorethamine Dry cooling Initially 1 h, then 15 min several times per day Dimethyl sulfoxide Apply over involved area; repeat 4–6 times per day for ≥7 d Paclitaxel Hyaluronidase Inject in and around extravasated area Tintinalli_Sec18_p1461-1522.indd 1519 8/2/19 8:37 PM 1520 SECTION 18: Hematologic and Oncologic Disorders TABLE 240-8 Recommendations for the Management of Cytokine Release Syndrome (CRS) Grade Clinical Features Management Grade 1 Fever or mild organ toxicity •   Treat fever with acetaminophen (ibuprofen is an alternative if not contraindicated) and hypothermia blanket (if needed) •   Maintenance IV fluids to prevent dehydration •   Assess for infection using blood and urine cultures and chest radiography •   If neutropenic, start empiric broad-spectrum antibiotics and filgrastim Grade 2 Hypotension, responds to IV fluids and/or low-dose vasopressors •   Initial IV fluid bolus with normal saline 500–1000 mL •   Administer a second IV fluid bolus if systolic blood pressure remains <90 mm Hg •   For hypotension refractory to two IV fluid boluses, administer anti–IL-6 therapy using tocilizumab 8 milligrams/kg IV or siltuximab 11 milligrams/kg IV •   If hypotension persists after two fluid boluses and anti–IL-6 therapy, start vasopressors, transfer to intensive care unit, obtain echocardiogram, and initiate hemodynamic monitoring Hypoxia, responds to Fio2 <40% •   Administer supplemental oxygen Organ toxicity •   Symptomatic management of organ toxicities Grade 3 Hypotension, required high-dose or multiple vasopressors •   IV normal saline fluid boluses as needed •   Tocilizumab and siltuximab as recommended for grade 2 CRS, if not previously administered •   Vasopressors as needed •   Transfer to intensive care unit, obtain echocardiogram, initiate hemodynamic monitoring •   Dexamethasone 10 milligrams IV every 6 h Hypoxia, requiring Fio2 >40% •   High–flow oxygen delivery and consider noninvasive positive-pressure ventilation Organ toxicity •   Symptomatic management of organ toxicities Grade 4 Hypotension, life-threatening •   IV fluids, anti–IL-6 therapy, vasopressors, and hemodynamic monitoring •   Methylprednisolone 1 gram IV daily Hypoxia, requiring ventilatory support •   Mechanical ventilation Organ toxicity •   Symptomatic management of organ toxicities Abbreviations: Fio2 = fraction of inspired oxygen; IL-6 = interleukin-6. TABLE 240-7 Common Monoclonal Antibodies (MAB) and Their Applications in Cancer Therapy MAB (origin) Target Indications Serious Toxicities Rituximab (human/ murine) CD20 Non-Hodgkin’s lymphoma Lymphocytic leukemia CRS Ofatumumab (human IgG1 MAB) CD20 Chronic lymphocytic leukemia unresponsive to chemotherapy Immunodeficiency Trastuzumab (humanized MAB) HER2/neu Breast cancer Metastatic GI cancers Cardiac disease Cetuximab (human MAB) EGFR Colon cancer Head and neck cancer Diarrhea Exanthema Bevacizumab (humanized IgG1 MAB) VEGF Metastatic colon cancer Breast cancer Renal cell cancer Non–small-cell lung cancer Glioblastoma Hypertension GI bleeding or perforation Thromboembolism Abbreviations: CD20 = B-leukocyte antigen CD20; CRS = cytokine release syndrome; EGFR = epidermal growth factor receptor; HER2 = human epidermal growth factor receptor 2; IgG = immunoglobulin G; VEGR = vascular endothelial growth factor. adverse reaction with monoclonal antibody therapy is cytokine release syndrome, where activated T cells release cytokines, with Il-6 as a key mediator.  CYTOKINE RELEASE SYNDROME Cytokine release syndrome is a potentially life-threatening systemic inflammatory reaction observed after infusion of agents targeting different immune effectors.

monoclonal antibody therapy is cytokine release syndrome, where activated T cells release cytokines, with Il-6 as a key mediator.  CYTOKINE RELEASE SYNDROME Cytokine release syndrome is a potentially life-threatening systemic inflammatory reaction observed after infusion of agents targeting different immune effectors. 65,67 Most commonly, affected patients develop fever, chills, tachycardia, and hypotension during or within 24 hours following drug administration. The syndrome may cause a broad spec trum of constitutional symptoms such as headache, myalgia, arthralgia, asthenia, and back or abdominal pain. Organ-related symptoms of cytokine release syndrome include bronchospasm, dyspnea, dysrhythmias, hypotension, confusion, oliguria, erythema, urticarial reaction, and pruritus. Symptoms of cytokine release syndrome that appear during or after first exposure to a “new” drug may be difficult to distinguish from anaphylaxis. 65 Treatment of cytokine release syndrome is guided by the severity, and all patients with cytokine release syndrome should be admitted to the hospital (Table 240-8).  IMMUNE CHECKPOINT INHIBITOR THERAPY Some tumor cells elaborate surface proteins that bind to receptors on T lymphocytes, inhibiting the ability of the T lymphocyte to kill the tumor cell. Immune checkpoint inhibitor therapy uses monoclonal antibodies that bind to either the tumor cell protein or the corresponding T-lymphocyte receptor, breaking the inhibition so that the T lymphocyte can kill the tumor cell. Current immune checkpoint inhibitors target either the cytotoxic T-lymphocyte–associated protein 4 (ipilimumab), the programmed cell death protein-1 on the tumor cell (pembrolizumab, nivolumab, or cemiplimab), or the programmed cell death ligand-1 on the T lymphocyte (atezolizumab, avelumab, or durvalumab). Most patients receive single-agent treatment with occasional use of combination therapy. Ipilimumab, nivolumab, and pembrolizumab have been in use for a longer time, so more instances of adverse effects arising from these drugs have been reported. Immune checkpoint inhibitor–induced immune-related adverse effects are defined as any toxicity with a potential immune-mediated cause. Although some immune-related adverse effects can present with potentially life-threatening symptoms, several immune-related endocrine adverse effects have an insidious onset and present with lowgrade, nonspecific symptoms that are difficult to diagnose. 68 Immune checkpoint inhibitors can attenuate tolerance and cause overwhelming Tintinalli_Sec18_p1461-1522.indd 1520 8/2/19 8:37 PM

entially life-threatening symptoms, several immune-related endocrine adverse effects have an insidious onset and present with lowgrade, nonspecific symptoms that are difficult to diagnose. 68 Immune checkpoint inhibitors can attenuate tolerance and cause overwhelming Tintinalli_Sec18_p1461-1522.indd 1520 8/2/19 8:37 PM CHAPTER 240: Emergency Complications of Malignancy 1521 inflammation, tissue damage, and autoimmunity. The main target tis sues are the GI tract, lungs, skin, pancreas, liver, and endocrine system.65 The adverse effects of immune checkpoint inhibitors vary with the specific agent and are more common with ipilimumab than nivolumab or pembrolizumab.65,68 The most frequent complications of ipilimumab are diarrhea and enterocolitis. 68 Typically, the onset of GI symptoms is 6 weeks after start of treatment. Hypophysitis, inflammation of the pituitary gland, and thyroiditis are common adverse effects. 68,69 Pancreatitis is associated more with combination therapy and with nivolumab than ipilimumab and pembrolizumab. Other adverse effects of immune checkpoint inhibitors include pneumonitis, dermatitis, adrenalitis, nephritis, vasculitis, anemia, and uveitis. 68 Awareness of the distinct adverse effects of immune checkpoint inhibitor therapy is important to appropriately diagnose and manage these complications. 68 The American Society of Clinical Oncology has published guidelines for the management of immune-related adverse effects of immune checkpoint inhibitor therapy. 70 Mild toxicities can be controlled using topical regi mens or oral antipruritics without use of systemic glucocorticoids.70 For serious immune-related adverse effects (neurologic, pulmonary, and cardiac toxicities), systemic glucocorticoids are used and anti–tumor necrosis factor-α therapy may be needed by patients who do not respond adequately to glucocorticoid treatment. REFERENCES The complete reference list is available online at www.TintinalliEM.com. Tintinalli_Sec18_p1461-1522.indd 1521 8/2/19 8:37 PM Tintinalli_Sec18_p1461-1522.indd 1522 8/2/19 8:37 PM This page intentionally left blank