Oncologic Emergencies in the ED: Diagnosis, Triage, and Management
Author: Robin R. Hemphill, MD, Assistant Professor of Emergency Medicine, Associate Program Director, Department of Emergency Medicine, Vanderbilt University, Nashville, TN.
Peer Reviewer: Richard B. Ismach, MD, MPH, Assistant Professor, Department of Emergency Medicine, Emory University School of Medicine, Atlanta, GA.
Cancer patients can present to the emergency department (ED) with myriad, life-threatening manifestations, some of which require prompt and definitive assessment and intervention. Evaluation of such patients frequently requires not only that the emergency physician perform a systematic physical examination and clinical history, but also that he or she communicates with the patient’s personal physician or oncologist and family to determine how aggressive life-saving interventions should be. The fact is, however, with advances in cancer therapy, that many life-threatening events once considered to signal terminal events now should be managed aggressively, since therapies are available that will contain the advanced disease to allow an acceptable quality of life.
What makes the assessment of cancer patients with acute deterioration challenging is that complications can involve a number of organ systems (e.g., hematological, cardiovascular, and neurological), and that without prompt intervention, some complications can be life-threatening. For example, pericardial tamponade caused by metastatic infiltration and effusion within the pericardial sac may present with unexplained hypotension, tachycardia, and narrowed pulse pressure, a triad suggesting the need for pericardiocentesis followed by more definitive intervention.
With respect to metabolic emergencies, the hypercalcemia that may be associated with such tumors as non-small cell lung carcinoma, breast cancer, or renal carcinoma can produce electrocardiographic changes terminating in bundle-branch block, bradycardia, and cardiac arrest. The metabolic changes occurring with tumor lysis syndrome that may be associated with lymphoma, including elevated serum potassium, phosphate, and uric acid levels, require prompt intervention to prevent cardiotoxicity. Rational management of these patients is complicated by the fact that the emergency physician must determine whether oncology-related emergencies represent transient or terminal events in the natural history of the disease and intervene appropriately.
Finally, hematological emergencies, among them neutropenia-associated fever, require a comprehensive evaluation to determine a possible source of bacterial or fungal infection and prompt administration of antibiotics. Neurological emergencies, which usually result from metastases to vital neurological structures such as the brain or spinal cord, may be confused with the more generalized debilitation that accompanies the late stages of cancer or, in some cases, metabolic abnormalities that produce musculoskeletal dysfunction. Immediate assessment with computed tomography (CT) or magnetic resonance imaging (MRI) scanning may be the only way to generate a definitive diagnosis and guide therapy.
With these issues in clear focus, the author of this review have identified the most important and common oncological complications that must be recognized by the ED physician and have outlined step-by-step diagnostic and treatment protocols to ensure favorable outcomes when aggressive therapy is warranted.— The Editor
Complications of the Cardiovascular System
Superior Vena Cava Syndrome (SVCS). Mechanical complications of cancer affect the superior vena cava by obstruction within the vessel, invasion of the vessel, or external compression of the vessel. This results in impaired blood flow to the right side of the heart. When a mass is the source of the compression, it usually is malignant and may be a primary or metastatic tumor or a malignant lymph node. Although the exact incidence of this disorder is not known, rates of between 3% and 8% of those patients with lung cancer or lymphoma have been reported.1 The symptoms of this syndrome may present abruptly (hemorrhage into a tumor causing acute enlargement or rapid tumor growth) or in a slow, insidious fashion. Those patients who have slow progression of symptoms often will not seek medical care until late in the course of their disease.
The severity of symptoms and onset may be influenced by several things. If the obstruction occurs above the entry of the azygous vein into the superior vena cave, the degree of blood return to the right side of the heart is less affected. Symptoms in this case may be less severe. If the obstruction occurs slowly, even if it is below the level of the azygous, there may be time for collateral circulation to develop and symptoms will be less severe. If obstruction develops rapidly in the region below the entry of the azygous, the patient may be severely symptomatic and acute intervention will be necessary.
Presentation of SVCS. SVCS manifests by complaints of extreme fatigue (due to poor blood return to the right side of the heart), dyspnea, chest pain, headache, face and neck swelling, flushing, poor vision, syncope, and confusion. These symptoms most often are notable upon awakening. Patients may complain of tightness in the shirt collar (Stokes sign) that may improve as the day progresses. Patients also may notice that their symptoms worsen if they bend forward. (See Table 1.)
| Table 1. Presentation of Superior Vena Cava Syndrome* | |
| • | Extreme fatigue (due to poor blood return to the right side of the heart) |
| • | Dyspnea |
| • | Chest pain |
| • | Headache |
| • | Face and neck swelling (e.g., Stokes sign) |
| • | Flushing |
| • | Poor vision |
| • | Syncope |
| • | Confusion |
| * These symptoms most often are notable upon awakening. | |
Since the onset of symptoms may be slow, the physical examination findings may be subtle. However, in many cases findings will be quite obvious. The examination may be notable for facial plethora, periorbital edema, and facial swelling that may extend to the neck and upper extremities. Conjunctival edema may be apparent, along with dilated veins along the thorax and upper extremities. The dilated veins of the upper extremities may not collapse as the arm is elevated above the head because of the elevated venous pressure caused by the obstruction. Less commonly, the patient may manifest with altered mental status or Horner’s syndrome.
Differential Diagnosis of SVCS. As stated, up to 90-95% of cases of SVCS are the result of malignancy.2 In adults, the most common malignancies include bronchogenic cancer (usually small cell) and non-Hodgkin’s lymphoma. Other malignant causes include thymic tumors, metastatic tumors, and mediastinal germ cell tumors.3 In children, malignancy also is the most common cause of SVCS. In this age group, the most common malignancies include non-Hodgkin’s lymphoma, Hodgkin’s disease, and acute lymphoblastic leukemia (ALL). Less common malignancies include thyroid cancer, malignant teratoma, thymoma, neuroblastoma, Ewing’s sarcoma, and rhabdomyosarcoma.4
Non-malignant causes of SVCS also occur. In the past, both tuberculosis and syphilis were common causes of this syndrome. Although now uncommon, these entities should be considered in high-risk patients. Other, less common causes of SVCS include goiters, mediastinal fibrosis, histoplasmosis, sarcoidosis, benign cysts, and ascending aortic aneurysm. A final, but important cause of SVCS is thrombosis of the vessel. Spontaneous occurrence of thrombosis with the superior vena cava is uncommon, but thrombosis can occur as a complication of central venous catheters. This complication is very treatable, and always should be considered in the patient with an indwelling catheter who complains of symptoms that are consistent with SVCS. Ultimately, the prognosis of the patient depends on the underlying cause of the syndrome.
Diagnosis of SVCS. Along with the physical examination findings, chest radiograph usually will show a mass within the mediastinum; it is seen most frequently in the right hemithorax.2 Pleural effusion also may be present.
Depending on the patient’s history, the development of this syndrome may be a devastating, but not entirely surprising, finding. However, if the syndrome is a new diagnosis in a previously healthy patient, a contrasted CT of the chest would be appropriate to help clarify the diagnosis, as well as coexisting local involvement, if a tumor is confirmed.5 Again, the differential of SVCS does include other treatable conditions such as an ascending thoracic aortic aneurysm. Therefore, an attempt should be made to make an exact diagnosis while the patient is in the ED. Those patients with indwelling catheters within the superior vena cava should be assumed to have a catheter-related thrombosis. The thrombosis may be visible on the CT scan when contrast is added, but in some cases venography will be needed to conclusively confirm the diagnosis.
Treatment of SVCS. At one time, SVCS secondary to a mass lesion was considered an oncologic emergency requiring immediate mediastinal irradiation. More recently, evidence suggests that, in adults, expedient efforts should be made to establish a definitive tissue diagnosis.6 However, the exact approach to making this tissue diagnosis is controversial because there is some risk in attempting tissue collection due to the increased venous pressure (bleeding complications).
Since the emergency medicine physician is not responsible for the decision about when to initiate mediastinal irradiation vs. making a tissue diagnosis, the task of the emergency medicine physician is to stabilize the patient and address easily treatable problems. After these initial stabilizing measures, consultation can be pursued to determine the next step (e.g., tissue diagnosis or immediate treatment). Therefore, if the patient presents with respiratory compromise, a carefully planned intubation should be undertaken. If the patient has stridor, administration of steroids may help decrease localized swelling. If the patient is known to have a type of cancer that may cause SVCS and he or she has severe central nervous symptoms, urgent empiric radiation therapy, with or without concurrent chemotherapy, may be necessary. Other interventions include surgical bypass and superior vena cava stenting.7 In these cases, the patient’s oncologist should be contacted to determine the best immediate care options. If no oncologist is available, the patient should be stabilized as much as possible and then transferred to a center that has both oncology and radiation therapy capabilities. While waiting for treatment, or during transfer, the patient should be maintained in a position with the head elevated, and airway control should be achieved.
As noted previously, thrombosis of the superior vena cava most commonly is seen in those patients with an indwelling central catheter. However, thrombosis also may occur secondary to partial obstruction or compression of the superior vena cava by a tumor. As is the case with SVCS and no thrombosis, therapy predominantly is directed toward treatment of the mass. If there is no response, fibrinolytic therapy or anticoagulation eventually may be required. For those patients who have thrombosis that is secondary to a central venous catheter, blood thinners or fibrinolytics may be used. This decision is best made in consultation with the patient’s oncologist.
Pericardial Disease Related to Malignancy. Involvement of the pericardium due to malignancy may occur by direct extension of tumor or from spread through the mediastinal lymphatic vessels.8 Postirradiation pericarditis also can result in an effusion-causing tamponade. It is uncommon for neoplastic constrictive pericarditis or postradiation fibrosis to result in constrictive pericarditis. Pericardial involvement due to cancer most commonly is seen in leukemia, lymphoma, lung cancer, melanoma, and breast cancer.9 Primary pericardial malignancies include mesotheliomas and sarcomas, but these are uncommon. Benign tumors of the pericardium or mediastinum, such as teratomas, fibromas, or angiomas also may cause pericardial fluid to accumulate. Finally, pericardial disease may be caused by some of the medications used in the treatment of cancer.
Diagnosis of Pericardial Disease. Neoplastic involvement of the pericardium most commonly presents as progressive shortness of breath, chest pain, and cough.9 Progression to frank shock with altered mental status and coma will result if it is left untreated. When the pericardial effusion collects quickly, the onset of these symptoms may be very dramatic. Physical examination findings may include tachycardia, jugular venous distention, hepatic engorgement, poor peripheral effusion, and a paradoxical pulse. If the patient is severely dehydrated, the classic features of pericardial tamponade may be absent. A pericardial friction rub may be present, but is uncommon. In severe cases, the patient may be hypotensive, tachycardic, cyanotic, and have altered mental status. Pulse pressure may be narrowed. Again, onset of symptoms may be abrupt or develop slowly over a prolonged period of time. (See Table 2.)
|
Table 2. Possible Physical Examination Findings in Pericardial Disease Related to Malignancy* |
|
| More common findings: | |
| • | Tachycardia |
| • | Jugular venous distention |
| • | Hepatic engorgement |
| • | Poor peripheral effusion |
| • | Paradoxical pulse (if the patient is severely dehydrated, the classic features of pericardial tamponade may be absent) |
| • | Pericardial friction rub (though uncommon) |
| In severe cases: | |
| • | Hypotension |
| • | Tachycardia |
| • | Cyanosis |
| • | Altered mental status |
| • | Narrowed pulse pressure |
| * Onset of symptoms may be abrupt or develop slowly over a prolonged period of time. | |
Chest radiograph may show cardiac enlargement, but if a pericardial effusion develops rapidly or if the findings are due to restrictive pericardial disease, the chest radiograph may be normal. In cases in which the effusion develops slowly, the pericardial sac may hold up to a liter of fluid with very few symptoms, but in this case the chest radiograph will show a dramatically enlarged "water bottle" heart. Electrocardiogram results often will be nonspecific, but total electrical alternans is considered pathognomonic of cardiac tamponade.
The signs and symptoms of malignant pericardial disease (either due to tamponade or restrictive pericardial disease) are nonspecific, and therefore, a high level of suspicion should be sustained for any patient with known malignancy who presents with symptoms of dyspnea and nonspecific chest pain. If there is evidence of elevated central venous pressure, this diagnosis should be strongly entertained until proven otherwise. The classic presentation of Beck’s triad (hypotension, distended neck veins, and distant heart sounds) rarely is identified.
The most useful test to evaluate for the presence of pericardial disease is echocardiography. The echocardiogram evaluates the size of a pericardial effusion as well as how much the heart is affected by the effusion. Tamponade is diagnosed when the right atrium or ventricle collapses in early diastole. The ultrasound is less useful in cases of restrictive pericarditis, but still may suggest poor diastolic filling and, in some cases, show a thickened and abnormal pericardium. A chest CT scan is another modality that can show a pericardial effusion and may help differentiate effusion from SVCS.
Both pericardial disease and SVCS may present with shortness of breath, chest pain, and tachycardia, as well as evidence of elevated central venous pressure. SVCS will not have a paradoxical pulse or hepatic congestion. A mediastinal mass on chest radiograph may suggest SVCS, but because pericardial involvement often results from direct tumor extension, it is possible that a mass may be present on the radiograph of the patient with a pericardial effusion. An echocardiogram or CT scan may be necessary to differentiate between these two entities. Pericardial tamponade also may be mistaken for a pulmonary embolism, particularly in this high-risk population.
Treatment of Pericardial Disease. As pressure builds up within the pericardium, right atrium, and ventricle, the initial compensatory mechanisms of the body cause an increase in the heart rate in an attempt to maintain stroke volume. Eventually, these mechanisms will fail and the patient will become increasingly symptomatic.
Once the diagnosis of tamponade due to pericardial fluid is made, the emergency medicine physician should stabilize the patient until definitive care can be initiated. Initial efforts should be made to control the airway, if necessary, and to initiate fluid resuscitation, which may help increase right-sided heart pressures and improve stroke volume. If this fails, the immediate treatment is either pericardiocentesis, pericardial window, or pericardiectomy. In patients with severe compromise, the removal of a relatively small amount of fluid (50-100 cc) may dramatically improve the patient’s condition. If possible, a catheter should be left within the pericardium to remove remaining fluid or fluid that recollects. If the emergency medicine physician is uncomfortable with pericardiocentesis, a cardiologist, if available, can assist with this procedure. Ultrasound guidance also may be helpful. Other options include the involvement of a general surgeon to place a pericardial window until more definitive care, such as chemotherapy, cardiac radiation, intrapericardial sclerosis, or pericardiectomy, can be performed. The treatment of restrictive pericardial disease generally will require surgical intervention to remove the pericardium.
Metabolic Complications of Malignancy
Hypercalcemia. Hypercalcemia of malignancy is one of the most common complications of malignancy and occurs in 10-20% of cancer patients at some point during their disease.10 If patients develop hypercalcemia, it generally is an indicator of advanced disease; these patients usually have a limited life expectancy. Mechanisms by which malignancies may cause an increase in the serum calcium level include the secretion of parathyroid hormone-related protein, secretion of bone-resorbing substances, or the presence of bone metastases that cause local destruction of the bone.11
Among the solid tumors, hypercalcemia most commonly is seen in non-small cell lung cancer, squamous cell cancers of the head and neck, breast cancer, renal cell carcinoma, and cholangiocarcinoma. Among the hematologic cancers, it most commonly is seen in multiple myeloma and lymphoma.12 (See Table 3.) The normal range of calcium may vary between institutions, but the upper limit of normal is approximately 10.5 mg/dL.13
| Table 3. Cancers that Commonly Cause Hypercalcemia | |
| Solid tumors: | |
| • | Non-small cell lung cancer |
| • | Squamous cell cancers of the head and neck |
| • | Breast cancer |
| • | Renal cell carcinoma |
| • | Cholangiocarcinoma |
| Hematologic cancers: | |
| • | Multiple myeloma and lymphoma (most common) |
Diagnosis of Hypercalcemia. The severity of symptoms depends upon the degree of elevation, the rate of increase, and the underlying disability of the individual. In many cases, the serum calcium rises slowly, and in these instances onset of symptoms related to the hypercalcemia will be somewhat insidious and nonspecific. However, when symptoms do develop, multiple organ systems are affected. Early manifestations include fatigue, depression, constipation, polydipsia, polyuria, and anorexia. The polyuria is a result of a reversible concentrating defect. Later, patients may have abdominal pain, obstipation, emesis, lethargy, seizures, altered mental status, and coma. Bone pain may or may not be present.
Electrocardiographic changes may be seen as the calcium levels increase and include prolongation of the PR and QRS intervals with shortening of the QT interval. At levels higher than 16 mg/dL, bundle branch blocks occur that may progress to complete heart block and cardiac arrest.
For the patient at risk for the development of hypercalcemia, the emergency medicine physician should be aware that not all acute elevations of calcium are the immediate result of the patient’s tumor. Further history should ascertain whether the patient has had any recent medication changes and/or changes in functional status. Thiazide diuretics can increase serum calcium levels, as can the hormonal treatments used in breast cancer patients. The predisposed cancer patient who becomes increasingly unable to ambulate also is at risk, as is the cancer patient who is receiving parenteral nutrition.
Treatment of Hypercalcemia. The responsibility of the emergency medicine physician is to make the diagnosis and then to begin initial stabilization measures. However, it is important to bear in mind that this may be an end-stage manifestation of the patient’s cancer. Despite intervention, these patients may not have a meaningful response or life span.14 As stabilization measures are instituted, the emergency medicine physician should attempt to contact the patient’s oncologist or primary care physician to determine the patient’s prognosis.
When treatment is initiated, several options exist. Hydration is the most important initial patient treatment for the emergency medicine physician to begin. Those patients with severe elevations of calcium have extracellular volume deficits. Therefore, initial management should focus on infusion of normal saline to improve extracellular volume and glomerular filtration rate. This simple intervention will help increase calcium excretion through the urine. Patients with normal renal function can be corrected within a few hours. As urine output improves, other electrolytes such as potassium, magnesium, and phosphate should be monitored to ensure they do not acutely decline. For those patients with severe elevations of calcium, therapy should be administered while the patient receives cardiac monitoring. Correction of fluid deficits is a temporary treatment of hypercalcemia and once it is stopped, if no other treatment is started, the hypercalcemia will reoccur.
Once fluid deficits have been corrected, diuretics may be added to the care of these patients. Loop diuretics, such as furosemide, improve urine excretion of calcium. In elderly people, the use of diuretics also may help prevent fluid overload. However, thiazide diuretics should be avoided because they decrease renal calcium excretion and may worsen the patient’s hypercalcemia.
Additional medications also are available, and in some cases the emergency medicine physician may need to initiate treatment. A class of agents called bisphosphates has high affinity for areas of high bone turnover. In areas of malignant bone involvement, these agents block bone resorption. These medications include pamidronate, etidronate, and clodronate. There is some evidence that pamidronate may be the most effective medication.15 The dose is 60-90 mg/d given intravenously. It can be given over several hours or over 24 hours. It is reasonable to contact an oncologist prior to the use of this medication for help with optimum dosing and plans for admission.
Secondary medications include corticosteroids, calcitonin, gallium nitrate, and plicamycin. However, controversy exists as to which medication is the most effective, and oncologists may have individual preferences. Depending on the type of malignancy, other treatments directed toward the specific malignancy also may be appropriate.
Tumor Lysis Syndrome. Tumor lysis syndrome (TLS) is a disorder that occurs when a patient with a large burden of tumor has rapid and acute destruction of tumor cells. Those patients with rapidly proliferating tumors or those with a very large tumor burden may experience spontaneous or treatment-related destruction of tumor cells. Death of these cells releases intracellular components resulting in hyperkalemia, hyperuricemia, and hyperphosphatemia with secondary hypocalcemia. In some patients, particularly those with underlying renal abnormalities, the sudden build-up of these electrolytes may overwhelm the ability of the kidneys to clear them. These abnormalities may lead to cardiac arrhythmias, renal failure, and death.
This disorder most commonly is seen in patients with lymphoma (particularly Burkitt’s) and leukemia, but may occur in a variety of solid tumors (e.g., non-small cell cancer, widely metastatic breast cancer).16 Because of the increasing use of outpatient chemotherapeutic regimens, these patients may present to the ED as they begin to have symptoms.
Diagnosis of Tumor Lysis Syndrome. The syndrome usually occurs within 6-72 hours after the initiation of therapy directed at a tumor and may last for 5-7 days.17 However, this syndrome can occur without recent treatment, so in the clinical setting this disorder always should be considered.
The clinical signs and symptoms reflect the developing electrolyte disorders and renal failure. Hyperkalemia may lead to weakness and altered mental status followed by cardiac dysryhthmias and death. Hyperphosphatemia and increased uric acid levels produce acute tubular necrosis and renal insufficiency. This results in decreased urine output, urine crystals, flank pain, and hematuria. Severely elevated phosphate levels may cause acute calcium precipitation in the soft tissues and kidneys. Hypocalcemia may cause carpopedal spasm, neuromuscular irritability, altered mental status, and seizures.
Lab tests generally will show elevated blood urea nitrogen, creatinine, potassium, phosphorus, and uric acid levels, and a decreased serum calcium level. Urine testing will show evidence of hematuria and crystals. Electrocardiographic abnormalities will depend on the degree of electrolyte abnormality, but commonly will reflect findings consistent with hyperkalemia. (See Table 4.)
| Table 4. Common Lab Test Results in Patients with Tumor Lysis Syndrome | |
| • | Elevated blood urea nitrogen level |
| • | Elevated creatinine level |
| • | Elevated potassium level |
| • | Elevated phosphorus level |
| • | Elevated uric acid level |
| • | Decreased serum calcium level |
| • | Urine (evidence of hematuria and crystals) |
| • | Electrocardiographic abnormalities (depend on degree of electrolyte abnormality, commonly will reflect findings consistent with hyperkalemia) |
Treatment of Tumor Lysis Syndrome. Ideally, the best treatment is to recognize high-risk patients and begin their cancer treatments in a controlled setting with the expectation that this syndrome may occur.17 Preferably, those patients felt to be high risk should be hospitalized and fully hydrated with close monitoring of urine output during the period of risk. Allopurinol also can be administered to control uric acid levels.
Because most patients at high risk will be treated as inpatients, the emergency medicine physician is most likely to be faced with the patient who has unexpectedly developed this syndrome, either spontaneously or as an unanticipated result of chemotherapy. The initial approach to the patient will depend on whether kidney function has been maintained. If adequate renal function remains, then the initial steps in treatment include aggressive hydration along with alkalinization of the urine. Alkalinization of the urine to a pH of greater than 7 will improve uric acid secretion; however, care must be taken to closely monitor the calcium level, as raising the pH may worsen existing hypocalcemia.18 The addition of furosemide or mannitol also may help improve urine output. Allopurinol may be given to lower uric acid levels and may be given in a 600-900 mg loading dose and then 100-300 mg twice daily during the period of highest risk.17 Electrolyte abnormalities should be treated in the standard manner. Elevation of potassium may be treated with alkalinization, insulin/glucose, and calcium. Calcium also can be given for severe hypocalcemia; however, if phosphate levels are severely elevated, this may cause precipitates of calcium and phosphate. If the kidneys are not functioning, or the patient does not respond to therapy, hemodialysis will be necessary.
Syndrome of Inappropriate Antidiuretic Hormone (SIADH). In oncology patients, the syndrome of inappropriate antidiuretic hormone (SIADH) is a paraneoplastic syndrome that results from the secretion of arginine vasopressin (also known as antidiuretic hormone). The increased production of vasopressin results in hyponatremia, which is the best-recognized characteristic of SIADH. Approximately 1-2% of patients with malignancy will develop SIADH, although those with small cell lung cancer may have rates of up to 10%.19
The secretion of arginine vasopressin causes increased water reabsorption in the collecting ducts of the kidneys, as well as an increased loss of sodium in the urine. Several possible mechanisms for the increase in arginine vasopressin exist. In oncology patients, it is usually the result of increased secretion by certain tumors. In patients with no malignancy, the lung itself may be able to secrete vasopressin (in response to infections), or changes in atrial pressures due to a primary lung disease may result in an increased secretion. Finally, some central nervous system diseases may cause increased release of arginine above and beyond the arginine produced by normal stimulation. Of note, some chemotherapeutic agents such as vincristine and cyclophosphamide also may cause SIADH.2
Diagnosis of SIADH. The major manifestations of SIADH result from hyponatremia. In some cases, the degree of hyponatremia will be minimal and patient will be asymptomatic. At lower levels (115 mEq/L), patients may complain of fatigue, emesis, myalgias, and poor appetite. As the sodium level falls below 100 mEq/L, patients may develop altered mental status, seizures, psychosis, and lethargy. Coma and death may follow.
The criteria for diagnosis of hyponatremia resulting from SIADH include hyponatremia with hypo-osmolality, elevated renal excretion of sodium (> 20 mEq/L), normal volume status, and an inappropriately elevated urine osmolality for the plasma osmolality.20 (See Table 5.)
| Table 5. Criteria for Diagnosis of Hyponatremia Resulting from SIADH* | |
| • | Hyponatremia with hypo-osmolality |
| • | Elevated renal excretion of sodium (> 20 mEq/L) |
| • | Normal volume status |
| • | Inappropriately elevated urine osmolality for the plasma osmolality |
| * No diuretics and no evidence of pre-existing renal disease, adrenal insufficiency, or hypothyroidism. Recent chemotherapeutic agents should be reviewed, and a search for pulmonary and central nervous system disease. | |
The patient should not be on any diuretics and there should be no evidence of pre-existing renal disease, adrenal insufficiency, or hypothyroidism. Additionally, recent chemotherapeutic agents should be reviewed, along with a search for pulmonary and central nervous system disease.
Treatment of SIADH. For mild degrees of hyponatremia felt to be secondary to a patient’s malignancy, immediate treatment may not be necessary. Referral and consultation with the patient’s oncologist may be the only steps required. Mild fluid restriction until the follow-up appointment is appropriate (500 cc/d). Ultimately, attempts should be made to treat the underlying malignancy. Patients who do not respond to fluid restriction may require therapy with demeclocycline. This medication causes a reversible nephrogenic diabetes insipidus that counteracts the influence of the excess vasopressin. If the syndrome is due to chemotherapeutic agents, those medications will need to be discontinued if the degree of hyponatremia becomes dangerous.
In those patients with more severe degrees of hyponatremia or those with significant symptoms related to their hyponatremia, urgent intervention will be needed. Normal saline can be initiated, or for those with seizures and altered mental status, 3% hypertonic saline (300-500 cc at a time over 3-4 hours) may be administered followed by 1 mg/kg of furosemide.2 The serum sodium level should not be raised by more than 1 mEq/L/hour. Rapid increases in serum sodium may result in central pontine myelinolysis. Close monitoring of electrolytes and urine output is critical; in the elderly, overall constant evaluation of fluid status is critical to prevent fluid overload during therapy. These patients will require intensive care admission and consultation with their oncologists.
Neurologic Emergencies Related to Malignancy
Epidural Spinal Cord Compression. Epidural spinal cord compression (ESCC) occurs when a tumor within the epidural space begins to compress upon the either the spinal cord or the cauda equina. This complication is seen in up to 5-10% of cancer patients and may be the initial presentation. The injury results from direct compression of the cord by the tumor or by ischemic cord injury that results from tumor involvement of the vascular supply.21 Patients with lung cancer, breast cancer, prostate cancer, lymphoma, sarcoma, multiple myeloma, and renal cell carcinoma are at particular risk.22 Almost all epidural masses occur as the result of extension of metastasis from the spine, especially the vertebral bodies. The vertebral body tumors arise from the hematogenous spread of tumor cells to the bone marrow within the vertebral bodies. The most common area involved is the thoracic section of the spine (the thoracic vertebrae are the most abundant, and therefore this is the section most commonly involved). Although most tumors do arise from the vertebral bodies, it is possible for some tumors to impinge upon the epidural space by growing through the intravertebral foramen. In this case, there will not necessarily be any bony involvement or destruction. Patients may have involvement of more than one area.23 As with many of the complications of malignancy, long-term prognosis depends on the type of malignancy causing the cord compression and how quickly the syndrome is recognized so that therapy can be initiated.
Intramedullary spinal cord metastasis also occurs but is less common than epidural cord compression. The solid tumors that may cause this include some that produce epidural involvement, including lung and breast cancer, as well as lymphoma. It is difficult to differentiate between intramedullary involvement and epidural involvement, but the former is much less common. As well, intramedullary involvement is more likely to present with a hemicord type of syndrome.24,25 Long-term prognosis for patients with intramedullary tumors is poor, but with intervention some of these patients will be able to maintain function until their malignancy becomes terminal.
Diagnosis of ESCC. Pain is present in 90-95% of patients with ESCC and it often is the initial symptom. The pain may precede any other symptoms by 1-2 months.21,26 The pain may be local or radicular, and is constant and progressive. Similar to lumbar disc disease, the pain may increase with straight leg raise or with maneuvers that increase intrathoracic pressure, such as the Valsalva maneuver.22 Unlike the pain associated with disc disease, the patients with ESCC may find that their pain is increased with recumbency rather than improved. Patients also may describe numbness, tingling, or dysesthesia, as well as difficulty ambulating. Constipation or difficulty urinating also may be present.
On physical examination, midline bony tenderness may be present. As the compression increases, the patient may develop objectively measurable sensory loss distal to the lesion. Ataxic gait may be present. These deficits can develop rapidly. By the time ESCC is diagnosed, bilateral weakness is present in approximately 75% of patients and many are no longer ambulatory.21,26 Autonomic dysfunction such as bowel or bladder dysfunction develops late and parallels the development of weakness. The duration and severity of symptoms before the syndrome is recognized and treated are the best predictors of whether neurologic function can be maintained and restored.22 (See Table 6.)
| Table 6. Physical Examination Findings Common in ESCC | |
| • | Midline bony tenderness (as the compression increases, patient may develop objectively measurable sensory loss distal to the lesion) |
| • | Ataxic gait |
| • | Bilateral weakness |
| • | Autonomic dysfunction (e.g., bowel or bladder dysfunction develops late and parallels the development of weakness) |
ESCC must be differentiated from intramedullary spinal metastases and other spinal epidural problems that can compress the thecal sac. These include disc herniation, supperative bacterial infections, bleeding, and other infections such as tuberculosis. Intradural diseases such as meningiomas and neurofibromas may present in a fashion similar to ESCC. Acute cord compression from any of the above diseases requires urgent intervention, but clearly the treatment will vary depending on the exact cause.
Plain films of the spine are useful if they are abnormal, but false-negatives occur in 10-17% of patients.21 The false-negative rate results from the fact that not all tumor invades the epidural space via the bone, and that 30-50% of bone must be destroyed before it will be visible on plain film. If the films are positive in a cancer patient who is experiencing back pain, the finding of vertebral body collapse and pedicle erosion both are associated with a high likelihood of ESCC. Radionuclide bone scans usually will be abnormal in the patient with ESCC, but again, in certain situations they can be falsely negative. Algorithms combining the use of both plain films and bone scanning suggest that if both studies are negative, the risk of ESCC may be as low as 2%.27 Despite this, further investigation is warranted for the cancer patient with progressive pain, radiculopathy, or neurologic symptoms.
Beyond the use of plain films and bone scanning there is some controversy as to the best approach for diagnoses of ESCC. Myelography combined with CT scanning can delineate extradural compression of the thecal sac. This technology may be more widely available than MRI at some institutions. It has the disadvantage of being invasive and uncomfortable, but can image the entire spinal axis in a single study. MRI of the spine with gadolinium enhancement is noninvasive and more sensitive than myelography for detecting bone and intramedullary lesions.25 It is more time consuming than CT myelography, but when available is the better choice. CT of the spine by itself generally will not be helpful.
Treatment of ESCC. For those patients with recent onset of symptoms or rapid progression of symptoms, immediate treatment is warranted. While treatment of the underlying lesion is critical, the pain that this process may cause should not be overlooked. The other treatment that can be initiated by the emergency medicine physician is the use of corticosteroids. While the benefit of steroids has been proven,28 the exact dosing to maximize effect while minimizing side effects has yet to be well-defined.29 One review suggests reserving the higher doses of dexamethasome (100 mg bolus) for those patients who have myelopathy.25 They recommend a rapid taper. Higher dose dexamethasone (96 mg/d) also was supported by a recent evidence-based literature review, which found that it was better supported by the literature than the use of moderate steroids (16 mg/d) in conjunction with radiotherapy.30 Other sources recommend the use of 4-10 mg of dexamethasone four times a day. If possible, the initial treatment of the patient with ESCC should be discussed with an oncologist or neurosurgeon. However, if the patient has severe and acute symptoms of ESCC, high-dose dexamethasone should be given.
After this initial treatment, the typical therapy for ESCC is to initiate radiation therapy at the level of the epidural compression. Surgical treatment may be appropriate to control pain, limit the progression of neurologic deficits, and to allow the spine itself to be stabilized. If the source of the tumor is not known, a tissue diagnosis could be made at the time of surgery. The difficulty with this approach is that many of these patients have diffuse disease at this point and have increased operative risk.
Since additional treatment options exist for some patients with ESCC, after this diagnosis is made the emergency medicine physician should contact the oncologist taking care of the patient to determine steroid dosing and the next options available to the patient. If this is a new diagnosis, the emergency medicine physician can initiate tests to help determine the source of the cancer, but the initial treating physician may need to be a neurosurgeon. This specialist can recommend steroid dosing and determine if operative intervention is possible. Additional input from an oncologist may allow for a multi-specialty approach to determine the best way to stop further neurologic decline.
Brain Metastasis. Cancer of the lung, breast, skin, gastrointestinal tract, and genitourinary system account for the majority of metastatic diseases to the brain.31 Intracranial metastases, which may consist of solitary or multiple lesions, occur in 20-30% of those patients who have a systemic cancer.
Diagnosis of Brain Metastasis. The clinical features of brain tumors result from direct destruction or compression of brain tissue by either the tumor itself or from tumor-associated brain edema. This results in compromise of vascular or cerebrospinal fluid pathways that may cause additional brain injury or elevations in the intracranial pressure (ICP).
Headache is one of the most common complaints of the patient with a brain tumor and is the presenting complaint in approximately 35% of patients. At some point in their illness, most patients with brain tumors will experience headaches.31 Brain tumors cause headaches due to alteration in ICP and traction or displacement of pain sensitive areas within the brain (cranial nerves, venous sinuses, dura mater). The headache associated with increased ICP typically is retro-orbital and is associated with nausea and vomiting. Classically, teaching states that this headache will be worst in the morning, with improvement upon arising. However, since there are other mechanisms that result in tumor-related headaches, this classical presentation is frequently not present. If the cranial nerves are involved, there may be complaint of blurred and double vision or visual field defects. If the ICP continues to worsen, alterations in mental status may develop.
Due to the localized tissue compression and destruction, focal neurologic deficits are common complaints in this population. These complaints may manifest as motor or sensory deficits, dysphasia, cerebellar symptoms, changes in personality, and seizures. (See Table 7.)
| Table 7. Common Physical Findings in Patients with Brain Metastasis | |
| • | Headache (retro-orbital, associated with nausea and vomiting) |
| • | Blurred and double vision or visual field defects (if cranial nerves involved) |
| • | Alterations in mental status (if the ICP continues to worsen) |
| • | Focal neurologic deficits (e.g., motor or sensory deficits, dysphasia, cerebellar symptoms, changes in personality, and seizures) |
Usually, these symptoms will develop slowly over a period of weeks to months. However, if there is an acute change in the ICP or hemorrhage into the tumor, life-threatening symptoms may develop rapidly and acute intervention will be necessary.
Diagnosis can be made with contrasted CT or MRI. Studies comparing these two modalities have not been done, but when available, a MRI with gadolinium contrast is preferred.32 In the patient with a known primary cancer that is recognized as producing brain metastasis, additional tissue diagnosis usually is not necessary. For those patients with no known primary cancer, a focused evaluation for a primary tumor should be initiated. This includes chest and abdominal CT, complete examination of the skin and breasts, rectal examination, and testicular examination when appropriate. A chest radiograph and complete physical examination should be done at the initial presentation, but the additional arrangements for CT scanning can be made with the patient’s primary care physician. If no primary tumor is identified, the patient may then require a brain biopsy.
Treatment of Brain Metastasis. Acute changes in mental status, new focal abnormalities, and acute seizures all may result from vasogenic cerebral edema. Urgent intervention may help prevent cerebral herniation. Initial management should address the ABCs. Once the patient is intubated, he or she should be hyperventilated to a pCO2 of 25-30 mmHg. This is the most rapid way of decreasing ICP. After airway management, the patient should receive intravenous dexamethasone 40-100 mg followed by similar doses every day. In addition, the patient may receive furosemide 40-120 mg intravenously. Finally, a 20-25% solution of mannitol at a dose of 0.5-2.0 mg/kg may be added. Fluid status must be closely monitored in these patients, particularly if they are debilitated from their known malignancy. Decisions about additional treatments such as chemotherapy, radiation therapy, or surgery can be discussed with an oncologist and neurosurgeon.
For less significant problems related to tumor edema, the patient may be given lower doses of dexamethasone to improve symptoms but limit side effects. At this point, less urgent additional measures such as pain control and exact diagnosis can be be explored. Approximately 70-80% of patients with brain metastasis will improve, at least temporarily, with dexamethasone.23
In all cases of intracranial metastasis, the decision of how aggressive treatment should be must take into account the status of the primary cancer, performance status of the patient, and the number of brain metastases.
Additional Complications Related to Malignancy
Hyperviscosity Syndrome. Hyperviscosity syndrome (HVS) most commonly is seen in certain cancers, but also may complicate diseases such as polycythemia vera, some collagen vascular diseases, and sickle cell anemia. As a result of cancer-produced substances, such as serum proteins or leukocytes, the normal viscosity of the blood may be increased; this may cause sludging, vascular stasis, and decreased perfusion at the microvascular level. When this occurs, multiple systems may be compromised. The most common causes of hyperviscosity syndrome include the dysproteinemias, IgG and IgA myelomas, IgM Waldenstrom’s macroglobulinemia, and leukemias. In the case of the leukemias, the risk of developing this syndrome occurs in those patients with granulocyte counts in excess of 100,000 and lymphocyte counts greater than 750,000.33
Diagnosis of HVS. The clinical presentation of HVS includes all or part of a triad that consists of bleeding, visual disturbances, and neurologic symptoms. (See Table 8.) The bleeding symptoms include gingival bleeding, epistaxis, hematuria, and rectal and vaginal bleeding. Early vision changes include blurring and diplopia that may progress to vision loss. Physical examination may show papilledema, retinal hemorrhage, or retinal detachment. The neurologic manifestations include headache, vertigo, ataxia, paresthesias, and mental status changes. Additional manifestations that are not considered part of the typical triad are cardiac complications, which include angina, myocardial infarction, and heart failure.33
| Table 8. Diagnosis of Hyperviscosity Syndrome (HVS) | |
| Classic Triad: | |
| • | Bleeding symptoms (e.g., gingival bleeding, epistaxis, hematuria, and rectal and vaginal bleeding) |
| • | Visual disturbances (e.g., early vision changes: blurring and diplopia that may progress to vision loss. Physical examination may show papilledema, retinal hemorrhage, or retinal detachment.) |
| • | Neurologic symptoms (e.g., headache, vertigo, ataxia, paresthesias, and mental status changes) |
The diagnosis of HVS is made by the recognition of the typical symptoms in a patient at risk. Laboratory testing in the patient with leukemia may increase suspicion if the white blood cell count is significantly high. For patients with other diseases that put them at risk for HVS, a serum viscosity level may be obtained.
Treatment of HVS. Perhaps the most important step in the treatment of this syndrome is recognition on the part of the emergency medicine physician. If therapy is initiated, early manifestations can be reversed. Initial management includes careful hydration and diuresis. This may be done as the patient’s oncologist is being contacted to arrange more aggressive treatment. For the patient with elevations of the white blood cell count, leukapheresis may be initiated; for those with dysproteinemias, plasmapheresis is used. In the case that no interventions are immediately available at an institution, phlebotomy should be performed with initial aliquots of 100-200 cc.34 The patient should then be transferred as soon as possible.
Neutropenic Fever. Infections are very common in patients with cancer. In some patients, the cancers themselves will impair the ability of the immune system to function, but in many cases the impairment of the immune system stems directly from the treatments used against the malignancy. Neutropenia is present when the counts of polymorphonuclear leukocytes plus bands falls below 500/mm3, and profound neutropenia is present when these counts fall below 100/mm3. Neutropenic patients experience increased frequency and severity of infections related to both the level and the duration of neutropenia.35 Cancer patients are at additional risk during their periods of neutropenia because they frequently have indwelling devices, invasive procedures due to complications of their malignancy, and other side effects from their chemotherapy (mucosal and skin breakdown) along with the neutropenia. Finally, some patients with malignancy will have had the spleen removed as part of the cancer staging, and all patients with Hodgkin’s disease should be asked about this. Asplenic patients are at risk for overwhelming sepsis from encapsulated organisms regardless of whether they are neutropenic.
Diagnosis of Neutropenic Fever. Patients are at greatest risk for neutropenia in the period from seven to 15 days after cytotoxic chemotherapy. Potentially serious infection should be assumed in the patient with neutropenia after a single temperature elevation of greater than 101.3°F, or when recurrent temperature elevations of 100.4°F occur over a 24-hour period.36 (See Table 9.)
| Table 9. Diagnosis of Neutropenic Fever | |
| Definition: | |
| • | Neutropenia with a single temperature elevation of > 101.3°F, or recurrent temperature elevations of 100.4°F occur over a 24-hour period |
| Physical examination: | |
| • | Evaluate common areas of infection: e.g., sinuses, throat, skin, lungs, urinary tract, prostate, and perirectal area. |
| • | Evaluate any indwelling devices for pain, swelling, redness, and drainage. |
Aside from the fever, the patient may have few signs to help localize the site of infection because of his or her limited immune response. Physical examination should evaluate the common areas of infection, such as sinuses, throat, skin, lungs, urinary tract, prostate, and perirectal area. If indwelling devices are present, they need to be evaluated for pain, swelling, redness, and drainage.
The patient should be completely cultured, including blood cultures from each indwelling catheter. Spinal tap may be reserved for those patients with localizing signs and symptoms. Complete blood count with platelets and a peripheral smear should be ordered to determine whether the patient truly is neutropenic. While fever in any cancer patient is reason for concern, the implications are not as significant if the patient is not actually neutropenic. Chest radiograph also should be done, although in the severely neutropenic patient the radiograph may be normal even when a pneumonia is present. Despite a complete work-up and search for the source of the fever, an infectious source may be identified in only 30-40% of patients.37
Treatment of Neutropenic Fever. Empiric treatment with broad-spectrum antibiotics has been the foundation of treatment for the patient with neutropenic fever. Infections are most commonly caused by gram-positive bacteria (Staphylococcus aureus, coagulase-negative staphylococci, and streptococcal species) and gram-negative aerobic bacteria (Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa).38,39 Additionally, infections with enterobacter species have been increasing.40 As stated, outcome depended upon the degree of neutropenia as well as the length of time the neutropenia persisted. Coverage against these organisms usually requires combination therapy with two or three drugs that may act synergistically.
After the initial evaluation and cultures, administer antibiotics to neutropenic patients with the aforementioned organisms in mind. If a clear source of infection is identified, tailor antibiotic selection to ensure coverage of the suspicious system; however, overall, the antibiotic selection should remain broad. When no clear source for infection is found, there are several appropriate options for coverage, including double therapy (antipseudomonal penicillin or cephalosporin and antipseudomonal aminoglycoside) or broad-spectrum monotherapy (antipseudomonal penicillin or imipenem). Patients that appear acutely ill should receive double antibiotic coverage.
Patients with indwelling devices need to have close attention given to the site where the catheter has been placed. Addition of vancomycin to the regimen for patients with indwelling devices is controversial, particularly if the site looks good. However, if the device has been in for a long period of time or if the patient is at a center with high rates of methicillin-resistant S. aureus, the addition of vancomycin may be considered. Discussion with the patient’s oncologist would be appropriate. Infections of the subcutaneous catheter tunnel usually will require catheter removal, as well as antibiotic therapy.36,41 Along with antibiotics, some oncologists may try to minimize the period of neutropenia by adding colony-stimulating factors (G-CSF and GM-CSF) to stimulate the growth and maturation of white blood cells. Given the cost of these agents and the limited value in the treatment of fever and neutropenia, use should be approved by the treating oncologist.42
The final consideration for the patient with neutropenic fever is whether he or she may receive outpatient treatment. Traditionally, these patients all have been admitted for broad-spectrum intravenous antibiotics.35 As with many other diseases, efforts are being made to identify a low-risk group of patients with neutropenic fever who may be managed as outpatients. Some suggested criteria for identification of neutropenic patients that may be at low risk when they have fever include: those with an anticipated neutropenia of fewer than seven days duration, those with solid tumor malignancy and no comorbid illnesses, stable medical condition, patients tolerating fluids, patients with home support and compliance, and a malignancy that has responded to therapy.43,44 An outpatient approach also may be possible in children who meet similar low-risk criteria.45 With all of these patients, discussion with the primary oncologist is mandatory, along with the ability for close scrutiny daily or every other day.
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