Author: Brit Long, MD (@long_brit, EM Chief Resident at SAUSHEC, USAF) // Edited by: Alex Koyfman, MD (@EMHighAK) & Justin Bright, MD (@JBright2021)

Case 1: A 55 year-old male with a history of hypertension and hyperlipidemia complains of fatigue, headache, shortness of breath, and blurry vision for the past four days. His exam is normal, but laboratory results show a WBC of 155,000, with differential showing elevated blasts. Chest Xray shows the following:

Case 2: A 48 year-old female with a history of breast cancer on active chemotherapy, last treatment ten days prior, presents with nausea in the setting of a 101.8 oF temperature. She called her oncologist, who told her to present to the ER due to the fever. Her initial vital signs show a temperature of 100.1 oF, HR 93, BP 116/68, RR 19, and saturation 96% on room air. She appears tired and cachectic. Exam shows dry mucous membranes with no evidence of mucositis, with clear lungs and normal skin.

These two patients present with an emergency related to malignancy. How should you manage these patients, and what are your next steps?

This is part II of the heme/onc emergencies review. In this post, we will pick up where we left off and cover the hematologic and therapy-related oncologic emergencies.

Hematologic Effects: A) Hyperviscosity syndrome/Leukostasis, B) Neutropenic Fever, C) Venous Thromboembolism (VTE)

A) Hyperleukocytosis occurs with WBC greater than 50,000 (classically greater than 100,000). Leukostasis occurs in the setting of hyperleukocytosis with symptoms and is an emergency. It is seen with acute myeloid leukemia (20% of patients) or chronic myeloid leukemia with blast crisis most commonly, but it can occur with other malignances. Symptoms are due to white cells plugging microvasculature and/or tissue hypoxemia with cytokine damage, often resulting in respiratory (30% of patients) and neurologic (40%) symptoms. If untreated, mortality at one week reaches 40%. Pulmonary symptoms include dyspnea and hypoxia. Of note, arterial pO 2 levels may be falsely decreased due to the elevated WBCs utilizing O 2 ! Neurologic signs/symptoms include vision changes, headache, dizziness, tinnitus, ataxia, confusion, and coma. Patients with hyperleukocytosis have increased risk of intracranial hemorrhage for at least one week after treatment! Close to 80% of patients will display fever, so most specialists and studies recommend antibiotic treatment concurrently.1-6 Myocardial ischemia, limb ischemia, and renal disease may also be present. Labs will show high WBC (often above 100,000), falsely elevated platelets, and hyperkalemia; however, DIC is present in 40% of patients!

Management involves lowering the WBC count by cytoreduction (induction chemotherapy or leukopheresis), so hematology/oncology must be emergently consulted. Adequate fluid resuscitation is vital to maintain perfusion to end organs. Only chemotherapy has been shown to reduce mortality, as opposed to leukopheresis. However, if chemotherapy is unobtainable emergently, then speak with your blood bank and oncologist about leukopheresis! Hydroxyurea (50-100 mg/kg/day) is also an option for asymptomatic hyperleukocytosis patients. DIC and tumor lysis syndrome are major risks during the treatment of leukostasis, and coagulation panel, CBC, and renal function panel with urinalysis are vital in monitoring.1,6,7 Prophylaxis with allopurinol with hydration is usually started with cytoreduction treatment to decrease the risk of tumor lysis syndrome. Disposition is simple: these patients must be admitted, preferentially to the ICU.

Go here for further discussion: http://www.emdocs.net/hyperviscosity-syndrome/

B) Neutropenic fever is a commonly treated condition in the ED. The cytotoxic medications used to treat malignancy have several effects on the body besides killing the cancer: the medications affect myelopoiesis (or production of blood/immune cells) and destroy the integrity of the gastrointestinal mucosa, allowing microbe translocation. Fever is often the earliest, and sometimes only, manifestation of an infection in these patients due to the muted inflammatory response.1,8 Many patients with cough and pneumonia will not show an infiltrate on chest Xray, which depends on the body’s neutrophil response to infection. The Infectious Diseases Society of America defines a neutropenic fever as a single oral temperature greater than 38.3oC or temperature >38.0oC for one hour. Notice this is an oral temperature, but if the patient has mucositis, then use tympanic membrane or axillary thermometry. Classically, rectal temperatures are avoided due to risk of local mucosal trauma and bleeding. Neutropenia requires an absolute neutrophil count (ANC) of < 1500 cells/microL, with severe defined as an ANC less than 500 cells/microL or an expected drop to < 500 over 48 hours.1,8 How is this calculated?

ANC = WBC count X ((PMN/100) + (Bands/100))

High-risk patients are those presenting with shock, ANC levels < 500, ANC levels that are low for > 7 days, or other organ dysfunction (liver/kidney).1,8-10 The Multinational Association for Supportive Care in Cancer (MASCC) risk index is a validated tool often used to calculate the risk of medical complications in neutropenic patients, with those above 21 points at low risk (often quoted as patients worthy of discharge and home treatment) and those below 20 points at high risk.11 To be considered low risk, the patient must have no hypotension, no COPD, age less than 60 years, no dehydration, have a solid tumor or hematologic malignancy, and minimal symptoms. Most importantly, talk to your oncologist about disposition and treatment of these patients early!

Surprisingly only 20 to 30% of fevers in neutropenic patients are due to infection. Bacteria are the most common infectious cause, and the species is usually part of the endogenous flora (up to 80%)!8 For bacterial pathogens, up to the mid-1980s the most common bacilli were gram-negative, but after that period, gram-positive bacteria became most common (60% of cases). Why is this? Increasing use of long-term central venous catheters, prophylactic and empiric antibiotics targeting Pseudomonas, and newer chemotherapeutic regimens are all causes of this transition.1,8 However, gram-negative infections are more serious, and with more resistant strains, there has been a slight shift back towards gram-negative infections. S. epidermidis is the most common gram-positive cause. Fungal pathogens are more common in high-risk patients with prolonged antibiotic use and increasing number of treatment cycles. Most viral pathogens affect those high-risk patients and are due to reactivation (70%), rather than primary infection.1,8

Management of these patients revolves around early recognition of neutropenic fever. First, obtain a quick set of vital signs with an accurate temperature, IV access, and labs including CBC and blood cultures with lactate. Chest Xray, urinalysis, renal function panel, liver function panel, and ECG are also recommended. Then complete a thorough exam including mucous membranes/HEENT, skin, lungs, heart, and perianal region (though no digital rectal exam)! Make sure to ask when their last dose of treatment was, as the ANC reaches its nadir of <500 at 12-14 days after day one of chemotherapy. If criteria for sepsis are met, then the clock starts! Start your resuscitation with fluids, with IV antibiotics right after blood cultures are obtained.1,8-10 Guidelines quote 60 minutes as the timeframe within which patients should be given bug juice after recognition.8,10,12 If antibiotics are delayed, mortality rates can reach 70%!13 Each hour delay of antibiotics in those with septic shock increases mortality by 8%!14 One United Kingdom audit demonstrated that only 18-26% of patients receive antibiotics within one hour.15

Remember, these patients are tricky in that often no clinical signs will be apparent due to the muted immune response, so once you have the ANC count with fever, start your treatment and talk with oncology! If suspicious before the ANC comes back, then start resuscitation and antibiotics as soon as you can. Infections in these patients can progress rapidly, leading to hypotension, shock, and death.

High risk patients (MASCC less than 20):

Empiric treatment within sixty minutes is aimed at treating the most likely and virulent pathogens. Broad-spectrum coverage includes gram-positive and negative bacteria. IDSA guidelines state those high-risk patients should start with cefepime 2g, meropenem 1g, or zosyn 4.5g. Ceftazidime 2g monotherapy has increasing resistance among gram-negative bacteria and does not adequately cover gram-positive bacteria. Vancomycin should only be added in the setting of the following: skin/soft tissue/central line infections, pneumonia, mucositis, or hemodynamic shock. If necrotizing mucositis, intraabdominal/pelvic infection, sinusitis, or perirectal cellulitis is present, then add anaerobic coverage.8-12 Monotherapy against Pseudomonas, as opposed to dual coverage, has equivalent outcomes with less adverse events! If penicillin allergic, use ciprofloxacin plus clindamycin or aztreonam plus vancomycin. An empiric antifungal agent should be added if fungal infection is suspected, after 4-7 days in high-risk patients with no change in temperature, and if reassessment/clinical studies have not demonstrated a cause of infection. 1,8-12

For central lines, there is a great deal of controversy surrounding the removal of these lines if they are suspected as the source. There is a grade 1B recommendation for removal of the central line for S. aureus, P. aeruginosa, or Candida. A pocket infection or deep infection along the central line track or port is also cause for removal.8-10 First, talk with your oncologist. They may want to keep the line and use it for antibiotics!

Low risk patients (MASCC greater than 20):

Success rates in outpatient treatment are actually around 80% in these patients, with 20% needing readmission. Those at risk for failing outpatient treatment includes age > 70 years, poor performance status at home, severe mucositis, and neutropenia less than 100.16 If you are sending home one of these patients, please speak with their oncologist and obtain follow up (next day would be nice). Teuffel found that inpatient versus outpatient treatment had no difference in efficacy.17 What regimen is used for outpatient treatment? Ciprofloxacin plus augmentin is classic, with ciprofloxacin and clindamycin another option for penicillin-allergic patients.8,18 See comment in PubMed Commons below

C) Venous Thromboembolism (VTE) is a common complication of cancer, with up to 15% of patients affected at some point in the disease course.19 In deep venous thrombosis (DVT), pain, tenderness, swelling, warmth, edema, and erythema can be found. Pulmonary embolism can present with dyspnea, tachypnea, and chest pain. Patients with malignancy are at increased due to hypercoagulability from the tumor and treatment. VTE is actually the second leading cause of noncancer-related death in these patients (infection is first)! Mortality is 4-8X higher in this subset of patients as well when compared to a patient with no malignancy. Brain, stomach, lung, pancreas, renal, uterus, and bladder cancers have the highest VTE rate.20 Risk factors include patient related (age, obesity, smoker, decreased mobility), cancer related (type of cancer, stage, histological type), treatment related (anticancer medications, radiation, recent surgery, peripheral line presence), and biochemical related (hemoglobin < 10g/dL, WBC >11X109/L, and platelets above 350 X109/L)25,39.20,21 In terms of risk assessment, the best score in patients with known malignancy is the modified Khorana score, which is well-validated in this patient population.21,22 Literature supporting the use of Wells or Geneva in this population is lacking.

If suspicious of VTE, CT chest for pulmonary embolism is preferred. With a concern for DVT, ultrasound is preferable. In terms of treatment once diagnosis is made, a parenteral anticoagulant is recommended.22-26 Low molecular weight heparin (LMWH) is often the preferred initial treatment, as the CLOT trial demonstrated decreased incidence of recurrent VTE in those with LMWH versus Coumadin.27 Twice daily enoxaparin is superior to once daily.28 If renal disease is present, anti-Xa monitoring will need to be completed by the inpatient team, but unfractionated heparin (UFH) can also be used, especially for those undergoing a future procedure or at high risk for bleeding (due to decreased half-life of UFH). Fondaparinux, an indirect factor Xa inhibitor given subcutaneously, is also used, though studies are inconclusive on VTE recurrence when compared to LMWH. The new direct FXa inhibitors such as apixaban and rivaroxaban lack evidence for the treatment of VTE in patients with malignancy. IVC filters are used for recurrent embolism while on anticoagulation or those with contraindications to anticoagulation. In terms of disposition, usually these patients are admitted. Pulmonary embolism severity index (PESI), simplified PESI, and the Geneva prediction tools for outpatient PE treatment lack evidence for use in patients with malignancy. 22-26,29,30

Therapy-Related Effects: A) Drug extravasation

A) Drug extravasation occurs when a medication escapes into extravascular space, through vessel leakage or direct infiltration.31 Risks include obesity, small/fragile veins, multiple venipunctures, patient movement, sensory deficits, device migration, device dwell time, and device misplacement.32 The incidence is rare at 01% over a 15 year period. This can occur through a central or peripheral device. Two classes exist based on potential of toxicity: irritant and vesicant. Irritants cause an inflammatory reaction with tightness, burning/aching, and phlebitis at the insertion site. Symptoms are short, with no long lasting problems. Irritants typically include bleomycin, carboplatin, cisplatin, etoposide, gemcitabine, cyclophosphamide, paclitaxel, topotecan, and cytarabine. Vesicants have the potential to cause severe tissue necrosis with long-lasting injury. Extravasation of these agents can cause damage and loss of the entire thickness of skin at the site with damage to underlying structures. Vesicants include amsacrine, dactinomycin, doxorubicin, vincristine, mitomycin, vinblastine, and vindesine.33-36

Unfortunately, this distinction of irritant versus vesicant is not absolute, as there are case reports of irritants such as paclitaxel causing severe damage. The best approach to injury is prevention, as in many of these oncologic emergencies. However, if a patient presents to the ED with extravasation, there are several avenues of management. Unfortunately there are no randomized clinical trials for specific interventions. Guidelines are available from the Oncology Nursing Society, which include: stop the infusion, elevate the affected extremity, and keep the needle/catheter in place and attempt aspiration of the material.37 Ice application is recommended for all agents except the vinca alkaloids (vincristine) and etoposide. In these classes, heat is needed. After aspirating as much of the medication as possible from the site, specific antidotes can be injected into the site. There are multiple reversal agents for the respective chemotherapeutic medications (shown below in table from UptoDate), so consulting oncology and plastic surgery is vital up front with these patients. If after aspirating and no reversal agent will be injected, then the line should be removed.33-37

Summary

Consult heme/onc quickly for all heme/onc emergencies.

for all heme/onc emergencies. Leukostasis occurs with WBC count greater than 50,000 with symptoms (usually 100,000), predominantly pulmonary and neurologic symptoms . 80% of patients will have fever, so treat for infection concurrently . Chemotherapy is the only treatment that decreases mortality, but if not available, leukopheresis is the next step. DIC and TLS are major risks of treatment.

. Neutropenic is defined as a single oral temperature greater than 38.3 o C or temperature >38.0 o C for one hour, with absolute neutrophil count (ANC) of < 1500 cells/microL, with severe defined as an ANC less than 500 cells/microL or an expected drop to < 500 over 48 hours 30% of fevers are due to infection, with gram positives accounting for 60% of infections. MASCC risk index can be helpful and is validated. Broad coverage targeting gram positives and pseudomonas is needed.

VTE is common in cancer, with 15% of patients with malignancy experiencing DVT/PE. Risks are broken down into patient, cancer, biochemical, and treatment related. Khorana score is validated for VTE risk stratification in this patient population CT PE and DVT US are the best tests. Anticoagulation with LMWH has the best literature support for treatment.

of patients with malignancy experiencing DVT/PE. Drug extravasation is exceedingly rare, with 0.01% of patients over a 15yr period experiencing extravasation. Two classes exist: irritant vs. vesicant. Best approach is prevention. If extravasation occurs, maintain the line to aspirate and inject antidote . Apply heat for alkaloids and etoposide, but ice for everything else . Consult plastic surgery .



References/Further Reading