Outpatient Chemotherapy: Hypersensitivity and Anaphylaxis (2001)

John Myers was 64 years old when he was diagnosed with inoperable metastatic non–small cell bronchogenic carcinoma. He was receiving a first cycle of paclitaxel and carboplatin chemotherapy. Twelve and six hours prior to therapy, Mr. Myers had taken an oral dose of dexamethasone, diphenhydramine, and ranitidine; 30 minutes prior to that the nurse had administered iv ondansetron 32 mg with dexamethasone 20 mg. Within minutes of the start of the paclitaxel infusion, Mr. Myers developed profound shortness of breath, facial flushing, severe back pain, agitation, and a sense of impending doom. Peggy Brown, age 46, had been diagnosed with small cell lung cancer and was receiving the last dose of a three-day cycle of etoposide (VP-16) at a rural outpatient clinic. A regimen of cisplatin and etoposide had been prescribed and she had completed the first two cycles of treatment without a problem. Almost immediately after the start of the etoposide infusion, however, the nurse observed that Ms. Brown was unusually restless. At first, her vital signs were stable and she had no complaints, but 30 minutes later she complained of feeling “warm all over,” developed total body erythema, and began wheezing. There was no physician on the site and the nurse had no standing orders to treat Ms. Brown’s respiratory distress. Lottie Shapiro, age 75, was receiving her fourth course of paclitaxel and carboplatin for non–small cell lung cancer. Premedications consisted of ranitidine 50 mg iv, diphenhydramine 50 mg iv, and ondansetron 32mg iv with dexamethasone 10 mg iv. After completion of the paclitaxel infusion, the nurse started the carboplatin infusion, and approximately 30 minutes later, Ms. Shapiro experienced extreme air hunger with wheezing and cyanosis. Her pulse was 110 beats per minute and her blood pressure was 100/60 mmHg in the absence of overt hypotension. What common etiology accounts for all three reactions? What would you do under these circumstances? In all these cases, quick assessments and interventions were essential to prevent the problem from escalating, as the patients were having adverse reactions, or more specifically, hypersensitivity reactions, to agents in their chemotherapy treatment protocols. A hypersensitivity reaction is an exaggerated or inappropriate immune response to contact with a specific allergen. Oncology nurses in the outpatient setting should be aware of the signs and symptoms of such a reaction because, if the physician is not available immediately, nurses are responsible not only for recognizing the symptoms of a hypersensitivity reaction, but also for treating it promptly. Understanding the pathophysiology, signs and symptoms, and treatment of a hypersensitivity reaction will ensure quick and appropriate intervention. THE COURSE OF A REACTION A hypersensitivity reaction is caused when the immune system is provoked by an antigen (such as a chemotherapeutic agent), stimulating the formation of certain IgE antibodies that attach to the receptors on mast cells and basophils. A subsequent exposure to the same antigen will trigger these antibodies, causing degranulation of the cell, and thereby releasing chemical mediators such as histamine, serotonin, slow-reacting substance of anaphylaxis (SRS-A), and eosinophil chemotactic factor of anaphylaxis (ECF-A). Released from the cells into the circulatory system, the chemical mediators produce an anaphylactic response 1 (see What Happens in Anaphylaxis, page 28). Certain chemotherapeutic agents (paclitaxel, for example) may produce what is known as an anaphylactoid response. Anaphylactoid reactions differ from anaphylactic reactions in that no prior exposure to the agent is necessary to induce the response. The agent itself, not the IgE antibodies, will bind directly to the surface of the cells, causing direct degranulation and a release of mediators. Anaphylactoid and anaphylactic reactions have identical signs and symptoms and are treated in the same manner. TABLETable 1: What Happens in AnaphylaxisTHE CAUSE OF REACTION Hypersensitivity and anaphylaxis are risks that may also occur in response to common premedications including ondansetron, dolasetron, granisetron, dexamethasone, and hydrocortisone. Although rarely reported, some of these reactions are severe. Antineoplastic agents are the most likely cause of hypersensitivity reactions (see Common Anti-tumor Agents, page 29). L-asparaginase is one of the agents most likely to trigger a hypersensitivity reaction (its principal side effect that limits treatment). A hypersensitivity reaction occurs in 10% to 25% of patients who take L-asparaginase as part of a combination therapy. 2 Symptoms include skin rashes, urticaria, arthralgia, and respiratory distress. Full anaphylaxis—resulting in shock, loss of consciousness, and, occasionally, death—may also occur. 2 THE TAXANES Paclitaxel. Without premedications, the number of patients who have hypersensitivity reactions as a result of paclitaxel has been reported to be as high as 10% to 16%. 3,4 It is possible that the diluent in paclitaxel, polyoxyethylated castor oil, is responsible for the histamine release and the hypersensitivity reaction in most cases. The mandatory use of premedications has reduced the incidence of these reactions to 1% to 3%, and has also reduced the severity of them. 3,4 A common premedication regimen consists of dexamethasone, diphenhydramine, and an H2-receptor antagonist such as ranitidine, cimetidine, or famotidine. Patients should be premedicated with oral dexamethasone 12 and six hours before each of the first and second infusions. Adverse reactions to paclitaxel usually occur within the first 10 minutes. Docetaxel. Although Tween 80, the diluent in docetaxel, differs from polyoxyethylated castor oil, patients taking docetaxel are equally susceptible to hypersensitivity reactions. 2 Most reactions will occur within minutes of the start of the first or second infusion; rarely, they may occur as late as the third. Common reactions include generalized pruritus, bronchospasm, generalized urticaria, severe hypotension, and angioedema. Fluid retention is also common. Premedication regimens are now used with some success to reduce the severity and incidence of reactions. Oral dexamethasone at 16 mg per day (such as 8 mg bid) for three days starting one day before the initiation of the docetaxel infusion, is recommended to minimize the risk of both hypersensitivity reaction and fluid retention. 5 Epipodophyllotoxins: Teniposide and etoposide. Approximately 6% of patients treated with teniposide and 1% to 3% of patients taking etoposide experience hypersensitivity reactions. 2 Patients with neuroblastoma have an unexplained higher incidence of reactions to teniposide (13%). 2 A reaction may occur with any dose, including the first, immediately or up to several hours after the infusion. With either agent, a reaction will manifest in dyspnea, wheezing, hypotension or hypertension, urticaria, pruritus, angioedema, facial flushing, or rash. Monoclonal antibodies: Trastuzumab and rituximab. Fever and chills are common during the first infusion of monoclonal antibodies, but they range in intensity from mild to moderate and rarely necessitate discontinuation of therapy. Symptoms of a hypersensitivity reaction may include nausea, pain at the tumor site, dyspnea, bronchospasm, angioedema, hypotension, and rash. Fatal anaphylaxis is rare. Premedicating the patient with acetaminophen and diphenhydramine may attenuate complications resulting from the infusion, and antihypertensive medications may be withheld 12 hours prior to therapy to reduce the severity of hypotension. BE AWARE Instruct your patient to report any unusual symptoms such as itching, flushing, pain, or dizziness. Be alert to restlessness, fidgeting, frequent changes of position, scratching, and changes in mood. Under the assumption that the symptoms are normal, some patients do not report them so it’s important to ask how they are feeling. A hypersensitivity reaction can escalate quickly, compromising the airway and cardiovascular integrity. Laryngeal edema and cardiovascular collapse are the most frequent causes of death. TABLETable 2: One Hospital’s HSR ProtocolRULES OF THUMB Prevention is the most important intervention in chemotherapy-related hypersensitivity reactions. Patient education regarding signs and symptoms is vital. Verify with the patient that oral premedications, if indicated, were taken correctly. TABLETable 3: Common Anti-tumor Agents Associated with Severe Hypersensitivity Reaction or AnaphylaxisPiggy-back all chemotherapy agents, including premedications, through a support bag of normal saline. (If normal saline is contraindicated, use a different compatible solution.) This allows immediate intravenous access should a hypersensitivity reaction occur. At the first sign of a reaction, discontinue the offending agent immediately and commence appropriate treatment. (See Commonly Used Drugs, page 30 for drugs used most often to manage hypersensitivity reactions, the recommended doses, routes of administration, and actions. 6) A hypersensitivity reaction “kit” should be accessible and standing orders for treatment established. The kit should contain emergency drugs including injectable corticosteroids, diphenhydramine, epinephrine, dopamine, and aminophylline. Syringes with needles, alcohol wipes, tourniquets, extra iv supplies, and bronchodilating inhalers should also be available (See One Hospital’s HSR Protocol, left.) As in all emergencies, it is important to know the ABCs: airway, breathing, and circulation. Administer oxygen immediately if the patient is experiencing respiratory difficulty. Monitor oxygen saturation throughout the reaction. Vital signs should be monitored every three to five minutes until stable. Infuse saline at a rapid rate (if not contraindicated) to avoid hypotension, but should it occur, place the patient in a supine or recumbent position, elevating the lower extremities, and administer medications as necessary. Careful documentation of a hypersensitivity reaction and its treatment is not only necessary for an accurate medical record, it helps the physician determine whether to rechallenge the patient with the offending agent. With early recognition and successful management of a hypersensitivity reaction, rapid retreatment with the same drug, in some cases, can be safe without incurring additional cost. 3 In one study, seven of 91 women undergoing paclitaxel-based chemotherapy developed hypersensitivity reactions. Six of those were rechallenged with paclitaxel solution starting at a infusion slower rate, and none of them had a second reaction. 3 An adverse reaction report should be completed and sent to the Department of Health and Human Services, and the appropriate pharmaceutical company should be notified. TABLETable 4: Commonly Used Drugs in the Treatment of Hypersensitivity Reaction or AnaphylaxisNURSES WHO KNOW Mr. Myers was in severe respiratory distress and suffering an anaphylactoid reaction to the paclitaxel, which the nurse immediately discontinued. She gave him epinephrine 1:10,000 1 mg iv, followed by diphenhydramine 50 mg iv. The physician ordered hydromorphone 2 mg iv as analgesia. Mr. Noble’s blood pressure, initially 190/100 mmHg, fell to 148/90 mmHg. Within 15 minutes it was 70/40 mmHg, and the normal saline infusion was increased to wide-open. His blood pressure gradually rose to 80/40 mmHg and the EMS transferred him to the hospital because of residual anterior chest pain and electrocardiographic evidence of anterior myocardial ischemia. Ms. Brown was experiencing a reaction to etoposide. The nurse discontinued the infusion, increased the saline infusion to a rapid rate, and administered oxygen per nasal cannula. When Ms. Brown’s breathing grew labored, the nurse administered iv diphenhydramine 50 mg and iv dexamethasone 20 mg. No fall in blood pressure was noted, and Ms. Brown’s symptoms subsided within a few minutes. She was monitored for one hour after which she returned home. The nurse phoned later in the day and confirmed that Ms. Brown was not experiencing further problems. Ms. Shapiro was having an anaphylactic reaction during the course of the carboplatin infusion that had been given after paclitaxel. The nurse, having discontinued the carboplatin infusion at the first signs of a problem, supplied oxygen at 3 L per nasal cannula. The nurse gave Ms. Shapiro iv diphenhydramine 50 mg, iv hydrocortisone 250 mg, and iv epinephrine 1 mg (1:10,000) and symptoms abated gradually. After an hour under observation, Ms. Shapiro was able to return home. The physician thought that she had had a delayed reaction to paclitaxel, and he chose not to rechallenge her with this drug. Later treatment with carboplatin resulted in no adverse reactions.