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Anaphylaxis: When Seconds Count
Recognizing an anaphylactic reaction and initiating emergency treatment can mean the difference between life and death for the patient. The authors review the common triggers, the different types of reactions, and appropriate interventions.
By Paul D. Salzberg, MD, and Ethan A. Singer, PhD, NP-C
According to the American Academy of Allergy, Asthma, and Immunology, more than 50 million Americans suffer from allergic diseases. Exposure to specific allergens, such as foods, drugs, insect stings, and latex rubber, produces a wide spectrum of allergic reactions, from mild symptoms to potentially fatal conditions. Anaphylaxis is a life-threatening allergic reaction triggered by exposure to various allergens (or antigens).
In the United States, approximately 1500 deaths a year are caused by anaphylaxis. Prompt emergency care probably can prevent many of these deaths. A thorough history and physical examination provide important information about a patient’s allergies to specific antigens, including potential anaphylactic reactions.
Emergency treatment includes airway protection, antihistamines, steroids, and beta agonists. Patients taking beta blockers may require additional treatment. This article underlines the critical role emergency care providers play in preventing and treating anaphylaxis by discussing signs and symptoms, common causes (or triggers), diagnosis, treatment, and patient education.
IMMEDIATE HYPERSENSITIVITY REACTION
Anaphylaxis is a systemic, immediate hypersensitivity reaction caused by exposure to a specific antigen. The table below lists the four types of hypersensitivity reactions, along with their signs and symptoms and general treatments. The immune system activates immunoglobulin E (IgE), which reacts with effector cells (mast cells and basophils). These cells, in turn, release histamine, serotonin, leukotrienes, and prostaglandins and induce a range of signs and symptoms, such as facial flushing, urticaria (hives), edema, bronchoconstriction, cough, cardiac arrhythmias, hypotension, nausea, vomiting, and diarrhea.
Cutaneous manifestations are most common, with urticaria and angioedema present in 88% of patients experiencing anaphylaxis. Swelling in the airway is the most life-threatening symptom, commonly causing
dyspnea, wheezing, stridor, and upper airway obstruction from severe edema.
Cardiovascular symptoms include dizziness, hypotension, and syncope related to third-spacing of intravascular fluid. Common gastrointestinal manifestations include nausea, vomiting, abdominal pains or cramps, and diarrhea. Although symptoms vary between anaphylactic patients, onset generally occurs seconds to minutes after exposure to an antigen and requires prompt treatment.
CAUSES OF ANAPHYLAXIS
Anaphylaxis has many possible causes, including foods, insect stings, medications, latex rubber, and radiographic dyes. In many cases, the cause is not identified and the reaction is described as idiopathic. Research has shown that up to two thirds of all anaphylactic reactions are idiopathic.
Foods. Allergies to foods cause up to one third of all anaphylactic reactions. Common culprits are shellfish, peanuts, eggs, milk, and tree nuts, such as walnuts, almonds, and pecans. Nuts (especially peanuts) and shellfish are the worst offenders.
People have reported significant anaphylactic reactions after simply touching one of these foods, so warn patients to read food labels carefully. These foods should never be mixed into recipes that will be ingested by a hypersensitive person.
Peanut allergy affects approximately 1.1% of the general population, or about 3 million Americans, representing a significant health concern. Researchers are unclear about the cause, but the incidence of peanut allergic reactions in children under age four has doubled in the last decade. Peanut-specific immunotherapy is currently being examined as a treatment option.
Insect stings. Allergies to insect stings are another significant cause of anaphylaxis, especially the Hymen-optera species (bee, wasp, yellow jacket, and hornet). In the United States, approximately 500 deaths a year occur from insect stings, and up to 3% of the population may be sensitized and at risk for some type of allergic reaction. Patients who report a significant reaction (urticaria, laryngeal edema, or severe hives) need to be taught to recognize symptoms and to seek immediate treatment. Those with a history of severe allergic reactions to insect stings should receive a prescription for an epinephrine auto-injector and should be shown how to use the device.
Medications. Any medication, whether prescription or over-the-counter, can cause an anaphylactic reaction. Exposure to the offending drug may produce IgE antibodies against that drug, which can initiate anaphylaxis. Patients can become sensitized at any age, even if they have taken the drug before without any problem.
Patients commonly report allergies to penicillin. However, a report in the Archives of Internal Medicine found that most people who think they are allergic to penicillin are not. About 6% to 10% of patients who are truly allergic to penicillin will have a cross-reaction to cephalosporins. The cross-reactivity of first- and
second-generation cephalosporins with penicillin is higher than that of third-generation cephalosporins. This is thought to be related to the fact that first-generation cephalosporins, such as cephalexin and cephalothin, have side chains similar to those of benzylpenicillin, which may cause an antigen-allergen reaction.
Medications administered parenterally (IV or IM) will cause anaphylaxis more rapidly than drugs given orally. Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) may produce a range of reactions, including bronchospasm, urticaria, and significant angioedema. Aspirin accounts for 3% of anaphylactic reactions in the United States every year, and research suggests that 10% of asthmatic patients may have aspirin-induced bronchospasm.
Latex rubber. Cases of latex rubber allergy have increased over the past two decades as the recognition of infectious diseases and the implementation of universal precautions (especially gloves) have become more prevalent in health care settings. Finding out if a patient is allergic to latex and recognizing the signs and symptoms of latex allergy is vital, because health care providers may inadvertently expose a patient to latex during examination and treatment. Latex is found in gloves, catheters, blood pressure cuffs, and many other medical supplies. Although many institutions are switching to latex-free products, many vendors still manufacture products containing latex, so the risk still exists for exposure. Between 8% and 17% of health care workers themselves are thought to have some form of latex allergy, although not all reactions are anaphylactic.
Symptoms of latex allergy vary from mild eczema to hives, pruritus, and angioedema. People allergic to latex may also be sensitive to bananas, kiwis, pears, pineapples, grapes, papayas, and other fruits.
Radiographic dyes. Some patients may report an allergy to certain dyes or contrast media used for imaging studies. Although the incidence of these allergies is generally low, practitioners should still ask about allergies to seafood or iodine to determine if an iodinated contrast material is safe to use. The use of low-osmolality nonionic agents has led to a four- to fivefold decrease in allergic reactions caused by contrast media injections. If ionic, iodinated contrast must be used, the patient may be premedicated with corticosteroids and antihistamines to reduce the risk of anaphylaxis.
DIAGNOSING ANAPHYLAXIS ACCURATELY
Anaphylaxis is a clinical diagnosis that can be made when at least two of the following are present:
- laryngeal edema, bronchospasm, and/or hypotension;
- cutaneous manifestations, including urticaria or rash;
- a history of exposure to an inciting antigen, followed by symptoms consistent with anaphylaxis; or
- laboratory confirmation of antigen-specific IgE through skin or blood testing.
Although most patients do not require specific laboratory testing, if a patient needs to be admitted to the hospital, certain tests may help the admitting physician or allergist confirm anaphylaxis. Two common tests are serum tryptase levels and plasma and urine histamine levels. These levels are only elevated up to six hours after an anaphylactic reaction, so emergency physicians should order these tests shortly after a patient has signs and symptoms of an allergic reaction.
Normal serum tryptase levels are below 11.7 ng/ml. Laboratory plasma histamine levels will rise within five minutes after the onset of anaphylaxis but will fall 30 to 60 minutes after exposure. Due to this short half-life in the blood, plasma histamine is often difficult to obtain. A 24-hour urine test for N-methylhistamine is more useful in the context of a hypersensitivity reaction when compared to a baseline urine collection obtained when the patient is symptom free.
Some foods high in histamine can cause false elevations. Tell patients to avoid alcoholic beverages, strawberries, chocolate, sauerkraut, tomatoes, and citrus fruits during the 24-hour urine collection period. Laboratory testing should be used along with the clinical evaluation of a patient to better determine a proper diagnosis of anaphylaxis.
PROMPT INTERVENTION
An acute attack of anaphylaxis requires prompt intervention. Primary treatment is to stabilize the patient according to advanced cardiac life support protocols. First, assess the patient’s airway and cardiovascular status. If he has significant respiratory angioedema and poor air exchange, endotracheal intubation may be required to provide sufficient oxygenation. Supplemental oxygen therapy is also necessary. With severe angioedema, obtain intravenous access with a crystalloid solution (0.9% normal saline solution or lactated Ringer’s solution) to replace fluid volume loss. Monitor the patient’s hemodynamic status closely for signs of hypotension or oxygen desaturation, indicating worsening anaphylaxis. If hypotension is present, the patient should be placed in a supine or Trendelenburg position. Remove obvious triggers, such as an insect stinger or intravenous medication. Most patients with anaphylaxis may be discharged from the emergency department after four to six hours of observation and resolution of symptoms. Those who fail to respond to treatment will require inpatient admission.
Several medications are used to treat anaphylaxis. The table below lists these drugs, along with their indications, dosages for adults and children, warnings and precautions, side effects, and potential interactions. They include epinephrine, antihistamines, corticosteroids, albuterol, and glucagon.
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Epinephrine. Epinephrine is the first-line drug to be given to a patient having an anaphylactic reaction. An alpha-receptor agonist, epinephrine reverses peripheral vasodilatation and reduces angioedema. It also has beta-receptor activity, which dilates the airways, increases the force of myocardial contraction, and suppresses histamine and leukotriene release, reducing inflammatory responses. A 1:1000 solution of epinephrine should be given SC or IM at a dose of 0.01 ml/kg of body weight (up to a maximum of 0.5 ml) every 10 to 15 minutes, as needed. The preferred site for IM epinephrine injection is the anterior thigh because this region provides a more rapid absorption than the deltoid muscle of the upper arm. If hypotension persists and the patient’s condition deteriorates, IV epinephrine (1:10,000 solution) can be administered at a dose of 0.5 ml to 1 ml every 10 to 20 minutes.
Fatality rates are high in cases of anaphylaxis where epinephrine administration is delayed. An auto-injection device is available for patients with known hypersensitivity or a history of anaphylaxis and is available by prescription in packages of two.
Antihistamines. In allergic reactions, an antigen interacts with and cross-links surface IgE antibodies on mast cells and basophils. Once the mast-cell-antibody-antigen complex is formed, a complicated series of events occurs that eventually leads to mast cell degranulation and the release of histamine and other chemical mediators from the mast cell or basophil (see illustration below). After its release, histamine can react with local or widespread tissues through histamine receptors.
Histamine receptor sites, histamine-1 (H1), and histamine-2 (H2) have a role in anaphylaxis. Acting on H1 receptors, histamine produces pruritus, vasodilation, hypotension, flushing, headache, tachycardia, bronchoconstriction, and increased vascular permeability. Targeting H2-receptor sites, histamine causes increased stomach acid production, nausea, and flushing.
Prompt treatment with antihistamines is highly recommended to alleviate the symptoms of anaphylaxis. Antihistamines are helpful in reducing histamine-mediated vasodilation and secondary edema. Commonly used drugs such as diphenhydramine provide H1 blockade. H1 antihistamines reduce vasodilation in small blood vessels in the nose, eyes, and airways and provide some anticholinergic effects toward drying secretions. Diphenhydramine (1 to 2 mg/kg, up to a maximum of 50 mg, given IV or IM) is the drug of choice when treating anaphylaxis. Concomitant administration of an H2 agonist such as ranitidine (1 mg/kg IV) or cimetidine (4 mg/kg IV) is also of value to provide antihistaminic effect.
Corticosteroids. The exact benefit of corticosteroids in anaphylaxis has not been well established; however, allergy specialists still advocate the use of intravenous steroids. These drugs help reduce swelling and inflammation in the airway and reduce IgE-mediated responses that might occur hours later. Steroids may take up to 12 hours to reduce inflammation.
Commonly prescribed corticosteroids include IV or IM methylprednisolone (1 to 2 mg/kg) repeated every six hours. Counsel patients about common side effects, including euphoria, increased appetite, facial flushing, and elevated glucose levels. Corticosteroids should not be given until epinephrine and antihistamines have been administered.
Albuterol. Bronchodilators are clinically indicated to reduce wheezing by relaxing smooth bronchial muscle around the airways. For patients with persistent wheezing, beta-2 agonists are helpful when treating anaphylaxis. Commonly, albuterol 0.5% solution can be administered by nebulized aerosol over several minutes. Albuterol 0.5% solution can be dosed for adults as 0.5 ml in 2.5 ml of 0.9% normal saline solution. Pediatric dosing is 0.03 to 0.05 ml/kg of albuterol in 2.5 ml of 0.9% normal saline solution. Bronchodilators should be considered for patients experiencing anaphylaxis who present with wheezing and respiratory distress.
Glucagon. Understanding the role of glucagon in anaphylaxis requires knowledge of specific cellular biochemistry. Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3’-5’-cyclic adenosine monophosphate) is a nucleotide (protein molecule) that plays an important role in many biological processes. Located in the cell’s fluid, cAMP is a secondary messenger, which means it relays a signal in the cell to transfer effects for a specific hormone. When a large amount of cAMP is produced in the cell’s fluid, hormones such as epinephrine or glucagon work more effectively.
As discussed earlier, epinephrine acts on beta-2 receptor sites of smooth muscles in the airways. When the beta-2 receptors are stimulated, cAMP is produced, relaxing the smooth muscle cells and opening the airways. If a patient is currently taking a beta blocking agent—especially a noncardioselective type, such as propranolol, naldolol, or sotalol—epinephrine may not effectively utilize beta-2 receptors. In these cases, cAMP is not produced, the bronchial smooth muscle cannot relax, and the patient’s airway remains compromised. To achieve bronchodilation and subsequent effective air exchange in a patient on beta blockers, 1 mg of IM or IV glucagon may be administered. Glucagon works by stimulating higher cAMP levels and overrides the alpha and beta receptors so that epinephrine does not require those receptor pathways to work. Glucagon has documented positive inotropic and chronotropic effects on the heart.
Patients treated with glucagon require close monitoring of their blood glucose levels because glucagon elevates serum glucose. Although current research has not directly studied its effects in anaphylaxis, glucagon acts independently of alpha and beta receptors and can counteract the systemic effects of anaphylaxis. Emergency care providers should consider glucagon therapy when treating the anaphylactic patient who is taking a beta blocker or is refractory to epinephrine.
DESENSITIZATION AND PRETREATMENT
If a patient thinks he might be exposed to a trigger (for example, a landscaper who is allergic to bee stings), desensitization or pretreatment, or both, may be attempted. The patient should be referred to an allergist for a series of desensitization injections to help him slowly develop antibodies against the particular antigen. Immunotherapy is recommended for patients who have anaphylactic reactions to insect stings. Studies show that immunotherapy may be 97% effective in preventing recurrent anaphylaxis.
Patients who are highly allergic to penicillin or other antibiotics may undergo protocols for oral or injectable desensitization to these antibiotics. Desensitization and immunotherapy should be performed by experienced health care providers in a well-equipped setting, because patients run the risk of anaphylaxis as they are exposed to the antigen.
Patients requiring radiocontrast agents for imaging studies may be given steroids and antihistamines before receiving the contrast media to reduce allergic reactions. Patients who are allergic to peanuts, latex, or other substances can also benefit from desensitization and immunotherapy.
PATIENT EDUCATION
Patients with known anaphylactic reactions should be advised to avoid exposure to the antigen. They should be instructed to call 911 immediately if they notice signs of anaphylaxis and to wear a medical alert bracelet or necklace or carry a key chain to advise emergency personnel of anaphylaxis risk. Also advise them to keep an auto-injector epinephrine kit and oral antihistamines on hand in case of antigen exposure.
Self-injecting epinephrine comes in two doses: 0.3 ml of a 1:1000 concentration for adults and 0.3 ml of a 1:2000 concentration for children. Training kits with empty syringe devices are also available for patient and family education. Warn patients that injecting epinephrine is not enough—they still need to visit a doctor or emergency department immediately for further treatment, even if their symptoms seem to subside.
In addition, patients with a history of anaphylaxis who are taking beta blockers may require a different medication for hypertension. Those with food allergies need to learn what foods to avoid that contain antigen triggers. Patients with a strong potential for re-exposure to an antigen should be referred to an allergist for possible desensitization therapy.
Suggested Reading
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Caplan EL, et al.: Fire ants represent an important risk for anaphylaxis among residents of an endemic region. J Allergy Clin Immunol 111(6):1274, 2003.
Castells MC, et al.: Exercise-induced anaphylaxis (EIA). Clin Rev Allergy Immunol 17(4):413, 1999.
Ellis AK and Day JH: Diagnosis and management of anaphylaxis. CMAJ 169(4):307, 2003.
Golden DB: Stinging Insect Allergy. Am Fam Physician 67(12):2541, 2003.
James CW and Gurk-Turner C: Cross-reactivity of beta-lactam antibiotics. Proc (Bayl Univ Med Cent) 14(1):106, 2001.
Neugut AL, et al.: Anaphylaxis in the United States: an investigation into its epidemiology. Arch Intern Med 161(1):15, 2001.
Pumphrey RS: Fatal posture in anaphylactic shock. J Allergy Clin Immunol 112(2):451, 2003.
Sicherer SH, et al.: Prevalence of seafood allergy in the United States determined by a random telephone survey. J Allergy Clin Immunol 114(1):159, 2004.
Simons FE, et al.: Epinephrine dispensing patterns for an out-of-hospital population: a novel approach to studying the epidemiology of anaphylaxis. J Allergy Clin Immunol 110(4): 647, 2002.
Solensky R, et al.: Lack of penicillin resensitization in patients with a history of penicillin allergy after receiving repeated penicillin courses. Arch Intern Med 162(7):822, 2002.
Tang AW: A practical guide to anaphylaxis. Am Fam Physician 68(7):1325, 2003.
Vermieren GL, et al.: Influence of ionic and non-ionic radiographic contrast media on leukocyte adhesion molecules. Mediators Inflamm 12(5):269, 2003.
Zak HN, et al.: Health-care workers and latex allergy. Arch Environ Health 55(5): 336, 2000.
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