The diagnosis and management of Anaphylaxis Policy


 DEFINITIONS OF ANAPHYLAXIS AND ANAPHYLACTOID EVENTS

· Anaphylaxis is defined as an immediate systemic reaction due to rapid, IgE mediated immune release of potent mediators from tissue mast cells and peripheral blood basophils.

· Anaphylactoid reactions are immediate systemic reactions that mimic anaphylaxis but are not caused by IgE-mediated immune responses.

· The temporal occurrence of these reactions is usually immediate but may be delayed depending on the route of exposure. Occasionally, biphasic reactions may occur.

EVALUATION AND MANAGEMENT OF PATIENTS WITH A HISTORY OF ANAPHYLAXIS

· A detailed history is important in the ultimate care of individuals who have had an anaphylactic or anaphylactoid episode.

· Proper timing of laboratory studies, such as blood tests or urine assays, is important in making these studies optimally useful.

· Effective treatment demands early recognition of the event.

· The possibility of anaphylaxis should be considered in any setting where medication or biologicals are given, especially by injection.

· Medical facilities should have an established protocol for prompt therapy of anaphylaxis. Supplies that are needed should be promptly available. Oxygen, aqueous epinephrine, injectable antihistamines, I.V. glucocorticosteroids, oropharyngeal airway and supplies to maintain IV fluid therapy are crucial.

· Phone numbers for paramedical rescue squads and ambulance services should be at hand.

· Protocols for the office staff and for patients should be available.

 

 

LATEX

· Latex (rubber) hypersensitivity is a significant medical problem and three groups are at higher risk of reactions: health care workers, children with spina bifida and genitourinary abnormalities, and workers with occupational exposure to latex.

· To identify IgE-mediated sensitivity, prick skin tests with latex extracts should be considered for patients who are members of high-risk groups or who have a clinical history of possible latex allergy. Although a standardized, commercial skin test reagent for latex is not yet available in the United States, many allergy centers have prepared latex extracts for clinical testing. In-vitro assays for IgE to latex may also be useful, although these tests are generally less sensitive than skin tests.

· Patients with spina bifida (regardless of a history of latex allergy) and other patients with a positive history of latex allergy ideally should have all medical/surgical/dental procedures performed in a latex-controlled environment.

· A latex-controlled environment is defined as an environment in which no latex gloves are used in the room or surgical suite and no latex accessories (catheters, adhesives, tourniquet, and anesthesia equipment) come into contact with the patient.

· In health care settings, general use of latex gloves having negligible allergen content, powder-free latex gloves, and non-latex gloves and medical articles should be considered in an effort to minimize exposure to latex allergen. Such a

·  combined approach may minimize latex sensitization of health care workers and patients and should reduce the risk of inadvertent reactions to latex in previously sensitized individuals.

· Patients with a history of latex allergy by history or skin testing should wear a medical identification bracelet and/or carry a medical identification card. If patients have a history of anaphylaxis to latex, it may be important for them to carry epinephrine and antihistamines for self-administration.

BETA-LACTAM ANTIBIOTICS

· Penicillin is the most frequent cause of anaphylaxis in humans and has been estimated to be responsible for 75% of anaphylactic deaths in the United States.

· Although allergic reactions may occur after administration of penicillin by any route, parenteral administration is most likely to induce severe reactions such as anaphylaxis. Oral administration appears considerably safer.

· Patients with a history of a prior penicillin reaction are six times more likely to experience a reaction on subsequent exposure, compared with those without a previous history.

· Over 80% of patients with a history of allergy to penicillin do not have penicillin-specific IgE antibodies as detected by skin testing.

· If a patient requires penicillin and has a past history of penicillin allergy, it is necessary to skin test the patient for the presence of penicillin-specific IgE antibodies before assuming that the patient will not be able to tolerate penicillin.

· Skin testing identifies patients who have IgE antibodies specific for penicillin, who, as a result, may be at risk of an immediate reaction if given penicillin.

· Skin testing for penicillin does not predict the later development of IgE-mediated reactions or reactions due to other immune mechanisms.

· IgE antibodies to minor determinants are most frequently implicated in anaphylactic reactions to penicillin.

· Evaluation by RAST or ELISA testing does not reliably rule out allergy to penicillin because of the insensitivity of the test and the lack of an appropriate minor determinant reagent.

· Patients with a history of possible allergic reaction to penicillin, who have a recommended indication for penicillin treatment, should be skin tested.

· After anaphylaxis there is an interval of time during which skin test results may not be reliable. This interval has been reported to vary from 1-2 weeks or longer.

· Skin testing is generally not recommended for a patient with a history of an exfoliative dermatitis (e.g. Stevens-Johnson Syndrome or toxic epidermal necrolysis) from penicillin or other beta-lactam medications.

· Patients with a positive family history but no personal history of penicillin allergy do not require penicillin skin testing because they are generally not at risk of having an allergic reaction to penicillin.

· If skin testing for penicillin using major (penicilloyl) and minor determinants (penicillin G and others) is negative, 97-99% of patients (depending on reagents used) will tolerate penicillin administration without risk of an immediate reaction. Using the above reagents, and proper technique by skilled personnel, serious reactions, including anaphylaxis and death from skin testing, are extremely rare.

· If a patient has a positive history and a positive skin test for penicillin, there is a 50% or greater chance of an immediate reaction if penicillin is given again.

· If the patient has a past history of an allergic reaction to penicillin, and the skin testing is positive to either major or minor determinants, the patient should receive an alternative antibiotic unless the indication for penicillin is clear. If administration of penicillin is mandatory in this setting, desensitization is indicated.

· If the patient has a past history of allergy to penicillin and the skin testing is negative to penicilloyl polylysine and penicillin G, there is a small chance that specific IgE antibodies to other minor determinants not contained in penicillin G may be present.

· Administration of ampicillin and amoxicillin is associated with the development of morbilliform rashes in 5-13% of patients. These patients should not be considered

  at risk of a life-threatening reaction to penicillin, and therefore do not require skin testing. On the other hand, if the rash to ampicillin or amoxicillin is urticarial or if the patient has a history of anaphylaxis, the patient should undergo penicillin skin testing before a future course of penicillin is given.

· Carbapenems (e.g., imipenem) should be considered cross-reactive with penicillin. The monobactam, aztreonam, rarely cross-reacts with penicillin.

· Cephalosporins and penicillins have a common beta-lactam ring structure and varying degrees of cross-reactivity have been documented. However, the risk of allergic reactions to cephalosporins in penicillin-allergic patients appears to be low (less than 10%). First generation cephalosporins may pose a greater risk than second or third generation cephalosporins.

· If a patient has a questionable history of penicillin allergy and requires a cephalosporin, penicillin skin testing can be considered to ensure the absence of penicillin-specific IgE antibodies.

· If there is consideration of cephalosporin use in a patient who has a history of an immediate-type reaction to penicillin, skin testing to major and minor determinants of penicillin should be done to determine if the patient has penicillin-specific IgE antibodies. If skin testing is negative, the patient can receive a cephalosporin at no greater risk than the general population.

· If there is consideration of cephalosporin use, in a patient with a history of penicillin allergy, who has a positive skin test to penicillin, the physician's recommendations may include: 1) administration of an appropriate alternative antibiotic; 2) a cautious graded challenge (test dosing) with appropriate monitoring, recognizing that there is, at least, a 5% chance of inducing an anaphylactic reaction; or 3) desensitization to the cephalosporin that is proposed for use.

· Patients with a history of IgE-mediated reaction to a cephalosporin, who require penicillin, should undergo penicillin skin testing. If the tests are negative, they can receive penicillin; if positive, they should either receive an alternative medication or undergo desensitization to penicillin.

· If a patient with a past history of allergy to one cephalosporin requires another cephalosporin, skin testing with the required cephalosporin can be done, recognizing that the negative predictive value is unknown. If the skin test for the cephalosporins is positive, control subjects can be tested to determine if the positive response was due to irritation or was IgE-mediated.

 

ASA/NSAIDs

· Aspirin (ASA) and non-steroidal anti-inflammatory drugs (NSAIDs) are associated with a variety of non-IgE-mediated adverse effects. These include systemic reactions, such as rhinoconjunctivitis, bronchospasm, urticaria, angioedema, and laryngeal edema.

· There is no definitive skin or in-vitro test to identify patients who are intolerant to ASA or NSAIDs. On the other hand, carefully performed oral ASA/NSAID challenges can be useful in making a more definitive diagnosis.

· Once a diagnosis has been made, avoidance is essential in preventing life-threatening reactions to these agents. This requires educating the patient about combination products (including over-the-counter medications) containing ASA or NSAIDs.

· Allergy/immunology specialists are frequently asked to clarify the risk of reactions to ASA/NSAIDs and to devise a strategy for dealing with these therapeutic dilemmas.

· It may be useful to refer a patient suspected of being intolerant to ASA or a NSAID to an allergist-immunologist and/or center where oral aspirin/NSAID challenges are performed routinely in a well equipped medical facility, because of the possibility of life-threatening reactions that can occur from such challenges.

· If the ASA/NSAID challenge is positive, pharmacologic desensitization and continued treatment with ASA or NSAIDs can be used if there is a medical indication for this type of medication.

 

· ANAPHYLACTOID REACTIONS TO RADIOGRAPHIC CONTRAST MATERIAL

· Anaphylactoid reactions to radiocontrast material (RCM) can occur after intravascular administration and during hysterosalpingograms, myelograms, and retrograde pyelograms.

· Anaphylactoid reactions to RCM are clinically indistinguishable from IgE-mediated immediate hypersensitivity anaphylactic reactions, although they do not appear to be associated with IgE or any other type of immunologic reaction.

· The treatment of anaphylactoid reactions to RCM is not different than the treatment of anaphylactic reactions caused by allergen-IgE interaction and resultant mast cell mediator release.

· Patients who have experienced previous anaphylactoid reactions from the administration of radiocontrast material (RCM) are at risk for a repeat reaction. Estimates of this risk range from 16-44% for procedures with high osmolality RCM. Therefore, the physician should consider other alternatives in managing such patients rather than procedures that require readministration of RCM.

· With pretreatment and the use of lower osmolar RCM the risk of repeat anaphylactoid reactions is reduced to approximately 1%.

· Pretreatment regimens for prevention of repeat anaphylactoid reactions have consisted of oral glucocorticosteroids, H1 and H2 antihistamines and other medications such as ephedrine.

 

 

             INSULIN ANAPHYLAXIS

· In general, the degree of insulin immunogenicity is in the following order: bovine > porcine > human. Although anaphylactic reactions to human insulin produced by recombinant DNA technology, are rare, they can occur.

·                       Insulin-induced anaphylaxis is characterized by the same                              manifestations as anaphylaxis from other causes.

· Patients are more likely to develop anaphylaxis from insulin administration if therapy is interrupted.

· Skin testing with insulin can aid in making the diagnosis of insulin-induced anaphylaxis. In addition, skin testing can be used to select the least allergenic insulin for administration to patients who have a history of immediate hypersensitivity reactions to insulin, yet require insulin.

· Patients with a history of anaphylaxis to insulin can be desensitized to insulin if no alternative medications exist to treat their disease.

PROTAMINE

· Intravenous administration of protamine, a polycationic protein used to reverse heparin anticoagulation, may cause anaphylaxis as well as transient elevations in pulmonary artery pressure and/or cardiovascular collapse.

· The pathogenesis of these acute reactions has not been proven but both non-immune and immune (IgE) mechanisms have been reported.

· Patients who previously required protamine-containing insulin or intravenous protamine are at significantly increased risk for developing anaphylaxis and other adverse reactions from intravenous protamine.

· Although intracutaneous tests with protamine may be helpful in identifying a possible IgE mediated response in selected cases, these tests must be interpreted with caution because they do not necessarily predict clinical sensitivity, and do not identify all patients at risk.

A variety of alternative approaches may be considered to avoid the need for protamine reversal of heparinization. Several alternative agents may be used for heparin reversal, but these are not readily available on an emergency basis. For patients at high risk for protamine reactions, one should attempt to obtain one of the alternative reversal agents prior to the procedure which requires heparin anticoagulation.

· Although pre-medication with antihistamines and corticosteroids may be considered in an effort to reduce protamine reactions, there are no controlled trials that have demonstrated that pre-medication is effective in this setting.

LOCAL ANESTHETICS

· Anaphylactic reactions to local anesthetics or constituents of local anesthetics have been reported, although IgE-mediated systemic anaphylaxis to these agents is rare.

· Local anesthetics are classified into groups including esters (aminobenzoate and benzoic acid subtypes), amides, ethers, and ketones.

· Provocative (graded) dose challenge should be considered when the cause of a reaction is unknown, or proof of safety is required before administration.

· Reactions to additives such as parabens or sulfites may occur but are rare and routine testing with these substances is not recommended.

· In patients who have had reactions to an ester type local anesthetic, an amide should be considered for provocative (graded) dose testing. If the patient had a reaction to an amide, another amide might be considered, since cross reactivity among amides has not been documented.

ANAPHYLAXIS DURING GENERAL ANESTHESIA, THE INTRAOPERATIVE PERIOD, AND THE POSTOPERATIVE PERIOD

· The incidence of generalized anaphylactic reactions during anesthesia have been reported to range from 1 in 4,000 to 1 in 25,000. Anaphylaxis during anesthesia can present as cardiovascular collapse, airway obstruction, flushing and/or edema of the skin.

· It may be difficult to differentiate between immune and non-immune mast cell mediated reactions and pharmacologic effects from the variety of medications administered during general anesthesia.

· Thiopental allergy has been documented by skin tests.

· Neuromuscular blocking agents such as succinylcholine can cause non-immunologic histamine release, but there have been reports of IgE mediated mechanisms in some cases.

· Reactions to opioid analgesics are usually due to direct mast cell mediator release rather than IgE dependent mechanisms.

· Antibiotics which are administered perioperatively can cause immunologic or non-immunologic generalized reactions.

· Protamine can also cause severe reactions via IgE-mediated or non-immunologic mechanisms.

· Latex is a potent allergen and IgE-mediated reactions to latex during anesthesia have been clearly documented. Patients with multiple surgical procedures (e.g. spina bifida patients) and health care workers are at greater risk of latex sensitization.

· Precautions for latex sensitive patients include avoiding the use of latex gloves and latex blood pressure cuffs as well as latex intravenous tubing ports and rubber stoppers from medication vials.

· Ethylene oxide anaphylactic reactions have been reported particularly in patients who have exposure to hemodialysis or who are undergoing plasmapheresis.

· Blood transfusions can elicit a variety of systemic reactions some of which may be IgE- mediated or mediated through other immunologic mechanisms.

· Methylmethacrylate (bone cement) has been associated with hypotension and various systemic reactions, although no allergic mechanism has yet been documented.

· The evaluation of allergic reactions to medications used during anesthesia can include skin testing to a variety of anesthetic agents.

· The management of anaphylactic reactions which occur during general anesthesia is similar to the management of anaphylaxis in other situations..

EXERCISE-INDUCED ANAPHYLAXIS

· Exercise-induced anaphylaxis is a unique form of physical allergy. Initial symptoms typically include fatigue, diffuse warmth, pruritus, erythema and urticaria, with progression to angioedema, gastrointestinal symptoms, laryngeal edema and/or vascular collapse.

· Factors that have been associated with exercise-induced anaphylaxis include medications, e.g. aspirin/other nonsteroidal anti-inflammatory agents or food ingestion prior to exercise.

· Patients with exercise-induced anaphylaxis may have a higher incidence of personal and/or family history of atopy.

· Exercise-induced anaphylaxis should be distinguished from other exercise-associated syndromes, such as cholinergic urticaria and exercise-induced asthma.

· Medications used prophylactically are generally not useful in preventing exercise-induced anaphylaxis.

· Exercise should be discontinued at the onset of symptoms of exercise-induced anaphylaxis and for some patients, exercise should be avoided in the immediate post-prandial period (4-6 hours after eating).

· The emergency management of exercise-induced anaphylaxis is the same as the treatment of anaphylaxis from other causes.

· Patients with exercise-induced anaphylaxis should carry epinephrine and should wear and/or carry Medic Alert identification denoting their condition.

 

 

IDIOPATHIC ANAPHYLAXIS

· Patients who develop idiopathic anaphylaxis present with the same constellation of symptoms that are seen in other types of anaphylactic/anaphylactoid reactions.

· Patients with idiopathic anaphylaxis should receive intensive evaluation, including a meticulous history with careful analysis of events surrounding the development of episodes of anaphylaxis.

· Clinical evaluation may indicate the need for specific laboratory studies which may help to exclude an underlying systemic disorder, e.g. systemic mast cell disease or hereditary/ acquired angioedema. Selective testing for specific IgE antibodies and carefully controlled challenge procedures may occasionally help to establish an etiology for recurrent episodes of anaphylaxis.

· The acute treatment of idiopathic anaphylaxis is the same as the treatment of other types of anaphylactic/anaphylactoid reactions. Various protocols have been developed for the prevention of idiopathic anaphylaxis, but the treatment, e.g. corticosteroids, beta agonists, antihistamines, often requires individualization.

· Education and support of patients with idiopathic anaphylaxis is an essential part of the management program.

PREVENTION OF ANAPHYLAXIS

· Major risk factors for of anaphylaxis include a prior history of such reactions, beta-adrenergic blocker or ACE inhibitor therapy and possibly patients on ACE inhibitors who have the multiple antibiotic sensitivity syndromes. Atopic background may be a risk factor for venom and latex-induced anaphylaxis and possibly anaphylactoid reactions to radiographic contrast material, but not for anaphylactic reactions to medications.

· Avoidance measures are successful if future exposure to drugs, foods, additives or occupational allergens can be prevented. Avoidance of stinging and biting insects is also possible in many cases. Prevention of systemic reactions during allergen immunotherapy is dependent on the specific circumstances involved.

· Avoidance management should be individualized, taking into consideration factors such as age, activity, occupation, hobbies, residential conditions, access to medical care and the patients' level of personal anxiety.

· Pharmacologic prophylaxis should be utilized to prevent recurrent anaphylactoid reactions to radiographic contrast material, fluorescein as well as to prevent idiopathic anaphylaxis. Pretreatment with glucocorticosteroids and antihistamines markedly reduces the occurrence of subsequent reactions.

· Allergen immunotherapy with the appropriate stinging insect venom should be recommended for patients with systemic sensitivity to stinging insects because this treatment is highly (90-98%) effective.

· Desensitization to medications that are known to have caused anaphylaxis can be effective. In most cases, the effect of desensitization is temporary and if the medication is required sometime in the future, the desensitization process must be repeated. Oral graded challenge to medications, such as aspirin, sulfasalazine or allopurinol may restore tolerance to anaphylaxis as long as the medication is administered on a continuous basis.

· Patient education may be the most important preventive strategy. Patients should be carefully instructed about hidden allergens, cross-reactions to various allergens, unforeseen risks during medical procedures and when and how to use self-administered epinephrine. Physicians should educate patients about the risks of future anaphylaxis, as well as the benefits of avoidance measures.