Anaphylaxis

Anaphylaxis The incidence of this potentially lethal biochemical reaction seems to be increasing with the size of our pharmacopeia. From biochemistry to blood pressure support, this article will help you recognize and manage the acute episode. journalArticle Phillip L. Lieberman, MD, University of Tennessee College of Medicine Dr. Lieberman is Clinical Professor of Medicine and Pediatrics at the University of Tennessee College of Medicine, Cordova, TN. Lieberman PL. Anaphylaxis. MedGenMed 1(1), 1999 [formerly published in Medscape Pulmonary Medicine eJournal 1(4), 1997]. Available at: http://www.medscape.com/viewarticle/408706 Medscape Medscape General Medicine [TM] 07/30/1999 1 1 <H3>Abstract</H3> Anaphylaxis is defined as an immediate systemic hypersensitivity event produced by IgE-mediated release of chemicals from mast cells and basophils. The reported incidence varies widely and is increasing as new drugs are added to our pharmacopeia. Anaphylaxis to injected antigen is more frequent, severe, and rapid in onset. Biochemically, anaphylaxis is related to the degranulation of mast cells and basophils with the subsequent release of chemical mediators, which are responsible for the symptoms. The most threatening manifestations of anaphylaxis are airways edema, bronchospasm and shock. Urticaria and angioedema are the most common signs and symptoms. "Late-phase response" refers to the recrudescence of symptoms after a temporary resolution, leading to "biphasic anaphylaxis." Usually, compensatory tachycardia occurs in response to the decreased effective vascular volume or vasodilatation. However, bradycardia may also be present as a result of the Bezold-Jarisch reflex, a cardio-inhibitory reflex originating in sensory receptors in the infero-posterior wall of the left ventricle. The differential diagnosis of anaphylaxis and anaphylactoid reactions includes other forms of shock and non-organic disease. Patients experiencing anaphylactoid reactions to aspirin are almost universally sensitive to any drug which inhibits prostaglandin synthetase activity. The beta-lactam ring contained in both penicillin and cephalosporins leads to immunologic cross-reactivity. Patients at risk for episodes of anaphylaxis should wear an identifying Medic Alert bracelet, keep an identification card listing their drug allergies , and carry a self-injection kit of epinephrine. Rapid recognition is essential in the management of the acute episode.<H3>Introduction and Incidence</H3> Anaphylaxis is defined as an immediate systemic hypersensitivity event produced by IgE-mediated release of chemicals from mast cells and basophils. The term "anaphylactoid reaction" designates a clinically similar event not mediated by antigen and IgE. The two terms are used interchangeably in this review. The exact incidence of anaphylaxis is unknown. However, approximations of incidence can be obtained from a review of epidemiologic studies. In Ontario, Canada, the incidence was recorded as 4 cases per 10 million population.[1] Recently in Munich, Germany, the incidence was found to be 9.79 cases per 100,000 population.[2] It is assumed that the incidence is increasing as new drugs are added to our pharmacopeia, and polypharmacy becomes the rule. Several factors can affect the incidence. These factors include atopy, route of administration of antigen, constancy of administration of antigen, time since last reaction, age and gender. Atopy is an important variable when antigen is administered by mucosal routes, such as orally, but not when it is administered parenterally. Thus atopic individuals are more prone to anaphylaxis to ingested substances such as food, but are not more prone to injected antigens such as insulin. The incidence of anaphylaxis to latex, exercise, oral radiocontrast material--as well as the incidence of idiopathic anaphylaxis--is higher in atopic individuals. The reasons for this increased predisposition are not entirely clear. However, atopic individuals do exhibit a state of basophil hyper-releasability. That is, basophils from patients with atopic disorders including asthma, food allergy, and atopic dermatitis exhibit enhanced spontaneous basophil histamine release compared to controls.[3] In addition, atopics may be predisposed because of autonomic nervous system dysfunction (blockade) noted in certain atopic disorders such as asthma. Anaphylaxis can occur via any route of administration of antigen. However, episodes are more frequent and oftentimes more severe when antigen is injected rather than ingested. In addition, the onset is more rapid after injection. Constancy of administration is an important variable. Interruptions in administration of antigen may predispose to a reaction. Insulin anaphylaxis, for example, is more frequent when administration of this drug has been interrupted and then resumed, such as occurs during episodes of diabetes occurring only during pregnancies.[4] The time since the last reaction is an important variable for many allergens--the longer the time between a previous reaction to a drug and the readministration of the drug, the less likely a repeat reaction is to occur. This is presumably due to the decreased synthesis of IgE as a result of the absence of exposure. Anaphylactic events to radiocontrast media, plasma expanders, anesthetics and hymenoptera are more likely to occur in adults than children. It is unclear whether this difference in incidence is a result of heightened sensitivity or simply increased exposure. Anaphylactic reactions to intravenous muscle relaxants, aspirin and latex occur more frequently in women, while reactions to insect stings occur more often in men. The difference in frequency of reactions to latex and insect stings may be related to exposure. For example, it is assumed that males are exposed to insect stings more frequently than females, and females are exposed to latex more frequently, due to the preponderance of females working in the healthcare field. Also, females may be more likely to have reactions to intravenous muscle relaxants because these drugs contain a quaternary ammonium moiety that is found in many cosmetics as well.<H3>Pathophysiology</H3> The most common mechanism for production of anaphylaxis and anaphylactoid events is related to the degranulation of mast cells and basophils with the subsequent release of chemical mediators, which are responsible for the symptoms. Degranulation can be mediated by IgE-antigen union or through direct histamine release (not involving IgE) (Table I). Other mechanisms, however, can produce clinically similar events. For example, disturbances in arachidonic acid metabolism with excessive formation of leukotrienes can cause events which are clinically indistinguishable from classical anaphylaxis. These episodes occur idiosyncratically with the ingestion of nonsteroidal anti-inflammatory drugs. Immune aggregate anaphylaxis can occur due to the presence of immune complexes such as occasionally occurs with the administration of intramuscular gamma-globulin. Other inflammatory pathways can also be involved in the production of symptoms (Table II). Anaphylactic and anaphylactoid events can be produced by or result in complement activation, recruitment of the contact system with formation of kinins, and activation of the clotting cascade. In addition, chemotactic factors released from mast cells and basophils can enlist a second wave of cell activation by activating other inflammatory cells. This phenomenon may be responsible for a relapse or recurrence of symptoms after the apparent resolution of an acute episode. Histamine is perhaps the best-characterized and most important mediator. Histamine acts through both H1 and H2 receptors to produce the clinical characteristic of anaphylaxis (Table III). The most threatening manifestations of anaphylaxis are airways edema, bronchospasm and shock. The pathophysiology of angioedema and bronchospasm is well characterized and not complex. However, the pathophysiologic events underlying shock are more complicated and can vary. Two events participate in the production of shock. The first of these is vasodilatation and the second is increased vascular permeability. Usually, the most significant of these is the increase in vascular permeability. This increase in vasopermeability produces a shift of fluid from the intravascular to extravascular space and can result in rapid and profound losses of intravascular volume. Up to 50% of intravascular volume can be lost within 10 minutes.[5] This loss in volume activates internal compensatory mechanisms.[6,7] The result is an elevation of serum catecholamines as well as the conversion of angiotensin I to angiotensin II. The major effect of this is an increase in peripheral resistance with, in some cases, complete resolution of the vasodilatation produced by histamine and other mediators. Thus, peripheral resistance can be relatively normal in spite of the presence of shock. These pathophysiologic changes must be considered during therapy. For example, because histamine is active via both H1 and H2 receptors, the use of both an H1 and H2 receptor antagonist is often necessary to control symptoms, especially those related to vasodilatation (hypotension, urticaria and angioedema). In addition, because patients may be in shock, despite the fact that they are maximally vasoconstricted by the recruitment of catecholamines and angiotensin II, correct management would be fluid replacement rather than vasoconstrictors. Finally, it should be noted that failure of patients to respond to endogenous compensatory mechanisms or to mobilize these mechanisms may predispose them to severe anaphylactic episodes. For example, patients who are taking angiotensin II blocking agents or beta-blockers may not respond to angiotensin II or epinephrine respectively and can have more profound episodes of hypotension. In fact, angiotensin levels have been inversely correlated with the severity of anaphylaxis in patients experiencing episodes due to hymenoptera stings.[8]<H3>Symptoms and Signs</H3> Urticaria and angioedema are the most common signs and symptoms (Table IV). In fact, the absence of cutaneous symptoms -- urticaria, angioedema and flush -- mitigate against the diagnosis of anaphylaxis. However, cardiovascular collapse with shock can occur immediately and without any cutaneous or respiratory symptoms in rare instances.[9] The next most common findings are related to the respiratory tract. They consist of manifestations of upper airway edema, shortness of breath and wheeze. Symptoms of hypotension occur next most commonly. These consist of dizziness, syncope, and measurable hypotension. Gastrointestinal findings including nausea, vomiting, diarrhea, and cramping abdominal pain follow in frequency. Rarely, there is rhinitis, headache, substernal pain and pruritus without rash. Symptoms usually begin within 5 to 30 minutes after antigen injection. After oral administration, there is often a delay, but symptoms usually occur within the first 2 hours. It should be noted, however, that symptoms after oral ingestion can be almost immediate in onset and can be fatal. There may be a direct relationship between the onset of symptoms after administration of antigen and their severity. That is, the more rapid the onset, the more severe the episode. The late-phase response refers to the recrudescence of symptoms after an apparent but temporary resolution. Patients suffering a late-phase response are said to experience "biphasic anaphylaxis." These recurrences may occur repeatedly after multiple temporary remissions. These recurrences are referred to as "protracted anaphylaxis". As noted, it is believed that these recurrent episodes are due to recruitment of other cells activated by chemotactic mediators released from mast cells and basophils. However, during such episodes, there can be continuous release of tryptase and histamine indicating that degranulation of mast cells and basophils may also be ongoing. Death can occur at any time during an episode of protracted anaphylaxis. Cardiac manifestations are varied and can be profound. Characteristically, a compensatory tachycardia occurs in response to the decreased effective vascular volume or vasodilatation. This sign has often been used to differentiate an anaphylactic episode from a vasodepressor reaction. However, bradycardia, presumably resulting from an increase in vagal tone, can also occur. It is thought that this is mediated through the Bezold-Jarisch reflex, which is a cardio-inhibitory reflex originating in sensory receptors in the inferoposterior wall of the left ventricle. This reflex is carried by unmyelinated vagal C fibers and is activated by ischemia. Hypoxemia can cause myocardial depression that persists for several days. This contributes to the hypotension. Coronary vasospasm with myocardial infarction can occur. These changes are of course accompanied by numerous electrocardiographic abnormalities including ST segment elevation, inversion of T waves, flattening of T waves, and arrhythmias. Cardiac enzymes are often elevated.<H3>Differential Diagnosis</H3> The differential diagnosis of anaphylaxis and anapyhlactoid reactions includes other forms of shock, nonorganic disease, and many other syndromes (Table V). A physician is faced with building a differential diagnosis in two settings. The first setting occurs when the patient presents after symptoms have resolved. In this instance, it must be determined retrospectively whether the episode was the result of anaphylaxis or some other cause. In the second setting, the patient presents during an event. In this case, the differential diagnosis, between anaphylaxis and other causes of shock, must be made immediately. Vasodepressor reactions are probably the events most commonly confused with anaphylaxis. These reactions are characterized by pallor, weakness, hypotension, sweating, nausea, sometimes vomiting and almost always bradycardia. In fact, bradycardia is one of the most helpful signs in distinguishing between vasodepressor reactions and anaphylaxis. However, as noted, bradycardia can occur during an anaphylactic event. The other distinguishing feature of vasodepressor reactions is the absence of urticaria, angioedema, flush, and other cutaneous symptoms. Other forms of shock, including cardiogenic, hemorrhagic and endotoxic shock, must be considered. However, it is usually easy to distinguish between these and anaphylaxis. A number of reactions have been grouped under the heading of "restaurant syndromes." These are reactions to monosodium glutamate (MSG), saurine and sulfites which can mimic anaphylaxis. MSG ingestion can produce flushing, chest pain, burning of the skin of the face, dizziness, paresthesias, sweating, palpitations, nausea, vomiting and headaches. Symptoms usually begin no later than 1 hour after the ingestion, but can be delayed up to 14 hours. This reaction to MSG has been referred to as the "Chinese restaurant syndrome". The mechanism of action involves transient acetylcholinosis. About 15% to 20% of the population seem to be susceptible. Spoiled fish contains saurine, a histamine-like chemical that, upon ingestion, produces symptoms identical to anaphylaxis. Patients taking isoniazid appear to be especially sensitive to this type of reaction.[10] The ingestion of sulfites can, in some patients, produce a syndrome mimicking anaphylaxis. Wheezing is usually the most prominent symptom. It should be noted that the relationship between MSG ingestion and true episodes of anaphylaxis has not been well-established. Challenge studies in patients experiencing episodes of idiopathic anaphylaxis have failed to substantiate a relationship between MSG, or the ingestion of other food additives, and the production of such events. Flush reactions often mimic anaphylaxis. There are several conditions that produce flush. These include carcinoid syndrome, postmenopausal flush, chlorpropamide -- alcohol-induced flush, idiopathic flush, flush due to medullary carcinoma of the thyroid, and flush related to autonomic epilepsy. It is not surprising that carcinoid tumors can produce flush, mimicking anaphylaxis, since in addition to serotonin, they can secrete other mediators including histamine, kallikrein, and neuropeptides, all of which may also play a role in anaphylactic episodes. Postmenopausal flush usually involves the face, neck, and upper chest. It usually last 3 to 5 minutes and occurs several times a day. Stress and alcohol can exacerbate this form of flush. It is distinguished from anaphylaxis by the absence of urticaria, angioedema, wheeze or hypotension. Alcohol and chlorpropamide ingested together can produce a flush associated with hypoglycemia. This flush usually occurs within 5 minutes of ingestion of alcohol and lasts about 15 minutes. As in postmenopausal flush, there is no urticaria, angioedema or hypotension. Medullary carcinoma of the thyroid produces substances much like those found in carcinoid tumors, and, therefore, can cause events similar to those seen in anaphylaxis. Such patients often have telangiectasias, mucosal neuromas, and a family history of this disease. Idiopathic flush occurs more frequently in women. It can be associated with syncope, palpitations, hypotension and diarrhea. Wheezing is absent. Several conditions are associated with excessive endogenous production of histamine. These include mastocytosis, certain leukemias, and ruptured hydatid cysts. Of course, the mediators of these diseases are identical to those found in anaphylaxis, and, therefore, the symptoms are also the same. There are several emotional disorders mimicking anaphylaxis. Some of these episodes, such as vocal cord dysfunction syndrome or panic attacks, are involuntary. Others are consciously induced, as in Münchausen's stridor. Panic attacks can be accompanied by flushing, tachycardia, gastrointestinal symptoms and shortness of breath. The absence of hypotension, urticaria and angioedema distinguishes panic attacks from anaphylaxis. Vocal cord dysfunction syndrome and Munchausen's stridor have similar presentations. Vocal cord dysfunction syndrome is an involuntary adduction of the vocal cords producing obstruction in inspiration and expiration. The patient is actually not aware of the process. On the other hand, in Münchausen's stridor, laryngeal spasm is self-induced. One can oftentimes distinguish these two disorders by distracting the patient by asking them to perform maneuvers such as coughing. In Münchausen's stridor, there is relief of symptoms with this maneuver.[11] The laboratory can occasionally be helpful in making a diagnosis of anaphylaxis. Certainly the measurement of 5-hydroxy-indoleacetic acid is useful in establishing the diagnosis of carcinoid syndrome. In addition, if the patient is seen shortly after an anaphylactic episode, serum tryptase can be obtained. Serum tryptase levels peak 1 to 1.5 hours after the onset of anaphylaxis and can remain elevated up to 5 hours. Measurement of plasma histamine is usually not as helpful as tryptase levels because plasma histamine is elevated no more than 1 hour after the onset of symptoms. However, a 24-hour urinary collection for histamine and histamine metabolites can be useful, because there is a more larger window of time during which this mediator and its metabolites are increased in the urine.<H3>Prevention</H3> Preventive measures may be divided into general and specific strategies. The first general measure is taking thorough drug allergy history. The adequate interpretation of this history requires a knowledge of the biochemical and immunologic cross-reactivity between drugs. For example, patients experiencing anaphylactoid reactions to aspirin are almost universally sensitive to any drug which inhibits prostaglandin synthetase activity. This is an example of biochemical cross-reactivity. The shared beta-lactam ring between penicillin and cephalosporins is an example of the immunologic cross-reactivity between drugs. Many patients are sensitive to both classes of these antibiotics. Physicians should be aware of these cross-reactivities when prescribing medications to patients with a history of anaphylaxis. Oral administration of medicatioins is preferable, since parenteral administration is more likely to produce severe reactions. If a drug is administered parenterally, the patient should remain in the office for 20 to 30 minutes after an injection. Patients at risk for episodes of anaphylaxis (hymenoptera-sensitive subjects, latex allergic patients, and people who have had reactions to commonly administered drugs, etc.) should wear an identifying Medic Alert bracelet or necklace (Medic Alert, 2323 Colorado Avenue, Turlock, California 95382) and should keep an identification card listing their drug allergies in their wallet or purse. They should always carry a self-injection kit of epinephrine. Such patients should avoid taking drugs which would enhance their chances of experiencing another episode of anaphylaxis or complicate the therapy of such an episode. For example, for the reasons noted above, they should avoid beta-adrenergic blocking agents, angiotensin converting enzyme inhibitors, or angiotensin blocking agents. In addition, they should not take drugs which would complicate the therapy. These include monoamine oxidase inhibitors and tricyclic antidepressants. Both of these drugs can make the administration of epinephrine hazardous by increasing its effect and therefore mandating a dosage adjustment. Monoamine oxidase inhibitors do so by preventing the catabolism of epinephrine, whereas tricyclic antidepressants do so by preventing the re-uptake of catechols into peripheral nerve endings. Re-uptake is necessary for the cessation of activity.Pretreatment. Occasionally susceptible patients are required to undergo a procedure or receive a drug that places them at increased risk. Examples are patients who have had previous reactions to radiocontrast media and must receive radiocontrast again, or patients who have had a previous reaction to penicillin and require this antibiotic. Techniques to prevent anaphylaxis in these situations have been divided into pretreatment regimens, provocation challenge regimens, and desensitization. Provocation challenge and desensitization are best handled by an allergist-immunologist, but pretreatment techniques are often used by the generalist. The most common pretreatment protocol was developed for the prevention of repeat reactions to radiocontrast material. This protocol is seen in Table VI. It is also useful for prevention of reactions occurring during plasma exchange, general anesthesia, the administration of fluorescein, and in subjects with cold urticaria who must undergo coronary bypass surgery.Prevention in Idiopathic Anaphylaxis. A puzzling group of patients are those who experience repeated episodes of anaphylaxis without evident cause. The term "idiopathic anaphylaxis" has been coined to refer to these individuals. Many such patients experience as many as 20 to 30 episodes of anaphylaxis during a lifetime. Some of these are life-threatening. The mechanism of production of these events is unknown. Such patients who experience only mild episodes 3 or 4 times a year may need no therapy. However, with more frequent episodes, the daily administration of an H1 and H2 antagonist can be helpful. Oral albuterol or ephedrine can also be useful in combination with the H1 and H2 antagonist. Prednisone has been employed successfully to prevent such episodes. Patients with episodes of this type should be referred to a specialist.<H3>Treatment of the Acute Episode</H3> This discussion will be limited to the office management of anaphylaxis. Table VII lists suggested equipment and medications which should be kept in the office to manage the acute event. This list should not be considered definitive-- each physician should judge the value of its content and include those items judged to be suitable for their practice. The most important principle in the management of the acute episode is rapid recognition. After recognition, the therapy can be classified into those measures which are performed immediately and those which can await further assessment (Table VIII). Assessing the patient's status, with emphasis on the airway and state of consciousness, is the first step. If the airway is compromised, it should be secured immediately. Blood pressure and pulse should be taken concurrently, and a rapid assessment of the patient's weight should be made to allow estimation of medication dosage. The patient should be placed in the supine position with legs elevated. However, because the supine position increases the work of breathing, this maneuver may be reconsidered if the patient is wheezing. In addition, this position can increase intrathoracic pressure, and reduce the pressure gradient between the right atrium and inferior vena cava. This limits the benefit of increased venous return. The most effective positioning must be determined by continual monitoring of the blood pressure and pulse. If the inciting agent was injected, a tourniquet can be placed proximally to the injection site. This tourniquet should be released every 5 minutes for a minimum of 3 minutes during the treatment. This procedure should not be continued for longer than 30 minutes. Oxygen should be started immediately.Epinephrine. Epinephrine, the drug of choice for immediate therapy, should be administered concomitantly with the measures described above. The dose and route of administration depends on the severity of the reaction, the age, and the weight of the patient. The intramuscular or subcutaneous route can be used in almost all cases of office management. In an adult, the dose of epinephrine is 0.3 to 0.5 mL (0.3 to 0.5 mg) of a 1:1000 aqueous solution. The pediatric dose is 0.01 mL/kg of the 1:1000 solution. Epinephrine may be given 2 to 3 times, as needed, at 10 to 15 minute intervals. As stated, the usual routes of administration are intramuscular or subcutaneous; intravenous administration is hazardous, and there is very little indication for it in most circumstances. However, if profound hypotension is present, and there is no response to other therapy, an intravenous dose may be given. The premixed intravenous preparation (1:10,000 solution) is available in a preloaded syringe (Astra). Alternatively, 1.0 mL of the 1:1000 solution can be diluted in 10 mL of saline to create a 1:10,000 concentration. Doses of 0.1 to 0.2 mL can be given by intravenous bolus every 5 to 20 minutes depending upon the response .[12] Of course, lower doses might be necessary for patients with underlying cardiovascular disease. Sublingual injection of epinephrine has been suggested if intravenous access cannot be obtained, because of the rich vascularity in this area. The same dose as for intramuscular use is injected into the posterior 1/3 of the sublingual area. If the agent responsible for the reaction was injected, 0.3 mL (0.1 - 0.3 mL in children) of a 1:1000 aqueous epinephrine solution could be injected into the allergen administration site to slow absorption.Antihistamines. Antihistamines may be dramatically effective in the control of cutaneous symptoms, and can also be helpful in the treatment of hypotension. The combined use of an H1 and H2 antagonist is usually superior to an H1 antagonist alone. An H2 antagonist appears to be superior to an H1 antagonist alone in the therapy of hypotension, flush and urticaria. The H2 antagonist can be administered intravenously. Therefore therapy could include diphenhydramine, 25 to 50 mg given intramuscularly or intravenously (12.5 to 25 mg in children) used together with either ranitidine, 1 mg/kg intravenously or cimetidine, 4 mg/kg intravenously. The H2 antagonist should be administered slowly since rapid administration has been associated with hypotension.Corticosteroids. Corticosteroids do not exert an immediate effect. Nonetheless, there is a clear rationale for their use based on the observation of biphasic and prolonged episodes. The effect of corticosteroids on prolonged inflammatory reactions in the respiratory tract indicate that these agents might also be helpful in protracted episodes of anaphylaxis. The intravenous or intramuscular route of administration can be utilized. The suggested adult dose of hydrocortisone is 100 mg to 1 g intravenously; the pediatric dose is 10 mg to 100 mg intravenously. Methylprednisolone may also be used at a dose of 80 to 125 mg intravenously in adults, and 40 mg intravenously in children. In addition, oral prednisone --60 mg in adults and 30 mg in children-- may be utilized for milder episodes prior to discharging the patient from the office or clinic.Beta-adrenergics. Beta-adrenergic agents have a role only for the treatment of wheeze not responding to epinephrine. The treatment is the same as for asthma. Such agents can be administered by compressor nebulizer or by metered dose inhaler using a spacer.Fluids. Hypotension not responding to epinephrine and H1 and H2 antagonists indicates that increased vasopermeability with fluid shifts, rather than vasodilatation, accounts for the fall in blood pressure. Therefore, restoration of intravenous volume is essential. This is best accomplished by the administration of large volumes of either crystalloids or colloids. In adults, depending on the blood pressure, 1,000 to 2,000 mL of lactated Ringers or normal saline solution should be administered at 5 to 10 mL/kg in the first 5 minutes.[12] Children should be given up to 30 mg/kg of crystalloid solution in the first hour. An alternative to crystalloid is the colloid, hydroxyethyl starch. Adults should receive a rapid infusion of 500 mL, followed by a slow infusion administered at a rate dictated by the response. It should be noted that in patients who have been receiving a beta-adrenergic blocking agent, massive amounts of fluids may be necessary. The total volume of crystalloid required to stabilize the patient could be greater than 5 to 7 liters.Vasopressors. Intravenous vasopressors may be indicated for the management of hypotension. However, as noted, their effectiveness may be diminished because hypotension, due to increased vascular permeability with resultant fluid shifts, frequently occurs in patients who have normal or increased peripheral resistance. Nonetheless, vasoconstrictors should be used in hypotensive patients. The vasopressor of choice is dopamine, administered at a rate of 2 to 20 mcg/kg/minute. This rate should be titrated against the blood pressure response.Atropine and Glucagon. Atropine and glucagon play a special role in patients who experience anaphylaxis while taking a beta-blocking agent because these patients may be unresponsive to adrenergic agents. In addition to massive fluid replacement, patients may require the administration of atropine or glucagon. Atropine is especially useful for managing bradycardia. It does not, however, increase the inotropic function of the heart. The dose is 0.3 to 0.5 mg administered subcutaneously every 10 minutes to a maximum of 2 mg. Glucagon exerts both a positive inotropic and chronotropic effect on the heart. Its action is independent of catecholamine receptors and therefore is not affected by beta-adrenergic blockade. Thus, glucagon is considered by some to be the drug of choice for patients who have been receiving beta-adrenergic blockers. The drug is given intravenously as a bolus dose of 1 to 5 mg followed by an infusion of 5 to 15 mcg/minute, titrated against the clinical response.Oxygen. In any patient with shortness of breath, wheeze, or hypotension, oxygen therapy should be administered. This may be given by nasal cannula at high flow rates of 4 L/min.Other Measures. Because of the possibility of a biphasic or protracted reaction, the patient should be observed subsequent to the cessation of symptoms. There is no established observation period. However, 2 hours seems reasonable for mild to moderate episodes and as long as 24 hours for more severe episodes.Admission. If treatment requires more than subcutaneous epinephrine, an H2 antagonist, or an aerosolized beta-agonist, immediate steps should be taken to transfer the patient to the hospital. Patients needing intravenous epinephrine, fluids and vasopressors such as dopamine cardiovascular monitoring and close observation. Whether these agents are given as life-saving measures in the office or delayed until cardiovascular monitoring can be instituted depends upon the judgement of the physician.<h4>Drugs Mentioned in This Article</h4><ul><li>Aminophylline <li>Atropine <li>Cimetidine <li>Diphenhydramine <li>Ephedrine sulfate <li>Epinephrine <li>Glucagon <li>Lidocaine <li>MAO <li>NSAIDS <li>Prednisone <li>Ranitidine </ul> <a name=""><h3>Table I - Pathophysiologic Classification of Anaphylaxis and Anaphylactoid Reactions</h3></a> <blockquote><center><TABLE BORDER="1"><TR VALIGN="TOP"><TD><ul><li>Anaphylaxis ( IgE-mediated reactions)<ul><li>Foods (such as peanuts, shellfish) <li>Drugs (such as antibiotics, insulin) <li>Insect bites and stings <li>Exercise (possibly) </ul><li>Anaphylactoid Reactions<ul><li>Direct release of mediators from mast cells and basophils <ul><li>Drugs (such as opiates) <li>Physical stimuli (such as cold and sunlight) <li>Exercise <li>Idiopathic </ul><li>Disturbances in arachidonic acid metabolism <ul><li>Aspirin <li>Other NSAIDs </ul><li>Administration of immune aggregates <ul><li>Dextran and albumin (possibly) <li>Intravenous gammaglobulin </ul><li>Cytotoxic <ul><li>Transfusion reactions to cellular elements </ul><li>Miscellaneous and multimediator activity <ul><li>Nonantigen/antibody-mediated complement activation <ul><li>Radiocontrast material <li>Dialysis membranes <li>Protamine reactions (possibly) </ul><li>Activation of contact system <ul><li>Radiocontrast material <li>Dialysis membranes </ul></ul></ul></ul> Ig=immunoglobulin; NSAID=nonsteroidal anti-inflammatory drug </TD></TR></TABLE></center></blockquote> <a name=""><h3>Table II - Mast Cell and Basophil Mediators that May Play A Role in Anaphylaxis and Anaphylactoid Reactions</h3></a> <blockquote><center><TABLE border=1 cellpadding=3><tr valign=bottom align=left><th>Mediator</th><th>Pathophysiologic Event</th><th>Possible Clinical Manifestations</th></tr><tr valign=top><td>Histamine</td><td> * Acts through H1, H2 receptors  * Increased vascular permeability  * Vasodilatation Contraction of smooth muscle  * Exocrine gland secretion  * Irritation sensory nerves</td><td> * Flush, urticaria, angioedema, wheeze, hypotension, abdominal cramps, diarrhea</td></tr><tr valign=top><td>Arachidonic acid metabolites: Lipoxygenase pathway (LTB4, LTC4, LTD4)</td><td> * Chemotaxis  * Contraction airway smooth muscle  * Increased vascular permeability  * Goblet and mucosal gland secretion</td><td> * Possible role in late phase response  * Possible production of wheeze and hypotension</td></tr><tr valign=top><td>Arachidonic acid metabolites: Cyclooxygenase pathway (PG D2, PG F2 a, Thromboxane A2)</td><td> * Peripheral vasodilatation  * Contraction airway smooth muscle  * Coronary vasoconstriction  * Goblet, submucosal gland secretion</td><td> * Flush, hypotension  * Possible production of wheeze  * myocardial ischemia</td></tr><tr valign=top><td>Prostaglandin generating factor of anaphylaxis</td><td>Formation of arachidonic acid metabolites of both cyclooxygenase and lipoxygenase pathways</td><td>Same as arachidonic acid metabolites above</td></tr><tr valign=top><td>Platelet activating factor</td><td> * Contraction airway smooth muscle  * Vascular permeability</td><td>Wheeze, hypotension</td></tr><tr valign=top><td>Eosinophil and neutrophil chemotactic factors</td><td>Infiltration of and activation of eosinophils and neutrophils</td><td>Unclear - theoretically could prolong and intensify reaction, producing late phase reaction</td></tr><tr valign=top><td>Tryptase</td><td> * May activate complement by cleavage C3 to C3a  * Cleaves fibrinogen  * Possibly has kallikrein activity</td><td>Unclear - may recruit other pathways of inflammation</td></tr></table></center></blockquote> <a name=""><h3>Table III - Involvement of Histamine Receptors in Anaphylaxis and Anaphylactoid Reactions</h3></a> <blockquote><center><TABLE BORDER="1"><TR VALIGN="TOP"><TD><ul><li>H1 receptor-mediated effects<ul><li>Vascular permeability <li>Smooth muscle contraction <li>Vasodilatation <ul><li>Endothelial cell relaxing factor (nitric oxide) <li>Direct effect </ul><li>Cardiac effects <ul><li>Increased rate of depolarization of sinoatrial node <li>Coronary artery vasospasm </ul><li>Stimulation of nerve endings <ul><li>Neuropeptide release <li>Pruritus <li>Vagal irritant receptors </ul><li>Increased mucous gland secretion (viscosity) </ul><li>H2 receptor-mediated effects<ul><li>Cardiac effects <ul><li>Positive inotropic effects <li>Positive chronotropic effects <li>Decreased fibrillation threshold </ul><li>Vasodilatation <li>Mucus glycoprotein secretion from goblet cells and bronchial glands <li>Requires both H1 and H2 receptors for maximum effect <li>Vasodilatation <ul><li>Hypotension <li>Flush <li>Headache </ul><li>Increased mucous gland secretion (amount) </ul></ul></TD></TR></TABLE></center></blockquote> <a name=""><h3>Table IV - Signs and Symptoms of Anaphylaxis Listed in Order of Frequency</h3></a> <blockquote><center><TABLE BORDER="1"><TR VALIGN="TOP"><TD><ul><li>Urticaria and angioedema <li>Dyspnea, wheeze <li>Dizziness, syncope, hypotension <li>Nausea, vomiting, diarrhea, cramping abdominal pain <li>Flush <li>Upper airway edema <li>Headache <li>Rhinitis <li>Substernal pain <li>Itch without rash <li>Seizure </ul></TD></TR></TABLE></center></blockquote> <a name=""><h3>Table V - Differential Diagnosis of Anaphylaxis and Anaphylactoid Reactions</h3></a> <blockquote><center><TABLE BORDER="1"><TR VALIGN="TOP"><TD><ul><li>Vasodepressor reactions <li>Other forms of shock <ul><li>Hemorrhagic <li>Cardiogenic <li>Endotoxic </ul><li>Restaurant syndromes <ul><li>Monosodium glutamate <li>Sulfites <li>Saurine (scombroidosis) </ul><li>Flush syndromes <ul><li>Carcinoid <li>Postmenopausal </ul><li>Chlorpropamide/ alcohol <li>Medullary carcinoma thyroid <ul><li>Autonomic epilepsy <li>Idiopathic </ul><li>Excess endogenous production of histamine syndromes <ul><li>Systemic mastocytosis <li>Urticaria pigmentosa <li>Basophilic leukemia <li>Acute promyelocytic leukemia (tretinoin treatment) <li>Hydatid cyst </ul><li>Nonorganic disease <ul><li>Panic attacks <li>Munchausen's stridor <li>Vocal chord dysfunction syndrome <li>Globus hystericus </ul><li>Hyperimmunoglobulin E, urticaria syndrome <li>Neurologic (seizure, stroke) <li>Pseudoanaphylaxis <ul><li>"Red man syndrome" (from vancomycin) </ul><li>Miscellaneous conditions <ul><li>Hereditary angioedema <li>Progesterone anaphylaxis <li>Urticarial vasculitis <li>Pheochromocytoma </ul></ul></TD></TR></TABLE></center></blockquote> <a name=""><h3>Table VI - Prevention of Anaphylactic Reactions to Radiocontrast and Other Agents</h3></a> <blockquote><center><ul><li>Document the need for the study <li>Obtain informed consent <li>Pretreat with: <TABLE border=1 cellpadding=3><tr valign=bottom align=left><th>Drug</th><th>Dose</th><th>Route</th><th>Time (hours before procedure)</th></tr><tr><td>Prednisone</td><td> 50 mg </td><td>oral</td><td>13, 7, and 1 </td></tr><tr><td>Diphenhydramine</td><td>50 mg</td><td>intramuscular</td><td>1</td></tr><tr><td>Ephedrine sulfate*</td><td>25 mg</td><td>oral</td><td>1</td></tr></table><li>Optional: <TABLE border=1 cellpadding=3><tr valign=bottom align=left><th>Drug</th><th>Dose</th><th>Route</th><th>Time (hours before procedure)</th></tr><tr><td>Cimetidine or Ranitidine</td><td>300mg</td><td>oral</td><td>2-3</td></tr></table><li>Use a low-osmolar radiocontrast agent in cases of radiocontrast readministration <li>Discontinue, if possible, beta-adrenergic blocking agents, ACE inhibitors, angiotensin blockers, MAO inhibitors, and tricyclic antidepressants </ul><TABLE><tr valign=top><td>*</td><td>When not contraindicated because of cardiovascular disease.</td></tr><tr><td colspan=2>ACE=angiotensin converting enzyme; MAO= monoamine oxidase</td></tr></table></center></blockquote> <a name=""><h3>Table VII - Equipment and Medication for Therapy of Anaphylaxis in Office</h3></a> <blockquote><center><TABLE BORDER="1"><TR VALIGN="TOP"><TD><ul><li>Primary<ol type=a><li>Tourniquet <li>1 mL & 5 mL disposable syringes <li>Oxygen tank and mask/nasal prongs <li>Epinephrine solution (aqueous) 1:1000 (1 cc amps and multidose vials) <li>Epinephrine solution (aqueous) 1:10,000 (commercially available preloaded in a syringe) <li>Diphenhydramine injectable <li>Ranitidine or cimetidine injectable <li>Injectable corticosteroids <li>Ambu bag, oral airway, laryngoscope, endotracheal tube, No. 12 needle <li>Intravenous set-up with large bore catheter <li>IV fluids, 2000 cc crystalloid, 1000 cc hydroxyethyl starch <li>Aerosol b2 bronchodilator and compressor nebulizer <li>Glucagon <li>Electrocardiogram <li>Normal saline 10 cc vial for epinephrine dilution </ol><li>Supporting<ol type=a><li>Suction apparatus <li>Dopamine <li>Sodium bicarbonate <li>Aminophylline <li>Atropine <li>IV "set-up" with needles, tape and tubing <li>Non-latex gloves </ol><li>Optional<ol type=a><li>Defibrillator <li>Calcium gluconate <li>Neuroleptics for seizures <li>Lidocaine </ol></ul></TD></TR></TABLE></center></blockquote> <a name=""><h3>Table VIII - Anaphylaxis</h3></a> <blockquote><center><TABLE BORDER="1"><TR VALIGN="TOP"><TD><ul><li>Immediate Action<ul><li>Assessment <ul><li>Check airway and secure if needed. <li>Rapidly assess level of consciousness <li>Assess vital signs </ul></ul><li>Treatment<ul><li>Give epinephrine <ul><li>Place patient in the supine position with legs elevated <li>Give oxygen <li>If the antigen (or other causal agent) has been injected, place a tourniquet proximal to the injection site </ul></ul><li>Evaluation-dependent options<ul><li>Peripheral intravenous fluids <li>H1 and H2 antagonist <li>Vasopressors <li>Corticosteroids <li>Glucagon or atropine <li>Electrocardiographic monitoring <li>Hospitalization </ul></ul></TD></TR></TABLE></center></blockquote> <ol><li>Orange RP, Donsky GJ: Anaphylaxis, in Middleton E, Reed CE, Ellis EF (eds): Allergy Principles and Practice. St. Louis, Mosby, 1978, p. 564. <li>Bresser H, Sandner C, Rakoski J: Anaphylactic Emergencies in Munich. J Allergy Clin Immunology 95:368, 1995. Abstract. <li>Lieberman P: Specific and Idiopathic Anaphylaxis: Pathophysiology and Treatment, Allergy, Asthma and Immunology from Infancy to Adulthood--3rd Edition, Edited by Bierman W, Parlman D, Sharpiro G, Busse W (W.B.Saunders Company), 1996, pp 297-320. <li>Lieberman P: Difficult Allergic Drug Reactions, Immunology and Allergy Clinics of North America. Kemp (ed), W. B. Saunders Company 11 (1), February 1991. <li>Fisher M: Clinical observations on the pathophysiology and implications for treatment, in Vincent JL (ed): Update in Intensive Care and Emergency Medicine. New York, Springer-Verlag, 1989, pp 309-16. <li>Hanashiro PK, Weil MH: Anaphylactic shock in man; Report of two cases with detailed hemodynamic and metabolic studies. Arch Intern Med 1967:119-129. <li>Fahmy NR: Hemodynamics, plasma histamine and catecholamine concentrations during an anaphylactoid reaction to morphine. Anesthesiology 55:329-331, 1981. <li>Hermann K, Ring J: Hymenoptera venom anaphylaxis: May decreased levels of angiotensin peptides play a role? Clin Exp Allergy 20:569-570, 1990. <li>Soreide E, Harboe SL: Severe anaphylactic reactions outside hospital: Etiology, symptoms and treatment. Acta Anaesthesiol Scand 32:339-342, 1988. <li>Settipane GA: The restaurant syndromes. Arch Intern Med 21:29-30, 1986. <li>Patterson R, Schatz M: Factitious allergic emergencies: Anaphylaxis and laryngeal 'edema'. J Allergy Clin Immunol 56:152-159, 1975. <li>Levy JH, Levi R: Diagnosis and treatment of anaphylactic/anaphylactoid reactions, in Assem E-SK (ed): Allergic Reactions to Anaesthetics. Clinical and Basic Aspects. Monogr Allergy. Basel, Karger, 1992, Vol 30, pp. 130-144. </ol> Related other Web sites: <ul><LI><a href="http://www.rxmed.com/illnesses/anaphylaxis.html">Anaphylaxis.</a> Patient information on the causes, prevention, diagnosis and treatment of anaphylaxis. Provided by RxMed. </UL>