Navigating the Updated Anaphylaxis Parameters

Anaphylaxis, an acute and potentially lethal multi-system clinical syndrome resulting from the sudden, systemic degranulation of mast cells and basophils, occurs in a variety of clinical scenarios and is almost unavoidable inmedical practice. Healthcare professionalsmust be able to recognize its features, treat an episode promptly and appropriately, and be able to provide recommendations to prevent future episodes. Epinephrine, administered immediately, is the drug of choice for acute anaphylaxis. The discussion provides an overview of one set of evidence-based and consensus parameters for the diagnosis and management of anaphylaxis.

W ith the clear objective of improving the quality of patient care through the provision of evidencebased and consensus guidelines for anaphylaxis, ''The Diagnosis and Management of Anaphylaxis: An Updated Practice Parameter'' was developed by the Joint Task Force on Practice Parameters, 1 which represents the American Academy of Allergy, Asthma and Immunology (AAAAI); the American College of Allergy, Asthma and Immunology (ACAAI); and the Joint Council of Allergy, Asthma and Immunology. This document updates and expands on its 1998 predecessor. 2 Because this effort involved many contributors, no single individual, including those who served on the Joint Task Force, is authorized to provide an official AAAAI or ACAAI interpretation of these practice parameters. The diagnosis and management of anaphylactic reactions must be individualized on the basis of unique features in particular patients.
In keeping with this spirit, the following discussion focuses on material deemed to be substantively updated or changed from the 1998 parameters. Any discussion that may depart from consensus or reflect personal opinion is clearly designated.

Background
Anaphylaxis is not a reportable disease, and both its morbidity and mortality are probably underestimated. A variety of statistics on the epidemiology of anaphylaxis have been published, but the lifetime risk per person in the United States and Canada is presumed to be 1 to 3%, with a mortality rate of 1%. [3][4][5][6][7] There is no universally accepted definition of anaphylaxis. Three proposed consensus definitions are presented. The World Allergy Organization, composed of 39 countries, proposed that older, traditional terminology, anaphylactic and anaphylactoid, be discarded in favour of immunologic and nonimmunologic anaphylaxis. 8 The Joint Task Force on Practice Parameters states, ''Anaphylaxis is an acute lifethreatening reaction that results from the sudden systemic release of mast cells and basophil mediators. It has varied clinical presentations, but respiratory compromise and cardiovascular collapse cause the most concern because they are the most frequent causes of anaphylactic fatalities.'' 1 More recently, the US National Institute of Allergy and Infectious Disease and the Food Allergy and Anaphylaxis Network (Chantilly, VA) convened two symposia, during which an international and interdisciplinary group of representatives and experts from 13 professional, government, and lay organizations attempted, among other tasks, to establish clinical criteria that would increase diagnostic precision in anaphylaxis. 9,10 The working definition pro-posed is the following: ''Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death.'' Anaphylaxis was considered to be highly likely if any one of the following was present: (1) acute onset (minutes to hours) with involvement of skin, mucosa, or both and at least one of the following: respiratory compromise, hypotension, or endorgan dysfunction; (2) two or more of the following that occur rapidly after exposure to a likely allergen for that patient (minutes to hours): involvement of skin or mucosa, respiratory compromise, hypotension or associated symptoms, persistent gastrointestinal symptoms; (3) hypotension after exposure to a known allergen for that patient (minutes to hours): age-specific low systolic blood pressure or greater than 30% decline from that individual's baseline.
Symposium participants believed that the presence of any one of the three criteria likely would identify anaphylaxis accurately in more than 95% of circumstances, but they agreed that validation by prospective multicentre clinical survey is necessary. 10

Clinical Manifestations of Anaphylaxis
In addition to the criteria included in the working definition, anaphylaxis might affect mentation (hypoxemia might cause acute impairment), and some patients might experience rhinitis, headache, uterine cramps, or a feeling of impending doom. Urticaria and angioedema are the most common manifestations (more than 90% in retrospective series) [11][12][13][14] but might be delayed or absent in rapidly progressive anaphylaxis. Urticaria and angioedema might be part of the continuum of anaphylaxis but do not constitute anaphylaxis if they are present in the absence of other physical signs and symptoms suggestive of the diagnosis. 1 Respiratory symptoms are the next most common manifestations, followed by dizziness, unconsciousness, and gastrointestinal symptoms. The more rapidly anaphylaxis occurs after exposure to an offending stimulus, the more likely the reaction is to be severe and potentially life-threatening. 15,16 Anaphylaxis often produces signs and symptoms within 5 to 30 minutes, but reactions sometimes may not develop for several hours. The response to anaphylaxis by a patient's intrinsic compensatory mechanisms (ie, endogenous catecholamines, angiotensin) also influences the extent of clinical manifestations and, when adequate, may be lifesaving independent of medical intervention.

Recurrent Anaphylaxis
Depending on the report, recurrent (biphasic) anaphylaxis occurs in up to 20% of patients who experience anaphylaxis. 11,[17][18][19][20][21][22] Signs and symptoms experienced during the recurrent phase of anaphylaxis may be equivalent to or worse than those observed in the initial reaction and may occur up to 38 hours after apparent remission. 22 Thus, it may be necessary to monitor patients 24 hours or more after apparent recovery from the initial phase. The updated parameters recommend that observation periods should be individualized and based on such factors as comorbid conditions and distance from the patient's home to the closest emergency facility, particularly since there are no reliable predictors of recurrent anaphylaxis on the basis of initial clinical presentation. 1

Diagnosis of Anaphylaxis
Anaphylaxis remains a clinical diagnosis based on probability and pattern recognition. No evaluation can conclusively prove causation of anaphylaxis without directly challenging the patient with the suspected agent, which is generally contraindicated owing to ethical and safety concerns. Cause and effect may often be demonstrated historically in patients who experience objective findings of anaphylaxis after inadvertent re-exposure to the offending agent. Virtually any agent capable of activating mast cells or basophils may potentially precipitate anaphylaxis. The most common identifiable causes of anaphylaxis are foods, medications, insect stings, and immunotherapy injections. 4,[23][24][25] Anaphylaxis to peanuts and/or tree nuts causes the greatest concern because of its life-threatening severity, especially in patients with asthma, and the tendency for patients to develop lifelong allergic responsiveness to these foods.
Idiopathic anaphylaxis, anaphylaxis with no identifiable cause, has accounted for about one-third of cases in most retrospective studies of anaphylaxis. 4,11,23 However, of 601 patients evaluated over two decades in a universityaffiliated practice (the largest retrospective series), 356 subjects (59%) were deemed to have idiopathic anaphylaxis. 14 Idiopathic anaphylaxis remains a diagnosis of exclusion, however. Serial histories and diagnostic tests for foods, spices, and vegetable gums occasionally identify a specific culprit in patients previously presumed to have idiopathic anaphylaxis. 24

Differential Diagnosis
Several systemic disorders share clinical features with anaphylaxis. The vasodepressor (vasovagal) reaction probably is the condition most commonly confused with anaphylactic reactions. In vasodepressor reactions, however, Kemp, Navigating the Updated Anaphylaxis Parameters urticaria are absent, dyspnea is generally absent, the blood pressure is usually normal or elevated, and the skin is typically cool and pale. Tachycardia is the rule in anaphylaxis. Bradycardia may be under-recognized in anaphylaxis, however. Brown and colleagues conducted sting challenges in 19 patients known to be allergic to jack jumper ants (Myrmecia). 26 All eight patients who became hypotensive developed bradycardia after an initial tachycardia.
Several conditions can cause abrupt and dramatic patient collapse and potentially be confused with anaphylaxis. Among conditions to consider are systemic mast cell disorders, myocardial dysfunction, pulmonary embolism, foreign-body aspiration (especially in children), acute poisoning, hypoglycemia, and seizure disorder. Specific signs and symptoms of anaphylaxis can present singly in other disorders. Examples are urticaria-angioedema (in the absence of other signs and symptoms suggestive of anaphylaxis), hereditary angioedema, asthma, and acute anxiety (eg, hyperventilation syndrome or panic attack). Postprandial syndromes (eg, scombroidosis), ''flushing syndromes'' (eg, metastatic carcinoid), and psychiatric disorders that can mimic anaphylaxis can also contribute to diagnostic confusion. 1

Role of Diagnostic Testing
Allergen-specific immunoglobulin E diagnostic skin testing may support a specific cause for anaphylaxis in some circumstances in which the patient has a compatible history (eg, venom or penicillin allergy). However, the immunochemistry of most drugs and biologic agents is not well defined, and reliable in vivo or in vitro testing is unavailable for most agents. 27 Measurement of serum markers of mast cell activation and degranulation may be useful to confirm anaphylaxis in equivocal cases. Tryptase is the only protein that is concentrated selectively in the secretory granules of all human mast cells. Its plasma levels during mast cell degranulation correlate with the clinical severity of anaphylaxis. 28 Since b-tryptase is stored in the secretory granules, its release may be more specific for mast cell activation than a-protryptase, which is secreted constitutively. 29 However, tryptase levels may not be elevated in all forms of anaphylaxis (eg, it is frequently normal in foodassociated anaphylaxis). 18,30 Plasma histamine levels become elevated within 5 to 10 minutes after mast cell activation but return to baseline levels after 30 to 60 minutes. Histamine and tryptase elevations do not necessarily correlate. In an emergency department study, elevated histamine levels were observed in 42 of 97 patients, but only 20 also exhibited increased tryptase levels. 30 Histamine levels correlate with the severity and persistence of cardiopulmonary manifestations but do not correlate with the development of urticaria during anaphylaxis. 30,31 Gastrointestinal signs and symptoms in anaphylaxis also have a greater association with histamine than with tryptase elevations. 30 The ratio of total tryptase (alpha + beta) to beta helps distinguish anaphylaxis from systemic mastocytosis. A ratio greater than 20:1 supports mastocytosis, whereas a ratio less than 10 supports anaphylaxis from another source. 32

Maintaining the Professional Edge through Anaphylaxis Preparedness
A suggested protocol to deal with anaphylactic episodes is available for reference, and appropriate equipment is available to treat the episode. A sequential approach to management is outlined in Table 1, and a sample treatment flowsheet is presented in Figure 1. It is important to stress that these steps are subject to physician discretion and that variations in sequence and performance rely on clinical judgment.
When a patient should be transferred to an emergency facility depends on the skill, experience, and clinical decision-making of the individual clinician. Ready access to telephone numbers for rescue squads or ambulance services may be helpful.
Both clinicians and office staff should maintain clinical proficiency in anaphylaxis management.
The emergency kit should be up-to-date and complete. Figure 2 provides a sample checklist to track the supplies needed to treat anaphylaxis and expiration dates for medications or fluids. Not all items need to be present in each office. Everyone directly involved in patient care should easily be able to locate necessary supplies, rapidly assemble fluids for intravenous administration, etc.

Acute Management of Anaphylaxis
In the management of anaphylaxis, judicious use of epinephrine and the maintenance of adequate oxygenation and effective circulatory volume are the most important considerations. Assessment and maintenance of airway, breathing, circulation, and mentation are essential, initial management steps. Altered mentation may reflect underlying hypoxia. Measurement of peak expiratory flow rate and pulse oximetry, where appropriate, may be useful to guide therapy. Patients are monitored continuously to facilitate prompt detection of any treatment complications.
The recumbent position is strongly recommended. In a retrospective review of prehospital anaphylactic fatalities in the United Kingdom, the postural history was known for 10 individuals. 33 Four of the 10 were associated with assumption of an upright or sitting posture and postmortem findings consistent with ''empty heart'' and pulseless electrical activity.

Epinephrine
Epinephrine is the treatment of choice for acute anaphylaxis. 1,34-37 All subsequent therapeutic interventions depend on the initial response to epinephrine and the severity of the reaction. Development of toxicity or inadequate response to epinephrine injections indicates that additional therapeutic modalities are necessary. There is no absolute contraindication to epinephrine administration in anaphylaxis. 1,38,39 The a-adrenergic effect of epinephrine reverses peripheral vasodilation, which alleviates hypotension and also reduces angioedema and urticaria. It may also minimize further absorption of antigen from a sting or injection. The b-adrenergic properties of epinephrine increase myocardial output and contractility, cause bronchodilation, and suppress further mediator release from mast cells and basophils. 40 Fatalities during witnessed anaphylaxis usually result from delayed administration of epinephrine and from severe respiratory and/or cardiovascular complications. In a retrospective review of six fatal and seven nonfatal episodes of food-induced anaphylaxis in children and adolescents, all patients who survived had received epinephrine before or within 5 minutes of developing severe respiratory symptoms. None of the patients with fatal attacks had received epinephrine prior to the onset of severe respiratory  Adapted from Lieberman P et al. 1 Kemp, Navigating the Updated Anaphylaxis Parameters symptoms. 18 Analysis of data from a national case registry of fatal food anaphylaxis in the United States indicates that few individuals (3 of 32) had epinephrine syringes available at the time of fatal reaction. 41 Similarly, Pumphrey determined that epinephrine was administered in 62% of the fatal anaphylactic reactions that he reviewed, only 14% prior to cardiac arrest. 42 Aqueous epinephrine 1:1,000 dilution, 0.2 to 0.5 mL (0.01 mg/kg in children; maximum dose 0.3 mg) administered intramuscularly or subcutaneously every 5 minutes, as necessary, should be used to control symptoms and sustain or increase blood pressure. The 5-minute interval between injections can be liberalized, if the clinician deems it appropriate, to permit more frequent injections. 1 Comparisons of intramuscular injections with subcutaneous injections have not been done during acute anaphylaxis. However, absorption is complete and more rapid (mean maximum plasma epinephrine concentration of 2,136 6 351 pg/mL at a mean time of 8 6 2 minutes) in asymptomatic children who receive epinephrine intramus-cularly in the thigh with an autoinjector. 43 Intramuscular injection into the thigh (vastus lateralis) in asymptomatic adults is also superior to intramuscular or subcutaneous injection into the arm (deltoid). 44 Spring-loaded, automatic epinephrine syringes administered intramuscularly and intramuscular epinephrine injections through a tuberculin syringe into the thigh in adults and children not experiencing anaphylaxis provide dose-equivalent plasma levels. 43,44 Similar studies comparing intramuscular injections with subcutaneous injections in the thigh have not yet been done, however.
The UK consensus panel on emergency guidelines and the international consensus guidelines for emergency cardiovascular care both recommend intramuscular epinephrine injections for anaphylaxis. [35][36][37] These guidelines also propose that epinephrine can be repeated every 5 minutes, as clinically needed, in both adults and children, 35,36 although the updated cardiovascular care guidelines (published after the updated anaphylaxis parameter) have modified the recommended frequency of intramuscular injections to every 15 to 20 minutes, as needed. 37 The guidelines provide no explanation or reference on which this change is based.
No established dosage or regimen for intravenous epinephrine in anaphylaxis is recognized (see the updated parameter 1 for sample infusion protocols). Because of the risk of potentially lethal arrhythmias, epinephrine should be administered intravenously only during cardiac arrest or to profoundly hypotensive patients who have failed to respond to intravenous volume replacement and multiple epinephrine injections in the thigh. Continuous hemodynamic monitoring is essential where it is available (eg, emergency department or intensive care facility). 45 However, the updated anaphylaxis parameter states that intravenous administration of epinephrine should not be precluded in a special circumstance in which the clinician deems its administration is essential after failure of several epinephrine injections and no such monitoring is available. Under such an extreme scenario, monitoring by available means (eg, electrocardiographic monitoring and every-minute pulse and blood pressure measurements) should be conducted. 1

Oxygen and Airway Adjuncts
Oxygen should be administered to patients with anaphylaxis who have pre-existing hypoxemia or myocardial dysfunction, have prolonged reactions, require multiple doses of epinephrine, or receive inhaled b 2 agonists. Continuous pulse oximetry or arterial blood gas determination (where available) should guide oxygen therapy if development of hypoxemia is a concern.
Given that adequate oxygenation also depends on ventilation, it may be necessary to establish and maintain an airway and/or provide ventilatory assistance. One of the easiest, quickest, and most effective ways to support ventilation involves a one-way valve face mask with oxygen inlet port (eg, Pocket-Mask [Laerdal Medical Corporation, Gatesville, TX] or similar device). Oxygen saturations comparable to endotracheal intubation have been demonstrated in patients who require artificial ventilation by mouth-to-mask technique with oxygen attached to the inlet port. Patients with adequate, spontaneous respirations may breathe through the mask.
Ambubags of less than 700 mL are discouraged in adults in the absence of an endotracheal tube since ventilated volume will not overcome the 150 to 200 mL of anatomic dead space to provide effective tidal volume. Recommended tidal volume during artificial ventilation is 6 to 7 mL/kg over 1.5 to 2 seconds. (Ambubags may be used in children provided that the reservoir volume of the device is sufficient. Avoid overinflation.) Endotracheal intubation or cricothyroidotomy may be considered where appropriate and provided that clinicians are adequately trained and proficient in this procedure.
The rate of administered oxygen depends on the device used and clinical response. A nasal cannula will deliver an oxygen concentration of 25 to 40% with a 4 to 6 L/min flow. A simple plastic face mask will deliver an oxygen concentration of 50 to 60% with an 8 to 12 L/min flow. By comparison, the one-way valve face mask with oxygen inlet valve permits ventilation with up to 50% oxygen at a flow rate of 10 L/min and approaching 90 to 100% if the opening of the mask is periodically occluded by the rescuer's tongue during mouth-to-mask ventilation.

Special Considerations for b-Adrenergic Antagonists
Patients taking b-adrenergic antagonists may be more likely to experience severe anaphylactic reactions characterized by paradoxical bradycardia, profound hypotension, and severe bronchospasm. Use of selective b 1antagonists does not reduce the risk of anaphylaxis since both b 1 and b 2 antagonists may inhibit the b-adrenergic receptor. [46][47][48] Epinephrine administered during anaphylaxis to patients taking b-adrenergic antagonists may be ineffective. In this situation, both glucagon administration and isotonic volume expansion (multiple liters, in some circumstances) may be necessary. Glucagon bypasses the b-adrenergic receptor and may reverse refractory bronchospasm and hypotension during anaphylaxis in patients on b-adrenergic antagonists by activating adenyl cyclase directly. [49][50][51] The recommended dosage for glucagon is 1 to 5 mg (20-30 mg/kg [maximum 1 mg] in children) administered intravenously over 5 minutes and followed by an infusion, 5 to 15 mg/min, titrated to clinical response. Protection of the airway against aspiration is important in severely drowsy or obtunded patients since glucagon may cause emesis. Placement in the lateral recumbent position may be sufficient for many of these patients.

Fluid Resuscitation
The patient whose hypotension persists despite epinephrine injections should receive intravenous crystalloid solutions or colloid volume expanders. (See Table 2 for age-dependent criteria for hypotension, as defined by international consensus guidelines for pediatric advanced life support.) Increased vascular permeability in anaphylaxis may permit transfer of 50% of the intravascular fluid into the extravascular space within 10 minutes. 52,53 Crystalloid volumes (eg, saline) of up to 7 L may be necessary. One to 2 L of normal saline should be administered to adults at a rate of 5 to 10 mL/kg in the first 5 minutes. Normal saline is preferred since lactated Ringer's may potentially contribute to metabolic acidosis and dextrose is rapidly extravasated from the intravascular circulation to the interstitial tissues. Large volumes are often required, but it may be appropriate to monitor patients with underlying congestive heart failure or chronic renal disease for signs of volume overload once the effective fluid deficit is replaced. Children should receive up to 30 mL/kg in the first hour. Adults receiving colloid solution should receive 500 mL rapidly, followed by slow infusion. 24 For intravenous volume replacement, one generally should insert the largest catheter needle possible into the largest secure peripheral vein available and use an administration set that permits rapid infusion of fluids. For example, large-bore cannula needles (14-16 gauge) and standard infusion sets (10-15 drops/mL) are preferred in adults. Intraosseous vascular access may be established in infants and children if urgent access is needed and reliable venous access cannot be achieved rapidly. The microdrop infusion set (60 drops/mL) is appropriate for keep-open intravenous lines and infusions of medications (eg, epinephrine or a vasopressor), but it does not permit rapid volume replacement.

Vasopressors
Vasopressors, such as dopamine (400 mg in 500 mL of 5% dextrose) administered at 2 to 20 mg/kg/min and titrated to maintain systolic blood pressure greater than 90 mm Hg, should be administered to increase cardiac output if epinephrine injections and volume expansion fail to alleviate hypotension. (See Table 2 for pediatric dosing of dopamine.) Dopamine increases the force and rate of myocardial contractions while maintaining or enhancing renal and mesenteric blood flow. In contrast, norepinephrine constricts renal arteries. Vasopressors would not be expected to work as well in those patients who have already experienced maximal vasoconstriction from their internal compensatory response to anaphylaxis. A critical care specialist may need to be consulted for any patient with intractable hypotension.

Role of Antihistamines and Corticosteroids
Antihistamines (H 1 and H 2 antagonists) support the treatment of anaphylaxis. However, these agents act much more slowly than epinephrine and should never be administered alone as treatment for anaphylaxis. Thus, antihistamines should be considered second-line treatment. 1 Several reports on the treatment of anaphylaxis have demonstrated that a combination of H 1 and H 2 antagonists is more effective than treatment with an H 1 antagonist alone. 24 Systemic corticosteroids have no role in the acute management of anaphylaxis since even intravenous administration of these agents may have no effect for 4 to 6 hours after administration. Although corticosteroids traditionally have been used in the management of anaphylaxis, their effect has never been evaluated in placebo-controlled trials. Corticosteroids administered during anaphylaxis might provide additional benefit for patients with asthma or other conditions recently treated with corticosteroids. 1

Prevention of Anaphylaxis
Basic principles to reduce the incidence of anaphylaxis and prevent future anaphylactic episodes in high-risk individuals are outlined in Table 3. An allergist-immunologist can provide comprehensive professional advice on these matters.
All patients at high risk of recurrent anaphylaxis should carry epinephrine syringes and know how to administer them. An EpiPen (Dey Laboratories, Napa, CA) is a spring-loaded, pressure-activated syringe with a single 0.3 mg dose (1:1,000 dilution) of epinephrine. It is easy to use and will inject through clothing. An EpiPen Jr., which delivers 0.15 mg (1:2,000 dilution) of epinephrine, is  N Prevention has paramount importance since optimal anaphylaxis treatment still fails some patients. General measures Obtain a thorough history to diagnose life-threatening food or drug allergy Identify cause of anaphylaxis and those individuals at risk of future attacks Provide instruction on proper reading of food and medication labels, where appropriate Avoidance of exposure to antigens and cross-reactive substances Optimal management of asthma and coronary artery disease Implement a waiting period of 20 to 30 min after injections of drugs or other biologic agents Consider a waiting period of 2 h if a patient receives an oral medication in the office he/she has never previously taken Specific measures for high-risk patients Individuals at high risk of anaphylaxis should carry self-injectable syringes of epinephrine at all times and receive instruction in proper use with a placebo trainer MedicAlert or similar warning bracelets or chains Substitute other agents for b-adrenergic antagonists, angiotensin-converting enzyme inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, and certain tricyclic antidepressants whenever possible Slow, supervised administration of agents suspected of causing anaphylaxis, orally if possible Where appropriate, use specific preventive strategies, including pharmacologic prophylaxis, short-term challenge and desensitization, and long-term desensitization