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Epinephrine: The Drug of Choice for AnaphylaxisVA Statement of the World Allergy Organization Stephen F. Kemp, Richard F. Lockey, F. Estelle R. Simons, on behalf of the World Allergy Organization ad hoc Committee on Epinephrine in Anaphylaxis Few controlled clinical trials, and no placebo-controlled Abstract: Anaphylaxis is an acute and potentially lethal multisystem trials, have been performed in anaphylaxis because of the allergic reaction. Most consensus guidelines for the past 30 years nature of the disease.19 Randomization to a nonepinephrine have held that epinephrine is the drug of choice and the first drug that treatment would be unethical because of the preponderance of should be administered in acute anaphylaxis. Some state that properly data showing that expeditious treatment with epinephrine is administered epinephrine has no absolute contraindication in this optimal, if not critical, for survival in many instances.20Y25 The clinical setting. A committee of anaphylaxis experts assembled by the following discussion reviews current evidence for the use of World Allergy Organization has examined the evidence from the epinephrine in anaphylaxis.
medical literature concerning the appropriate use of epinephrine foranaphylaxis. The committee strongly believes that epinephrine is currently underused and often dosed suboptimally to treat anaphy-laxis, is underprescribed for potential future self-administration, that The traditional nomenclature for anaphylaxis reserves most of the reasons proposed to withhold its clinical use are flawed, the term anaphylactic for immunoglobulin E (IgE)Ydependent and that the therapeutic benefits of epinephrine exceed the risk when reactions and the term anaphylactoid for IgE-independent given in appropriate intramuscular doses.
events, which are clinically indistinguishable. The WorldAllergy Organization, a worldwide federation of national and Key Words: anaphylaxis, epinephrine, management, prevention regional allergy and clinical immunology societies andorganizations dedicated to raising awareness and advancing (WAO Journal 2008;S18YS26) excellence in clinical care, education, research, and training inallergy and clinical immunology, recommends that this Epinephrine is the treatment of choice and the first drug terminology be replaced with immunologic (IgE-mediated administered for acute anaphylaxis, as confirmed inter- and non-IgEYmediated [eg, IgG and immune complex nationally by most consensus anaphylaxis guidelines pub- complementYmediated]) and nonimmunologic anaphylaxis.26 lished in the English language over the past 30 years.1Y17 Therefore, in this article, the term anaphylaxis refers to both Therapeutic recommendations for epinephrine use in anaphy- immunologic and nonimmunologic anaphylaxis.
laxis are largely based on clinical pharmacology studies,clinical observation, and animal models.
Anaphylaxis often occurs outside of a medical setting, A literature search of Medline (1966 to present) was for example, after food ingestion or an insect sting, and the conducted using the key words anaphylaxis and epinephrine onset may be sudden and without warning. Severity varies and articles from the personal anaphylaxis file collections of from episode to episode even with an identical stimulus in the the authors were also included. Cross-references were same patient. Recognition and diagnosis of anaphylaxis is accessed when deemed appropriate. References have been sometimes difficult for health care professionals and for categorized by degree of evidence, where possible27 (Fig. 1).
individuals without medical training.18 ANAPHYLAXIS IN PERSPECTIVE Received for publication April 15, 2008; accepted April 17, 2008 Anaphylaxis is an acute and potentially lethal multi- From the World Allergy Organization Ad Hoc Committee on Epinephrine in system allergic reaction in which some or all of the following Anaphylaxis: Richard F. Lockey, MD, Chairman (USA); Stephen F. Kemp, signs and symptoms occur: diffuse erythema, pruritus, MD (USA); Kirsten Beyer, MD (Germany); Constance H. Katelaris, MB,BS, PhD (Australia); Todor A. Popov, MD, PhD (Bulgaria); Mario urticaria and/or angioedema; bronchospasm; laryngeal Sa´nchez-Borges, MD (Venezuela); F. Estelle R. Simons, MD (Canada).
edema; hypotension; cardiac arrhythmias; feeling of impend- Supported by an unrestricted educational grant from Dey Laboratories, Napa, ing doom; unconsciousness and shock. Other earlier or concomitant signs and symptoms can include itchy nose, Acknowledgment: This article was originally published in Allergy. Kemp SF, eyes, pharynx, genitalia, palms, and soles; rhinorrhea; change Lockey RF, Simons FER, on behalf of the World Allergy Organization adhoc Committee on Epinephrine in Anaphylaxis. Epinephrine: the drug of in voice; metallic taste; nausea, vomiting, diarrhea, abdominal choice for anaphylaxis. A statement of the World Allergy Organization cramps, and bloating; lightheadedness; headache; uterine (WAO). Allergy 2008;63:1061Y1070.
cramps; and generalized warmth.
Reprints: Richard F. Lockey, MD, USF Division of Allergy and Clinical The US National Institute of Allergy and Infectious Immunology, 13000 Bruce B. Downs Blvd (VAR 111D), Tampa, FL33612. E-mail: rlockey@health.usf.edu Diseases (Bethesda, Md) and the Food Allergy and Anaphy- Copyright * 2008 by World Allergy Organization laxis Network (Chantilly, Va) convened symposia in 2004 and WAO Journal & July 2008, Supplement 2 Copyright @ 2008 World Allergy Organization. Unauthorized reproduction of this article is prohibited.
WAO Journal & July 2008, Supplement 2 Epinephrine: The Drug of Choice for Anaphylaxis FIGURE 1. Categorization of evidence. Adapted from Shekelle et al.27 2005, during which an international and interdisciplinary not involving vital organs, should be treated immediately and group of representatives and experts from 16 professional, as necessary with appropriate intramuscular doses of epineph- government, and lay organizations attempted, among other rine in an attempt to prevent more severe anaphylaxis from tasks, to establish clinical criteria that would increase diagnostic precision in anaphylaxis.16 The working definition Conversely, symptoms clearly attributable to another proposed is the following: BAnaphylaxis is a serious allergic diagnosis for which the clinical probability is much higher, for reaction that is rapid in onset and may cause death.[ The group example, generalized pruritus, urticaria, and angioedema proposed that anaphylaxis is likely to be present clinically if associated with new-onset acute urticaria and/or angioedema, any one of 3 criteria is satisfied within minutes to hours: (1) or with an exacerbation of chronic urticaria and/or angioe- acute onset of illness with involvement of skin, mucosal dema, do not necessarily have to be treated with epinephrine.
surface, or both, and at least one of the following: respiratory Thus, there are 2 schools of thought as to when compromise, hypotension, or end-organ dysfunction; (2) 2 or epinephrine should be given intramuscularly for anaphylaxis more of the following occur rapidly after exposure to a likely or what appear to be early symptoms of anaphylaxis. One allergen: involvement of skin or mucosal surface, respiratory recommends that epinephrine should be given as described, by compromise, hypotension, or persistent gastrointestinal symp- the US National Institute of Allergy and Infectious Diseases toms; and (3) hypotension develops after exposure to a known and the Food Allergy and Anaphylaxis Network,16 whereas allergen for that patient: age-specific low blood pressure or another group would go even further and recommend that decline of systolic blood pressure of greater than 30% epinephrine should be administered as early as possible after compared with baseline.16 The group concluded that these the onset of the least serious or minor symptoms, particularly criteria Bare likely to capture more than 95% of cases of when the offending agent or allergen is administered anaphylaxis.[ The implication from this definition could be parenterally. Evidence demonstrates that parenteral delivery interpreted to mean that more than just cutaneous and other of the offending allergen or causative agent is associated with even less severe symptoms need to be present before more rapid absorption and potentially catastrophic anaphylaxis epinephrine is administered. However, the Anaphylaxis Work- than the oral route of administration. However, any route of ing Group report also states that, BThere undoubtedly will be administration, oral or parenteral, can cause anaphylaxis and patients who present with symptoms not yet fulfilling the begin with minor symptoms and result in anaphylactic death.
criteria of anaphylaxis yet in whom it would be appropriate to Foods, medications, insect stings, and allergen immu- initiate therapy with epinephrine, such as a patient with a notherapy injections are the most common provoking factors history of near-fatal anaphylaxis to peanut who ingested for anaphylaxis, but it can be induced by any agent capable of peanut and within minutes is experiencing urticaria and producing a sudden degranulation of mast cells or basophils.28 generalized flushing.[ Anaphylaxis caused by diagnostic and therapeutic interven- In summary, anaphylaxis occurs as part of a clinical tions is almost unavoidable in medical practice and occurs in a continuum. It can begin with relatively minor symptoms and variety of clinical scenarios.16 The lifetime individual risk of rapidly progress to a life-threatening respiratory and cardio- anaphylaxis is presumed to be 1% to 3%, with a mortality vascular reaction. Delaying treatment until the development of rate of 1%,28 and the prevalence of anaphylaxis may be multiorgan symptoms, as under the clinical criteria for increasing.29 Therefore, all physicians must be able to diagnosis by the Anaphylaxis Working Group report, may be recognize anaphylaxis, treat it appropriately, and provide risky because the ultimate severity of anaphylaxis is difficult recommendations to prevent future episodes.
or impossible to predict at the time of onset of the episode.
Signs and symptoms of anaphylaxis vary, but cutaneous Therefore, some of the authors and members of the World features (generalized erythema, pruritus, urticaria, and angio- Allergy Organization Ad Hoc Committee on Epinephrine and edema) are the most common overall.28 Reactions may be Anaphylaxis recommend that any symptoms of anaphylaxis, immediate and uniphasic, or they may be delayed in onset, such as generalized pruritus, erythema, urticaria, and angioe- biphasic (recurrent), or protracted. Biphasic anaphylaxis dema alone, and any other systemic symptom including those occurs in 1% to 20% of anaphylaxis, and symptoms may * 2008 World Allergy Organization Copyright @ 2008 World Allergy Organization. Unauthorized reproduction of this article is prohibited.


WAO Journal & July 2008, Supplement 2 FIGURE 2. Adrenergic effects of epinephrine. Adapted from Simons.40 recur 1 hour to 72 hours (most within 8 hours) after apparent The A-adrenergic properties of epinephrine cause bronchodila- resolution of the initial phase.30 The severity of the initial tion, increase myocardial output and contractility, and suppress phase of an anaphylactic reaction is not predictive of further mediator release from mast cells and basophils.41,42 either biphasic or protracted anaphylaxis, although failure to Epinephrine administered in low concentrations (eg, 0.1 Kg/kg) give an adequate dose of epinephrine initially may be paradoxically can produce vasodilation, hypotension, and associated with increased risk of biphasic anaphylaxis.
increased release of inflammatory mediators.39,43 Monitoring of patients for 24 hours or more after apparent Epinephrine administration enhances coronary blood recovery from the initial phase may be necessary in more flow. Two mechanisms are probably responsible: an increased severe cases because life-threatening manifestations of duration of diastole compared with systole and a vasodilator anaphylaxis may recur. Data are limited concerning the effect caused by increased myocardial contractility. These frequency with which 2 or more doses of epinephrine are actions usually offset the vasoconstrictor effects of epinephr- needed to treat anaphylaxis (reports range from 16% to 36%), ine on the coronary arteries.39,44 and multiple cofactors may be involved.31Y33 Rapid achievement of peak plasma and tissue epinephrine Respiratory compromise and cardiovascular collapse levels seems to optimize survival because retrospective human cause most fatalities.28,34 An analysis of 202 anaphylaxis studies demonstrate that delayed administration is associated fatalities occurring in the United Kingdom from 1992 to with poor outcomes.20,21 However, epinephrine administration 2001 ascertained that the interval between initial onset of during anaphylaxis is not always effective, and patients may still food anaphylaxis symptoms and fatal cardiopulmonary die.20Y25 Reasons may be multifactorial and include delayed arrest averaged 25 to 35 minutes, which was longer than for administration, inadequate doses, inappropriate route of admin- insect stings (10Y15 minutes) or for drugs (mean, 5 minutes istration, use of epinephrine that has passed its expiration date, in hospital; 10Y20 minutes prehospital).34 leading to inadvertent administration of an inadequate dose, or an Increased vascular permeability during anaphylaxis can underlying disease, such as poorly controlled asthma, cardiovas- shift up to 35% of intravascular fluid to the extravascular space cular disease, mastocytosis, and perhaps other serious systemic within 10 minutes.35 The intrinsic compensatory response to disorders.40,45 A study done in a canine model also demonstrates anaphylaxis (endogenous epinephrine and other catechola- that achievement of peak epinephrine plasma levels and mines, as well as angiotensin II, endothelin-1, etc) also hemodynamic recovery is not as effective when epinephrine influences the extent of clinical manifestations and, when administration is delayed until hypotension has developed.46 adequate, may be lifesaving independent of medical inter- Epinephrine has a relatively narrow therapeutic window vention, which sometimes contributes to diagnostic and (relative benefit vs risk; Fig. 3). Common pharmacological therapeutic confusion. Because mast cells accumulate at effects that occur at recommended doses via any route of sites of coronary atherosclerotic plaques and IgE antibodies administration include agitation, anxiety, tremulousness, bound to mast cells can trigger mast cell degranulation, some headache, dizziness, pallor, or palpitations.39 Rarely, and investigators have suggested that anaphylaxis may lead to usually associated with overdosage or overly rapid rate of myocardial ischemia by promoting plaque rupture.36,37 intravenous infusion, epinephrine administration might con- Stimulation of the H1 histamine receptor may also produce tribute to or cause myocardial ischemia or infarction,47Y52 coronary artery vasospasm.37,38 pulmonary edema,53,54 prolonged QTc (QTc = QT intervaldivided by the square root of the RR interval [in seconds] of PHARMACOLOGY OF EPINEPHRINE the electrocardiogram) interval,55 ventricular arrhythmias, The pharmacology of epinephrine is reviewed in detail accelerated hypertension, and intracranial hemorrhage in elsewhere (Fig. 2).39,40 At recommended dosages and routes of adults and children alike.41,56 Nonetheless, some patients administration, the >-adrenergic vasoconstrictive effects reverse have survived massive overdoses of epinephrine, with no peripheral vasodilation, which alleviates hypotension and also evidence of myocardial ischemia.57,58 Particularly vulnerable reduces erythema, urticaria, and angioedema. Local injection of populations are those individuals at the extremes of age and epinephrine may also minimize further absorption of antigen from those with hypertension, peripheral vascular disease, ischemic a sting or injection, but this has not been studied systematically.
heart disease, or untreated hyperthyroidism (increased number * 2008 World Allergy Organization Copyright @ 2008 World Allergy Organization. Unauthorized reproduction of this article is prohibited.
WAO Journal & July 2008, Supplement 2 Epinephrine: The Drug of Choice for Anaphylaxis FIGURE 3. Therapeutic window of epinephrine. Adapted from Simons.18 of A-adrenergic receptors in the vasculature of these indivi- oids for intravenous injection; and (10) vasopressors (eg, duals render the myocardium more sensitive to A-adrenergic dopamine or norepinephrine). Glucagon, an automatic defi- effects of epinephrine).59 Certain medications might also brillator, and 1-way valve face mask with oxygen inlet port are increase the risk of adverse events from drug interactions.13,18,42,59 other supplies that some clinicians might find desirable Some medications decrease the effectiveness of endogenous depending on the individual clinical setting.13 catecholamine stores or exogenously administered epinephrine Assessment and maintenance of airway, breathing, (A-adrenergic blockers), interfere with intrinsic compensatory circulation, and mentation are necessary before proceeding to responses to hypotension (angiotensin-converting enzyme inhi- other management steps. Patients are monitored continuously to bitors and possibly angiotensin II receptor blockers), or impede facilitate prompt detection of any clinical changes or treatment epinephrine metabolism and lead to increased plasma and tissue complications. Placement of a patient in the recumbent position concentrations (tricyclic antidepressants and monoamine oxidase with elevation of the lower extremities is strongly recommended inhibitors). The A-adrenergic antagonists and >-adrenergic because management in the sitting or upright position has antagonists can also potentially exaggerate pharmacological contributed to poor outcomes in some patients.34 effects of epinephrine by permitting unopposed >-adrenergic(vasoconstrictor) and A-adrenergic (vasodilator) effects, respec- When to Administer Epinephrine tively. Cocaine and amphetamines sensitize the myocardium to Epinephrine should be administered simultaneously with effects of epinephrine, thus increasing the risk of toxicity.
the above measures.12Y14 By expert consensus based on However, none of these circumstances pose an absolute anecdotal evidence, there is no absolute contraindication to contraindication to epinephrine administration for anaphylaxis.13 epinephrine administration in anaphylaxis.13 It can be adminis-tered in doses appropriate for the severity of the reaction, MANAGEMENT OF ANAPHYLAXIS regardless of the initial signs and symptoms of anaphylaxis. All Physician and other health care professionals who subsequent therapeutic interventions depend on the initial perform procedures or administer medications should have response to epinephrine. Development of toxicity or inadequate available the basic therapeutic agents used to treat anaphy- response to epinephrine injections indicates that additional laxis4,7,13: (1) stethoscope and sphygmomanometer; (2) therapeutic modalities are necessary.13 Table 1 outlines a tourniquets, syringes, hypodermic needles, large-bore needles sequential approach to anaphylaxis treatment. Modalities used (eg, 14- or 16-gauge); (3) injectable aqueous epinephrine in concert with epinephrine are reviewed in detail elsewhere.10Y14 1:1000 (1 mg in 1 mL; physicians are being urged to expressdoses in mass concentration, eg, 1 mg in mL, rather than as Epinephrine Injections ratios, eg, 1:1000, which have been identified as a source of Expert consensus and anecdotal evidence indicate dosing errors with epinephrine and other medications); (4) aqueous epinephrine 1:1000 dilution (1 mg in 1 mL), 0.2 to equipment and supplies for administering supplemental 0.5 mg (0.01 mg/kg in children; maximum dose, 0.3 mg) oxygen; (5) equipment and supplies for administering administered intramuscularly every 5 to 15 minutes or as intravenous fluids; (6) oral or laryngeal mask airway; (7) necessary, depending on the severity of the anaphylaxis, diphenhydramine or similar injectable antihistamine; (8) should be used to control symptoms and sustain or increase ranitidine or other injectable H2 antihistamine; (9) corticoster- blood pressure.12Y14 Efficacy comparisons of intramuscular * 2008 World Allergy Organization Copyright @ 2008 World Allergy Organization. Unauthorized reproduction of this article is prohibited.
WAO Journal & July 2008, Supplement 2 sponsive or severely hypotensive patients who have failed to TABLE 1. Management of Acute Anaphylaxis respond to intravenous volume replacement and several I. Immediate intervention epinephrine injections.13 One group of investigators suggest a. Assessment of airway, breathing, circulation, and adequacy of mentation b. Administer epinephrine intramuscularly every 5 to 15 minutes, in appropriate doses, as necessary, depending on the presenting signs andsymptoms of anaphylaxis, to control signs and symptoms and prevent TABLE 2. Clinical Scenarios for Epinephrine Use Outside of a progression to more severe symptoms, such as respiratory distress, hypotension, shock, and unconsciousness.
For Discussion Purposes II. Possibly appropriate subsequent measures depending on response Clinical Findings Use of Epinephrine? a. Place patient in recumbent position and elevate lower extremities Generalized urticaria develops in a Pro: inject immediately; past b. Establish and maintain airway 28-yr-old fire antYallergic anaphylaxis and current c. Administer oxygen individual stung by ant while findings away from medical playing in the yard. Currently d. Establish venous access receives ant immunotherapy based Con: do not inject immediately; e. Isotonic sodium chloride solution intravenously for fluid replacement on positive skin test response to wait for symptoms involving III. Specific measures to consider after epinephrine injections, fire ant whole body extract but another organ system where appropriate is not yet at maintenance dosage a. Consider epinephrine infusion (6 wk of therapy on conventional buildup schedule).
1 and H2 antihistamines c. Consider nebulized A A 45-yr-old yellow jacketYallergic Pro: inject immediately in view 2 agonist (eg, albuterol [salbutamol]) for bronchospasm resistant to epinephrine farmer has just been stung after of past severe anaphylaxis; low disturbing nest with tractor. History risk of serious side effects from d. Consider systemic corticosteroids of hypotension and rapid syncope in injected epinephrine; some risk e. Consider vasopressor (eg, dopamine) past stings. Currently receives of severe symptoms because he f. Consider glucagon for patient taking A-blocker venom immunotherapy but is not has not reached maintenance g. Consider atropine for symptomatic bradycardia yet at maintenance (last dose was Con: do not inject immediately; 1 mL [L]). No current symptoms.
h. Consider transportation to an emergency department or an intensive wait for symptoms A 17-yr-old individual develops Pro: inject immediately; rapid onset i. For cardiopulmonary arrest during anaphylaxis, high-dose epinephrine paroxysmal sneezing within of symptoms may be associated and prolonged resuscitation efforts are encouraged, if necessary 5 min of receiving allergen with severe anaphylaxis; (see reference for specific details) immunotherapy injection low risk of serious sideeffects from injected epinephrine; Adapted from Lieberman et al.13 antihistamines are second-lineagents in anaphylaxis injections to subcutaneous injections have not been done Con: do not inject immediately; during acute anaphylaxis. However, absorption is complete wait for other symptoms if and more rapid and plasma levels are higher in asymptomatic suspect sneezing could be dueto transient respiratory irritant adults and children who receive epinephrine intramuscularly exposure or seasonal allergy in the anterolateral thigh (vastus lateralis).60,61 In overweight exacerbation if it occurs during and obese individuals, the thickness of the subcutaneous fat pollen season of a pollen-allergic pad may preclude intramuscular access.62Y64 Table 2 provides some examples of clinical scenarios where the pros and cons A 7-yr-old child with mild Pro: inject immediately; history is of epinephrine use might be weighed.65,66 persistent asthma and clinical strongly suggestive of past history of peanut allergy anaphylaxis; safety of cookie Epinephrine autoinjectors, which are easy to use and (wheeze, hives that Bget is uncertain; signs and severity will inject through clothing, are currently available in 2 better after vomiting[) of anaphylaxis can vary from fixed doses: 0.15 mg and 0.3 mg. The potential exists for experiences sudden cough and episode to episode in the same overdosage in infants receiving the 0.15 mg, overdosage in wheeze while playing outside individual; delayed treatment or 15 min after eating a cookie in treating anaphylaxis with some small children receiving the 0.3 mg dose, and for school cafeteria; has no other salbutamol (albuterol) alone underdosage in many adolescents receiving the 0.15 mg symptoms; has albuterol could have adverse outcome; dose.17,40 The relative benefits and risks of dosage might vary metered-dose inhaler and low risk of serious side effects with each individual, but autoinjectors with 0.15 mg of epinephrine autoinjector available from injected epinephrine epinephrine are recommended for otherwise healthy children Con: do not inject immediately; who weigh 10 to 25 kg (22Y55 lb) and autoinjectors with for possible asthma (eg,exercise-induced or pollen 0.3 mg of epinephrine for children who weigh approxi- exposure), assess response mately 25 kg (55 lb) or more.17,40 Providing parents with to salbutamol first.
an epinephrine ampule, syringe, and needle is not an ap- Anaphylaxis occurs as part of a continuum, and delaying treatment until multiorgan propriate option unless autoinjectors are not available for dysfunction is present is risky. The recommendations in this table apply regardless of comorbid conditions because there is no absolute contraindication to epinephrineadministration during anaphylaxis. Physicians and other health care professionals should Intravenous Epinephrine instruct patients at risk for anaphylaxis outside of a medical facility to err on the side ofcaution and self-administer epinephrine if there is any doubt anaphylaxis is either present Epinephrine (1:10,000 or 1:100,000 dilutions) should be or imminent.
administered by infusion during cardiac arrest or to unre- Adapted from Sicherer and Simons.65 * 2008 World Allergy Organization Copyright @ 2008 World Allergy Organization. Unauthorized reproduction of this article is prohibited.
WAO Journal & July 2008, Supplement 2 Epinephrine: The Drug of Choice for Anaphylaxis that the early use of intravenous epinephrine is safe, effective, For example, a questionnaire based on the clinical scenario of and well tolerated when the rate is titrated to clinical response, a child with peanut-induced anaphylaxis was used in a random but this has not been evaluated systematically in a cohort study sample of 468 pediatricians in the United States.74 About half comparing this modality to epinephrine intramuscular (56%) agreed that the scenario represented anaphylaxis and that treatment with epinephrine was indicated. Most (81%)correctly chose to discharge the child home with self- Inhaled Epinephrine injectable epinephrine and either to refer to an allergist or to Some physicians recommend inhalation of epinephrine recommend further diagnostic testing (86%). Similar surveys as an alternative to injection during anaphylaxis, but perioral have been done in other countries (several studies are cited in paresthesias, bad taste, and gastrointestinal effects are dose- Pongracic and Kim75).
limiting, and it may not achieve prompt significant increases in Studies have also demonstrated that many health care plasma epinephrine concentrations.68,69 No direct comparisons professionals are uncertain about how to use an epinephrine have been made between the inhaled and the intramuscular autoinjector and thus cannot properly instruct their routes of epinephrine administration.
patients.76,77 Available resources may help physicians developtreatment plans and resolve any therapeutic quandaries.17,18,65 FOLLOW-UP AND OBSERVATION Examples of written action plans can be downloaded over the AFTER ANAPHYLAXIS Internet (see Additional Educational Resources).
Observation periods should be individualized and based on such factors as comorbid conditions and distance from the UNDERUTILIZATION OF EPINEPHRINE BY patient's home to the closest emergency facility, particularlybecause there are no reliable predictors of biphasic anaphy- PATIENTS, PARENTS, AND CAREGIVERS laxis.13 After resolution of the acute episode, patients should Fatalities during witnessed anaphylaxis, most of which be discharged with an epinephrine autoinjector and properly occur outside of a medical facility, usually result from delayed instructed on how to self-administer it in case of a subsequent administration of epinephrine. In a retrospective review of 6 episode. They should receive an individualized Anaphylaxis fatal and 7 nonfatal episodes of food-induced anaphylaxis in Emergency Action Plan.18 Patients should also have ready children and adolescents, all subjects who survived had access to emergency medical services to facilitate prompt received epinephrine before or within 5 minutes of developing transportation to the closest emergency department (ED) for severe respiratory symptoms. None of the subjects with fatal treatment after injecting the additional epinephrine.
attacks received epinephrine before the onset of severerespiratory symptoms.20 Analysis of data from a nationalcase registry of fatal food anaphylaxis in the United States USE OF EPINEPHRINE BY HEALTH indicates that very few individuals (7/63) had epinephrine CARE PROFESSIONALS autoinjectors available at the time of fatal reaction.23,25 Numerous guidelines on anaphylaxis have been pub- Similarly, Pumphrey21 determined that although epinephrine lished, but physicians and other health care professionals often was administered in 62% of the fatal anaphylactic reactions in do not follow them. For example, investigators determined by the United Kingdom that he reviewed, in only 14% was it questionnaire that only 4 (5%) of 78 senior house officers given before cardiac arrest. In a follow-up analysis of 48 beginning ED responsibilities in the United Kingdom would cases of fatal food anaphylaxis from 1999 to 2006, Pumphrey administer epinephrine appropriately and with the proper dose and Gowland24 reported that 19 (40%) had received and route of administration, as outlined in the UK Resuscita- epinephrine autoinjectors, but more than one half of the tion Council guidelines on anaphylaxis.70 Other reports have fatalities occurred in patients whose previous clinical reactions examined treatment patterns in the ED settings of civilian71 had been so mild that, in the opinion of the investigators, it was and military hospitals72 in the United States and observed unlikely that a physician would have prescribed a precau- that epinephrine injections were administered during acute tionary epinephrine syringe.
anaphylaxis to 16% and 50% of patients, respectively, as Multiple factors may contribute to the lack of available recommended by consensus anaphylaxis guidelines. Retro- epinephrine for administration during anaphylaxis that occurs spective analysis of a national reporting database on ED visits outside of a medical facility. An international survey in the United States from 1993 to 2004 revealed 12.4 million conducted under the auspices of the World Allergy Organiza- allergy-related visits to the ED, approximately 1% of all ED tion determined that epinephrine autoinjectors were available visits based on International Classification of Diseases, Ninth in about half of surveyed countries, and that the cost of an Revision, Clinical Modification coding. Anaphylaxis coding autoinjector in some countries was equivalent to the monthly was rare (0.01% of all ED visits), although epinephrine was salary of an average citizen.78 Of 39 countries, autoinjectors administered in 50% of those coded with anaphylaxis.
containing 0.15-mg and 0.3-mg doses were available in 17 Epinephrine administration documented in patients with (44%) and 22 (56%), respectively.
acute allergic conditions was infrequent (11%), and the trend Adherence to an action plan to keep epinephrine available of use declined over the period of interest from 19% to 7% at all times and to inject it during anaphylaxis is another concern.
Kemp and colleagues79 determined in a follow-up survey of Primary care physicians have demonstrated similar patients that 32 (47%) of 68 did not have the recommended knowledge gaps in their knowledge pertaining to anaphylaxis.
epinephrine autoinjector with them when they again * 2008 World Allergy Organization Copyright @ 2008 World Allergy Organization. Unauthorized reproduction of this article is prohibited.
WAO Journal & July 2008, Supplement 2 TABLE 3. Preventive Measures to Reduce the Risk Based on available evidence, the benefit of using appropriate doses of intramuscular epinephrine in anaphylaxis I. General measures far exceeds the risk (evidence category IV). Consensus Obtain thorough history to diagnose life-threatening food or drug allergy opinion and anecdotal evidence recommend epinephrine Identify cause of anaphylaxis and those individuals at risk for future attacks administration Bsooner rather than later,[ that is, when the Provide instruction on proper reading of food and medication labels, where initial signs and symptoms of anaphylaxis occur, regardless of their severity, because fatalities in anaphylaxis usually result Avoidance of exposure to antigens and cross-reactive substances from delayed or inadequate administration of epinephrine.
Optimal management of asthma and coronary artery disease Experts may differ on how they define the clinical threshold by Implement a waiting period of 20 to 30 min after injections of drugs or other which they define and treat anaphylaxis. However, they have no disagreement whatsoever that appropriate doses of In the physician's office, consider a waiting period of 2 h if a patient receives an oral medication he/she has never previously taken intramuscular epinephrine should be administered rapidly II. Specific measures for high-risk patients once that threshold is reached. There is no absolute contra- Individuals at high risk for anaphylaxis should carry self-injectable syringes indication to epinephrine administration in anaphylaxis, and of epinephrine at all times and receive instruction on proper use with all subsequent therapeutic interventions depend on the initial response to epinephrine. Development of toxicity or inade- MedicAlert (MedicAlert Foundation, Turlock, Calif) or similar warning quate response to epinephrine injections indicates that bracelets or chains additional therapeutic modalities are necessary. All individuals Substitute other agents for A-adrenergic blockers, angiotensin-converting at increased risk of anaphylaxis should have an anaphylaxis enzyme inhibitors, tricyclic antidepressants, and monoamine oxidaseinhibitors, whenever possible action plan and carry epinephrine autoinjectors for self- Agents suspected of causing anaphylaxis should be given orally if possible; administration. Such individuals (and their caregivers, as if the intravenous route is needed, a slow supervised rate of administration appropriate) should be assessed regularly for adherence with these recommendations and for the ability to demon- Where appropriate, use specific preventive strategies, including pharmaco- strate proper epinephrine administration technique with a logical prophylaxis, short-term challenge and desensitization, and placebo device.
Modified from Kemp.88 ADDITIONAL EDUCATIONAL RESOURCES experienced anaphylaxis from a previously identified culprit.
In contrast, 31 (91%) of 34 patients with idiopathic anaphylaxis(that is, no culprit could be identified) had epinephrine available at the time of a subsequent episode. Implementation of an World Allergy Organization (www.worldallergy.org) educational protocol with emphasis on carrying epinephrine increased the frequency of adherence from 53% to 92% over the American Academy of Allergy, Asthma, and Immunol- ensuing 10 years.80 Other studies have similarly reported that ogy (AAAAI) (www.aaaai.org) 50% to 75% of patients prescribed epinephrine carry it with American College of Allergy, Asthma, and Immunology them, of whom 30% to 40% can demonstrate proper adminis- tration technique.81Y84 Still others carry epinephrine but choose Joint Council of Allergy, Asthma, and Immunology not to use it during anaphylaxis32,85Y87 or prefer to seek emergency medical assistance.21 Food Allergy and Anaphylaxis Network (FAAN) (www.
Few studies thus far have examined management of anaphylaxis in school or day care settings. These are reviewed Allergy UK (www.allergyuk.org) in detail elsewhere.75 Protection of children at risk for Anaphylaxis Canada (www.anaphylaxis.org) anaphylaxis in school, day care, or other settings requires an The Web sites of other national and regional allergy/ interdisciplinary approach.9 Several resources are available immunology organizations also provide useful perspectives.
for help in the school or day care setting (see AdditionalEducational Resources).
Action Plans for Health Care Professionals PRECAUTIONS FOR THE PATIENT AT RISK Spanish language versions of the following AAAAI Optimizing prevention (Table 3) is crucial because anaphylaxis materials are now available: The AAAAI Anaphy- future anaphylaxis may be fatal despite appropriate manage- laxis Emergency Action Plan, Killer Allergy information page, ment. An allergist-immunologist can provide comprehensive AAAAI Anaphylaxis Tips to Remember brochure, and AAAAI professional advice on these matters and should be consulted Anaphylaxis Easy Reader page.
if he/she is not already involved in the anaphylaxis plan of FAAN (English language version: www.foodallergy.org/ care. All patients at risk for future anaphylaxis should carry at actionplan.pdf; Spanish language version: www.foodallergy.
least 1 epinephrine syringe and know how to administer it.
* 2008 World Allergy Organization Copyright @ 2008 World Allergy Organization. Unauthorized reproduction of this article is prohibited.
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Doi:10.1016/j.bbrc.2007.12.168

Available online at www.sciencedirect.com Biochemical and Biophysical Research Communications 367 (2008) 687–692 Lysosome mediated Kir2.1 breakdown directly influences inward rectifier current density John A. Jansen, Teun P. de Boer, Rianne Wolswinkel, Toon A.B. van Veen, Marc A. Vos, Harold V.M. van Rijen, Marcel A.G. van der Heyden * Department of Medical Physiology, Division Heart & Lungs, University Medical Center Utrecht, Yalelaan 50, 3584 CM Utrecht, The Netherlands

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