Anaphylaxis epinephrine

In anaphylaxis, epinephrine appears to have an optimal benefit-to-risk ratio when it is administered promptly by intramuscular injection [1-6]. 

Anaphylaxis Epinephrine is the drug of choice for the immediate treatment of anaphylactic shock. The catecholamine is sometimes supplemented with antihistamines and corticosteroids, but these agents are not as efficacious as epinephrine nor as rapid-acting. 

Smith PL. Kagey-Sobotka A. Blecker ER. Traystman R, Kaplan AP. Gralink H. Valentine MD. Permut S. Lichtenstein LM Physiologic manifestations of human anaphylaxis. J Clin Invest 1980 60 1072. Stark BJ. Sullivan TJ Biphasic and protracted anaphylaxis. J Allergy Clin Immunol 1986 78 76-83. Sullivan TJ Cardiac disorders in penicillin-induced anaphylaxis association with intravenous epinephrine therapy. JAMA 1982 248 2161. 

Simons FE, Peterson S, Black CD Epinephrine dispensing patterns for an out-of-hospital population a novel approach to studying the epidemiology of anaphylaxis. J Allergy Clin Immunol 2002 10 647-651. 

Rangaraj S, Tuthill D, Burr M. Alfaham M Childhood epidemiology of anaphylaxis and epinephrine in Wales 1994-1999. J Allergy Clin Immunol 2000 109 S75. 

It has been stated that adults with mastocytosis as well as children with bullous lesions and with more severe involvement, and especially those with previous reactions, are at increased risk for anaphylaxis [4]. Thus, we recommend that patients at risk carry an emergency kit for self-medication which includes epinephrine and, as warranted, an antihistamine and a corticosteroid [38]. 

Among the antianaphylactic drugs, epinephrine (adrenaline) is the essential substance. In the acute treatment of the anaphylaxis in addition to the classical ABC (airway, breathing, circulation) rule for cardiopulmonary resuscitation [26, 27], one can apply the AAC rule (antigen off, adrenaline, cortisone) [18], Other drugs playing a role in the treatment of anaphylaxis include antihistamines (Hi-antagonists). 

Brown SG, Blackman KE, Stenlake V, Heddle RJ Insect sting anaphylaxis prospective evaluation of treatment with intravenous adrenaline and volume resuscitation. Emerg Med J 2004 21 149-154. Lieberman P Use of epinephrine in the treatment of anaphylaxis. Curr Opin Allergy Clin Immunol 2003 3 313-318. 

Simons FE First-aid treatment of anaphylaxis to food focus on epinephrine. J Allergy Clin Immunol 2004 113 837-844. 

For nearly a century, epinephrine (adrenaline) has been the cornerstone of the acute management of anaphylaxis [1-6], a sudden-onset multi-systemic allergic reaction that can cause death. The World Health Organization lists epinephrine as an essential medication for anaphylaxis [7], Where national guidelines are available for the acute management of anaphylaxis, they universally recommend injection of epinephrine as the initial medication of choice [8]. 

In this review, we will describe the pharmacologic activity of epinephrine in anaphylaxis, the evidence base for its use, epinephrine dosing and routes of administration, epinephrine autoinjector use in first-aid treatment, reasons for failure to inject epinephrine promptly, reasons for occasional apparent lack of response, and future directions in epinephrine research. 

Table 1. Pharmacologic activities of epinephrine relevant to anaphylaxis... 

With regard to epinephrines potential adverse cardiac effects, it is important to remember that in anaphylaxis, the heart is a target organ. Mast cells located between myocardial fibers, in perivascular tissue, and in the arterial intima are activated through IgE and other mechanisms to release chemical mediators of inflammation, including histamine, leukotriene C4, and prostaglandin D2. Coronary artery spasm, myocardial injury, and cardiac dysrhythmias have been documented in some patients before epinephrine has been injected for treatment of anaphylaxis, as well as in patients with anaphylaxis who have not been treated with epinephrine [11, 12]. 

Serious adverse effects of epinephrine potentially occur when it is given in an excessive dose, or too rapidly, for example, as an intravenous bolus or a rapid intravenous infusion. These include ventricular dysrhythmias, angina, myocardial infarction, pulmonary edema, sudden sharp increase in blood pressure, and cerebral hemorrhage. The risk of epinephrine adverse effects is also potentially increased in patients with hypertension or ischemic heart disease, and in those using (3-blockers (due to unopposed epinephrine action on vascular Ui-adrenergic receptors), monoamine oxidase inhibitors, tricyclic antidepressants, or cocaine. Even in these patients, there is no absolute contraindication for the use of epinephrine in the treatment of anaphylaxis [1,5,6]. 

The current evidence base for the injection of epinephrine in the initial acute treatment of anaphylaxis includes clinical experience during nearly a century of use, observational studies, epidemiological studies, fatality studies, and randomized controlled trials in people at risk for anaphylaxis although not actually experiencing it at the time of the study. Moreover, the pharmacology of epinephrine has been... 

Given the unexpected occurrence of anaphylaxis, the rapidity with which symptoms evolve after exposure to the trigger, and the observation that delay in epinephrine injection is associated with fatality [15, 16], randomized controlled trials of epinephrine in anaphylaxis will not be easy to conduct however, it is time to consider the possibility of performing such trials. Future directions with regard to studies of the optimal dose and optimal route of administration of epinephrine in anaphylaxis that do not involve a placebo control will be outlined at the end of this review [17]. 

Epinephrine is administered by a variety of different routes in anaphylaxis, except for the oral route, which is not feasible because of rapid inactivation of epinephrine in the gastrointestinal tract by catechol-O-methyltransferase and monoamine oxidase [9]. The initial intramuscular epinephrine doses of 0.3-0.5 mg currently recommended for adults with anaphylaxis are low compared with the doses required for resuscitation following cardiac arrest [1, 2,4,18]. 

Optimal use of epinephrine autoinjectors for first-aid treatment of anaphylaxis in community settings is hampered by several issues. In most countries, these include the availability of only two pre-measured epinephrine doses and only a few different needle lengths, and the need to replace outdated autoinjectors at 12- to 18-month intervals due to degradation of the epinephrine solution they contain. 

Physicians face a dilemma with regard to prescribing an optimal epinephrine dose in an autoinjector for first-aid treatment of people at risk for anaphylaxis in a community setting, because only two pre-measured epinephrine doses, 0.15 and 0.3 mg, are... 

Lack of appropriate dose options and needle length options should not deter physicians from prescribing epinephrine autoinjectors for the first-aid out-of-hospital treatment of anaphylaxis. 

Up to 20% of anaphylaxis episodes in adults, and up to 6% of episodes in children, are biphasic or protracted, and involve recurrent or persistent symptoms without any ongoing or additional exposure to the anaphylaxis trigger. Administering too little epinephrine too late during treatment of the initial symptoms of an anaphylaxis episode is one of the factors reported to increase the risk of biphasic or protracted anaphylaxis [27]. 

Retrospective studies involving a review of emergency department records [28], or a cross-sectional survey [29], indicate that 16-19% of people who require an initial dose of epinephrine in food-triggered anaphylaxis in community settings subsequently required a second dose. 

Currently, many physicians advise their patients at risk for anaphylaxis in the community to carry two epinephrine doses with them at all times [30]. In school settings, it has been proposed that one epinephrine autoinjector should be available for each child at risk, along with several extra autoinjectors available as back-up for all children at risk [31]. 

Although epinephrine autoinjectors are widely dispensed for first-aid treatment of anaphylaxis in some countries, they are neither available nor affordable in many others [33]. In these situations, physicians sometimes equip patients at risk for anaphylaxis in the community with an epinephrine ampule and a disposable 1-ml syringe. Some physicians also recommend this approach for infants, for whom, as noted previously, no appropriate epinephrine dose is available in an autoinjector formulation. 

Published clinical scenarios outline the available options in making these decisions [36], It is impossible to predict the outcome of a future anaphylaxis episode with certainty based on the history of a previous episode [37]. Therefore, when in doubt, erring on the side of caution is generally advised prescribe one or more epinephrine autoinjectors, and advise the person at risk or the caregiver of a child at risk to inject epinephrine promptly in an anaphylaxis episode [36]. 

Many people who have experienced anaphylaxis in the community and are therefore at risk for recurrence have never received a prescription for an epinephrine autoinjector from an emergency department physician [38, 39] or from their primary care physician. Some of those who have received a prescription for an epinephrine autoinjector do not follow through and get it filled [40]. Even if they do get the epinephrine autoinjector dispensed, they may fail to carry it with them at all times [41]. Adherence to instructions to carry epinephrine can be improved with regular input from a healthcare professional [42] however, healthcare professionals need to master the complexities of epinephrine autoinjector use [43] before instructing others. People who have survived a mild anaphylaxis episode that was not treated at all, or was treated only with an antihistamine or an asthma puffer, sometimes fail to inject epinephrine because they erroneously assume that their subsequent reactions will also be mild [44]. 

Rarely, anaphylaxis progresses so rapidly that the initial first-aid dose of epinephrine which, as noted previously, is low relative to the initial epinephrine dose of 1 mg used in resuscitation, is ineffective even if given promptly. More commonly, anaphylaxis progresses because epinephrine is given too late, or administered in a suboptimal dose for the patient s body mass (weight), or through a suboptimal route [5]. 

Preparedness for first-aid treatment of anaphylaxis in the community involves not only a prescription for epinephrine autoinjectors, but also an Anaphylaxis Emergency Action Plan, appropriate medical identification, and anaphylaxis education. 

Epinephrine autoinjectors should be prescribed in the context of a written Anaphylaxis Emergency Action Plan that is developed with the input of the person at risk for anaphylaxis, or the caregiver(s) of the child at risk [45]. The Plan should remind the person at risk about the common symptoms and signs of anaphylaxis, stress the importance of prompt epinephrine injection, and clearly state that Hj-antihistamines... 

There are no new medications available for the acute treatment of anaphylaxis [17]. Epinephrine, with its multiple relevant life-saving pharmacologic actions, is likely to remain the initial drug of choice in anaphylaxis for the foreseeable future. 

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