Epinephrine in anaphylaxis

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. 

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]. 

Ongoing epinephrine research relevant to human anaphylaxis is critically important. In its absence, the use of epinephrine in anaphylaxis treatment in the 21st century will continue to be based mostly on clinical experience, or worse, on expedience, instead of on clinical science. 

Tripelennamine, an ethylene-diamine-derivative antihistamine (25 to 50 mg p.o. q. 4 to 6 hours), is indicated in rhinitis, allergy symptoms, allergic reactions to blood or plasma, and as an adjunct to epinephrine in anaphylaxis. 

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. 

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. 

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... 

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]. 

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

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. 

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. 

Jarvinen KM, Sicherer SH, Sampson HA, Nowak-Wegrzyn A Use of multiple doses of epinephrine in food-induced anaphylaxis in children. J Allergy Clin Immunol 2008 122 133-138. 

It is usual to give a sedating antihistamine, for example chlorphenamine 10 mg by intramuscular or slow intravenous injection, because of the relatively short half-life of epinephrine (adrenaline), and because of the active role of histamine in anaphylaxis. In addition, the inflammatory reaction can be moderated by the administration of a corticosteroid, such as hydrocortisone 200 mg by intramuscular or slow intravenous injection. Corticosteroids may take several hours to act, but can be of some help in so-called biphasic anaphylactic reactions. 

Newman BR, Schultz LK. Epinephrine-resistant anaphylaxis in a patient taking propranolol hydrochloride. Ann Allergy 1981 47(l) 35-7. 

Lieberman P. Use of epinephrine in the treatment of anaphylaxis. Curr Opin Allerg Clin Immunol 2003 3 313-318. 

Unfortunately the still low number of available 1-ASP preparations limits the number of possible switches. If one wants to take advantage of 1-ASP s oncolytic potential over a longer period of time, new approaches are required. Concomitant infusion of epinephrine in parallel to 1-ASP [148] may be helpful with respect to anaphylaxis but does not solve the basic problem of immunogenicity and altered pharmacokinetics. 

Epinephrine activates all adrenoceptors, whereas norepinephrine has minimal agonist activity at [J -adrenoceptors. This difference is important in anaphylaxis because adrenoceptor activation is needed to provide a bronchodilatory effect that will oppose the anaphylaxis-induced airway obstruction. The aj-adrenoceptor agonist effect of epinephrine opposes the anaphylaxis-induced vasodilation and, to some extent, the vascular leak (administration of fluid is also a cornerstone of the treatment of anaphylaxis), while the Pj-adrenoceptor agonist effect helps maintain cardiac output. 

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 for the out-of-hospital treatment of anaphylaxis in infants and children a population-based study. Ann Allergy Asthma Immunol 2001 86 622-626. 

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). 

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... 

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]. 

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. 

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