The Role of Epinephrine in the Treatment of Anaphylaxis Anne K
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The Role of Epinephrine in the Treatment of Anaphylaxis Anne K. Ellis, MD, and James H. Day, MD, FRCP(C) Address Beneficial Effects of Epinephrine Division of Allergy, Kingston General Hospital, 76 Stuart Street, in Anaphylaxis Kingston, ON K7L 2V7, Canada. Epinephrine is both an alpha (α) and a beta (β) adrener- E-mail: [email protected] gic receptor agonist. Through α-adrenergic stimulation, Current Allergy and Asthma Reports 2003, 3:11–14 epinephrine increases peripheral vascular resistance, Current Science Inc. ISSN 1529-7322 Copyright © 2003 by Current Science Inc. improving blood pressure and coronary artery perfusion, reversing peripheral vasodilation, and decreasing angioedema and urticaria [5]. β-1 adrenergic stimulation Epinephrine is the cornerstone of anaphylaxis manage- has positive inotropic and chronotropic effects on the ment. Its administration should be immediate upon evi- myocardium, and β-2 adrenergic effects include bron- dence of the occurrence of anaphylaxis. Delays in chodilation [6]. β-adrenergic receptors also increase administration may be fatal. The most appropriate admin- intracellular cyclic adenosine monophosphate (cAMP) istration is 0.3 to 0.5 mL of 1:1000 dilution intramuscu- production in mast cells and basophils, which inhibits larly for adults and 0.01 mg/kg for children, given in the further inflammatory mediator release [7,8]. lateral thigh. Patients with known anaphylactic reactivity should be prescribed an epinephrine auto-injector to be carried at all times for treatment of potential recur- Dosage and Routes of Administration rences. Education of the patient or parent regarding the for Epinephrine proper use of this tool is paramount. Some discrepancy exists in the literature concerning the appropriate dosage of epinephrine for anaphylaxis. Most North American references suggest 0.3 to 0.5 mL of Introduction a 1:1000 dilution (0.3 to 0.5mg) [9–14], whereas British Anaphylaxis is the clinical syndrome representing the and European literature tends to suggest higher doses of most severe of systemic allergic reactions. It results from 0.5 to 1.0 mg for most adult patients [2–4,15]. Almost immunologically induced mast cell or basophil mediator all references, however, have concordance with a dosing release after exposure to a specific antigen in previously scheme of 0.01 mg/kg in pediatric patients [2– sensitized persons, with release of pre-formed mediators 4,16•,17]. This dose can be repeated, if necessary, until stored in granules (especially histamine). The release of clinical improvement or symptoms of hyperadrenalism these mediators results in smooth-muscle spasm, an (eg, palpitations, tremor, uncomfortable apprehension, increase in vascular permeability, vasodilation, myocar- anxiety) occur. dial depression, and reflex activation of vagal effector Until recently, the subcutaneous (SC) route was pathways, leading to the classic features of anaphylaxis, accepted as equally efficacious as intramuscular (IM) which include some combination of flushing; urticaria administration, although the British and European liter- and angioedema; wheezing; hypotension; nausea; vomit- ature has always advocated the IM route [18]. Subcuta- ing; diarrhea; and myocardial ischemia [1]. neous absorption of medication, however, is highly Epinephrine has a pivotal role as first-line treatment dependent on cutaneous blood flow, which is already for acute anaphylaxis [1–4]. Although other medica- compromised in anaphylaxis, and can be aggravated fur- tions play an auxiliary role in the management (H1 and ther by epinephrine administration, given its known H2 antagonists, corticosteroids, beta-2 agonists), their potent vasoconstrictor activity [19]. Recently, consensus use is not discussed here. In this article, the mechanism guidelines released by a United Kingdom project team of action of epinephrine, the appropriate dosing, the [3] universally recommended IM administration of epi- route of administration (including discussions concern- nephrine, supported by ensuing letters to the editor ing the use of intravenous epinephrine), and the use of [20,21]. Recent studies have demonstrated definitively epinephrine auto-injectors for out-of-hospital anaphy- that the IM route in both children [22•] and adults laxis are reviewed. [23•] yielded a faster onset to peak absorption and 12 Anaphylaxis and Drug Allergy significantly higher plasma epinephrine levels than the more rapid fall in epinephrine levels, and baseline levels SC route. An important finding from the adult study was were reached within 10 minutes. SC administration, how- that IM absorption was superior when administered into ever, was associated with a rise to peak epinephrine con- the thigh as opposed to the deltoid region. Therefore, centration by 4 minutes and sustained elevation of arterial the current recommended route of administration of epinephrine concentrations over the ensuing 60 minutes epinephrine is an IM injection into the lateral aspect of of study. Administration of epinephrine via eye drops has the thigh. been shown to be completely ineffective [29]. A recent pilot animal study [31] evaluated the possibility of sublin- Intravenous epinephrine gual administration of epinephrine, and preliminary Perhaps the single remaining controversy in the manage- results demonstrate epinephrine absorption from a 10-mg ment of anaphylaxis lies in the appropriate indication for sublingual tablet to be comparable with an IM injection of intravenous administration of epinephrine. Many authors 0.03 mg of epinephrine in rabbits. caution that intravenous epinephrine is potentially hazard- In view of these studies, the literature does not support ous as it can produce potentially fatal tachyarrhythmias, the use of inhaled or conjunctival administration of epi- myocardial infarction, and other complications such as nephrine. Sublingual epinephrine is a promising alterna- intracerebral hemorrhage [24–26]. In spite of the inherent tive but it is still in early pre-clinical phases of testing. dangers of this route, there is an acknowledged clinical role for this mode of administration. Increasingly, management Epinephrine and concomitant beta-blockade articles now endorse the use of intravenous epinephrine An anaphylactic state in persons receiving concurrent beta- for serious cases of anaphylaxis, in which intravascular vol- blocker therapy may not respond to treatment. Anaphy- ume is severely depleted with associated hypotension, or laxis in these patients may be especially severe, protracted, there is significant airway compromise, to achieve the and resistant to conventional treatment. Beta-blockers rapid, optimal absorption of epinephrine [18,27]. Ideally, modify the expected anti-anaphylactic actions of epineph- there should be electrocardiographic monitoring available, rine, which are mediated through β1 and β2 adrenoceptor and the procedure should be undertaken by experienced stimulation, thereby facilitating unopposed α-adrenergic personnel only. and reflex vagotonic effects that can lead to augmented The most appropriate dosing of intravenous epineph- mediator release, including bronchoconstriction and rine is perhaps one of the other reasons for a lack of enthu- bradycardia. Unopposed α-adrenoceptor activation in the siasm by certain authors, as no consensus exists in the presence of excessive adrenaline may also constrict coro- literature on this issue. Frequently cited [18] is the sugges- nary arteries and dangerously exaggerate epinephrine's sys- tion by Barach et al. [5] of using a 1:100 000 dilution given temic pressor effects [32]. at 1 to 2 mL (10–20 mg) per minute at an initial dose of 0.75 to 1.5 mg/kg. This may be followed by an infusion if Epinephrine auto-injectors prolonged treatment is required. The additional dilution to All patients who have experienced a documented episode 1:100 000 is thought to enhance the safety of the intrave- of anaphylactic reactivity should be prescribed, and nous route. Alternatively, other authors suggest using 1- to instructed in the use of, an epinephrine auto-injector. Cur- 5-mL aliquots of 1:10 000 dilution with or without an rently, the EpiPen and the EpiPen Jr. (Dey; Napa, CA) are ensuing infusion of 1 to 4 mg/min [2,28]. the only commercially available auto-injectors of epineph- Clearly, the rapid administration of IM epinephrine rine for patient use, as the preloaded epinephrine syringe remains the most important treatment for anaphylaxis. (Ana-kit) is no longer manufactured [33]. Both models When necessary, careful IV administration of epinephrine provide a standardized dose injection IM, and the package for severe anaphylaxis with profound hypotension should insert instructs the patient to inject into the thigh [34], be considered. thus providing the established ideal route of administra- tion. The EpiPen provides 0.3 mg of epinephrine and is Unconventional administration routes usually prescribed to adults and children weighing more for epinephrine than 30 kg. The EpiPen Jr. contains 0.15 mg of epineph- Other routes of administration of epinephrine have been rine, which is an ideal dose for a child weighing 15 kg, but tested in an experimental setting, including the inhaled, would overdose a lighter child and underdose a heavier conjunctival, and sublingual routes. Inhaled epinephrine child, given the appropriate dosing of epinephrine in chil- studies have yielded conflicting results. One report showed dren at 0.01mg/kg. In practice, both the EpiPen and the that epinephrine was present systemically