First-aid treatment of anaphylaxis to food: Focus on epinephrine

Posted on: Mon, 05/17/2004 - 12:52am
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First-aid treatment of anaphylaxis to food: Focus on epinephrine

F. Estelle R. Simons MD, FRCPC,

From the Section of Allergy and Clinical Immunology, Department of Pediatrics and Child Health; and the Department of Immunology, National Training Program in Asthma and Allergy, University of Manitoba, Winnipeg, Manitoba, Canada

Received 15 January 2004; Revised 15 January 2004; accepted 18 January 2004 Winnipeg, Manitoba, Canada Available online 10 May 2004.

Abstract
Avoiding food triggers for anaphylactic reactions (severe acute systemic allergic reactions) is easier said than done. Most episodes of anaphylaxis to food occur unexpectedly in the community in the absence of a health care professional. All individuals at risk should therefore have an emergency action plan in place. The cornerstone of first-aid treatment of anaphylaxis is epinephrine injected intramuscularly in the vastus lateralis muscle (lateral aspect of the thigh). In this review, we focus on epinephrine. We examine a therapeutic dilemma: the issue of epinephrine dose selection in an individual for whom no optimal fixed-dose auto-injector formulation exists, and a therapeutic controversy: the issue of epinephrine injection versus an oral H1-antihistamine in anaphylaxis episodes that appear to be mild. The pharmaceutical industry could address the first of these issues by providing a wider range of epinephrine fixed doses in easy-to-use auto-injectors, or by providing adjustable epinephrine doses in auto-injectors. The second issue could be addressed in part by development of alternative routes of epinephrine administration for the first-aid, out-of-hospital treatment of anaphylaxis.

Historically, anaphylaxis was triggered mainly by biological substances such as antitoxin or by medications, and usually occurred in a health care setting.[1.] Currently, food is the most common trigger of anaphylaxis, and most episodes occur unexpectedly in the community in the absence of a trained health care professional. [2. and 3.] Anaphylaxis is defined as an acute systemic allergic reaction that varies in severity from mild to life-threatening or fatal and may be rapidly progressive. Individuals who have had such a reaction (or for children, their caregivers) should be equipped with an anaphylaxis emergency action plan[4., 5. and 6.] and with injectable epinephrine for first-aid treatment,[6., 7., 8. and 9.] defined as treatment before or during transport to an emergency department.

Here, we review the current scientific evidence on which the first-aid treatment of anaphylaxis is based. We focus chiefly on epinephrine and address 2 difficult issues in first-aid treatment with this life-saving medication: the dilemma of epinephrine dose selection in individuals for whom no optimal fixed-dose auto-injector formulation exists, and the controversial issue of epinephrine injection versus an oral H1-antihistamine in anaphylaxis episodes that appear to be mild.

1. Epinephrine in the first-aid treatment of anaphylaxis
1.1. Pharmacologic activity
Epinephrine is a direct-acting sympathomimetic -adrenergic and -adrenergic agonist with cyclic adenosine monophosphate-mediated, complex, bidirectional pharmacologic effects on many target organs[10.] ( Fig 1). Achieving high plasma and tissue epinephrine concentrations rapidly appears to be critical for reversal of hypotension[11.] and possibly for survival. Epinephrine has a narrow toxic-therapeutic index (risk-to-benefit ratio). Administered to individuals of any age, in therapeutic doses, by any route, including inhalation, it may cause pharmacologic adverse effects such as anxiety, fear, restlessness, headache, dizziness, palpitations, pallor, and tremor. [12. and 13.] Rarely, and especially after overdose, it may lead to ventricular arrhythmias, angina, myocardial infarction, pulmonary edema, sudden sharp increase in blood pressure, and intracranial hemorrhage. The risk of epinephrine adverse effects may be increased in individuals with some pre-existing cardiovascular, central nervous system, or thyroid diseases; in persons using monoamine oxidase inhibitors, which block epinephrine metabolism; or in those using tricyclic antidepressants or cocaine, in whom epinephrine duration of action is prolonged. [12.] There is, however, no absolute contraindication to epinephrine use in anaphylaxis.

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Fig 1. Pharmacology of epinephrine. In anaphylaxis, epinephrine's 1-adrenergic effects (vasoconstriction, increased peripheral vascular resistance, and decreased mucosal edema) and some of its 2-adrenergic effects (bronchodilation and decreased mediator release from mast cells and basophils) are of primary importance. Low epinephrine concentrations may paradoxically enhance release of histamine and other mediators from mast cells and basophils and result in vasodilation.[10.]

1.2. Evidence base for epinephrine use in anaphylaxis
Recommendations for epinephrine dosing in the first-aid, out-of-hospital treatment of anaphylaxis are based on anecdotal experience and vary with regard to maximum initial dose (0.2 mg to 0.5 mg in adults; 0.01 mg/kg to a maximum of 0.3 mg/kg in children), route of injection (subcutaneous vs intramuscular), and interval between doses (5-30 minutes).[6., 7., 8. and 9.] Prospective, randomized, double-blind, placebo-controlled clinical trials of epinephrine in individuals actually experiencing anaphylaxis are unethical because prompt treatment with epinephrine is deemed critically important for survival. Also, such studies would be difficult to conduct because anaphylaxis episodes usually occur without warning in a nonmedical setting and differ in severity among individuals and from one episode to another in the same individual; consequently, baseline measurements and frequent timed measurements would be hard to obtain.

Despite the absence of clinical trials, evidence from clinical pharmacology studies, epidemiologic studies, and other investigations supports the use of epinephrine in anaphylaxis.[6., 7., 8. and 9.] Based on the observation that subcutaneous administration of epinephrine causes skin blanching at the injection site as a result of the powerful 1 vasoconstrictor effect of the drug, it was hypothesized that retention of epinephrine at the site of subcutaneous injection might lead to a delay in absorption into the systemic circulation. This hypothesis was initially tested in a randomized, blind study in children at risk for anaphylaxis in whom the time to peak plasma epinephrine concentration (tmax), accompanied by prompt physiologic effects, was 8

Posted on: Mon, 05/17/2004 - 6:06am
erik's picture
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Hi Allison,
Thanks for the article. [img]http://uumor.pair.com/nutalle2/peanutallergy/smile.gif[/img] There is lots of interesting information in there.

Posted on: Tue, 04/12/2005 - 11:02am
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I found section 2.2 interesting.

Posted on: Thu, 08/11/2005 - 11:25pm
erik's picture
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raising

Posted on: Thu, 08/11/2005 - 11:53pm
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Joined: 01/03/2002 - 09:00

Wow, 86% use epi too late. That is very interesting. Also, addresses the epi vs. Benadryl issue that there have been threads about on here.

Posted on: Fri, 08/12/2005 - 12:04am
erik's picture
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Quote:Originally posted by Carefulmom:
[b]Wow, 86% use epi too late. That is very interesting. Also, addresses the epi vs. Benadryl issue that there have been threads about on here.[/b]
Yes.. an informative post (thanks Allison!) It seems quite essential to use the epi-pen promptly - something to remember.

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