Epinephrine and its Use in Anaphylaxis: Current Issues

Keith J. Simons; F. Estelle R. Simons

Curr Opin Allergy Clin Immunol. 2010;10(4):354-361.

Epinephrine Auto-injectors for Anaphylaxis in Community Settings

For patients at risk of anaphylaxis recurrence in the community, epinephrine should preferably be prescribed in an auto-injector formulation.

Identification of Patients who need an Epinephrine Auto-injector

Physicians generally agree that epinephrine auto-injectors should be prescribed for patients with a history of upper or lower respiratory symptoms, hypotension, or shock in anaphylaxis, those with a history of anaphylaxis from certain triggers including foods (such as peanut, tree nuts, and shellfish), insect stings or exercise, and those with idiopathic anaphylaxis.^[16,38]

Physicians face a quandary as to whether to prescribe epinephrine auto-injectors for other types of patients, for example, those with a history of acute generalized hives after exposure to a known trigger.^[38] In this situation, it might be helpful to recall that some patients dying from anaphylaxis, for whom epinephrine auto-injectors had not been prescribed, had experienced mild anaphylaxis symptoms on previous occasions before their demise. It might also be helpful to consider patient-specific risk factors that increase the likelihood of severe or fatal anaphylaxis.^[8•] These include age of the patient (infants, teens, the elderly), comorbid diseases, including asthma, cardiovascular disease, and mastocytosis, and concurrent medications, including beta-blockers and ACE inhibitors. Other patients might be at increased risk because of defects in mediator degradation pathways; abuse of ethanol or other chemical substance; interruption of routine; living alone or in a remote area, or lacking reliable transportation or means of communication.^{[2,8•,12,24,25•]}

Use of Epinephrine Auto-injectors

Currently, the optimal way of providing first-aid treatment with epinephrine (adrenaline) for anaphylaxis in the community is through an auto-injector.^{[2–8•,12,16]} The first-aid dose of epinephrine, 0.01 mg/kg of a 1 mg/ml (1 : 1000) formulation to a maximum dose of 0.5mg in an adult or 0.3mg in a child, is based on tradition and clinical consensus rather than on randomized controlled trials. Most anaphylaxis guidelines recommend injecting it from an auto-injector intramuscularly in the mid-anterolateral aspect of the thigh.^[3–5] Fatality studies suggest that in some patients, there is only a brief window of time during which the low first-aid dose of epinephrine is effective.^[17,29–31] If anaphylaxis has progressed to cardiopulmonary arrest and resuscitation is required, this low dose is unlikely to be effective, as the dose for resuscitation is 1 mg, administered as an intravenous bolus.^[8•]

On the basis of clinical consensus, the epinephrine dose can be repeated every 5–15 min, as needed.^[3,4,6] On the basis of a report in which ten deaths from anaphylaxis in a community setting occurred within minutes of patients being placed or maintained in the upright position, which led to the empty inferior vena cava/empty ventricle syndrome,^[39] patients should remain supine or recumbent after receiving an epinephrine injection.

Multiple doses of epinephrine are needed by patients with severe or protracted anaphylaxis symptoms that are not relieved by the initial dose and by those with biphasic or multiphasic anaphylaxis. The number of patients reported to require more than one dose of epinephrine differs from study to study. In two prospective studies in which all or most patients with anaphylaxis after allergen immunotherapy injections received epinephrine injections promptly,^{[36•,37•]} although biphasic reactions occurred in 23 and 10% of the patients, respectively, additional epinephrine was not given to any patient. In a retrospective review^[40] of emergency department records, 13% of patients with anaphylaxis from all triggers received additional epinephrine. In a retrospective review^[41] of emergency department records of children with food-related anaphylaxis, 12% received more than one dose of epinephrine.

Advances in Epinephrine Auto-injector Design

In most countries, there are only two fixed epinephrine doses (0.15 and 0.3 mg) available in auto-injector formulations^[42] [EpiPen (Dey LP, Napa, California, USA); Adrenaclick and Twinject (Sciele, Division of Shionogi, Japan); and Anapen (Lincoln Medical, Salisbury, Wiltshire, UK)]. It is, therefore, difficult to dose infants and young children weighing less than 15 kg accurately, or to dose large teens and adults accurately. Also, in most countries, the auto-injectors available have a relatively short needle length and might not achieve intramuscular injection in some adults^[18] or even in some children,^[19•] in whom the distance from the skin to the vastus lateralis muscle has been measured by using computed tomographic scans of the thigh^[18] or ultrasound of the thigh.^[19•] In addition, most epinephrine auto-injectors available have a shelf-life of only 12–18 months.^[12]

Progress is being made in overcoming some of these limitations (Table 3).^[43] In the United Kingdom, other European countries, and Australia, a 0.5 mg epinephrine dose Anapen is now available in addition to the 0.15mg dose and the 0.3mg dose. The 0.5mg dose Anapen has a maximum shelf-life of 24 months. In Canada and the United States, a re-designed EpiPen is now available. This device is intuitively easier to hold correctly, the 'needle' end is clearly labeled with words and an arrow, and the needle is automatically covered after injection.

Reasons for Lack of Use of Epinephrine Auto-injectors and Apparent Lack of Response

Epinephrine auto-injectors are underused by patients for a variety of reasons, as outlined in Table 4.^{[8•,12,38,42,44–46]} In some countries, they are not available.^[42] In others, they are not affordable^[42] or not prescribed when indicated, for example, at the time of discharge from an emergency department after treatment for an acute anaphylaxis episode,^[44] or because previous reactions were considered to be mild.^[38] Existing alternatives to auto-injectors cannot be depended upon to produce high tissue concentrations of epinephrine rapidly.^[8•,12,34] These include drawing up epinephrine from an ampule (takes too long and the dose is often inaccurate),^[12] using an unsealed syringe prefilled with epinephrine by the patient's physician (shelf-life is only 3–4 months),^[34] or using a chlorofluorocarbon-containing epinephrine metered-dose inhaler [difficult to inhale enough epinephrine to relieve nonrespiratory symptoms (20 puffs needed in a child; 30 puffs needed in an adult)].^[12]

Many patients do not have their epinephrine auto-injector(s) with them at the time an anaphylaxis episode occurs.^[45•] In school settings, many children are at risk for delay in anaphylaxis treatment because of restricted access to their epinephrine auto-injectors.^[46] Other reasons for not using an epinephrine auto-injector in the treatment of anaphylaxis in the community are listed in Table 4.

Failure to respond to epinephrine injection is uncommon. Potential reasons for this include rapid progression of anaphylaxis, delay in epinephrine injection, delayed absorption of epinephrine due to injection through a suboptimal route or site, the empty ventricle syndrome as previously described, or concurrent use of a medication that interferes with optimal epinephrine effect^[8•,12] (Table 4).

Epinephrine, the Cornerstone of Emergency Preparedness

Anaphylaxis education about when, why, and how to use an epinephrine auto-injector, remains critically important. Healthcare professionals need to be trained to use epinephrine auto-injectors in order to train those at risk for anaphylaxis and their caregivers how to use them correctly and safely.^[8•,47] More than 15 000 unintentional injections from epinephrine auto-injectors, for example, into a finger, thumb, or hand were voluntarily reported to the American Association of Poison Control Centers from 1994 to 2007.^[48•] These unintentional injections potentially lead to injury and to the so-called 'lost dose hazard'.^[47,48•] The latter is defined as the outcome of an anaphylaxis episode in someone whose epinephrine dose is completely lost when unintentionally self-injected by their caregiver, or, partially lost when someone with anaphylaxis unintentionally self-injects epinephrine into their own finger, thumb, or other body part, leading to profound local vasoconstriction and delayed epinephrine absorption.

Epinephrine auto-injectors should be prescribed along with a personalized anaphylaxis emergency action plan^[2,8•] that lists common signs and symptoms of anaphylaxis, and instructs the patient to inject epinephrine promptly, then call emergency medical services or go to an emergency department. Many different anaphylaxis emergency action plans are in use; however, none of them has been validated for efficacy or cost-effectiveness.^[49] Medical identification jewelry (e.g. Medic Alert, Turlock, California, USA) should be worn at all times by patients at risk. A personalized anaphylaxis information card is available (www.aaaai.org) for carrying in a wallet or backpack.^[2]

An important aspect of long-term risk reduction in anaphylaxis involves follow-up of the patient at regular intervals. Such visits should include reassessment of his or her ability to use an epinephrine auto-injector correctly and coaching with regard to any improvements needed. They also offer the opportunity to improve the management of comorbidities such as asthma or cardiovascular disease, discuss the benefits and risks of concurrent medications such as beta-blockers and ACE inhibitors, review strategies for avoidance of allergen triggers, and, if relevant, begin or continue immunomodulation such as subcutaneous immunotherapy to prevent stinging insect venom anaphylaxis.^[8•]

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Cite this: Epinephrine and its Use in Anaphylaxis: Current Issues - Medscape - Aug 01, 2010.

Abstract and Introduction
Practical Pharmacology of Epinephrine
Evidence Base for Epinephrine Use in Anaphylaxis
Epinephrine Auto-injectors for Anaphylaxis in Community Settings
Future Role of Epinephrine in Anaphylaxis
Conclusion
References

Table 1. Practical pharmacology of epinephrine
Beneficial effects
Through alpha-1 adrenergic receptors: vasoconstriction, increased peripheral vascular resistance (most organs)^a, increased blood pressure and relief of hypotension and shock; decreased mucosal edema and relief of upper airway obstruction and angioedema/hives
Through alpha-2 adrenergic receptors: decreased insulin release
Through beta-1 adrenergic receptors: increased heart rate and force of cardiac contractions^b
Through beta-2 adrenergic receptors: bronchodilation, vasodilation, decreased release of mediators (histamine, tryptase, and others)^c
Adverse effects
Through alpha-1 adrenergic receptors: pallor, headache
Through beta-1 adrenergic receptors: palpitations
Through beta-2 adrenergic receptors: tremor, vasodilation^c, increased release of mediators
Through central CNS stimulation: anxiety
Intrinsic limitations
Rapidly metabolized when given by any parenteral route (half-life in children after intramuscular injection, 43 min)
Inactivated in the gastrointestinal tract when swallowed
Therapeutic dose in anaphylaxis is similar to the dose that leads to mild transient adverse effects^d
Epinephrine in solution breaks down to inactive substances over months to years, even when stored in a sealed container (no exposure to oxygen) in acidic solution containing antioxidants.

CNS, central nervous system. Data from ^{[1,2,8•,12]}.
^aVasodilator effect in skeletal muscle through beta-2 receptors.
^b Leads to increased coronary artery blood flow.
^c Epinephrine has complex biphasic effects; for example, at very low doses, unintended effects such as occur.
^d Refers to initial dose of 0.01 mg/kg to a maximum of 0.3–0.5mg (adult) and 0.3mg (child).

Table 2. Epinephrine: pros and cons of different routes of administration in anaphylaxis ^a
Intramuscular
Pros
Epinephrine has a vasodilation effect in skeletal muscle
Skeletal muscle is highly vascular, leading to rapid absorption
Drug injected into vastus lateralis reaches the central circulation promptly
Peak pharmacologic effects are achieved promptly
Benefit-to-risk ratio perceived to be optimal when this route is used for first-aid treatment
Most commonly recommended route worldwide
Cons
Currently available auto-injector needle lengths and gauges are not optimal for intramuscular injection in overweight or obese people
Not effective if muscle perfusion is poor or absent due to shock or cardiorespiratory arrest
Subcutaneous
Pros
Readily accessible sites of injection
Cons
Epinephrine, even in a 1 : 100 000 dilution, leads to vasoconstriction/blanching of subcutaneous tissue^c
Epinephrine slows its own absorption from subcutaneous tissue^c
Subcutaneous tissue is poorly vascularized compared with skeletal muscle^b
Low tissue epinephrine levels potentially lead to increased vasodilation and increased mediator release
Rapid epinephrine absorption is more critical in anaphylaxis than in asthma
Intravenous
Pros
Optimal route of administration for patients with severe anaphylaxis who have not responded to intramuscular epinephrine and/or are experiencing profound hypotension or shock, or in whom cardiorespiratory arrest is imminent
Cons
Establishing a peripheral intravenous route for epinephrine administration may be difficult in the above patients
Narrower benefit-to-risk ratio than epinephrine administered by other routes, partly attributed to iatrogenic error
For safe administration in hypotension or shock, it is optimally given through an infusion pump and central line by physicians trained and experienced in continuous dose titration of vasopressors against continuously monitored heart rate and function, blood pressure, and oxygenation
Errors in epinephrine dosing combined with errors in assessment of cardiac rate and function and blood pressure can be catastrophic for the patient

Data from ^{[1,8•,12–18,19•,20•]}.
^a Other routes of administration include inhalation through a metered-dose inhaler or face mask/nebulizer and compressor; by this route, epinephrine might relieve respiratory symptoms, but it is difficult to achieve sufficiently high tissue concentrations to relieve other systemic anaphylaxis symptoms.
^b After subcutaneous injection, median time to peak epinephrine levels is 34 min. Median time to cardiac arrest in anaphylaxis is 5–30 min, depending on the anaphylaxis trigger.
^c Epinephrine is widely used in surgery to provide hemostasis and to slow absorption of local anesthetics from skin, mucosa, subcutaneous tissue, and submucosal tissue.

Table 3. Epinephrine auto-injectors ^a
	EpiPen	Adrenaclick^b	Anapen
Doses (mg)	0.15, 0.3	0.15, 0.3	0.15, 0.3, 0.5
Excipients
Sodium chloride	6mg	1.3/2.6mg^c	Present; mg n/a
Sodium metabisulfite	1.67mg	Bisulfite 0.225/0.45mg	Present; mg n/a
Other	HCl	Chlorobutanol 0.75/1.5mg	HCl
Exposed needle length (cm)	1.3/1.48	1.29/1.32	1.30
Needle gauge (G)	22	25	27
Needle protection	Yes	No	No
Description
Weight (g)	75.5 (with case)	45.4 (with case)	28.8
Length (cm)	15.6 (with case)	16 (with case)	16.9
Shelf-life (months)^d	12–18	12–18	21 (0.15 mg), 24 (0.3 mg, 0.5 mg)
Availability^e	'Worldwide'	USA, Canada	Europe, Australia
Cost^f	Variable	Variable	Variable
Number of doses per auto-injector	1	1	1

HCl, hydrochloric acid; n/a, not available.
^aSeveral novel epinephrine auto-injectors are in development, including INT01/INT02 that measures 8.6 × 5.1 × 1.6cm.^[43]
^b Adrenaclick and Twinject are similar auto-injectors except that Adrenaclick contains one epinephrine dose and Twinject contains two doses.
^c Where two numbers are shown, the first number refers to the 0.15mg dose and the second number refers to the 0.3mg dose.
^d Stored in original sealed container, protected from light, at room temperature 20–25°C with excursions permitted to 15–30°C; 'do not refrigerate, do not freeze'.
^e See text for details; at time of publication, auto-injectors were available in 45/195 countries worldwide and availability was gradually improving.
^f Cost of one auto-injector to the patient depends on many different factors. Dispensing fees and taxes may be added to the base (wholesale) cost. Government subsidies or private insurance or rebates might decrease the price; however, age restrictions may apply to subsidies (e.g. epinephrine auto-injectors are available at no charge to children less than 16 years of age in the United Kingdom), and additional factors such as co-pays and limitations on number of auto-injectors per year might apply to private insurance.

Table 4. Epinephrine auto-injectors in anaphylaxis: reasons for lack of use and apparent lack of response
Lack of use of epinephrine auto-injectors (common)
Not available for purchase in many countries
Not prescribed by physician
Not affordable
Prescription not filled or picked up
Not accessible when anaphylaxis occurred
Not used because:
Patient used another medication, e.g. H₁-antihistamine or asthma puffer^a
Reaction seemed to be mild
Reaction seemed to improve quickly
Patient was unsure when to inject
Patient was afraid to inject
Epinephrine was past expiry date
Previous systemic allergic reaction improved quickly^b
Apparent lack of response to epinephrine (uncommon)
Rapid progression of anaphylaxis
Empty ventricle syndrome
Patient taking another medication^c that interfered with epinephrine effect
Epinephrine injected too late
Epinephrine dose too low
On a mg/kg basis for body weight of patient
Due to auto-injector being past the expiry date
Delayed absorption
Route of injection not optimal
Site of injection not optimal
Epinephrine injected using incorrect technique, e.g. not enough force
Adverse reaction to sodium metabisulfite preservative in the epinephrine solution (rare)

Data from ^{[8•,12,38,39,42,44–46]}.
^aH₁-antihistamines relieve hives and flushing, but do not relieve respiratory symptoms or shock. Beta-2 adrenergic agonists relieve bronchospasm but do not relieve upper airway obstruction or shock.
^b Subsequent episodes in the same patient may be less, equally, or more severe.
^c For example, beta-adrenergic blocker by any route of administration (oral, ophthalmic solution), or angiotensin-converting enzyme Inhibitor.

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