Safety of epinephrine for anaphylaxis in the emergency setting

doi:10.5847/wjem.j.issn.1920-8642.2013.04.001

Abstract

Abstract:

BACKGROUND: While epinephrine is the recommended first-line therapy for the reversal of anaphylaxis symptoms, inappropriate use persists because of misunderstandings about proper dosing and administration or misconceptions about its safety. The objective of this review was to evaluate the safety of epinephrine for patients with anaphylaxis, including other emergent conditions, treated in emergency care settings.
METHODS: A MEDLINE search using PubMed was conducted to identify articles that discuss the dosing, administration, and safety of epinephrine in the emergency setting for anaphylaxis and other conditions.
RESULTS: Epinephrine is safe for anaphylaxis when given at the correct dose by intramuscular injection. The majority of dosing errors and cardiovascular adverse reactions occur when epinephrine is given intravenously or incorrectly dosed.
CONCLUSION: Epinephrine by intramuscular injection is a safe therapy for anaphylaxis but training may still be necessary in emergency care settings to minimize drug dosing and administration errors and to allay concerns about its safety.

Key words: Allergy, Anaphylaxis, Epinephrine, Safety, Cardiovascular side effects

Joseph P Wood, Stephen J Traub, Christopher Lipinski. Safety of epinephrine for anaphylaxis in the emergency setting[J]. World Journal of Emergency Medicine, 2013, 4(4): 245-251.

Figures/Tables 5

Table 1

Table 2

Table 3

Cardiovascular events reported with epinephrine given for anaphylaxis and other conditions

Reports	Patient (s)	IV epinephrine dosing(dilution)	Cardiovascular event (s)
Horak et al, 1983^[25]	23 year-old female, penicillin-induced anaphylaxis	0.3 mg	Severe myocardial ischemia
Butte et al, 1999^[26]	11 year-old male, croup with severe respiratory distress	0.5 mL (by nebulizer diluted in 3 mL 0.9% saline)	Increased heart rate, ventricular tachycardia, myocardial infarction
Johnston et al, 2003^[27]	40 year-old female with reaction to pseudoephedrine and diphenhydramine taken for acute sinusitis (no hypotension or respiratory compromise)	1 mL (1:1 000)	Pulseless ventricular tachycardia
Anchor et al, 2004^[28]	1. 60 year-old female, NSAID-induced angioedema 2. 76 year-old male, idiopathic anaphylaxis	1. 0.3 mL (1:1 000) 2. 0.2 mL (1:1 000)	1. Intermittent ventricular tachycardia 2. Immediate blood pressure spike, tachycardia, and nonspecific ST changes by ECG
Arfi et al, 2005^[29]	14 year-old male, IVIg-induced anaphylaxis	0.01 mL/kg (1:1 000)	Acute myocardial ischemia
Putland et al, 2006^[30]	220 cases with severe asthma (retrospective)	Average epinephrine infusion rate was 1.5 μg/min (range=0.5 to 13.3 μg/min) Total dose range=15 to 99 551 μg Duration of infusion, 10 min to 11.4 days (median 19.5 h)	1. Supraventricular tachycardia (n=2; both SVT) 2. Hypotension requiring treatment (n=4) 3. Objective evidence of myocardial ischemia, elevated troponin (n=2) 4. Sinus tachycardia (n=23) 5. Chest pain without ECG or marker changes (n=2)
Shaver et al, 2006^[31]	29 year-old female, penicillin-induced anaphylaxis	0.1 mg (1:10 000)	Acute myocardial infarction
Izgi et al, 2010^[32]	37 year-old female, amoxicillin-induced anaphylaxis	1^st dose: 0.5 mg (1:10 000) 2^nd dose: 0.5 mg (1:10 000) 3^rd dose (undiluted): 1 mg (1: 1 000)	Severe myocardial ischemia
Kanwar et al, 2010^[6]	1. 23 year-old female, seafood anaphylaxis 2. 52 year-old female, seafood anaphylaxis 3. 33 year-old female, IV iron sulfate anaphylaxis 4. 34 year-old male, seafood anaphylaxis	1. 2 doses of 1 mg (1:10 000) 2. 0.3 mg (1:1 000) 3. 0.3 mg (1:1 000) 4. 1 mg (1:10 000)	1. Cardiogenic shock / severe left ventricular dysfunction 2. Severe left-sided chest pain, new-onset ST elevations 3. Right-sided coronary artery dissection 4. Sustained ventricular tachycardia that resolved spontaneously
Cunnington et al, 2013	43 year-old female, flucloxacillin anaphylaxis	2 doses of 0.5 mg (0.5-mL 1: 1 000 solution) given intramuscularly	5 minutes following a second dose, the patient complained of typical ischemic chest discomfort. ECG demonstrated 1-mm ST-segment depression in the anteroseptal chest leads. Pain and ECG changes resolved spontaneously after 30 minutes. Labs (6 hours later) showed elevated high-sensitivity troponin I level of 530 ng/L (upper limit of normal 30 ng/L).

Table 3

Table 4

Safety of epinephrine given for conditions other than anaphylaxis

Reports	Patients	Epinephrine dosing &administration	Efficacy	Adverse effects
Pliss et al, 1981^[36]	n=25 Acute asthma Age 17-47 years	0.3 mL 1:1 000 [SC] 0, 20, & 40 minutes (0.9 mg total dose) 0.16 mg epinephrine aerosol 0, 10, 20, 30, 40, & 50 minutes (0.96 total dose)	Parenteral epinephrine superior to inhaled epinephrine for severe asthma (patients with greater degree of obstruction)	No significant differences between groups for change in BP, PR, or RR. 70% [SC group] vs. 17% [inhaled] complained of palpitations or tremor Parameters approached normal in both groups as treatment progressed
Becker et al, 1983^[37]	n=40 Acute asthma Age 6-17 years	0.4 mL 1:1 000 [SC] (0.1 mL/kg, 0.4 mg total dose) 0.5% salbutamol by mask and nebulizer using 100% oxygen (6-10 L/min flow) for 5-10 minutes	No significant difference between groups for pulmonary index, HR, RR, SBP, DBP, FEV1, FVC, percent FEV1/FVC, and FEF 25%-75% (absolute or normalized) Increased HR with salbutamol at 15 and 30 minutes (no change for epinephrine) Decrease in RR with salbutamol (no change for epinephrine) Decrease in DBP with epinephrine	Increased HR with salbutamol at 15 and 30 minutes (no change for epinephrine) Decrease in RR with salbutamol (no change for epinephrine) Decrease in DBP with epinephrine Nausea, vomiting, tremor, headache, palpitations, excitement, and pallor were noted in 50% of patients given epinephrine
Cydulka et al, 1988^[38]	n=95 Acute asthma Age 15-96 years(patients with history of recent MI or angina excluded)	0.3 mL 1:1 000 [SC] 0, 20, 40 minutes (0.9 mg total dose)	Regardless of age, SC epinephrine rapidly and effectively reversed hypoxemia and improved pulmonary function	No significant change in HR No increase in ventricular arrhythmias across ages
Ledwith et al, 1995^[39]	n=56 Croup with stridor and barking cough Age 0->60 months	0.5 mL 2.25% racemic epinephrine in 2.0 mL normal saline by nebulizer	Effective with patients having a sustained response to a single dose of racemic epinephrine, but success depended on observation period to manage potential relapse	No adverse events reported and investigators' conclusion was that racemic epinephrine was safe
Lin et al, 1996^[40]	n=90 Acute asthma Children	2 mL (5.0 mg) terbutaline in 2 mL 0.9% saline for inhalation over 10 minutes 0.01 mL/kg 1:1 000 epinephrine [SC to deltoid] (maximum 0.3 mL)	The clinical severity score and spirometry of both groups were significantly improved after treatment Epinephrine had better mean oxygen saturation, frequency of oxygen desaturation, and FEF 25%-75% For patients with initial FEV1 <60% of predicted, epinephrine treatment was more effective in the improvement of FEV1, FEF 25%-75%, and oxygen saturation	Significantly more adverse effects occurred epinephrine (47% vs. 11%, P=0.0002) which included pallor, tremor, dizziness, headache, palpitation, soreness of legs, numbness of extremities, cold sweating, general weakness and nausea
Plint et al, 2000^[41]	n=121 Acute asthma Age 1-17 years	0.03 mL/kg salbutamol (5 mg/mL) made up in 3 mL normal saline given by mask and nebulizer with oxygen at 5 L/min 0, 20, 40 minutes (maximum 1 mL) 0.03 mL/kg racemic epinephrine (20 mg/mL) made up in 3 mL normal saline given by mask and nebulizer with oxygen at 5 L/min 0, 20, 40 minutes (maximum 1 mL)	No significant difference in change in pulmonary index score or oxygen saturation between groups Significantly greater decrease in HR and increase in RR with salbutamol No difference in requirement for supplemental oxygen, length of emergency department stay, admissions, or length of hospital stay	No significant difference in rate of pallor, nausea, increased heart rate, or tremor Patients treated with epinephrine had significantly higher rate of minor adverse effects including excess nasal discharge, cough, sneezing, stinging nostrils, sore throat, and agitation
Smith et al, 2003^[42]	n=27 Life-threatening asthma Age 19-58 years	In 24/27 pts, 50 μg loading dose and 1 mg of a 1:10 000 solution (200 μg total dose) 14/24 pts also received continuous IV epinephrine between 3 and 20 μg/min (80% of pts received 1 mg over 1 hour) 3/24 pts received IV epinephrine infusion only, either 1 mg over one hour or 1-2 μg/min for 2 hours (300 μg total dose)	Retrospective chart review of safety only. Efficacy not reported	No patient had an arrhythmia other than sinus tachycardia No major adverse effects No incidences of cardiac ischemia, hypotension, neurologic defect or death Only transient hypertension at intubation that resolved with sedation IV epinephrine safe in young adults with life-threatening asthma
Mull et al, 2004^[43]	n=66 Acute bronchiolitis Age 0-10 months	0.9 mg/kg of 2.25% nebulized racemic epinephrine in 2 mL of 0.9% isotonic sodium chloride given by mask with 100% oxygen at 6 L/min 0, 30, 60 minutes 0.15 mg/kg of 0.5% nebulized albuterol sulfate in 2 mL of 0.9% isotonic sodium chloride given by mask with 100% oxygen at 6 L/min 0, 30, 60 minutes	Successfully relieves respiratory distress No significant difference in clinical score, respiratory rate, or room air saturation over time between the groups No significant difference in relapse rate between the groups	Adverse effects occurred infrequently 1 infant vomited from the epinephrine group vs. 5 from the albuterol group 1 infant exhibited pallor in the epinephrine group
Adoun et al, 2004^[44]	n=38 Acute severe asthma	3 mg nebulized epinephrine given over 20 minutes 5 mg nebulized terbutaline given over 20 minutes	Equal increase in PEF and decrease in RR between groups No synergism with both agents	No adverse events observed
Langley et al, 2005^[45]	n=62 Hospitalized bronchiolitis Age 6 weeks to 24 months	0.5 mL of 2.25% nebulized racemic epinephrine by mask with oxygen at 5-7 L/min q 1-4 h 1.5 mg (>10 kg), 1.25 mg (>6 kg-<10 kg), or 0.75 mg (<6 kg) nebulized albuterol sulfate by mask with oxygen at 5-7 L/min given in 3 mL normal saline q 1-4 h	Successfully relieves respiratory distress without overall significant difference in efficacy between groups Racemic epinephrine significantly better for wheezing on day 2 and entire hospital stay	Adverse events including tremor, vomiting, or pallor were not significantly difference between the groups

Table 4

Table 5

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Epinephrine	Epinephrine, IM; autoinjector or 1:1 000 solution
	Weight, 10-25 kg: 0.15 mg epinephrine autoinjector (IM to anterolateral thigh)
	Weight, >25 kg: 0.3 mg epinephrine autoinjector (IM to anterolateral thigh)
	Epinephrine (1:1 000 solution, 0.01 mg/kg per dose; maximum dose=0.5 mg per dose (IM, anterolateral thigh)
	Epinephrine doses might need to be repeated every 5-15 minutes
	Consider continuous epinephrine infusion for persistent hypotension (ideally with continuous noninvasive monitoring of blood pressure and heart rate); alternatives are endotracheal or intraosseous epinephrine
Others	Place patient in Trendelenburg position
	Bronchodilator (β2-agonist; albuterol)
	Metered-dose inhaler (child: 4-8 puffs; adults: 8 puffs) or
	Nebulized solution (child: 1.5 mL; adult: 3 mL) q 20 minutes or continuously as needed
	H₁ blocker: less-sedating second-generation
	antihistamines recommended
	Corticosteroids
	Prednisone at 1 mg/kg with a maximum dose of 60-80 mg orally or
	Methylprednisolone at 1 mg/kg with a maximum dose of 60 to 80 mg IV
	Supplemental oxygen therapy
	IV fluids in large volumes if patients present with orthostasis, hypotension, or incomplete response to IM epinephrine
	Vasopressors (other than epinephrine) for refractory hypotension, titrate to effect
	Glucagon for refractory hypotension, titrate to effect
	Child: 20-30 µg/kg
	Adult: 1-5 mg
	Dose can be repeated or followed by infusion of 5-15 µg/min
	Atropine for bradycardia, titrate to effect

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