Epinephrine for rapid treatment of anaphylaxis – an overview

Anaphylaxis Sudden and severe allergic reaction Typically occurs within minutes of exposure to the allergen and almost always within two hours Reaction results in release of chemicals in the blood and body tissue encouraging the dilation of blood vessels, leading to a decrease in blood pressure and fluid leaks (often resulting in hives and swelling)

Anaphylaxis – common causes Foods, such as peanuts Tree nuts, i.e. almonds, walnuts, hazel, brazil, and cashew nuts Shellfish, i.e. shrimp and lobster Dairy products Eggs Insect stings, i.e. wasps, bees, ants Latex Medications Exercise

Anaphylaxis Signs Rapid, weak pulse Flushed or pale skin Abnormal lung sounds Loss of consciousness Symptoms Swelling of tissues Hives Itching Nausea, vomiting, diarrhea Dizziness or fainting Difficulty breathing

Diagnostic criteria Anaphylaxis is highly likely when any ONE of the following three criteria is fulfilled: Criterion 1 — Acute onset of an illness (minutes to several hours) involving the skin, mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula) and at least one of the following: Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak expiratory flow, hypoxemia). OR Reduced blood pressure (BP) or associated symptoms and signs of end-organ dysfunction (eg, hypotonia [collapse] syncope, incontinence). (See 'Criterion 3' below.) Criterion 2 — Two or more of the following that occur rapidly after exposure to a LIKELY allergen for that patient (minutes to several hours): Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen lips- tongue-uvula). Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak expiratory flow, hypoxemia). Reduced BP or associated symptoms and signs (eg, hypotonia [collapse], syncope, incontinence). Persistent gastrointestinal symptoms and signs (eg, crampy abdominal pain, vomiting). Criterion 3 — Reduced BP after exposure to a KNOWN allergen for that patient (minutes to several hours) Source: UpToDate: Anaphylaxis: Rapid recognition and treatment; Accessed 5/27/2015

Epinephrine Drug of choice for emergency treatment of severe allergic reactions Epinephrine acts on both alpha and beta adrenergic receptors Lessens vasodilation and increased vascular permeability that occurs during anaphylaxis, which can lead to loss of intravascular fluid volume and hypotension Causes bronchial smooth muscle relaxation that helps reduce bronchospasm, wheezing and shortness of breath Alleviates itching, hives and angioedema (generalized swelling) and may be effective in relieving gastrointestinal and genitourinary symptoms associated with anaphylaxis because of relaxer effects on smooth muscle of stomach, intestine, uterus, and urinary bladder

Epinephrine autoinjectors in schools Exploratory, cross-sectional, web-based survey of 6,019 U.S. schools that participated in the EpiPen4Schools program during the school year 919 anaphylactic events reported in 607 schools 852 anaphylactic events with analyzable data Triggers varied seasonally with food listed most frequently overall (62.5%) 88.8% occurred in students 21.9% occurred in individuals with no known allergies 74.7% were treated with epinephrine autoinjector (EAI); 8.5% received a second epinephrine injection Of the 204 individuals not treated with an EAI, 77.0% received antihistamines, 12.7% received another treatment, and 8.3% received no treatment 79.6% were transported to the hospital White MV, Hogue SL, et al. EpiPen4Schools pilot survey: occurrence of anaphylaxis, triggers, and epinephrine administration in a U.S. school settings. Allergy Asthma Proc 2015 Apr 20.

Early epinephrine treatment for food- induced anaphylaxis (FIA) Chart review study – all patients who presented to the emergency department with FIA between January 1, 2004, and December 31, emergency department visits for FIA identified during the study period 234 patients (61%) received epinephrine 164 (70%) received early epinephrine treatment (before arrival to ED) 70 (30%) first received epinephrine in ED (late treatment). Patients who received early epinephrine treatment were: Older (7.4 vs 4.3 years; P =.008) More likely to have a known food allergy (66% vs 34%; P <.001) More likely to own an epinephrine autoinjector (80% vs 23%; P <.001) Patients treated early were less likely to be hospitalized (17% vs 43%; P <.001). After adjusting for age, sex, and race, the patients who received early epinephrine treatment remained at significantly decreased risk of hospitalization compared with those who received late epinephrine treatment (odds ratio 0.25 [95% CI, ]) Fleming JT, Clark S, et al. Early treatment of food-induced anaphylaxis with epinephrine is associated with a lower risk of hospitalization. J Allergy Clin Immunol Pract 2015 Jan-Feb;3(1):57-62.

From the package insert CONTRAINDICATIONS There are no absolute contraindications to the use of epinephrine in a life-threatening situation WARNINGS Only inject into the anterolateral aspect of the thigh – do not inject into buttock Accidental injection into the digits, hands or feet may result in loss of blood flow to the affected area Do note inject intravenously Administer with caution in patients who have heart disease, including patients with cardiac arrhythmias, coronary artery or organic heart disease, or hypertension. In such patients, or in patients who are on drugs that may sensitize the heart to arrhythmias, e.g., digitalis, diuretics, or anti- arrhythmics, epinephrine may precipitate or aggravate angina pectoris as well as produce ventricular arrhythmias. It should be recognized that the presence of these conditions is not a contraindication to epinephrine administration in an acute, life-threatening situation. Epinephrine is light sensitive and should be stored in the carrier tube provided - before using, check to make sure the solution in the auto-injector is not discolored or contains a precipitate PRECAUTIONS Epinephrine autoinjectors are not intended as a substitute for immediate medical care. In conjunction with the administration of epinephrine, the patient should seek immediate medical or hospital care. More than two sequential doses of epinephrine should only be administered under direct medical supervision. The effects of epinephrine may be potentiated by tricyclic antidepressants and monoamine oxidase inhibitors. Some patients may be at greater risk of developing adverse reactions after epinephrine administration: hyperthyroid individuals, individuals with cardiovascular disease, hypertension, or diabetes, elderly individuals, pregnant women, pediatric patients under 30 kg (66 lbs.) body weight using adult autoinjector and pediatric patients under 15 kg (33 lbs.) body weight using child autoinjector INFORMATION FOR PATIENTS Epinephrine may produce symptoms and signs that include an increase in heart rate, the sensation of a more forceful heartbeat, palpitations, sweating, nausea and vomiting, difficulty breathing, pallor, dizziness, weakness or shakiness, headache, apprehension, nervousness, or anxiety. ADVERSE REACTIONS Adverse reactions to epinephrine include transient, moderate anxiety; apprehensiveness; restlessness; tremor; weakness; dizziness; sweating; palpitations; pallor; nausea and vomiting; headache; and/or respiratory difficulties. These symptoms occur in some persons receiving therapeutic doses of epinephrine, but are more likely to occur in patients with hypertension or hyperthyroidism. Arrhythmias, including fatal ventricular fibrillation, have been reported in patients with underlying cardiac disease or certain drugs [see PRECAUTIONS, Drug Interactions]. Rapid rises in blood pressure have produced cerebral hemorrhage, particularly in elderly patients with cardiovascular disease. Angina may occur in patients with coronary artery disease. The potential for epinephrine to produce these types of adverse reactions does not contraindicate its use in an acute life-threatening allergic reaction. Accidental injection into the digits, hands or feet may result in loss of blood flow to the affected area (see WARNINGS). Adverse events experienced as a result of accidental injections may include increased heart rate, local reactions including injection site pallor, coldness and hypoaesthesia or injury at the injection site resulting in bruising, bleeding, discoloration, erythema or skeletal injury.

From UpToDate In patients of all ages, epinephrine administered in therapeutic doses by any route often causes mild transient pharmacologic effects, such as anxiety, restlessness, headache, dizziness, palpitations, pallor, and tremor. These symptoms and signs are similar to those occurring during the physiologic "fight or flight" response due to endogenous epinephrine that occurs normally in sudden frightening or life-threatening situations. Anaphylaxis itself can lead to angina, myocardial infarction, and cardiac arrhythmias in the absence of any exogenous epinephrine or before exogenous epinephrine is administered. “To reiterate, there are no absolute contraindications to the use of epinephrine in the treatment of anaphylaxis. The risk of death or serious neurologic sequelae from hypoxic-ischemic encephalopathy due to inadequately treated anaphylaxis usually outweighs other concerns. Existing evidence clearly favors the benefit of epinephrine administration in anaphylaxis. Sound clinical judgment is essential.” Source: UpToDate, Anaphylaxis: Rapid recognition and treatment, accessed 5/27/2015

Reports of adverse events and epinephrine autoinjectors 256 reports that were submitted FDA during sample period, October 2011-September (DrugLib caveats that information is not vetted and should not be considered as verified clinical evidence) Reports by Reaction Type Accidental exposure (131) Contusion (13) Drug ineffective (51) Injection site pallor (13) Injury associated with device (44)Heart rate increased (13) Expired drug administered (40)Pain (11) Injection site pain (23)Injection site discoloration (9) Hypoesthesia (19) Pain in extremity (16)

Risk of cardiovascular complications and overdose Observational cohort study; April 2008-July 2012; patients in ED who met diagnostic criteria for anaphylaxis. Outcomes assessed were overdose and adverse CV event, including arrhythmia, cardiac ischemia, stroke, angina, and hypertension. 573 patients, of whom, 301 (57.6%) received at least 1 dose of epinephrine 362 doses of epinephrine were administered to 301 patients: 67.7% intramuscular (IM) autoinjector, 19.6% IM injection, 8.3% subcutaneous injection, 3.3% intravenous (IV) bolus, and 1.1% IV continuous infusion. 8 CV adverse events and 4 overdoses with 8 different patients. All the overdoses occurred when epinephrine was administered IV bolus. Adverse CV events were associated with 3 of 30 doses of IV bolus epinephrine compared with 4 of 316 doses of IM epinephrine (10% vs 1.3%; odds ratio 8.7 [95% CI, ], P =.006). Risk of overdose and adverse CV events is significantly higher with IV bolus epinephrine administration. Analysis of the data supports the safety of IM epinephrine and a need for extreme caution and further education about IV bolus epinephrine in anaphylaxis. Campbell RL, Bellolio MF, et al. Epinephrine in anaphylaxis: higher risk of cardiovascular complications and overdose after administration of intravenous bolus epinephrine compared with intramuscular epinephrine.J Allergy Clin Immunol Pract Jan-Feb;3(1):76-80.

Unintentional injections The rate of unintentional injections of epinephrine from autoinjectors is increasing, with more than 15,000 such events being reported voluntarily to the American Association of Poison Control Centers from 1994 to Source: UpToDate, Prescribing epinephrine for anaphylaxis self-treatment, accessed 5/27/2015

Epinephrine digital injections Retrospective cohort study of cases reported to 6 poison centers during 6 years (Texas Poison Center Network database) 365 epinephrine injections to the hand identified for the 6-year period 213 were digital injections; 127 had follow-up All patients had complete resolution of symptoms None were hospitalized or received hand surgery consultation or surgical care Significant systemic effects not reported Pharmacologic vasodilatory treatment used in 23% (29/127) Ischemic effects documented for 4 patients; 2 had symptom resolution within 2 hours All 4 patients received vasodilatory therapy and were discharged home, with complete resolution of symptoms Muck AE, Bebarta VS, et al. Six years of epinephrine digital injections: absence of significant local or systemic effects. Ann Emerg Med 2010 Sep;56(3):270-4.

Reluctance to use epinephrine In response to Campbell RL, Li JT, et al. Emergency department diagnosis and treatment of anaphylaxis: a practice parameter. Ann Allergy Asthma Immunol 2014 Dec;113(6): Dr. Stadtmauer wrote “Injectable epinephrine: an epidemic of misuse” for Medscape (accessed 2/19/2015) “It’s time to face the fact that there is an epidemic of miscommunication about the use of epinephrine for allergic emergencies” “It is epinephrine underuse that has consistently been shown to be the issue in anaphylactic emergencies, and overdose is actually quite rare” At rest plasma epinephrine levels are ng/ml Levels 10 times that amount have been measured in persons exercising, and even higher than that in people under mental stress The standard adult dose of self-injecting epinephrine raises the level of epinephrine in the body about 10 times baseline