Continuing Education Activity

Epinephrine is one of the most commonly used agents in various settings as it functions as medication and hormone. It is currently FDA-approved for various situations, including emergency treatment of type 1 hypersensitivity reactions, including anaphylaxis, induction, and maintenance of mydriasis during intraocular surgeries and hypotension due to septic shock. It also has several off-label uses. This activity will highlight the mechanism of action, adverse event profile, pharmacology, monitoring, and relevant interactions of epinephrine, pertinent for members of the interprofessional team in treating patients with conditions where this agent is indicated.

Objectives:

• Outline the various indications for epinephrine.
• Review the mechanism of action of epinephrine.
• Identify the potential adverse events associated with epinephrine.
• Summarize the importance of interprofessional communication, improving care coordination among the interprofessional team when initiating epinephrine therapy.

Indications

Epinephrine is one of the most commonly used agents in various settings as it functions as medication and hormone. It is currently FDA-approved for various situations, including emergency treatment of type 1 hypersensitivity reactions, including anaphylaxis, induction, and maintenance of mydriasis during intraocular surgeries and hypotension due to septic shock.[1] Off-label uses of epinephrine include, but are not limited to, ventricular fibrillation, pulseless ventricular tachycardia, asystole, pulseless electrical activity (PEA), croup, and severe asthma exacerbations unresponsive to standard treatment.[2][3] In the operating room (OR) setting, epinephrine is also used as a local anesthetic block. Produced by the adrenal medulla, epinephrine plays a vital role in the body’s acute stress response by stimulating the sympathetic nervous system.[4]

Mechanism of Action

Epinephrine is a sympathomimetic catecholamine that exerts its pharmacologic effects on both alpha and beta-adrenergic receptors using a G protein-linked second messenger system. It has a greater affinity for beta receptors in small doses. However, large doses produce selective action on alpha receptors. Through its action on alpha-1 receptors, epinephrine induces increased vascular smooth muscle contraction, pupillary dilator muscle contraction, and intestinal sphincter muscle contraction. Other significant effects include increased heart rate, myocardial contractility, and renin release via beta-1 receptors. Beta-2 effects produce bronchodilation, which may be useful as an adjunct treatment of asthma exacerbations and vasodilation, tocolysis, and increased aqueous humor production.

Administration

Depending on the diagnosis, epinephrine administration can be in various forms. For the treatment of anaphylaxis, epinephrine is preferably injected intramuscularly into the anterolateral aspect of the thigh due to rapid absorption. Subcutaneous injection is also an option. For advanced cardiovascular life support (ACLS), patients can receive epinephrine intravenously or intraosseous if needed. Another route of administration is through an endotracheal tube often used in neonatal resuscitation.

Adverse Effects

Adverse Effects Listed by System

• Central nervous system (CNS): Anxiety, dizziness, nervousness, agitation, headache, Parkinson disease exacerbation
• Cardiovascular: Arrhythmias, chest pain, hypertension, palpitations, tachycardia, cerebrovascular accidents, ventricular ectopy, vasospasm, tissue ischemia
• Dermatologic: Gangrene at the injection site (especially in buttocks), skin necrosis with extravasation
• Endocrine: Hyperglycemia, hypokalemia, lactic acidosis
• Gastrointestinal: Nausea, vomiting, increase in AST and ALT
• Neuromuscular: Tremors, weakness
• Renal: Decreased renal perfusion
• Respiratory: Dyspnea, pulmonary edema

The more common side effects include tachycardia, hypertension, headache, anxiety, apprehension, palpitations, diaphoresis, nausea, vomiting, weakness, and tremors.

Drug Interactions

• Alpha-adrenergic blockers: Antagonizes pressor effects
• Antihypertensives: Antagonizes pressor effects
• Vasodilators: Antagonizes pressor effects
• Diuretics: Antagonizes pressor effects
• Beta-adrenergic blockers: Potentiates pressor effects
• Monoamine oxidase (MAO) inhibitors: Potentiates pressor effects
• Catechol-o-methyltransferase (COMT) inhibitors: Potentiates pressor effects

Careful monitoring of vital signs is crucial, especially in patients with polypharmacy.

Contraindications

There are no absolute contraindications against using epinephrine. Some relative contraindications include hypersensitivity to sympathomimetic drugs, closed-angle glaucoma, anesthesia with halothane. Another unique contraindication to be aware of is catecholaminergic polymorphic ventricular tachycardia.[5] As is the case with prescribing any medication, all practitioners should use clinical judgment and evaluate the benefits versus risks with epinephrine.

Select circumstances indicate the need for additional assessment before using epinephrine, as discussed below.

Pregnancy

Epinephrine is considered a pregnancy Category C medication under the old FDA categorization system. There are no well-controlled studies in humans, although animal studies have shown a teratogenic risk during organogenesis. It is capable of crossing the placenta. Epinephrine use requires caution when maternal blood pressure is 130/80 mm Hg and greater.

Labor and Delivery

Due to its effect on beta-2 adrenergic receptors causing tocolysis, epinephrine opposes the actions of oxytocin on the uterus and may delay labor. It also requires caution during anaphylaxis-induced hypotension in pregnancy as it may lead to uterine vasoconstriction, thus decreasing oxygen delivery to the fetus.[6]

Breastfeeding

More clinical studies are needed to determine if epinephrine is excreted through breast milk.

Pediatrics

Epinephrine is effective at a dilution of between 1 to 100,000 and 1 to 400,000 for mydriasis induction and maintenance in pediatric intraocular surgeries.

Geriatrics

Due to the expected decrease in renal, hepatic, and cardiac function of geriatric patients, epinephrine should be started at the lower end of the dosing regime and titrated appropriately for clinical effect.

Location

Several locations should be avoided when injecting epinephrine, specifically the digits, nose, penis, and toes, as these areas are more prone to ischemia. Avoid using epinephrine in tissues supplied by end arteries.

Monitoring

When administered parenterally, epinephrine has a rapid onset but a short duration of action. When given intravenously, it has a half-life of fewer than 5 minutes. Metabolism is primarily in the liver, along with various other locations such as the kidneys, skeletal muscle, and mesenteric organs. It is degraded into an inactive metabolite named vanillylmandelic acid by MAO and COMT and excreted into the urine. However, a small amount of the drug is excreted unchanged as well.

Epinephrine is a hormone that produces widespread effects. Certain effects need monitoring. Tachycardia and hypertension are expected effects when giving epinephrine intravenously, so it is important to titrate the drug carefully while monitoring hemodynamics. Epinephrine is also used with anesthetic agents to provide analgesia. In locations where extravasation of epinephrine has occurred, prevention and treatment of ischemia-induced necrosis are necessary. The infiltrated area should receive treatment with a 10 mL to 15 mL saline solution containing 5 mL to 10 mg of phentolamine, an alpha-adrenergic blocking agent. A study showed how hospitalized patients in the ICU with finger ischemia were associated with the use of vasopressors, including epinephrine.[7]

Renal impairment requires monitoring as epinephrine causes renal blood vessel constriction and can decrease urine impairment. In patients with chronic kidney disease (CKD) and various other renal pathologies, clinical judgment is necessary. Researchers discovered a new enzyme named renalase produced by the kidneys and responsible for metabolizing epinephrine. Some studies have shown how renalase is deficient in CKD, making epinephrine levels greater in CKD. [8] During intraocular use, epinephrine requires dilution; otherwise, corneal endothelial damage can result from the administration of undiluted concentrations of sodium bisulfite.

Toxicity

Administration of excess epinephrine that leads to supra-therapeutic levels may cause predictable adverse effects that warrant supportive treatment. Overdose may cause elevated arterial pressures leading to cerebrovascular accidents. Pressor effects can be minimized by using an alpha-adrenergic blocker or by the usage of vasodilators such as nitrites. Pulmonary edema can also present due to the underlying mechanism of peripheral vasoconstriction along with myocardial stimulation.[9] Respiratory support may be needed alongside an alpha-adrenergic blocking drug to decrease vasoconstriction and enhance vascular flow. Due to strong beta-1 adrenergic effects on cardiac tissue, epinephrine toxicity may lead to potentially fatal cardiac arrhythmias or ischemia. Treatment involves the administration of beta-adrenergic blocking agents such as metoprolol.

Enhancing Healthcare Team Outcomes

With numerous medications readily available for a variety of medical conditions for inpatient and outpatient settings, epinephrine is not often a topic of discussion until a patient exhibits severe medical deterioration. Because of its physiologic effects, epinephrine is a common agent used in "code" situations, including ventricular fibrillation and PEA. These situations require the expertise and skills of the entire interprofessional healthcare team comprised of physicians, nurses, pharmacists, EMTs, and other health professionals. During these circumstances, there is a team leader, usually an attending clinician, who oversees and makes medical decisions for the patient. The clinician, along with the help of other healthcare professionals and students, interprets EKGs and indicates if and when epinephrine is required. From an emergency medical technician standpoint in prehospital settings, epinephrine comes already prepared for administration, versus other hospital settings where the person administering the drug must draw it with a syringe. Interprofessional communication is vital during these times, so all healthcare professionals are aware of the necessary steps required to resuscitate the patient.

The proper dosage of medication must be administered within an appropriate period to limit the risk of toxicity; thus, there should be a pharmaceutical consult on these cases. Communication among all team members must be fluid, as all members function as an interprofessional team, not as individuals operating in silos of expertise. Researchers recently conducted a randomized, double-blinded trial in the United Kingdom whose primary endpoint was to examine the survival rate at thirty days of out-of-hospital cardiac arrests, with secondary outcomes to study the rate of survival until hospital discharge with favorable neurologic outcome. The study included more than 8,000 patients; roughly half were given parenteral epinephrine or saline placebo, with appropriate standard care. The conclusion was that there was a higher thirty-day survival with epinephrine as opposed to saline placebo. However, there was no improvement in neurologic outcome.[10]

Interprofessional management of epinephrine therapy will yield the best patient outcomes with the fewest adverse effects. [Level 5]