AHFS Class:

• alpha- and beta-Adrenergic Agonists 12:12.12

Generic Name(s):

• Epinephrine

• Racepinephrine

• Epinephrine Hydrochloride

• Racepinephrine Hydrochloride

Epinephrine is an endogenous catecholamine that is the active principle of the adrenal medulla; epinephrine acts directly on both α- and β-adrenergic receptors.

Sensitivity Reactions

Epinephrine is the drug of choice in the emergency treatment of severe acute anaphylactic reactions, including anaphylactic shock.163,169,172,193,195,196,197,200,212,228 The drug is used to relieve clinical manifestations such as urticaria, pruritus, angioedema, hypotension, and respiratory distress, which may result from reactions to drugs, contrast media, latex, insect stings, foods (e.g., milk, eggs, fish, shellfish, peanuts, tree nuts), or other allergens, as well as from idiopathic or exercise-induced anaphylaxis.163,195,197,212 Epinephrine should be given to all patients with signs of systemic reactions, particularly hypotension, airway swelling, or breathing difficulty.196 Recommendations for the use of epinephrine in anaphylaxis are largely based on clinical pharmacology studies, observational studies, retrospective studies, and animal models; however, the available data provide compelling evidence to support the prompt use of epinephrine in patients with anaphylaxis.197,200 When administered at the recommended dosages and routes of administration, beneficial pharmacologic effects mediated by both the α- and β-adrenergic properties of the drug (e.g., increased blood pressure, increased force and rate of cardiac contraction, bronchodilation, decreased airway mucosal edema, and suppression of mediator release) are observed.197,200 Patients with anaphylactic shock may require rapid volume resuscitation and vasopressor therapy; epinephrine also is used for its vasopressor effects for the treatment of anaphylactic shock and cardiac arrest associated with anaphylaxis.196,212

Epinephrine should be administered immediately by IM injection as soon as anaphylaxis is diagnosed or strongly suspected.196,197,228 Initial administration by IM injection is preferred, mainly because of safety considerations.196,197,198,199 Serious adverse effects have occurred after IV administration of epinephrine, in part because of confusion regarding correct dosages and routes of administration for the different indications (e.g., treatment of anaphylaxis versus treatment of cardiac arrest).197,199,200,201 (See Dosage and Administration: Administration.) However, IV administration of epinephrine may be necessary in extreme situations such as in anaphylactic shock, cardiac arrest, or in unresponsive or severely hypotensive patients who have failed to respond to multiple IM injections; close hemodynamic monitoring is critical during IV administration of the drug.196,197,198,199,200,201,228 Epinephrine also may be administered subcutaneously, but absorption and subsequent achievement of peak plasma concentrations after subcutaneous injection are slower and may be substantially delayed in patients with shock.196,197 Although oral inhalation has been recommended, the drug may be absorbed too slowly and/or inadequately to be effective in treating allergic manifestations other than laryngeal angioedema.

Cardiac arrest secondary to anaphylaxis should be managed with standard advanced cardiovascular life support (ACLS) measures; alternative vasoactive drugs (e.g., vasopressin, norepinephrine) may be considered in patients who do not respond to epinephrine, and other therapeutic agents such as antihistamines, inhaled β₂-adrenergic agents, and IV corticosteroids also may be useful.196,197 (See Uses: Advanced Cardiovascular Life Support and Cardiac Arrhythmias.)

Patients receiving β-adrenergic blocking agents have an increased incidence and severity of anaphylaxis, and may develop a paradoxical response to epinephrine; glucagon or ipratropium may be considered for the treatment of anaphylaxis in these patients.197,228

Advanced Cardiovascular Life Support and Cardiac Arrhythmias

Epinephrine is used for its α-adrenergic effects to increase blood flow and facilitate return of spontaneous circulation (ROSC) in patients with cardiac arrest.172,179,193,212,400,401,402,403 The drug may be administered by IV, intraosseous (IO)†, endotracheal, or intracardiac injection during cardiopulmonary resuscitation (CPR).172,193,212,400,401,402,403 The principal benefits of epinephrine in patients with cardiac arrest result from increases in aortic diastolic blood pressure and in coronary and cerebral perfusion pressure during resuscitation.400,401,403 The value and safety of the β-adrenergic effects of epinephrine are controversial because they may increase myocardial work and reduce subendocardial perfusion.179,180,400,401

High-quality CPR and defibrillation are integral components of ACLS and the only proven interventions to increase survival to hospital discharge.400,401 Other resuscitative efforts, including drug therapy, are considered secondary and should be performed without compromising the quality and timely delivery of chest compressions and defibrillation.400,401 The principal goal of pharmacologic therapy during cardiac arrest is to facilitate ROSC, and epinephrine is considered the drug of choice for this use.400,401

Despite epinephrine's widespread use in ACLS and evidence of beneficial physiologic effects in both animals and humans, there currently is no evidence demonstrating that the drug improves survival to hospital discharge.161,175,179,180,184,185,400 The current evidence does, however, support that the drug improves survival to hospital admission (when the arrest occurs outside of the hospital setting) and the potential for achieving ROSC.184,400 The American Heart Association (AHA) states that it is reasonable to administer epinephrine 1 mg IV/IO every 3-5 minutes during adult cardiac arrest.400,401 Although higher doses of epinephrine may increase the rate of ROSC, numerous studies comparing standard (1 mg) versus high-dose (e.g., 0.1-0.2 mg/kg) epinephrine have not demonstrated any advantage of the higher doses with regards to survival (i.e., survival to discharge with or without good neurologic recovery, survival to hospital admission).400 While high-dose epinephrine may improve coronary perfusion and increase vascular resistance to promote initial ROSC during cardiac resuscitation, these same effects may result in increased myocardial dysfunction and occasionally a severe hyperadrenergic state in the postresuscitation period.161,179,400 AHA does not recommend the routine use of high-dose epinephrine in cardiac arrest; however, high-dose epinephrine may be considered in certain circumstances (e.g., overdosage of β-adrenergic or calcium-channel blocking agents).400,401,403

Management of cardiac arrest is based on the patient's arrest rhythm (i.e., ventricular fibrillation, pulseless ventricular tachycardia, pulseless electrical activity [PEA], or asystole).400,401 As the rhythm is likely to evolve over the course of resuscitation, the appropriate management strategy should be adapted accordingly.401 In adults with ventricular fibrillation or pulseless ventricular tachycardia resistant to initial CPR attempts and at least one defibrillation shock, epinephrine may be administered with the goal of increasing myocardial blood flow during CPR and achieving ROSC;400,401 however, the optimal timing of epinephrine administration, particularly in relation to defibrillation, is not known and may vary based on patient-specific factors and resuscitation conditions.400 In adults with asystole or PEA, epinephrine may be given as soon as feasible after the onset of cardiac arrest based on studies demonstrating improved survival to hospital discharge and increased ROSC when the drug was administered early during the course of treatment for a nonshockable rhythm.400,401 In previous ACLS guidelines, vasopressin was recommended as an alternative to epinephrine in the treatment of adult cardiac arrest;161,175,401 however, vasopressin has been removed from the current ACLS guideline because of equivalence of effect with epinephrine and efforts to simplify the management approach when therapies are found to be equivalent.400,405

Once a patient achieves ROSC, appropriate postcardiac arrest care should be initiated immediately because of evidence indicating that systematic postresuscitation care can improve the likelihood of patient survival with good quality of life.400,401,404 Because hemodynamic instability is common after cardiac arrest, epinephrine infusion may be used in the postresuscitation period to optimize blood pressure, cardiac output, and systemic perfusion after ROSC.402,403,404 Epinephrine also may be used during the periarrest period in adults who require inotropic or vasopressor support, in particular for the treatment of symptomatic bradycardia; although not a first-line drug, epinephrine may be considered in patients who are unresponsive to atropine therapy, or as a temporizing measure while awaiting availability of a pacemaker.401

In contrast to adults, cardiac arrest in infants and children is not usually precipitated by a primary cardiac cause, but is more often the result of progressive respiratory failure or shock.403 In addition to high-quality CPR, ventilation is extremely important in pediatric advanced life support (PALS) because of the high percentage of asphyxial arrests that occur in pediatric patients.403 Similar to adults, vasopressors are used during pediatric cardiac arrest to restore spontaneous circulation although no specific pediatric studies have demonstrated the effectiveness of any vasopressor in this setting.402,403 AHA states that it is reasonable to administer epinephrine during pediatric cardiac arrest.402 The drug also may be used for hemodynamic support during the postresuscitation period.402,403 Epinephrine also is used in the emergency treatment of infants and children with bradycardia and cardiopulmonary compromise (with a palpable pulse) and is included in current PALS guidelines for this use; epinephrine is recommended in this situation when bradycardia persists despite ventilation, oxygenation, and chest compressions.403 Drugs are rarely needed during the resuscitation of neonates; because hypoxemia and inadequate lung inflation are common causes of bradycardia in the newborn infant, establishing adequate ventilation is the most important corrective measure in these patients.213,214

Epinephrine also has been used in the treatment of syncope resulting from atrioventricular (AV) nodal block.172,193 However, permanent pacemaker implantation is the treatment of choice for third-degree and advanced second-degree AV nodal block (complete heart block).182

Septic Shock

Epinephrine is used for the treatment of hypotension associated with septic shock, generally as a second-line agent.195,204,205,207,208,209,235,238

Vasopressors such as epinephrine are used in the management of shock to restore blood pressure and tissue perfusion after initial fluid resuscitation is attempted.195,204,205,206,208,210 The Surviving Sepsis Campaign International Guidelines for Management of Sepsis and Septic Shock recommend norepinephrine as the vasopressor of choice in adults with septic shock; if adequate blood pressure is not achieved, epinephrine may be added.204,205,208 Epinephrine is a potent vasoconstrictor with predominantly β-adrenergic effects at low doses and α-adrenergic effects at higher doses.206,235 Epinephrine administration can be associated with an increased rate of arrhythmias, decreased splanchnic blood flow, and increased blood lactate concentrations.204,206,208,209,235 Despite these adverse effects, there is no clinical evidence indicating that the drug is associated with worse outcomes than norepinephrine, and therefore, some experts suggest that epinephrine should be considered when an additional agent is needed to maintain adequate blood pressure during septic shock.204,207,209,210 In a double-blind, randomized controlled study comparing the effects of epinephrine and norepinephrine in intensive care patients, including a subgroup with septic shock, no substantial difference in 28- or 90-day mortality or time to achieve mean arterial pressure (MAP) goals was observed between the treatment groups; however, 13% of patients who received epinephrine were withdrawn from the study as a result of lactic acidosis or tachycardia.207,208 In another study in patients with septic shock, there was no difference in all-cause mortality, hemodynamic stabilization, resolution of organ dysfunction, or adverse events between patients receiving epinephrine and those receiving norepinephrine plus dobutamine.209

Epinephrine should not be used in cardiogenic shock because it increases myocardial oxygen demand, nor should it be used in hemorrhagic or traumatic shock.172,206,208,212

Local Vasoconstriction

Epinephrine may be added to solutions of some local anesthetics to decrease the rate of vascular absorption of the anesthetic, thereby localizing anesthesia and prolonging the duration of anesthesia; the risk of systemic toxicity from the local anesthetic is also decreased.172,215,216

Epinephrine has been applied topically to control superficial bleeding from arterioles or capillaries in the skin, mucous membranes, or other tissues. Bleeding from larger vessels is not controllable by topical application of epinephrine.

Premature Labor

Epinephrine has been used to relax uterine musculature and inhibit uterine contractions in premature labor; however, the cardiovascular effects and other adverse effects limit the usefulness of the drug for this purpose. (See Cautions: Pregnancy.) Other β-agonists (e.g., terbutaline) are preferred.165,173 Some manufacturers state that epinephrine injection should be avoided during the second stage of labor.195

Bronchospasm

Asthma

Epinephrine and racepinephrine hydrochloride are used for the symptomatic treatment of asthma.160,166,190,191,192,194,196,236 Racepinephrine is commercially available as an oral bronchodilator for self-medication for the temporary relief of mild symptoms of intermittent asthma (e.g., wheezing, chest tightness, shortness of breath).190,192,236 Once a diagnosis of asthma has been confirmed by a clinician, use of a nonprescription (over-the-counter, OTC) bronchodilator may be appropriate in patients with mild intermittent asthma; because asthma may be life-threatening, those with more severe asthma (i.e., persistent asthma) or worsening asthma (symptoms not relieved within 20 minutes or with maximum recommended dosages, increasing frequency of asthma attacks) should consult a clinician for other treatment options.166,190,192 An epinephrine preparation for oral inhalation use no longer is commercially available in the US.166,223,236

While orally inhaled epinephrine was once widely used for its bronchodilating effects in the management of reversible airway obstruction,191,194 the drug has been replaced by more selective and rapid-acting agents (e.g., inhaled β₂-adrenergic agonists), and epinephrine is not recommended as a drug of choice for the rapid relief of asthma in current asthma management guidelines.160,192,202,203 In the stepped-care approach to antiasthmatic therapy, most experts currently recommend use of a selective short-acting inhaled β₂-adrenergic agonist (e.g., albuterol, levalbuterol, pirbuterol) on an intermittent, as-needed basis to control acute symptoms (e.g., cough, wheezing, dyspnea).148,160,162,174 Less β₂-selective bronchodilators such as epinephrine generally are not recommended because of their potential to cause excessive cardiac stimulation (e.g., increased heart rate, myocardial irritability, increased oxygen demand), particularly at high doses.160,162,196 For information on the stepped-care approach for drug therapy in asthma, see Asthma under Uses: Bronchospasm, in Albuterol 12:12.08.12

Epinephrine also has been used parenterally for the treatment of severe asthma.160,193,194,196 Subcutaneous or IM epinephrine is the drug of choice for acute asthma attacks potentially associated with anaphylaxis but otherwise is reserved for severe asthma exacerbations when inhaled or parenteral β₂-selective agents are not readily available or are ineffective.160,162,174,196 Subcutaneous administration of epinephrine also may be useful when tachypnea and low tidal volume may prevent effective therapy with an orally inhaled β₂-adrenergic agonist or when orally inhaled therapy is not effective. Epinephrine also has been used IV for the treatment of severe asthma exacerbations; however, there is no evidence that the drug improves outcomes when compared with the selective inhaled β₂-adrenergic agonists.193,196

Upper GI Hemorrhage

Epinephrine injection has been used as an endoscopic treatment modality for the management of acute nonvariceal upper GI bleeding†; when used for this purpose, a dilute solution of epinephrine (in 0.9% sodium chloride injection) is injected into and around the ulcer base during endoscopy to produce tamponade and achieve hemostasis.229,230,231,232,233,234 Such therapy should not be used alone and should be combined with an additional endoscopic hemostatic modality (e.g., clips, thermocoagulation).229,230,231,232,233,234

For uses of epinephrine in the treatment of glaucoma or as a mydriatic, see 52:24. For use of epinephrine as a vasoconstrictor and hemostatic in the eye and mucosa, see 52:24.

Administration

USP has changed its labeling standard for single-entity drug products to no longer allow the use of ratios to express drug concentrations. 226,227This labeling change was prompted by numerous reports of serious medication errors caused by confusion with different ratio expressions. 200,226Effective May 1, 2016, all single-entity preparations of epinephrine injection, USP should be labeled only in terms of strength per mL (i.e., mg/mL). 227While concentrations of some epinephrine preparations were historically expressed in ratios (e.g., 1:1000 or 1:10,000), such designation is no longer acceptable because of the risk of dosing errors. 226,227

Epinephrine usually is administered by IM, subcutaneous, or IV injection, or by continuous IV infusion.163,169,172,193,195,212 Epinephrine also has been administered by intraosseous (IO) injection† in the setting of advanced cardiovascular life support (ACLS), generally when IV access is not readily available; onset of action and systemic concentrations are comparable to those achieved with venous administration.401,403 If vascular access (IV or IO) cannot be established during cardiac arrest, epinephrine may be administered endotracheally; however, this method of administration results in lower plasma concentrations compared with the same dose given intravascularly.175,193,401,403 Epinephrine also has been administered by intracardiac injection (into the left ventricular chamber) during cardiac arrest;161,172,193,212 however, this route of administration is not recommended in current ACLS guidelines.400,401,403

The appropriate concentration and route of administration of epinephrine should be selected carefully; serious adverse effects (e.g., cerebral hemorrhage) have occurred after concentrated solutions of epinephrine intended for IM administration were administered IV.163,197,199,200,201,212,221 Because of the risks associated with IV use, epinephrine generally should be administered by the IV route only in extreme situations (such as in the treatment of septic or anaphylactic shock, cardiac arrest, or when the patient is unresponsive to multiple IM injections).196,197,198,199,200,201,204,228 Dilute solutions of epinephrine (e.g., 0.1 mg/mL) should always be used when administering the drug IV.101,172,200,212 Commercially available epinephrine solutions for IM or subcutaneous injection are tenfold more concentrated (1 mg/mL) and should not be administered IV without dilution.172,212

Solutions of epinephrine should be inspected visually for particulate matter and discoloration prior to administration.195 Epinephrine injection must not be used if it is discolored or cloudy or contains any particulate matter.195

Parenteral Administration

IM or Subcutaneous Administration

Epinephrine injection solution containing epinephrine 1 mg/mL may be administered IM or subcutaneously, but IM injection into the buttock should be avoided.169,195 (See Cautions: Adverse Effects.) When used for the treatment of anaphylaxis, epinephrine should be administered by IM (preferred) or subcutaneous injection into the anterolateral aspect of the thigh; injection into or near smaller muscles (i.e., deltoid muscle) is not recommended because of possible differences in absorption.169,195,197,219,221 Following subcutaneous administration, absorption and subsequent achievement of peak plasma concentrations may be slower and substantially delayed if shock is present.196 Repeated injections of epinephrine should not be administered at the same site because of the risk of possible tissue necrosis due to vasoconstriction.169,195

Epinephrine is commercially available in a prefilled auto-injector for the emergency treatment of allergic reactions.163,219,221 When IM or subcutaneous epinephrine is used for self-medication , patients and their caregivers should be instructed about proper administration techniques using the auto-injector provided by the manufacturer.163,164,219,221 Patients should seek immediate medical or hospital care in conjunction with self-administration of the drug.163,219,221 First aid providers should be familiar with auto-injectors in order to assist patients experiencing an anaphylactic reaction, and they should be able to administer epinephrine using an auto-injector if a patient is unable to self-administer the drug, provided that state law permits it and a valid prescription exists.217 When using the auto-injector, the appropriate weight-based dose should be injected IM or subcutaneously into the anterolateral aspect of the thigh.163,164,219,221 The injection may be administered through clothing if necessary.163,219,221 Some manufacturers recommend massaging the injection area for several seconds after the drug is administered.164 The auto-injectors are overfilled and most of the solution will remain in the device after injection of the appropriate dose; however, the auto-injector cannot be reused.164,220,222 The respective manufacturer's prescribing information should be consulted for additional instructions on use of prefilled epinephrine auto-injectors.163,164,219,220,221,222

IV Administration

For IV administration, epinephrine is commercially available as a 0.1-mg/mL solution.193,212 This concentration also may be prepared by diluting the commercially available 1-mg/mL epinephrine injection with a suitable diluent.101 Various methods have been described for diluting epinephrine solutions for IV administration.101,195,238 Commercially available epinephrine 1-mg/mL injection should not be administered IV unless the solution is further diluted.101,195,238

In emergency situations, diluted solutions of epinephrine may be administered by slow IV injection or as a continuous IV infusion.193,195,197 Extreme caution is recommended when epinephrine is administered by direct IV injection since the risk of overdosage and adverse cardiovascular effects is substantially higher with such administration; the drug should be administered slowly with close hemodynamic monitoring.193,196,198,228

During cardiac resuscitation, epinephrine may be administered IV into a central or peripheral line.212,401 IV access should be established and the drug administered without interrupting chest compressions.401 To ensure delivery of the drug into the central compartment, each dose of epinephrine given by peripheral injection should be followed by a 20-mL flush of IV fluid and the extremity should be elevated during and after drug administration.401 Although central venous access is advantageous because higher plasma drug concentrations can be achieved and physiologic monitoring for return of spontaneous circulation (ROSC) can be performed, placement of a central line can potentially interrupt cardiopulmonary resuscitation (CPR).401 Central line placement should be avoided in patients who are candidates for pharmacologic reperfusion (e.g., with thrombolytic therapy).401

During resuscitation in infants and children, a peripheral IV line may be established if it can be done rapidly.403 Central venous access is not recommended as the initial route of vascular access during an emergency because of the expertise and time required for establishing a central line.403 If, however, both central and peripheral lines are available, the central venous route is preferred.403 Whereas venous access can be challenging in critically ill infants and children, IO access can be achieved rapidly with minimal complications.403

To minimize the risk of necrosis, continuous IV infusions of epinephrine should be infused into a large vein.195 A catheter tie-in technique should be avoided because obstruction to blood flow around the tubing may cause stasis and increase local concentration of the drug.195 Care must be taken to avoid extravasation because local necrosis may result. 195

Standardize 4 Safety

Standardized concentrations for epinephrine have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. 249,250Multidisciplinary expert panels were convened to determine recommended standard concentrations. 249,250Because recommendations from the S4S panels may differ from the manufacturer's prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label. 249,250 For additional information on S4S (including updates that may be available), see [Web].249,250

Endotracheal Administration

If vascular access (IV or IO) is not possible during cardiac resuscitation, lipid-soluble drugs such as epinephrine may be administered via an endotracheal tube.403 However, studies have shown conflicting results regarding the effectiveness of endotracheal versus vascular administration of the drug.403 Epinephrine administered via an endotracheal tube should be diluted in 5-10 mL of 0.9% sodium chloride or sterile water in adults or flushed with a minimum of 5 mL of 0.9% sodium chloride injection in pediatric patients.401,403 Absorption of epinephrine, administered via endotracheal tube, may be increased by diluting the drug in sterile water instead of 0.9% sodium chloride.401

Oral Inhalation

Epinephrine and racepinephrine also have been administered via oral inhalation using a nebulizer, aerosol, or intermittent positive-pressure breathing (IPPB) apparatus for the treatment of asthma. However, an oral inhalation preparation of epinephrine is no longer commercially available in the US.166,223,236

Topical Administration

Solutions of epinephrine hydrochloride also are applied topically as a spray or on cotton or gauze to the skin, mucous membranes, or other tissues.

Dosage

Dosage of epinephrine salts is expressed in terms of epinephrine. Dosage of racepinephrine hydrochloride is expressed in terms of racepinephrine; racepinephrine is about one-half as active as epinephrine.

Sensitivity Reactions

Adult Dosage

For the emergency treatment of allergic reactions, including anaphylaxis, the usual adult dose of epinephrine is 0.2-0.5 mg (0.2-0.5 mL of a 1-mg/mL solution) administered IM or subcutaneously; the dose may be repeated every 5-15 minutes as necessary.163,169,195,196,197,200,212,228 A maximum single dose of 0.5 mg in adults is recommended.169,197 IM administration is preferred since absorption and subsequent achievement of peak plasma concentrations may be slower and substantially delayed following subcutaneous administration of the drug if shock is present.196

For self-administration of epinephrine using a prefilled auto-injector (e.g., EpiPen^®), an IM or subcutaneous dose of 0.3 mg is recommended.163,219,221 For severe persistent anaphylaxis, repeated doses may be needed; if more than 2 sequential doses are needed, subsequent doses should be administered under direct medical supervision.163,219,221

In extreme circumstances (e.g., anaphylactic shock, cardiac arrest, or no response to initial IM injections), IV administration may be necessary since absorption of epinephrine may be impaired with subcutaneous or IM administration.175,196,198,200,201,228 The usual adult IV dose of epinephrine for the treatment of anaphylaxis ranges from 0.1 to 0.25 mg (1-2.5 mL of a 0.1-mg/mL solution); the dose may be repeated every 5-15 minutes as needed.193,212 Although there is no established dosage for continuous IV infusions of epinephrine, some studies have demonstrated efficacy at IV infusion rates of 2-15 mcg/minute, titrated based on severity of the reaction and clinical response.196,228

Patients with anaphylaxis who respond to therapy require observation for possible recurrence even if there is an intervening asymptomatic period; length of observation time has not been established.175 Symptoms may recur within 1-36 hours after the initial reaction.175 The duration of direct observation and monitoring after an episode of anaphylaxis should be individualized based on the severity and duration of the anaphylactic event as well as other factors (e.g., response to treatment, pattern of previous anaphylactic reactions, comorbidities, patient reliability, access to medical care).228 Some experts suggest that patients with moderate to severe anaphylaxis should be observed for a minimum of 4-8 hours after treatment.228

Pediatric Patients

For the treatment of anaphylaxis in pediatric patients, the recommended dose of epinephrine is 0.01 mg/kg (0.01 mL/kg of a 1-mg/mL solution) by IM or subcutaneous injection.169,195,197,212,218 Single IM or subcutaneous doses should not exceed 0.3-0.5 mg (depending on the patient's weight).169,195,197,211,212,218 The dose may be repeated every 5-15 minutes as necessary.169,195,197,212,228 Some clinicians state that doses may be repeated at 20-minute to 4-hour intervals depending on the severity of the condition and patient response.211

For self-administration of epinephrine in children using a prefilled auto-injector, a dose of 0.15 or 0.3 mg, depending on body weight, should be injected IM or subcutaneously; 0.3 mg is recommended for patients weighing at least 30 kg and 0.15 mg is recommended for patients weighing 15-30 kg.163,219,221 If doses less than 0.15 mg are considered more appropriate, alternative injectable forms of the drug should be used.163,219,221 For severe persistent anaphylaxis, repeat doses may be needed; however, if more than 2 sequential doses of epinephrine are needed, subsequent doses should only be administered under direct medical supervision.163,219,221

If IV administration is necessary for the treatment of anaphylaxis in pediatric patients, some clinicians recommend an initial IV epinephrine dose of 0.01 mg/kg (0.1 mL/kg of a 0.1-mg/mL solution).101 If repeated doses are required, a continuous IV infusion should be initiated at a rate of 0.1 mcg/kg per minute, and increased gradually to 1.5 mcg/kg per minute to maintain blood pressure.101 A slow, continuous, low-dose infusion is preferred to repeat IV injections because the drug may be titrated to effect.101

Advanced Cardiovascular Life Support and Cardiac Arrhythmias

For ACLS during cardiac arrest, epinephrine preferably is administered IV but also may be instilled directly into the tracheobronchial tree via an endotracheal tube or administered by IO injection or intracardially.172,193,212,401 (See Dosage and Administration: Administration.) Although endotracheal administration of epinephrine is possible, IV or IO administration is preferred because of more predictable drug delivery and pharmacologic effect.401 IO administration of epinephrine may be particularly useful in children when IV access is not readily available.403

Adult Dosage

When used for cardiac resuscitation in adults, epinephrine doses ranging from 0.1-1 mg have been used.172,193,212,400,401 In ACLS guidelines, a standard dosage of epinephrine (defined as 1 mg every 3-5 minutes by IV/IO injection) is recommended during adult cardiac arrest.400,401 Current evidence indicates that higher doses (e.g., 0.1-0.2 mg/kg) do not provide any benefits in terms of survival or neurologic outcomes compared with the standard dose and may be harmful.115,118,175,400

The optimum dose of epinephrine during cardiac resuscitation has been a subject of controversy.103,104,115,116,117,118,119,120,121,122,123,125,126,127,177,178,179 Many clinicians had questioned the commonly used doses of 0.5-1 mg because of concern that these doses were not based on body weight, and thus may be lower than necessary for optimum cardiovascular effects.103,104,117,119,121,127,161 Interest in high doses of epinephrine was stimulated by animal studies indicating that such doses (e.g., 0.045-0.2 mg/kg) provided optimal improvement in hemodynamics, including ROSC, and timely achievement of successful cardiopulmonary resuscitation (CPR).103,105,106,107,108,115,117,118,119,120,121,126,128,161 Results of several clinical studies, including randomized controlled studies, found no substantial improvement in survival rates to hospital discharge nor trend for improved neurologic outcomes in patients with cardiac arrest receiving higher than usual doses of epinephrine, despite evidence of increased rates of ROSC and higher initial resuscitation rates with high-dose therapy.103,109,110,111,116,117,118,121,123,125,175,177,178,180,400 A retrospective study of functional neurologic outcomes (assessed by measurement of cerebral performance category) of patients with ventricular fibrillation who received high IV dosages of epinephrine during cardiac resuscitation found that such dosages were independently associated with unfavorable neurologic outcomes.154 Patients with unfavorable neurologic outcomes after resuscitation had received substantially higher median cumulative doses (i.e., 4 mg [range: 2-8 mg]) of epinephrine than those with favorable neurologic outcomes who received a median cumulative dose of 1 mg (range: less than 1-3 mg).154 These findings persisted after neurologic outcomes were stratified by duration of CPR and other potentially confounding conditions were considered.154 Based on the currently available evidence, the American Heart Association (AHA) states that it is reasonable to administer standard-dose epinephrine (1 mg every 3-5 minutes) during cardiac arrest in adults; high-dose epinephrine should not be used routinely, but may be considered in certain situations (e.g., overdosage of β-adrenergic or calcium-channel blocking agents).400,401

The optimal timing of epinephrine administration, particularly in relation to defibrillation, is not known and may vary based on patient-specific factors and resuscitation conditions.400 In adults with asystole or pulseless electrical activity (PEA), epinephrine may be given as soon as feasible after the onset of cardiac arrest based on studies demonstrating improved survival to hospital discharge and increased ROSC when the drug was administered early during the course of treatment for a nonshockable rhythm.400,401

If IV or IO access cannot be established during cardiac arrest, epinephrine may be administered via the endotracheal route.401 Although the optimal dose of epinephrine administered via an endotracheal tube remains to be established, some experts state that typical doses should be 2-2.5 times those administered IV.401

If epinephrine is used for hemodynamic support following cardiac resuscitation, the usual IV dosage in adults is 0.1-0.5 mcg/kg per minute; the infusion rate should be titrated to patient response.404

If epinephrine is used for the treatment of symptomatic bradycardia in adults, an initial infusion rate of 2-10 mcg/minute has been recommended and should be titrated to patient response.401 Intravascular volume and support should be assessed as needed.401

Pediatric Dosage

When used for pediatric advanced life support (PALS), the usual IV or IO dose of epinephrine is 0.01 mg/kg (0.1 mL/kg of a 0.1-mg/mL solution), up to a maximum single dose of 1 mg,402,403 and the usual dose of epinephrine administered via an endotracheal tube is 0.1 mg/kg (0.1 mL/kg of a 1-mg/mL solution), up to a maximum single dose of 2.5 mg.403 The same IV, IO, or endotracheal dose should be repeated every 3-5 minutes if needed.402,403 Higher doses are not recommended because of the potential for harm, particularly in cases of asphyxia, and lack of survival benefit.181,403 AHA states, however, that high-dose epinephrine may be considered in exceptional circumstances (e.g., β-adrenergic blocking agent overdose).403

In a prospective, randomized, double-blind study of 68 children who received either 0.01 mg/kg (standard dose) or 0.1 mg/kg (high dose) of epinephrine as rescue therapy for in-hospital cardiac arrest after failure of CPR and an initial dose of 0.01 mg/kg (standard dose) of epinephrine, high-dose rescue therapy was not associated with any benefits.181 High-dose epinephrine rescue therapy did not improve the survival rate at 24 hours compared with standard-dose therapy, and appeared to be harmful in children with asphyxia-precipitated cardiac arrest.181 In addition, a trend toward reduced rate of survival at 24 hours was observed among children who received high-dose therapy as compared with standard-dose therapy.181 Also, the rates of ROSC or survival to hospital discharge were not significantly different between the 2 groups.181

For postresuscitation stabilization in pediatric patients, epinephrine may be administered by IV or IO infusion at a rate of 0.1-1 mcg/kg per minute; the rate of infusion should be adjusted based on patient response.403 Although low-dose IV infusions (less than 0.3 mcg/kg per minute) generally produce predominantly β-adrenergic effects, while higher-dose IV infusions (exceeding 0.3 mcg/kg per minute) generally result in α-adrenergic vasoconstriction,403 there is substantial interindividual variation in response, and infusion dosage should be titrated to the desired effect.403

The usual neonatal IV dose of epinephrine is 0.01-0.03 mg/kg (0.1-0.3 mL/kg of a 0.1-mg/mL solution).213,214 AHA states that higher IV doses are not recommended; in pediatric and animal studies, administration of IV doses in the range of 0.1 mg/kg have been associated with exaggerated hypertension, decreased myocardial function, and worsening neurologic function.213 In addition, the sequence of hypotension followed by hypertension is likely to increase the risk of intracranial hemorrhage, especially in neonates.161 IV administration of epinephrine (0.01-0.03 mg/kg per dose) is the preferred route in neonates, since there are limited data available on endotracheal administration of epinephrine.213,214 If the endotracheal route is used, doses of 0.01 or 0.03 mg/kg will likely be ineffective.213 Although safety and efficacy have not been established, endotracheal administration of a higher dose (0.05-0.1 mg/kg) while IV access is being obtained may be considered.213,214

In one retrospective study in children and neonates who received either mean doses of 0.01 mg/kg (standard dose) or 0.12 mg/kg (high dose) of epinephrine administered IV, via an endotracheal tube, or by IO infusion during CPR after cardiac arrest occurring during a hospital stay, high doses of the drug were not associated with improvements in rates of ROSC, short- or long-term survival rates, or overall outcome scores.156 In this study, the time to ROSC was substantially shorter in patients receiving standard doses of epinephrine than in those receiving higher doses.156 In addition, high-dose epinephrine may be associated with adverse effects such as increased myocardial oxygen consumption during cardiac resuscitation, a postarrest hyperadrenergic state with tachycardia, hypertension and ventricular ectopy, myocardial necrosis, and worse postarrest myocardial dysfunction.161 Additional clinical studies are needed to evaluate fully the optimum dosage regimen of epinephrine in pediatric patients.156

For the emergency treatment of infants and children with bradycardia and cardiorespiratory compromise (with a palpable pulse), epinephrine may be given at a dose of 0.01 mg/kg (0.1 mL/kg of a 0.1-mg/mL solution) by IV/IO injection, and repeated every 3-5 minutes as needed; alternatively, an endotracheal dose of 0.1 mg/kg (0.1 mL/kg of a 1-mg/mL solution) may be given if IV/IO access is not available.403

Septic Shock

For the treatment of hypotension during septic shock in adults, the manufacturer suggests an IV infusion rate of 0.05-2 mcg/kg per minute.195 The infusion rate may be increased in increments of 0.05-0.2 mcg/kg per minute every 10-15 minutes to achieve the desired blood pressure goal.195 The duration of therapy or total dose required is not known; continuous epinephrine infusion may be necessary for several hours or days until the patient's hemodynamic status improves.195 If epinephrine is used in pediatric patients with septic shock, some clinicians have recommended an IV infusion rate of 0.05-0.3 mcg/kg per minute, titrated to effect.204,237

When therapy is discontinued, the infusion rate should be decreased gradually (e.g., by reducing the infusion rate every 30 minutes over a 12- to 24-hour period).195

Bronchospasm

Parenteral Dosage

For the treatment of severe asthma exacerbations when orally inhaled, selective short-acting β₂-adrenergic agonists are not available, an expert panel of the National Asthma Education and Prevention Program (NAEPP) states that epinephrine 0.3-0.5 mg may be given subcutaneously every 20 minutes for 3 doses in adults and adolescents older than 12 years of age.160 Alternatively, some clinicians recommend a subcutaneous epinephrine dose of 0.01 mg/kg (using a 1-mg/mL solution), divided into 3 doses of approximately 0.3 mg each, administered at 20-minute intervals.196 For the treatment of severe asthma exacerbations in children 12 years of age or younger, 0.01 mg/kg of epinephrine (0.01 mL/kg using a 1-mg/mL solution), but no more than 0.3-0.5 mg per dose, may be administered by subcutaneous injection at 20-minute intervals for 3 doses.160

For the treatment of bronchospasm in adults, some manufacturers recommend an epinephrine dose of 0.1-0.25 mg (1-2.5 mL of a 0.1-mg/mL solution) by slow IV injection.193 If IV administration of epinephrine is required for the management of asthma attacks in pediatric patients, some clinicians recommend a slow IV injection of 0.01 mg/kg in neonates and an initial IV dose of 0.05 mg (which may be repeated at 20- to 30-minute intervals) in infants.193,211

Oral Inhalation Dosage

For the temporary relief of mild symptoms of intermittent asthma, the usual dose of 2.25% racepinephrine inhalation solution (equivalent to 1% epinephrine) in adults and children 4 years of age or older is 1-3 inhalations; doses should not be repeated more often than every 3 hours.190 Patients should be advised to seek medical assistance immediately if symptoms are not relieved within 20 minutes or become worse.190

Local Vasoconstriction

As a topical hemostatic, solutions containing epinephrine in concentrations of 0.002-0.1% have been sprayed or applied with cotton or gauze to the skin, mucous membranes, or other tissues. In conjunction with local anesthetics, epinephrine may be used in concentrations of 0.002-0.02 mg/mL. The most frequently used concentration is 0.005 mg/mL.

Adverse Effects

Epinephrine may cause fear, anxiety, tenseness, restlessness, headache, tremor, dizziness, lightheadedness, nervousness, sleeplessness, excitability, and weakness. In patients with parkinsonian syndrome, the drug increases rigidity and tremor. Patients with diabetes mellitus may experience transient increases in blood glucose concentrations.169,195 Epinephrine may aggravate or induce psychomotor agitation, disorientation, impaired memory, assaultive behavior, panic, hallucinations, suicidal or homicidal tendencies, and psychosis characterized by clear consciousness with schizophrenic-like thought disorder and paranoid delusions in some patients. Nausea, vomiting, sweating, pallor, respiratory difficulty, or respiratory weakness and apnea may also occur. It may be advisable to warn patients of possible adverse effects.

Epinephrine causes ECG changes including a decrease in T-wave amplitude in all leads in normal persons. Disturbances of cardiac rhythm and rate may result in palpitation and tachycardia. In patients with a perfusing rhythm, epinephrine may cause tachycardia, ventricular ectopy, tachyarrhythmias, hypertension, and vasoconstriction.175 In patients with coronary insufficiency and/or ischemic heart disease, epinephrine may aggravate or precipitate angina pectoris by increasing cardiac work and accentuating the insufficiency of the coronary circulation. Epinephrine can cause potentially fatal ventricular arrhythmias including fibrillation, especially in patients with organic heart disease or those receiving other drugs that sensitize the heart to arrhythmias.195 (See Drug Interactions.)

Epinephrine hydrochloride injection has been reported to cause syncope characterized by pallor, unconsciousness, and tachycardia in 4 children in doses varying from 0.05-0.2 mg subcutaneously.43 One of the children was later treated with 0.75 mg (0.15 mL of the longer-acting 5 mg/mL aqueous suspension, which is no longer commercially available in the US) subcutaneously with no such complication.43

Overdosage or inadvertent IV injection of usual subcutaneous doses of epinephrine may cause hypertension. (See Acute Toxicity.) Subarachnoid hemorrhage and hemiplegia have resulted from hypertension, even following subcutaneous administration of usual doses. To avoid the possibility of dangerously high blood pressure from epinephrine therapy, blood pressure should be monitored closely during IV administration of the drug.195

Epinephrine can cause tissue necrosis and sloughing at the site of injection as a result of local vasoconstriction.195 (See Cautions: Precautions and Contraindications.) Repeated injections of epinephrine can increase the risk of necrosis.169,195 Tissue necrosis may also occur in the extremities, kidneys, and liver. Fatal gas gangrene has occurred in patients receiving IM injection of epinephrine oil suspension (no longer available) in the buttocks. Gangrene of the lower extremities also may occur if epinephrine is infused into an ankle vein.195 It has been postulated that epinephrine-induced vasoconstriction reduces the oxygen tension of tissues, enabling anaerobic Clostridium welchii which may be present in the patient's feces and on the buttocks to multiply. IM injection of the drug into the buttocks should be avoided. If gas gangrene is suspected after epinephrine administration, treatment should be instituted immediately.

Prolonged use or overdosage of epinephrine can result in severe metabolic acidosis because of elevated blood concentrations of lactic acid. It has been proposed that epinephrine may cause hyperuricemia by its vasoconstrictor action in the kidneys; however, elevated BUN has been reported only rarely in cases of overdosage. IV use of epinephrine may initially constrict renal blood vessels and decrease urine formation.195

Absorption of epinephrine from the respiratory tract following large doses by oral inhalation may result in adverse effects similar to those occurring after parenteral administration. Rarely, bronchial irritation and edema may occur. In some patients, severe prolonged asthma attacks may be precipitated. Rebound bronchospasm may occur when the effects of epinephrine end. Arterial oxygen tension, already reduced during asthmatic attacks, may be further reduced following oral inhalation of epinephrine. Dryness of pharyngeal membranes may follow oral inhalation and may be prevented by rinsing the mouth with water immediately after use of the drug. If epinephrine inhalation is inadvertently swallowed, epigastric pain may occur.

Precautions and Contraindications

Vasopressor therapy is not a substitute for replacement of blood, plasma, fluids, and/or electrolytes.212 Blood volume depletion should be corrected as fully as possible before epinephrine therapy is instituted.195

Because severe local adverse effects (e.g., tissue necrosis) may occur, extravasation of epinephrine infusions must be avoided.195 The site of infusion should be checked frequently for free flow and the infused vein should be observed for blanching. 195 Infusion into leg veins, especially in geriatric patients or those with occlusive vascular diseases (e.g., atherosclerosis, arteriosclerosis, diabetic endarteritis, Buerger's disease) should be avoided.195 If blanching is observed in the infused vein, changing the infusion site periodically may be advisable.195 If extravasation occurs, 10-15 mL of sodium chloride solution containing 5-10 mg of phentolamine mesylate should be infiltrated (using a syringe with a fine hypodermic needle) liberally throughout the affected area, which is identified by a cold, hard, and pallid appearance.195 Immediate and conspicuous local hyperemic changes occur if the area is infiltrated within 12 hours; therefore, phentolamine should be administered as soon as possible after extravasation is noted.195

Epinephrine should not be administered in the digits, hands, or feet.195 Accidental injection into the digits, hands, or feet may result in loss of blood flow to the affected area and has been associated with tissue necrosis.195

Particular attention should be paid to the appropriate concentration and route of administration of epinephrine since serious adverse effects (e.g., cerebral hemorrhage) have occurred after concentrated solutions of epinephrine intended for IM administration were administered IV.163,197,199,200,201,212,221 Because of the risks associated with IV use, epinephrine generally should be administered by the IV route only in extreme situations (such as in the treatment of septic or anaphylactic shock, cardiac arrest, or when the patient is unresponsive to multiple IM injections).196,197,198,199,200,201,204 (See Dosage and Administration: Administration.)

Racepinephrine, a racemic mixture of epinephrine, shares the toxic potentials of epinephrine, and the usual precautions of epinephrine therapy should be observed. Adverse reactions to epinephrine may be most likely to occur in hypertensive or hyperthyroid patients, and the drug must be administered with extreme caution, if at all, to such patients. Epinephrine should be administered with caution to geriatric patients, patients with diabetes mellitus, hyperthyroidism, Parkinson's disease, pheochromocytoma, or cardiovascular diseases (including cardiac arrhythmias, coronary artery disease, and organic heart disease), and/or those with a history of sensitivity to sympathomimetic amines.163,195 Coronary insufficiency is usually considered to be a contraindication to parenteral use of the drug. The drug must be used cautiously in patients with bronchial asthma and emphysema who may also have degenerative heart disease.212 Epinephrine injection should be used with caution in patients with psychoneurotic disorders.212

Some commercially available formulations of epinephrine hydrochloride or racepinephrine hydrochloride contain sulfites that can cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals.102 The overall prevalence of sulfite sensitivity in the general population is unknown but probably low; such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals.102 The presence of sulfites in a parenteral epinephrine preparation and the possibility of allergic-type reactions should not deter use of the drug when indicated for the treatment of serious allergic reactions or for other emergency situations.102 Epinephrine is the preferred treatment for such conditions, and currently available alternatives to epinephrine may not be optimally effective.102 The possibility of adverse reactions to sulfite(s) contained in the preparation should be considered in asthmatic patients who show paradoxical worsening of respiratory function following use of the drug or whose symptoms worsen or in whom bronchodilatory response decreases with increasing use of the drug.

Patients considering self-medication with racepinephrine as a bronchodilator should be advised to use the drug only if they have been diagnosed by a clinician as having asthma; patients also should be advised that the drug should not be used for self-medication if they ever have been hospitalized for asthma or are currently receiving a prescription drug for the management of this condition unless otherwise directed by a clinician.190,192 These patients also should be advised not to use the drug if they have cardiovascular disease, hypertension, diabetes mellitus, thyroid disease, angle-closure (narrow-angle) glaucoma, seizures, a psychiatric or emotional condition, or difficulty urinating because of prostatic hypertrophy unless directed by a clinician.190,192 In addition, patients should be advised not to exceed recommended dosages or frequency of administration unless otherwise instructed by a clinician.190,192 Patients should contact their clinician if their symptoms are not relieved within 20 minutes or become worse, more than the recommended dosage is required, or asthma attacks become more frequent (i.e., more than 2 asthma attacks in a week).190,192 Patients should be cautioned that racepinephrine can cause hypertension and tachycardia, which could increase the risk of cardiovascular disease, stroke, or death.190,192 Foods, beverages, and dietary supplements that contain stimulants (e.g., caffeine) should be avoided.190,192

There are no absolute contraindications to the use of epinephrine in life-threatening conditions.200 Relative contraindications to epinephrine include shock (other than anaphylactic and septic shock), known hypersensitivity to sympathomimetic amines, coronary insufficiency, and cardiac dilatation, as well as use in most patients with angle-closure glaucoma or organic brain damage.193,195,212 The drug is contraindicated for use during general anesthesia with agents such as cyclopropane and halogenated hydrocarbon anesthetics (e.g., halothane).193,212 (See Drug Interactions: General Anesthetics.) In conjunction with local anesthetics, epinephrine is contraindicated for use in certain areas (e.g., fingers, toes, ears).172,212

Pregnancy

Pregnancy

Epinephrine usually inhibits spontaneous or oxytocin-induced contractions of the pregnant human uterus and may delay the second stage of labor.195 In dosages sufficient to reduce uterine contractions, the drug may cause a prolonged period of uterine atony with hemorrhage.195 If used during pregnancy, epinephrine may cause anoxia to the fetus and/or spontaneous abortion.195 When administered in advanced cardiovascular life support (ACLS) during cardiac resuscitation, epinephrine may decrease blood flow to the uterus;195 however, the woman must be resuscitated for survival of the fetus.196 Some manufacturers state that epinephrine should be avoided during the second stage of labor;195 parenteral administration of the drug to maintain blood pressure during spinal anesthesia for delivery can cause acceleration of fetal heart rate and should not be used in obstetric patients when maternal systolic/diastolic blood pressure exceeds 130/80 mm Hg.212 Epinephrine should be administered cautiously by oral inhalation to pregnant patients. Epinephrine should be used during pregnancy only if the potential benefits justify the possible risks to the fetus.195,212 There is some evidence to support that epidural administration of some local anesthetics (e.g., lidocaine) with epinephrine during labor is safe.224,225

Sympathomimetic Agents

Epinephrine must not be administered concomitantly with other sympathomimetic agents (e.g., isoproterenol) because of the possibility of additive effects and increased toxicity.212

- and Beta-Adrenergic Blocking Agents

The cardiac and bronchodilating effects of epinephrine are antagonized by β-adrenergic blocking drugs such as propranolol, and the vasoconstriction and hypertension caused by high doses of epinephrine are antagonized by α-adrenergic blocking agents such as phentolamine. Because of their α-adrenergic blocking properties, ergot alkaloids can reverse the pressor response to epinephrine. Concomitant use of β-adrenergic blocking drugs (e.g., propranolol) may also potentiate the pressor effects of epinephrine.195

Cardiac Glycosides

Epinephrine should not be used in patients receiving excessive dosages of other drugs (e.g., cardiac glycosides) that can sensitize the heart to arrhythmias.212

Diuretics

Concomitant use of diuretics may antagonize the pressor effect and potentiate the arrhythmogenic effects of epinephrine.195,212 Some diuretics also may potentiate the hypokalemic effects of epinephrine.195

General Anesthetics

Administration of epinephrine in patients receiving cyclopropane or halogenated hydrocarbon general anesthetics that increase cardiac irritability and seem to sensitize the myocardium to epinephrine may result in arrhythmias including PVCs, tachycardia, or fibrillation. Epinephrine is contraindicated for use with chloroform, trichloroethylene, or cyclopropane and should be used cautiously, if at all, with other halogenated hydrocarbon anesthetics such as halothane. Epinephrine may not be absorbed rapidly enough to cause serious adverse effects when applied topically as a hemostatic in patients undergoing short surgical procedures such as tonsillectomy and adenoidectomy using halothane anesthesia. Prophylactic administration of lidocaine or prophylactic IV administration of propranolol 0.05 mg/kg may protect against ventricular irritability if epinephrine is used during anesthesia with a halogenated hydrocarbon anesthetic. In one study, arrhythmias occurring after parenteral use of epinephrine during general anesthesia responded promptly to IV propranolol 0.05 mg/kg.

Hypotensive Agents

Epinephrine may antagonize the neuronal blockade produced by guanethidine (not commercially available in the US), resulting in loss of antihypertensive effectiveness.195,212 The vasopressor effect of epinephrine also may be antagonized by rapidly acting vasodilators (e.g., nitrates) and other antihypertensive agents.195,212

Monoamine Oxidase Inhibitors

Monoamine oxidase (MAO) is one of the enzymes responsible for epinephrine metabolism.195 The manufacturer states that epinephrine should be administered with caution in patients receiving an MAO inhibitor because severe, prolonged hypertension may result.172,193,195

Oxytocic Drugs

Concomitant use of epinephrine with oxytocics may result in severe, persistent hypertension.212

Other Drugs

Tricyclic antidepressants such as imipramine, some antihistamines (especially diphenhydramine, tripelennamine, and dexchlorpheniramine), and thyroid hormones may potentiate the effects of epinephrine, especially on heart rhythm and rate. Potentiation by tricyclic antidepressants or antihistamines may result from inhibition of tissue uptake of epinephrine or norepinephrine or by increased adrenoreceptor sensitivity to epinephrine. Concomitant use of catechol- O -methyltransferase (COMT) inhibitors (e.g., entacapone), clonidine, or doxapram also may potentiate the pressor effects of epinephrine and quinidine may potentiate the arrhythmogenic effects of epinephrine.195

Concomitant use of corticosteroids or theophylline also may potentiate the hypokalemic effects of epinephrine.195

Epinephrine should not be used to counteract circulatory collapse or hypotension caused by phenothiazines; a reversal of epinephrine's pressor effects resulting in further lowering of blood pressure may occur.195

Because epinephrine may cause hyperglycemia, patients with diabetes mellitus receiving epinephrine may require increased dosage of insulin or oral hypoglycemic agents.

Acute Toxicity

Pathogenesis

Autopsy findings in patients who died of epinephrine overdosage revealed evidence of circulatory collapse, and most organs and veins were congested with blood. In test animals, there is evidence that death is the result of respiratory arrest caused by hypertension. Death resulting from epinephrine overdosage may partially depend on factors other than the dose received; some patients have died following IV doses not exceeding 10 mg while others have survived doses as high as 30 mg IV or 110 mg subcutaneously.

Manifestations and Treatment

After overdosage or inadvertent IV administration of usual subcutaneous doses of epinephrine, systolic and diastolic blood pressure rise sharply; venous pressure also rises. Cerebrovascular or other hemorrhage and hemiplegia may result, especially in geriatric patients. Because epinephrine is rapidly inactivated in the body, treatment of acute toxicity is mainly supportive. If necessary, the pressor effects of the drug may be counteracted by rapidly acting α-adrenergic blocking drugs such as phentolamine. Prolonged hypotension may follow, and another pressor agent such as norepinephrine may be required. Pulmonary edema may result from pulmonary arterial hypertension; administration of a rapidly acting α-adrenergic blocking drug and/or intermittent positive-pressure respiration may be required if pulmonary edema interferes with respiration. Respiratory difficulties including hyperventilation sometimes preceded by a brief period of apnea may also occur. Epinephrine overdosage causes transient bradycardia followed by tachycardia and may cause other potentially fatal cardiac arrhythmias. PVCs may appear within 1 minute after injection and may be followed by multifocal ventricular tachycardia (prefibrillation rhythm). Atrial tachycardia, occasionally accompanied by atrioventricular block, may occur after the drug's effects on the ventricles subside. Prolonged ECG changes and substantial changes in serum AST (SGOT) concentration were considered evidence of possibly permanent myocardial injury caused by overdosage of epinephrine in 2 patients. Arrhythmias, if they occur, may be counteracted by a β-adrenergic blocking drug such as propranolol. Kidney failure, metabolic acidosis, and cold, white skin may also occur.

Pharmacology

Epinephrine acts directly on both α- and β-adrenergic receptors of tissues innervated by sympathetic nerves except the sweat glands and arteries of the face. It is believed that β-adrenergic effects result from stimulation of the production of cyclic adenosine-3',5'-monophosphate (AMP) by activation of the enzyme adenyl cyclase, whereas α-adrenergic effects result from inhibition of adenyl cyclase activity. The main effects of therapeutic parenteral doses of epinephrine are relaxation of smooth muscle of the bronchial tree, cardiac stimulation, and dilation of skeletal muscle vasculature.

Respiratory Effects

Epinephrine relaxes bronchial smooth muscle by stimulation of β₂-adrenergic receptors and constricts bronchial arterioles by stimulation of α-adrenergic receptors when administered parenterally or by oral inhalation. In patients with bronchial constriction, the drug relieves bronchospasm, reduces congestion and edema, and increases tidal volume and vital capacity. However, decreased arterial oxygen tension may not be increased and may be further reduced. Respiration rate is increased briefly, but epinephrine has no clinical value as a respiratory stimulant. In some patients receiving the drug IV, respiratory stimulation may be preceded by a brief period of apnea, probably caused by a direct inhibition of the respiratory center.

Epinephrine inhibits histamine release and antagonizes the effect of the mediator on end organs. As a result, the drug may reverse bronchiolar constriction, vasodilation, and edema produced by this mediator.

Cardiovascular Effects

Systemically absorbed epinephrine acts on β₁-adrenergic receptors in the heart producing a positive chronotropic effect through the sinoatrial node and a positive inotropic effect on the myocardium.175 Cardiac output, oxygen consumption, and the work of the heart are increased, and cardiac efficiency is decreased. Epinephrine increases the irritability of the heart muscle and often alters the rhythmic function of the ventricles, especially after large doses or when the heart has been sensitized to this action by other drugs including digitalis and certain anesthetics or by acute myocardial infarction. Arrhythmias including ventricular extrasystoles and fibrillation may result. In patients with cardiopulmonary arrest, epinephrine can convert asystole to sinus rhythm. Epinephrine has a direct constricting effect on coronary arteries, but this effect is overcome by indirect vasodilation caused by enhanced cardiac metabolism secondary to cardiac stimulation. As a result, coronary blood flow is increased. Cardiac stimulation produced by epinephrine increases left atrial pressure, and peripheral vasoconstriction causes redistribution of blood from the systemic to the pulmonary circulation. Pulmonary arterial hypertension and increased pulmonary capillary filtration pressure may occur; pulmonary edema may result.

Epinephrine constricts arterioles in the skin, mucous membranes, and viscera after parenteral administration by its effect on α-adrenergic receptors and reduces cutaneous blood flow, especially in the hands and feet. Topically applied epinephrine produces local vasoconstriction and hemostasis in bleeding from small vessels but does not control bleeding from larger vessels. Small doses of parenterally administered epinephrine dilate arterioles of the skeletal muscles as a result of stimulation of β-adrenergic receptors, whereas larger doses stimulate α-adrenergic receptors and cause constriction of these arterioles. With usual therapeutic doses of the drug, the dilator effects predominate; blood flow to the skeletal muscle is increased and total peripheral resistance is decreased. Systolic blood pressure is moderately increased, mainly because of increased cardiac output; however, diastolic blood pressure may be decreased as a result of vasodilation. Doses of epinephrine large enough to constrict blood vessels in the skeletal muscle, however, cause an increase in peripheral resistance and elevate both systolic and diastolic blood pressure. When the drug's effects on α-adrenergic receptors end, the effect on β-adrenergic receptors persists and hypotension may result.

Constriction of renal blood vessels by epinephrine, especially after IV administration, initially reduces renal blood flow and increases renal vascular resistance. Urine flow and excretion of sodium, potassium, and chloride are decreased. Renal blood flow and urine flow may then increase as a result of elevated blood pressure. Glomerular filtration rate is not greatly altered by the drug; alterations in electrolyte and water excretion may be caused by renal vascular changes, a direct tubular action, or an indirect effect through the posterior pituitary. Very large IV or intra-arterial doses of epinephrine may cause total renal shutdown which may be prolonged by trapping of the drug in the vessels as a result of vasoconstriction.

Metabolic Effects

Epinephrine increases glycogenolysis in the liver, reduces glucose uptake by tissues, and inhibits insulin release in the pancreas, resulting in hyperglycemia. Muscle glycogenolysis also increases, and lactic acid blood concentrations are elevated. Transient hyperkalemia may also occur and may be followed by more prolonged hypokalemia. Epinephrine has calorigenic activity; oxygen consumption may increase by as much as 20-30% after parenteral administration of usual doses. Body temperature may be elevated, partly because of cutaneous vasoconstriction. Blood concentrations of free fatty acids are increased as a result of increased lipolysis in adipose tissue, and plasma concentrations of cholesterol, phospholipids, and low-density lipoproteins are also generally elevated. Fat may be deposited in muscles and liver.

Other Effects

Epinephrine has no direct effect on cerebral arterioles or cerebral blood flow. However, elevations in cerebral blood flow and oxygen consumption may occur secondary to increased blood pressure. The drug is not a powerful CNS stimulant but may cause restlessness, apprehension, headache, and tremor, probably resulting from peripheral effects. In patients with parkinsonian syndrome, epinephrine increases rigidity and tremor by an unknown mechanism.

Epinephrine generally relaxes smooth muscles of the GI tract by stimulation of either α- or β-adrenergic receptors but contracts the pyloric and ileocecal sphincters by stimulation of α-adrenergic receptors. Because these effects are transient, inconsistent, and usually occur only with doses causing marked cardiovascular response, they have no therapeutic application.

The effects of epinephrine on the uterus are probably mediated through both α- and β-adrenergic receptors in the myometrium and vary with hormonal influences, the route of administration, and the dose given. The drug usually inhibits spontaneous or oxytocin-induced contractions of the pregnant human uterus and may delay the second stage of labor. Transient uterine hyperactivity frequently occurs after the drug is discontinued. In dosage sufficient to reduce uterine contractions, epinephrine may cause prolonged uterine atony with hemorrhage. Use of the drug during pregnancy may cause anoxia in the fetus.

Pharmacokinetics

Absorption

Orally ingested epinephrine is rapidly metabolized in the GI tract and liver; pharmacologically active concentrations are not reached when the drug is given orally. Epinephrine is well absorbed after subcutaneous or IM injection; absorption can be hastened by massaging the injection site. Both rapid and prolonged absorption occur after subcutaneous injection of the longer-acting aqueous suspension (no longer commercially available in the US). Epinephrine also is absorbed following endotracheal administration, although serum concentrations achieved may be only 10% of those with an equivalent IV dose.161 After oral inhalation of epinephrine absorption is slight and the effects of the drug are restricted mainly to the respiratory tract. Absorption increases somewhat when larger doses are inhaled, and systemic effects may occur.

Epinephrine has a rapid onset and short duration of action when solutions of the drug are administered parenterally or by oral inhalation. Subcutaneous administration of epinephrine hydrochloride injection in patients with asthmatic attacks may produce bronchodilation within 5-10 minutes and maximal effects in about 20 minutes. Following subcutaneous injection of the longer-acting aqueous epinephrine suspension, the onset of action is as rapid as that occurring after subcutaneous administration of epinephrine hydrochloride aqueous injection; however, the effects are more prolonged and may persist for several hours. After oral inhalation of epinephrine, bronchodilation usually occurs within 1 minute.

Distribution

Epinephrine crosses the placenta but not the blood-brain barrier. The drug is distributed into milk.

Elimination

The pharmacologic actions of epinephrine are terminated mainly by uptake and metabolism in sympathetic nerve endings. Circulating drug is metabolized in the liver and other tissues by a combination of reactions involving the enzymes catechol- O -methyltransferase (COMT) and monoamine oxidase (MAO). The major metabolites are metanephrine and 3-methoxy-4-hydroxymandelic acid (vanillylmandelic acid, VMA) both of which are inactive. About 40% of a parenteral dose of epinephrine is excreted in urine as metanephrine, 40% as VMA, 7% as 3-methoxy-4-hydroxyphenoglycol, 2% as 3,4-dihydroxymandelic acid, and the remainder as acetylated derivatives. These metabolites are excreted mostly as the sulfate conjugates and, to a lesser extent, the glucuronide conjugates. Only small amounts of the drug are excreted unchanged.

Chemistry and Stability

Chemistry

Epinephrine is an endogenous catecholamine which is the active principle of the adrenal medulla. Both the endogenous substance and the official preparation are the levorotatory isomer which is 15 times more active than is the dextrorotatory isomer. The drug is also commercially available as racepinephrine hydrochloride, which is a racemic mixture of the hydrochlorides of the enantiomorphs of epinephrine. Racepinephrine is about one-half as active as the levorotatory isomer.

Epinephrine may be obtained from the adrenal glands of animals or prepared synthetically; that obtained from animals may contain up to 4% norepinephrine. Epinephrine occurs as a white to nearly white, microcrystalline powder or granules. Epinephrine is only very slightly soluble in water and in alcohol but readily forms water soluble salts (such as the hydrochloride and bitartrate) with acids.

Racepinephrine hydrochloride occurs as a fine, white powder and is freely soluble in water and sparingly soluble in alcohol. Racepinephrine hydrochloride oral inhalation has a pH of 2-3.5.

Stability

Epinephrine, epinephrine salts, racepinephrine hydrochloride, and preparations containing the drugs gradually darken on exposure to light and air and must be stored in tight, light-resistant containers. Epinephrine injection should be stored at room temperature (approximately 25°C). Freezing of racepinephrine hydrochloride oral inhalation should be avoided. In some commercially available injections, the air has been replaced with nitrogen to avoid oxidation. Withdrawal of doses from multiple-dose vials introduces air into the vials, subjecting the remaining epinephrine to oxidation. Oxidation of the drug imparts first a pink, then a brown color; epinephrine preparations must not be used if they have a pinkish or darker than slightly yellow color or contain a precipitate. Racepinephrine hydrochloride solutions must not be used if they are brown or contain a precipitate. Commercially available epinephrine preparations may contain a variety of preservatives including the antioxidants, sodium bisulfite or sodium metabisulfite, and bacteriostatic agents. Commercially available preparations vary in stability, depending on the form in which epinephrine is present and on the preservatives used. The manufacturer's directions should be followed with respect to storage requirements for each product.

Epinephrine is readily destroyed by oxidizing agents or alkalies including sodium bicarbonate, halogens, permanganates, chromates, nitrates, nitrites, and salts of easily reducible metals such as iron, copper, and zinc.175 Epinephrine injection has been reported to be physically incompatible with many drugs, but the compatibility depends on several factors (e.g., concentration of the drugs, specific diluents used, resulting pH, temperature). Specialized references should be consulted for specific compatibility information. Epinephrine may be mixed with 0.9% sodium chloride injection but is incompatible with 5% sodium chloride injection. Stability of epinephrine in 5% dextrose injection decreases when the pH exceeds 5.5.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Only references cited for selected revisions after 1984 are available electronically.

43. Speer F, Tapay NJ. Syncope in children following epinephrine. Ann Allergy . 1970; 28:50-4. [PubMed 5526412]

100. Barach EM, Nowak RM, Lee TG et al. Epinephrine for treatment of anaphylactic shock. JAMA . 1984; 251:2118-22. [PubMed 6708262]

101. Committee on Infectious Diseases, American Academy of Pediatrics. Red book: 2015 report of the Committee on Infectious Diseases. 30th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2015.

102. Food and Drug Administration. Sulfiting agents; labeling in drugs for human use; warning statement. [21 CFR Part 201] Fed Regist . 1986; 51:43900-5.

103. Emergency Cardiac Care Committee and Subcommittees, American Heart Association. Guidelines for cardiopulmonary resuscitation and emergency cardiac care. JAMA . 1992; 268:2171-2302. [PubMed 1404767]

104. Paradis NA, Koscove EM. Epinephrine in cardiac arrest: a critical review. Ann Emerg Med . 1990; 19:1288-1301. [PubMed 2240726]

105. Lindner KH, Ahnefeld FW, Bowdler IM. Comparison of different doses of epinephrine on myocardial perfusion and resuscitation success during cardiopulmonary resuscitation in a pig model. Am J Emerg Med . 1991; 9:27-31. [PubMed 1898700]

106. Brown CG, Taylor RB, Werman HA et al. Effect of standard doses of epinephrine on myocardial oxygen delivery and utilization during cardiopulmonary resuscitation. Crit Care Med . 1988; 16:536-9. [PubMed 3359792]

107. Brown CG, Werman HA, Davis EA et al. Comparative effect of graded doses of epinephrine on regional brain blood flow during CPR in a swine model. Ann Emerg Med . 1986; 15:1138-44. [PubMed 3752642]

108. Kosnik JW, Jackson RE, Keats S et al. Dose-related response of centrally administered epinephrine on the change in aortic diastolic pressure during closed-chest massage in dogs. Ann Emerg Med . 1985; 14:204-8. [PubMed 3977143]

109. Lindner KH, Ahnefeld FW, Prengel AW. Comparison of standard and high-dose adrenaline in the resuscitation of asystole and electromechanical dissociation. Acta Anaesthesiol Scand . 1991; 35:253-6. [PubMed 2038933]

110. Stiell IG, Hebert PC, Weitzman BN et al. A study of high-dose epinephrine in human CPR. Ann Emerg Med . 1992; 21:606.

111. Callaham M, Madsen CD, Barton CW et al. A randomized clinical trial of high-dose epinephrine and norepinephrine versus standard-dose epinephrine in prehospital arrest. Ann Emerg Med . 1992; 21:606-7.

112. Anonymous. Advances in the management of cardiac arrest: clinical conference. West J Med . 1986; 145:670-5. [PubMed 3798915]

113. Otto C, Yakaitis R. The role of epinephrine in CPR: a reappraisal. Ann Emerg Med . 1987; 16:743-8. [PubMed 3592328]

114. Callaham M. Epinephrine doses in cardiac arrest: is it time to outgrow the orthodoxy of ACLS? Ann Emerg Med . 1989; 18:1011-2.

115. Gonzalez ER, Ornato JP. The dose of epinephrine during cardiopulmonary resuscitation in humans: what should it be? DICP, Ann Pharmacotherapy . 1991; 25:773-777.

116. Callaham M, Barton CW, Kayser S. Potential complications of high-dose epinephrine therapy in patients resuscitated from cardiac arrest. JAMA . 1991; 265:1117-1122. [PubMed 1995996]

117. Paradis NA, Martin GB, Rosenberg J et al. The effect of standard- and high-dose epinephrine on coronary perfusion pressure during prolonged cardiopulmonary resuscitation. JAMA . 1991; 265:1139-1144. [PubMed 1996000]

118. Ornato JP. High-dose epinephrine during resuscitation: a word of caution. JAMA/ . 1991; 265:1160-1.

119. Koscove EM, Paradis NA. Successful resuscitation from cardiac arrest using high-dose epinephrine therapy: a report of two cases. JAMA . 1988;259:3031-4. [PubMed 3273478]

120. Callaham M, Madsen CD, Barton CW et al. A randomized clinical trial of high-dose epinephrine and norepinephrine vs standard-dose epinephrine in prehospital cardiac arrest. JAMA . 1992; 268:2667-72. [PubMed 1433686]

121. Callaham M. High-dose epinephrine in cardiac arrest. West J Med . 1991; 155:289-90. [PubMed 1949784]

122. Brown CG, Martin DR, Pepe PE et al. A comparison of standard-dose and high-dose epinephrine in cardiac arrest outside the hospital. N Engl J Med . 1992; 327:1051-5. [PubMed 1522841]

123. Stiell IG, Hebert PC, Weitzman BN et al. High-dose epinephrine in adult cardiac arrest. N Engl J Med . 1992; 327:1045-50. [PubMed 1522840]

124. Mattana J, Singhal PC. High-dose epinephrine in cardiopulmonary resuscitation. N Engl J Med . 1993; 328:735. [PubMed 8433741]

125. Barton C, Callaham M. High-dose epinephrine improves the return of spontaneous circulation rates in human victims of cardiac arrest. Ann Emerg Med . 1991; 20:722-5. [PubMed 2064091]

126. Hebert P, Weitzman BN, Stiell IG et al. Epinephrine in cardiopulmonary resuscitation. J Emerg Med . 1991; 9: 487-95. [PubMed 1787297]

127. Goetting MG, Paradis NA. High-dose epinephrine improves outcome from pediatric cardiac arrest. Ann Emerg Med . 1991; 20:22-6. [PubMed 1984722]

128. Schleien CL, dean JM, oehler RC et al. Effect of epinephrine on cerebral and myocardial perfusion in an infant animal preparation of cardiopulmonary resuscitation. Circulation . 1986; 73:809-17. [PubMed 3948377]

129. Meyer JM, Wenzel CL, Kradjan WA. Salmeterol: a novel, long-acting beta 2-agonist. Ann Pharmacother . 1993; 27:1478-87. [PubMed 7905757]

130. Brogden RN, Faulds D. Salmeterol xinafoate: a review of its pharmacological properties and therapeutic potential in reversible obstructive airways disease. Drugs . 1991; 42:895-912. [PubMed 1723379]

131. Kelly HW. Issues and advances in the pharmacotherapy of asthma. J Clin Pharm Ther . 1992; 17:271-81. [PubMed 1361192]

132. Lipworth BJ. Risks versus benefits of inhaled β₂-agonists in the management of asthma. Drug Safety . 1992; 7:54-70. [PubMed 1346963]

133. Sears MR, Taylor DR, Print CG et al. Regular inhaled beta-agonist treatment in bronchial asthma. Lancet . 1990; 336:1391-6. [PubMed 1978871]

134. Anon. Warnings from the CSM. Int Pharm J . 1991; 5:247-8.

135. Spitzer WO, Sussa S, Ernst P et al. The use of β-agonists and the risk of death and near death from asthma. N Engl J Med . 1992; 326:501-6. [PubMed 1346340]

136. Palmer JBD, Jenkins MM. β₂-agonists in asthma. Lancet . 1991; 337:43. [PubMed 1670660]

137. Dahl R. β₂-agonists in asthma. Lancet . 1991; 337:43. [PubMed 1670660]

138. Löfdahl CG, Svedmyr N. Beta agonists—friends or foes? Eur Respir J . 1991; 4:1161-5. Editorial.

139. Kamada AK, Spahn JD, Blake KV. Salmeterol: its place in asthma management. Ann Pharmacother . 1994; 28:1100-2. [PubMed 7803888]

140. Wanner A. Is the routine use of inhaled β-adrenergic agonists appropriate in asthma treatment? Yes. Am J Respir Crit Care Med . 1995; 151:597-9. [PubMed 7881643]

141. Sears MR. Is the routine use of inhaled β-adrenergic agonists appropriate in asthma treatment? No. Am J Respir Crit Care Med . 1995; 151:600-1. [PubMed 7881644]

142. Lai CKW, Twentyman OP, Holgate ST. The effect of an increase in inhaled allergen dose after rimiterol hydrobromide on the occurrence and magnitude of the late asthmatic response and the asssociated change in nonspecific bronchial responsiveness. Am Rev Respir Dis . 1989; 140:917-23. [PubMed 2572192]

143. Suissa S, Ernst P, Boivin JF et al. A cohort analysis of excess mortality in asthma and the use of inhaled beta-agonists. Am J Respir Crit Care Med . 1994; 149(3 Part 1):604-10. [PubMed 8118625]

144. O'Connor BJ, Aikman SL, Barnes PJ. Tolerance to the nonbronchodilator effects of inhaled beta 2-agonists in asthma. N Engl J Med . 1992; 327:1204-8. [PubMed 1357551]

145. Cockcroft DW, McParland CP, Britto SA et al. Regular inhaled salbutamol and airway responsiveness to allergen. Lancet . 1993; 342:833-7. [PubMed 8104272]

146. Mullen ML, Mullen B, Carey M. The association between β-agonist use and death from asthma: a meta-analytic integration of case-control studies. JAMA . 1993; 270:1842-5. [PubMed 8105113]

147. Reviewers' comments (personal observations) on Salmeterol 12:12.

148. National Institutes of Health, National Heart, Lung, and Blood Institute. Global Initiative for asthma: global strategy for asthma management and prevention NHLBI/WHO Workshop Report. Bethesda, MD: National Institutes of Health. 1995 Jan:77-100. NIH/NHLBI Publication No. 95-3659.

149. Devoy MAB, Fuller RW, Palmer JBD. Are there any detrimental effects of the use of inhaled long-acting β₂-agonists in the treatment of asthma? Chest . 1995; 107:1116-24.

150. McFadden ER Jr. Perspectives in β₂-agonist therapy: vox clamantis in deserto vel lux in tenebris? J Allergy Clin Immunol . 1995; 95:641-51.

151. Crane J, Burgess C, Pearce N et al. Asthma deaths in New Zealand. BMJ . 1992; 304:1307. [PubMed 1606438]

152. Crane J, Pearce N, Flatt A et al. Prescribed fenoterol and death from asthma in New Zealand, 1981-83: case-control study. Lancet . 1989; 1:917-22. [PubMed 2565417]

154. Behringer W, Kittler H, Sterz F et al. Cumulative epinephrine dose during cardiopulmonary resuscitation and neurologic outcome. Ann Intern Med . 1998; 129:450- 6. [PubMed 9735082]

155. Cummins RO, Hazinski MF. The next chapter in the high-dose epinephrine story: unfavorable neurologic outcomes? Ann Intern Med . 1998; 129:501-2. Editorial.

156. Carpenter TC, Stenmark KR. High-dose epinephrine is not superior to standard-dose epinephrine in pediatric in-hospital cardiopulmonary arrest. Pediatrics . 1997; 99403-8.

157. Pearlman DS, Chervinsky P, LaForce C et al. A comparison of salmeterol with albuterol in the treatment of mild-to-moderate asthma. N Engl J Med . 1992; 327:1420-5. [PubMed 1357554]

158. D'Alonzo GE, Nathan RA, Henochowicz S et al. Salmeterol xinafoate as maintenance therapy compared with albuterol in patients with asthma. JAMA . 1994; 271:1412-6. [PubMed 7909853]

159. Drazen JM, Israel E, Boushey HA et al. Comparison of regularly scheduled with as- needed use of albuterol in mild asthma. N Engl J Med . 1996; 335:841-7. [PubMed 8778601]

160. National Asthma Education and Prevention Program. Expert panel report III: guidelines for the diagnosis and management of asthma. Bethesda, MD: National Institutes of Health National Heart Lung, and Blood Institute. (NIH publication No. 97-4051) 2007 Jul. Available from the National Heart, Lung, and Blood Institute website. [Web]

161. . Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Part 6: advanced cardiovascular life support: section 6: pharmacology II: agents to optimize cardiac output and blood pressure. The American Heart Association in collaboration with the International Liaison Committee on Resuscitation. Circulation . 2000; 102(8 Suppl):I129-35.

162. National Asthma Education and Prevention Program. Expert panel report: guidelines for the diagnosis and management of asthma. Update on selected topics 2002. Bethesda, MD: National Institutes of Health National Heart Lung, and Blood Institute. (NIH publication No. 02-5074) 2003 Jun.

163. Meridian Medical Technologies. EpiPen^® and EpiPen^® Jr (epinephrine) auto-injector prescribing information. Columbia, MD; 2014 Apr.

164. Meridian Medical Technologies. EpiPen^® and EpiPen^® Jr (epinephrine) auto-injector patient information and instructions for use. Columbia, MD; 2014 Apr.

165. American College of Obstetricians and Gynecologists (ACOG) Committee on Practice Bulletins. Management of preterm labor. Washington, DC; American College of Obstetricians and Gynecologists: 2003 May. Practice Bulletin No. 43.

166. Armstrong Pharmaceuticals, Inc. Primatene^® Mist (epinephrine) product information. West Roxbury, MA; 2015 Apr.

167. The United States pharmacopeia, 27th rev, and The national formulary, 22nd ed. Rockville, MD: The United States Pharmacopeial Convention, Inc; 2004:710-1.

169. Par Pharmaceutical, Inc. Adrenalin^® (epinephrine injection 1 mg/mL) prescribing information. Chestnut Ridge, NY; 2015 Dec.

171. Epinephrine. In: Briggs GG, Freeman RK, Yaffe SJ. Drug in pregnancy and lactation: a reference guide to fetal and neonatal risk. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2002:483-4.

172. Hospira. Epinephrine injection 1 mg/mL prescribing information. Lake Forest, IL: 2015 Nov.

173. American College of Obstetricians and Gynecologists (ACOG) Committee on Technical Bulletins. Preterm labor. Technical Bulletin No. 206. Washington, DC: American College of Obstetricians and Gynecologists; 1995 Jun.

174. National Institutes of Health, National Heart, Lung, and Blood Institute. Global initiative for asthma: global strategy for asthma management and prevention NHLBI/WHO Workshop Report. Bethesda, MD: National Institutes of Health. 2007 Dec 19. NIH/NHLBI Publication No. 02-3659. Available from website. Accessed Jul 27, 2008. [Web]

175. The American Heart Association. Guidelines 2005 for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2005; 112(Suppl I): IV1-211.

176. Eigel B. (American Heart Association, Dallas, TX): Personal communication; 2006 Apr 27.

177. Spöhr F, Wenzel V, Böttiger BW. Drug treatment and thrombolytics during cardiopulmonary resuscitation. Curr Opin Anaesthesiol . 2006; 19:157-65. [PubMed 16552222]

178. Vandycke C, Martens P. High dose versus standard dose epinephrine in cardiac arrest - a meta-analysis. Resuscitation . 2000; 45:161-6. [PubMed 10959014]

179. Zhong JQ, Dorian P. Epinephrine and vasopressin during cardiopulmonary resuscitation. Resuscitation . 2005; 66:263-9. [PubMed 16039036]

180. Paradis NA, Wenzel V, Southall J. Pressor drugs in the treatment of cardiac arrest. Cardiol Clin . 2002; 20:61-78. [PubMed 11845545]

181. Perondi MBM, Reis AG, Paiva EF et al. A comparison of high-dose and standard-dose epinephrine in children with cardiac arrest. New Engl J Med . 2004; 350:1722-30. [PubMed 15102998]

182. Epstein AE, DiMarco JP, Ellenbogen KA et al. 2012 ACCF/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol . 2013; 61:e6-75.

184. Jacobs IG, Finn JC, Jelinek GA et al. Effect of adrenaline on survival in out-of-hospital cardiac arrest: A randomised double-blind placebo-controlled trial. Resuscitation . 2011; 82:1138-43. [PubMed 21745533]

185. Olasveengen TM, Sunde K, Brunborg C et al. Intravenous drug administration during out-of-hospital cardiac arrest: a randomized trial. JAMA . 2009; 302:2222-9. [PubMed 19934423]

190. Nephron Pharmaceuticals Corporation. S2 (racepinephrine inhalation solution, USP 2.25%) product information. Orlando, FL; 2015 Feb.

191. von Mutius E, Drazen JM. A patient with asthma seeks medical advice in 1828, 1928, and 2012. N Engl J Med . 2012; 366:827-34. [PubMed 22375974]

192. Food and Drug Administration, HHS. Labeling for bronchodilators to treat asthma; cold, cough, allergy, bronchodilator, and antiasthmatic drug products for over-the-counter human use. Final rule. Fed Regist . 2011; 76:44475-89. [PubMed 21796845]

193. Hospira. Epineprhine injection 0.1 mg/mL prescribing information. Lake Forest, IL; 2016 Mar.

194. Arthur G. Epinephrine: a short history. Lancet Respir Med . 2015; 3:350-1. [PubMed 25969360]

195. Belcher Pharmaceuticals. Epinephrine injection USP 1 mg/mL prescribing information. Largo, FL. 2016 Feb.

196. Vanden Hoek TL, Morrison LJ, Shuster M et al. Part 12: cardiac arrest in special situations: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation . 2010; 122(18 Suppl 3):S829-61.

197. Simons FE, Ardusso LR, Bilò MB et al. World allergy organization guidelines for the assessment and management of anaphylaxis. World Allergy Organ J . 2011; 4:13-37. [PubMed 23268454]

198. Campbell RL, Bellolio MF, Knutson BD 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 . 2015 Jan-Feb; 3:76-80.

199. Lieberman P, Simons FE. Anaphylaxis and cardiovascular disease: therapeutic dilemmas. Clin Exp Allergy . 2015; 45:1288-95. [PubMed 25711241]

200. Kemp SF, Lockey RF, Simons FE et al. Epinephrine: the drug of choice for anaphylaxis-a statement of the world allergy organization. World Allergy Organ J . 2008; 1(7 Suppl):S18-26.

201. Wood JP, Traub SJ, Lipinski C. Safety of epinephrine for anaphylaxis in the emergency setting. World J Emerg Med . 2013; 4:245-51. [PubMed 25215127]

202. Simons FE. Nonprescription availability of theophylline, epinephrine and ephedrine for asthma. CMAJ . 1987; 137:789. [PubMed 3442767]

203. Bel EH. Clinical Practice. Mild asthma. N Engl J Med . 2013; 369:549-57. [PubMed 23924005]

204. Rhodes A, Evans LE, Alhazzani W et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med . 2017; 43:304-377. [PubMed 28101605]

205. Cawcutt KA, Peters SG. Severe sepsis and septic shock: clinical overview and update on management. Mayo Clin Proc . 2014; 89:1572-8. [PubMed 25444488]

206. Vincent JL, De Backer D. Circulatory shock. N Engl J Med . 2013; 369:1726-34. [PubMed 24171518]

207. Myburgh JA, Higgins A, Jovanovska A et al. A comparison of epinephrine and norepinephrine in critically ill patients. Intensive Care Med . 2008; 34:2226-34. [PubMed 18654759]

208. Hollenberg SM. Vasoactive drugs in circulatory shock. Am J Respir Crit Care Med . 2011; 183:847-55. [PubMed 21097695]

209. Annane D, Vignon P, Renault A et al. Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomised trial. Lancet . 2007; 370:676-84. [PubMed 17720019]

210. Gamper G, Havel C, Arrich J et al. Vasopressors for hypotensive shock. Cochrane Database Syst Rev . 2016; 2:CD003709.

211. Tschudy MM, Arcara KM eds. The Harriet Lane handbook: a manual for pediatric house officers. 19th ed. Philadelphia, PA: Elsevier Mosby; 2012:782-83.

212. Amphastar Pharmaceuticals. Epinephrine injection prescribing information. So. El Monte, CA; 2008 Nov.

213. Kattwinkel J, Perlman JM, Aziz K et al. Part 15: neonatal resuscitation: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation . 2010; 122(18 Suppl 3):S909-19. [PubMed 20956231]

214. Wyckoff MH, Aziz K, Escobedo MB et al. Part 13: Neonatal Resuscitation: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation . 2015; 132(18 Suppl 2):S543-60. [PubMed 26473001]

215. Brown RS, Rhodus NL. Epinephrine and local anesthesia revisited. Oral Surg Oral Med Oral Pathol Oral Radiol Endod . 2005; 100:401-8. [PubMed 16182160]

216. Council on Clinical Affairs, American Academy of Pediatric Dentistry. Guideline on Use of Local Anesthesia for Pediatric Dental Patients. Pediatr Dent . 2015 Sep-Oct; 37:71-7.

217. Markenson D, Ferguson JD, Chameides L et al. Part 17: first aid: 2010 American Heart Association and American Red Cross Guidelines for First Aid. Circulation . 2010; 122(18 Suppl 3):S934-46.

218. Hegenbarth MA, American Academy of Pediatrics Committee on Drugs. Preparing for pediatric emergencies: drugs to consider. Pediatrics . 2008; 121:433-43. [PubMed 18245435]

219. Sanofi-Aventis. Auvi-Q^® (epinephrine injection 0.3 mg, 0.15 mg auto-injector) prescribing information. Bridgewater, NJ; 2014 Feb.

220. Sanofi-Aventis. Auvi-Q^® (epinephrine injection 0.3 mg, 0.15 mg auto-injector) patient information. Bridgewater, NJ; 2014 Feb.

221. Amedra Pharmaceuticals. Adrenaclick^® (epinephrine injection 0.3 mg, 0.15 mg auto-injector) prescribing information. Horsham, PA; 2014 Oct.

222. Amedra Pharmaceuticals. Adrenaclick^® (epinephrine injection 0.3 mg, 0.15 mg auto-injector) patient information. Horsham, PA; 2013 Apr.

223. Food and Drug Administration. FDA briefing document from the nonprescription drug advisory committee meeting. February 26, 2014. From FDA website. [Web]

224. Ralston DH, Shnider SM. The fetal and neonatal effects of regional anesthesia in obstetrics. Anesthesiology . 1978; 48:34-64. [PubMed 339784]

225. Abboud TK, David S, Nagappala S et al. Maternal, fetal, and neonatal effects of lidocaine with and without epinephrine for epidural anesthesia in obstetrics. Anesth Analg . 1984; 63:973-9. [PubMed 6496982]

226. Institute for Safe Medication Practices. Acute Care Medication Safety Alert Newsletter: Farewell to ratio expressions on single entity drug labels. Horsham, PA; 2015 Dec. From ISMP website. [Web]

227. United States Pharmacopeia and National Formulary (USP 39 NF 34). Rockville, MD: United States Pharmacopeia Convention; 2016:99.

228. Lieberman P, Nicklas RA, Randolph C et al. Anaphylaxis--a practice parameter update 2015. Ann Allergy Asthma Immunol . 2015; 115:341-84. [PubMed 26505932]

229. Park WG, Yeh RW, Triadafilopoulos G. Injection therapies for nonvariceal bleeding disorders of the GI tract. Gastrointest Endosc . 2007; 66:343-54. [PubMed 17643711]

230. Gralnek IM, Dumonceau JM, Kuipers EJ et al. Diagnosis and management of nonvariceal upper gastrointestinal hemorrhage: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy . 2015; 47:a1-46.

231. Hwang JH, Fisher DA, Ben-Menachem T et al. The role of endoscopy in the management of acute non-variceal upper GI bleeding. Gastrointest Endosc . 2012; 75:1132-8. [PubMed 22624808]

232. Barkun AN, Bardou M, Kuipers EJ et al. International consensus recommendations on the management of patients with nonvariceal upper gastrointestinal bleeding. Ann Intern Med . 2010; 152:101-13. [PubMed 20083829]

233. National Institute for Health and Clinical Excellence. Acute upper gastrointestinal bleeding overview. Manchester, England. 2016 Feb. From NICE website. [Web] [Web]

234. Laine L, Jensen DM. Management of patients with ulcer bleeding. Am J Gastroenterol . 2012; 107:345-60; quiz 361. [PubMed 22310222]

235. Herget-Rosenthal S, Saner F, Chawla LS. Approach to hemodynamic shock and vasopressors. Clin J Am Soc Nephrol . 2008; 3:546-53. [PubMed 18256381]

236. Mondal P, Kandala B, Ahrens R et al. Nonprescription racemic epinephrine for asthma. J Allergy Clin Immunol Pract . 2014 Sep-Oct; 2:575-8.

237. Brierley J, Carcillo JA, Choong K et al. Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the American College of Critical Care Medicine. Crit Care Med . 2009; 37:666-88. [PubMed 19325359]

238. BPI Labs. Epinephrine injection (1 mg/mL) prescribing information. Freehold, NJ; 2014 July.

249. ASHP. Standardize 4 Safety: pediatric continuous infusion standard. Updated 2024 Mar. From ASHP website. Updates may be available at ASHP website. [Web]

250. ASHP. Standardize 4 Safety: adult continuous infusion standard. Updated 2024 Mar. From ASHP website. Updates may be available at ASHP website. [Web]

400. Link MS, Berkow LC, Kudenchuk PJ et al. Part 7: Adult Advanced Cardiovascular Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation . 2015; 132(18 Suppl 2):S444-64.

401. Neumar RW, Otto CW, Link MS et al. Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation . 2010; 122(18 Suppl 3):S729-67.

402. de Caen AR, Berg MD, Chameides L et al. Part 12: Pediatric Advanced Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation . 2015; 132(18 Suppl 2):S526-42. [PubMed 26473000]

403. Kleinman ME, Chameides L, Schexnayder SM et al. Part 14: pediatric advanced life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation . 2010; 122(18 Suppl 3):S876-908.

404. Peberdy MA, Callaway CW, Neumar RW et al. Part 9: post-cardiac arrest care: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation . 2010; 122(18 Suppl 3):S768-86.

405. Neumar RW, Shuster M, Callaway CW et al. Part 1: Executive Summary: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation . 2015; 132(18 Suppl 2):S315-67.