Epinephrine, also called Adrenaline is a non-selective Beta and alpha receptor agonist. 

It causes vasoconstriction and bronchodilation.

Epinephrine Uses:

Thus, it is used to treat anaphylactic reactions where patients develop shortness of breath, wheezing, skin rash and low blood pressure.

Adrenaline/ epinephrine is also used in patients with:

• cardiac arrest, asystole,

• ventricular fibrillation or pulseless ventricular tachycardia unresponsive to initial defibrillation, and

• pulseless electrical activity.

It is used as an inotropic agent in hypotension unresponsive to volume resuscitation, and symptomatic bradycardia unresponsive to atropine.

It causes bronchodilation and is thus used to treat bronchospasm and viral croup.

It may be added to local anesthetics to decrease their systemic absorption and increase their duration of action.

It is occasionally injected at the site of bleeding as in variceal bleeding causing vasoconstriction and securing the bleeding site.

It is also used as a mydriatic agent during intraocular surgery.

Epinephrine uses in Emergency:

Epinephrine use in Anaphylaxis:

Anaphylaxis is a medical emergency.

Patients develop generalized body itching, urticaria, lips & facial swelling, difficulty in breathing, wheezing, and low blood pressure.

Anaphylaxis usually follows a bee sting, food allergens such as peanuts, fish, milk, and eggs, medicines like penicillin and sulfonamides, and vaccination.

If anaphylaxis is not treated promptly, it may result in death.

Epinephrine is a potent vasoconstrictor. It promptly relieves airway edema, itching, hypotension, and shock.

It is important to note that antihistamines and glucocorticoids only treat the cutaneous symptoms of anaphylaxis and have a delayed onset of action.

Epinephrine should be administered as soon as signs of anaphylaxis are recognized.

It should be administered as an IM injection in the mid-outer thigh.

(Ref: Epinephrine for First-aid Management of Anaphylaxis)

EpiPens and Epinephrine autoinjectors in anaphylaxis:

The role of EpiPens and Epinephrine autoinjectors is increasingly being utilized for the early management of anaphylaxis.

Epinephrine autoinjectors should be used by the patients even in less severe cases (also termed as impending anaphylaxis).

Current guidelines recommend that patients who are at risk of anaphylaxis should carry at least two epinephrine autoinjectors because of the biphasic nature of the disease.

EpiPens and autoinjectors are costly but compared to treatment in the emergency visits and the risk of deaths, they may be cost-effective.

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Epinephrine in Asthma, angioedema, and allergic reactions:

Although safe alternatives such as albuterol, glucocorticoids, magnesium sulfate, and aminophylline now exist for the treatment of asthma, the role of epinephrine can never be underestimated.

Epinephrine can be used in patients with life-threatening asthma that does not get better with conventional treatment.

It acts as a bronchodilator and also relieves airway edema because of its alpha-agonist activity.

Epinephrine may be hazardous in elderly patients with atherosclerotic cardiovascular disease or several cardiac risk factors.

In severe asthma, the heart rate increases because of respiratory failure and hypoxemia.

Furthermore, in severe bronchospasm, inhalational therapies may not work.

One recently conducted study did not find any serious adverse effects such as arrhythmias, hypertension and myocardial infarction with the use of epinephrine in asthmatics.

Subcutaneous epinephrine may paradoxically decrease the heart rate.

This is because the patient can breath after the injection and the oxygenation saturations improve resulting in the normalization of heart rate.

In rare cases, it can also be administered as an intravenous infusion. It may be used as the last resort to avoid intubating the patient.

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Epinephrine in Cardiac Arrest:

Epinephrine is recommended by the AHA in patients with asystole and non-shockable rhythm.

It is also reasonable to use in patients with a shockable rhythm after two failed defibrillations.

It has also been shown to improve survival in patients who have an out of the hospital cardiac arrest when it is administered within 20 minutes.

A delay in the administration of epinephrine in patients with OHCC (Out of hospital cardiac arrest) was associated with worse neurological outcomes.

Similarly, investigators of the "A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest" noted significantly higher rates of survival in patients who received epinephrine but there was no significant difference in the rates of favorable neurologic outcomes.

Epinephrine is ideally administered as an intravenous bolus in cardiac arrest, but intraosseous administration in pediatric patients was equally effective in one study.

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Epinephrine in Shock:

Shock is a state of reduced peripheral perfusion. Shock can be cardiogenic, hypovolemic, neurogenic, or anaphylactic.

The initial treatment of most patients with shock is fluid resuscitation. Medicines used to treat shock include dopamine, dobutamine, norepinephrine, epinephrine, phenylephrine, and vasopressin.

Compared to dopamine, epinephrine was found to be more effective in one study in patients with fluid-refractory shock.

Epinephrine vs Norepinephrine in cardiogenic shock post-myocardial infarction:

Epinephrine was found to be as effective in improving arterial pressure and cardiac index compared to nor-epinephrine in patients with cardiogenic shock post-myocardial infarction.

However, its use was associated with a higher incidence of refractory shock.

Epinephrine was also found to be associated with a three-fold increase in the risk of death in patients with cardiogenic shock compared to other vasopressors.

Other studies have reported that the early use of epinephrine (within the first 24 hours after admission to ICU) may be associated with greater hemodynamic improvements in patients with nor-epinephrine-refractory shock.

Epinephrine Dose in Adults

Epinephrine dose in asystole/pulseless arrest, pulseless Ventricular tachycardia, and ventricular fibrillation:

Intravenous dose:

• 1 mg IV every 3-5 minutes until the return of spontaneous circulation;
• Higher doses of epinephrine up to 0.2 mg/kg may be used for the treatment of calcium channel blockers and beta-blocker overdose.

Endotracheal dose:

• 2-2.5 mg diluted in 5 to 10 ml of normal saline or distilled water (preferably distilled water) every 3-5 minutes until intravenous or intraosseous access has been established or till the return of spontaneous circulation.
• Endotracheal epinephrine may cause false-negative CO2 results, therefore, alternative methods of endotracheal tube confirmation should be used.

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Adrenaline Dose in the treatment of bradycardia unresponsive to atropine: 

Intravenous infusion: 

• 2-10 mcg/minute or 0.1-0.5 mcg/kg/minute.

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Epinephrine dose in asthma:

Subcutaneous dose:

• 0.3-0.5 mg ( 1:1000 [1 mg/mL] solution) every 20 minutes for 3 doses

Nebulizer dose:

• Add 0.5 mL (~10 drops) to a nebulizer and dilute with 3 mL of NS; administer over ~15 minutes every 3-4 hours as needed.

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Epinephrine dose in anaphylaxis and allergic reactions: 

Intramuscular injection in the anterior thigh is the preferred site for injection compared to the subcutaneous route.

Intramuscular and subcutaneous dose:

• 0.2-0.5 mg ( 1:1000 [1 mg/mL] solution) every 5-15 minutes. In severe cases, the interval may be shortened.

Intravenous:

• Patients who are in refractory shock and in a cardiopulmonary arrest may be given intravenous injections of:

0.1 mg ( 1:10,000 [0.1 mg/mL] solution) over 5 minutes;

• Patients in profound shock not responsive to volume resuscitation or those requiring repeated injections of epinephrine may be given intravenous infusions at 1-4 mcg/minute to prevent the need to repeat injections frequently or may initiate with an infusion at 5-15 mcg/minute.

Epinephrine pen for Self-administration following severe allergic reactions (eg, insect stings, food): 

• One dose for every 10-20 minutes of travel time to a medical emergency facility is recommended by the WHO.
• If more than two doses are required, it should be given under direct medical supervision.
• Auvi-Q™/ Epipen®/ Twinject®: I.M., SubQ: 0.3 mg; Repeat the dose if required.

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Epinephrine injection for a severe and fluid resistant hypotensive shock:

Intravenous infusion: 

• 0.1-0.5 mcg/kg/minute

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Epinephrine dose for mydriasis during intraocular surgery: 

Intraocular dose:

• Must dilute 1: 1000 (1 mg/mL) solution to a concentration of 1:100,000 to 1: 1,000,000 (10 mcg /mL to 1 mcg /mL) prior to intraocular use.
• May use as an irrigation solution as needed during the procedure or may administer intracamerally (ie, directly into the anterior chamber of the eye) with a bolus dose of 0.1 mL of a 1: 100,000 to 1: 400,000 (10 mcg/mL to 2.5 mcg /mL) dilution.

Epinephrine dose in Children:

Epinephrine dose in Severe Asthma:

Note: Not recommended for routine management of asthma

Racemic epinephrine (2.25% solution):

• Children ≥4 years and Adolescents:

  • Administer 0.5 mL diluted with 3-5 mL of Normal saline with a nebulizer over 15 minutes every 3 to 4 hours as needed.

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Epinephrine Dose in asystole or pulseless arrest:

Intravenous or intraosseous route:

• 0.01 mg/kg (0.1 mL/kg of 1:10,000 solution) (maximum single dose: 1 mg); every 3-5 minutes until return of spontaneous circulation

Endotracheal route:

• 0.1 mg/kg (0.1 mL/kg of 1:1000 solution) (maximum single dose: 2.5 mg) every 3-5 minutes until return of spontaneous circulation or intravenous or intraosseous access is established.

Note: Endotracheal administration may cause transient hypotension and reduce coronary perfusion

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Epinephrine dose in Bradycardia:

Intravenous or intraosseous:

• 0.01 mg/kg (0.1 mL/kg of 1:10,000 solution) (maximum dose: 1 mg or 10 mL); may repeat every 3-5 minutes as needed

Endotracheal:

• 0.1 mg/kg (0.1 mL/kg of 1:1000 solution) (maximum single dose: 2.5 mg); doses as high as 0.2 mg/kg may be effective; may repeat every 3-5 minutes as needed until I.V./I.O. access established

Continuous infusion:

• I.V., I.O.: 0.1-1 mcg/kg/minute; titrate dosage to desired effect

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Epinephrine dose in Croup (laryngotracheobronchitis) and airway edema: 

Nebulization:

Racemic epinephrine (2.25% solution):

• 0.05-0.1 mL/kg (maximum dose: 0.5 mL) diluted in 2 mL NS, may repeat dose every 20 minutes.

L-epinephrine:

• 0.5 mL/kg of 1:1000 solution (maximum dose: 5 mL) diluted in NS, may repeat the dose every 20 minutes; Note: Racemic epinephrine 10 mg = 5 mg L-epinephrine.

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Epinephrine dose in Hypersensitivity reactions: 

Intramuscular is the preferred route as the subcutaneous route is less reliable and absorption may be slow. For self-administration, a single dose for every 20 minutes of travel time is recommended by the WHO.

Intramuscular and subcutaneous dose:

• 0.01 mg/kg (0.01 mL/kg/dose of 1:1000 solution) not to exceed 0.3-0.5 mg every 5-15 minutes

Autoinjector dose:

• 10-25 kg: 0.15 mg Intramuscular in the mid-outer thigh
• >25 kg: 0.3 mg

Autoinjectors (EpiPen® Jr, EpiPen®, Twinject®):

• 15-29 kg: 0.15 mg; if anaphylactic symptoms persist, dose may be repeated in 5-15 minutes
• ≥30 kg: 0.3 mg; if anaphylactic symptoms persist, dose may be repeated in 5-15 minutes

Intravenous dose:

• 0.01 mg/kg (0.1 mL/kg of 1:10,000 solution) not to exceed 0.5 mg every 20 minutes; may use continuous infusion (0.1 mcg/kg/minute) to prevent frequent doses in more severe reactions

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Epinephrine dose in fluid resistant shock and hypotension

Continuous intravenous infusion:

• 0.1-1 mcg/kg/minute; rarely up to 5 mcg/kg/minnute may be used

Subcutaneous administration:

• 0.01 mg/kg (0.01 mL/kg of 1:1000 solution)  every 20 minutes for 3 doses (maximum of 0.5 mg in a single dose)

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Adrenaline as an Inotropic agent: 

Continuous infusion rate:

• 0.1-1 mcg/kg/minute

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Adrenaline dose in Postresuscitation infusion to maintain cardiac output or stabilize: 

Continuous infusion rate:

• 0.1-1 mcg/kg/minute;
• Doses of less than <0.3 mcg/kg/minute generally produce β-adrenergic effects doses higher than (>0.3 mcg/kg/minute) generally produce alpha-adrenergic vasoconstriction.

Pregnancy Risk Factor: C

• Epinephrine crosses the placenta and may cause fetal anoxia.
• Use during pregnancy when the potential benefit to the mother outweighs the possible risk to the fetus.
• Excretion in breast milk is not known. Caution should be exercised in breastfeeding women.

Dose in kidney impairment:

• No dosage adjustment provided in the manufacturer's labeling. 

Dose in Liver disease:

• No dosage adjustment provided in manufacturer's labeling. 

Adrenaline/ Epinephrine Side effects:

• Angina,
• angle-closure glaucoma,
• anorexia,
• anxiety,
• arrhythmias,
• cold extremities,
• confusion,
• difficulty in micturition,
• dizziness,
• dry mouth,
• dyspnoea,
• headache,
• hyperglycemia,
• hypersalivation,
• hypertension (risk of cerebral haemorrhage),
• hypokalemia,
• insomnia,
• metabolic acidosis,
• mydriasis,
• myocardial infarction,
• nausea,
• pallor,
• palpitation,
• psychosis,
• pulmonary edema (on excessive dosage or extreme sensitivity),
• restlessness,
• sweating,
• tachycardia,
• tissue necrosis at the injection site,
• tissue necrosis of the bowel,
• tissue necrosis of extremities,
• tissue necrosis of kidneys,
• tissue necrosis of the liver,
• tremor,
• urinary retention,
• vomiting, and
• weakness.

Epinephrine Contraindications

• Arteriosclerosis (in adults),
• arrhythmias,
• cerebrovascular disease,
• cor pulmonale,
• diabetes mellitus,
• elderly,
• hypercalcemia,
• hypertension,
• hyperthyroidism,
• hypokalaemia,
• ischaemic heart disease,
• obstructive cardiomyopathy,
• occlusive vascular disease,
• organic brain damage,
• phaeochromocytoma,
• prostate disorders,
• psychoneurosis,
• severe angina, and
• susceptibility to angle-closure glaucoma

Epinephrine (adrenaline) (systemic): Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use   

Risk Factor C (Monitor therapy).
Alpha1-Blockers	May diminish the vasoconstricting effect of Alpha-/Beta-Agonists. In the same way, Alpha-/Beta Agonists could antagonize Alpha1Blocker vasodilation.
Antidiabetic Agents	Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents.
AtoMOXetine	Might increase the hypertensive effects of Sympathomimetics. AtoMOXetine could increase the tachycardic effects of Sympathomimetics.
Benperidol	Might reduce the therapeutic effects of EPINEPHrine Systemic.
Beta-Blockers (Beta1 selective)	Might reduce the therapeutic effects of EPINEPHrine Systemic.
Beta-Blockers (Nonselective).	May increase the hypertensive effects of EPINEPHrine Systemic. Arotinolol, Carvedilol, and Labetalol are exceptions.
Beta-Blockers (with Alpha-Blocking Properties	Might reduce the therapeutic effects of EPINEPHrine Systemic.
Cannabinoid-Containing Products	Sympathomimetics may increase the tachycardic effects of Sympathomimetics. Cannabidiol is an exception.
Chloroprocaine	May enhance the hypertensive effect of Alpha-/Beta-Agonists.
CloZAPine	May diminish the therapeutic effect of Alpha-/Beta-Agonists.
Inhibitors of COMT	Might decrease metabolism of COMT Substrates.
Doxofylline	Doxofylline may be more toxic or harmful if taken with Sympathomimetics.
Guanethidine	May increase the arrhythmogenic effects of Sympathomimetics. The hypertensive effects of Sympathomimetics may be enhanced by Guanethidine.
Monoamine Oxidase Inhibitors	Might increase the hypertensive effects of EPINEPHrine Systemic.
Solriamfetol	Sympathomimetics could increase the hypertensive effects of Solriamfetol.
Spironolactone	May diminish the vasoconstricting effect of Alpha-/Beta-Agonists.
Sympathomimetics	May increase the toxic/adverse effects of other Sympathomimetics.
Tedizolid	Might increase the hypertensive effects of Sympathomimetics. Tedizolid could increase the tachycardic effects of Sympathomimetics.
Risk Factor D (Regard therapy modification)
BenzylpenicilloylPolylysine	Alpha-/Beta-Agonists may diminish the diagnostic effect of BenzylpenicilloylPolylysine. Management: A histamine skin test may be used as a positive control in order to determine if a patient is able to mount a wheal or flare response.
Topical Cocaine	Sympathomimetics may increase hypertensive effects. Management: If possible, consider other options to this combination. Concurrent use of this combination can cause significant elevations in blood pressure and heart rate. You should also be aware of any signs of myocardial injury.
Hyaluronidase	May enhance the vasoconstricting effect of Alpha-/Beta-Agonists. Management: Avoid the use of hyaluronidase to enhance dispersion or absorption of alpha-/beta-agonists. Clinically, it may be indicated to use hyaluronidase in patients who are receiving alpha/beta-agonists for other purposes.
Inhalational Anesthesia	Systemic may increase the arrhythmogenic effects of EPINEPHrine (Systemic). Patients who are currently receiving or have received inhalational anesthetics should be administered epinephrine with extra caution. Monitor for cardiac arrhythmias and use lower doses than usual.
Linezolid	Sympathomimetics may increase hypertensive effects. Patients receiving linezolid should be reduced in initial doses and closely monitored for an increased pressor response. There are no recommendations for dose adjustments.
Promethazine	This may reduce the vasoconstricting effects of EPINEPHrine Systemic. Management: If patients are experiencing vasoconstrictive effects from promethazine, there may be alternatives to epinephrine. When treating hypotension caused by promethazine overdose, you should consider using phenylephrine and norepinephrine.
Serotonin/Norepinephrine Reuptake Inhibitors	May enhance the tachycardic effect of Alpha-/Beta-Agonists. Serotonin/Norepinephrine Reuptake Inhibitors may enhance the vasopressor effect of Alpha-/Beta-Agonists.
Tricyclic Antidepressants	DirectActing may increase the vasopressor effects of Alpha/Beta-Agonists. Patients on tricyclic antidepressants should avoid direct-acting alpha/beta-agonists. Monitor for increased pressure effects when combined and reduce the initial doses of alpha/beta-agonists.
Risk Factor X (Avoid Combination)
Blonanserin	Might reduce the therapeutic effects of EPINEPHrine Systemic.
Bromperidol	Might reduce the therapeutic effects of EPINEPHrine Systemic.
Ergot Derivatives	May enhance the hypertensive effect of Alpha-/Beta-Agonists. Ergot Derivatives may enhance the vasoconstricting effect of Alpha-/Beta-Agonists. There are exceptions: Ergoloid Mesylates and Nicergoline.
Lurasidone	EPINEPHrine (Systemic), may increase the hypotensive effects of Lurasidone.

Monitor:

• Monitor Pulmonary functions, heart rate, blood pressure, site of infusion for blanching, and extravasation.
• Cardiac monitor and blood pressure monitoring are required during continuous infusion.
• If using to treat hypotension, assess intravascular volume and support as needed. 

How to administer Epinephrine:

• Central line administration via an infusion pump is preferred for intravenous infusions.
• Epinephrine solutions for injection can be administered intramuscular, intraosseous, endotracheally, intravenous or SubQ.
• Subcutaneous administration is less reliable and has slow absorption.
• For anaphylaxis, Intramuscular administration in the anterior thigh is the preferred site (avoid administration into the buttocks).
• In obese patients, administer into the lower thigh or even the calf muscles.

Endotracheal administration in cardiac arrest:

• Dilute in sterile water. Stop compressions, spray drug quickly down tube.
• Follow immediately with several quick insufflations and continue chest compressions.
• Endotracheal administration may cause false-negative reading with exhaled CO 2 detectors.

Extravasation management:

• Use phentolamine as an antidote. Mix 5 mg phentolamine with 9 mL of NS.
• Inject a small amount of this dilution into the extravasated area. Blanching should reverse immediately.
• Monitor site. If blanching should recur, additional injections of phentolamine may be needed.

Usual Infusion Concentrations:

Adult I.V. infusion: 

• 1 mg in 250 mL (concentration: 4 mcg /mL) or 4 mg in 250 mL (concentration: 16 mcg /mL) of D 5 W or NS

Pediatric I.V. infusion: 

• 16 mcg /mL, 32 mcg /mL, or 64 mcg /mL Incompatible in sodium bicarbonate.

Adrenaline/ Epinephrine Mechanism of Action :

• Epinephrine stimulates beta-adrenergic receptors, resulting in relaxation and stimulation of the bronchial tree's smooth muscle, stimulation of myocardium, and dilation of the skeletal muscles (in small doses).

Metabolism: The liver and adrenergic neuron via COMT or MAO metabolize these metabolites. 

Inactive metabolites are excreted from the urine. 

Epinephrine brands in US:

• Adrenalin
• Asthmanefrin
• Auvi-Q
• EpiPen 2-Pak
• EpiPen Jr 2-Pak
• S2
• Twinject

Epinephrine Brand Names: Canada

• Adrenalin
• Epi E-Z Pen
• EpiPen
• EpiPen Jr
• Twinject

Epinephrine brands in Pakistan:

ADECAINE WITH ADRENALINE  ( P.D.H. PHARMACEUTICALS (PVT) LTD )

 Injections : 2 ml :

Lignocaine : 20 mg/ml :

Adrenaline : 0.001%w/v :

100 injections pack : Rs.250

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ADRENALINE  (VENUS PHARMA)

 Injections : 1 mg/ml :

10 ml injection : Rs. 11.52

1 ml injection 100 injections per pack : Rs. 158.75

25 ml injection : Rs.21

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L-CAINE  (OPHTH-PHARMA (PVT) LTD)

 Lignocaine : 20 mg/ml :

 Adrenaline : 0.001%w/v :

10 ml injection 50 injections per pack : Rs.  950

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LIGNOCAIN (SHIFA LABORATORIES.(PVT) LTD )

Lignocaine : 2%w/v :

50 ml injection pack : Rs. 44

   Lignocaine : 20 mg/ml :

     Adrenaline : 0.001%w/v :

50 ml injection 10 injections per pack : Rs. 44

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LIGNOCAINE WITH ADRENALINE (LAHORE CHEMICAL & PHARMACEUTICALS WORK (PVT) LTD )

 Lignocaine : 20 mg/ml :

Adrenaline : 0.001 %w/v :

10 ml injection 50 injections per pack : Rs.0.00

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M B-CAIN (MULTINATIONAL BUISNESS LINK)

Lignocaine : 2%w/v :

10 ml injection 50 injections per pack : Rs. 600     Lignocaine : 20 mg/ml :

Adrenaline : 0.001 %w/v :

10 ml injection 50 injections per pack Rs. 650

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MEDICAINE  (HOSPITAL SUPPLY CORPORATTION)

Lignocaine : 20 mg/ml :

    Adrenaline : 0.001 %w/v :

1.8 ml injection 50 carts per pack : Rs. 676

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XYLEX-AD (VENUS PHARMA)

Lignocaine : 20 mg/ml :

  Adrenaline : 0.001 %w/v :

10 ml injection 50 injections per pack : Rs. 660

  Lignocaine : 20 mg/ml :

Adrenaline : 0.001 %w/v :

2 ml injection 100 injectiona per pack : Rs. 235.43 

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XYLOCAINE WITH ADRENALINE (BARRETT HODGSON PAKISTAN (PVT) LTD)  

    Lignocaine : 10 mcg/ml :

Adrenaline : 5mcg/ml :

10 ml injection 50 injections per pack : Rs. 810

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XYLODOS (DOSACO LABORATORIES)

Lignocaine : 20 mg/ml :

Adrenaline : 0.001%w/v :

2 ml injection : Rs. 3

Lignocaine : 2 %w/v :

50 ml injection : Rs. 0.00

    Lignocaine : 20 mg/ml :

  Adrenaline : 0.001 %w/v :

50 ml injection : Rs. 16

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XYLOX ADRENAUNE (VENUS PHARMA)

Lignocaine : 0 :

    Adrenaline : 0 :

50 ml injection : Rs. 11.76