Adrenaline (Epinephrine) Nebulized

Mechanism

Pharmacological Class and Group

Direct sympathomimetic agonist of alpha-1, alpha-2, beta-1 and beta-2 adrenergic receptors of synthetic or purified origin.

Mechanism of Action

Adrenaline administered by direct micronebulization on the laryngeal respiratory mucosa acts immediately, facilitating mechanical deinflammation of the subgloris and restoring air flow:

Molecular Mechanism of Upper Airway Decongestion

1. Postsynaptic Alpha-1 Stimulation (Mucosal Vasoconstriction): It binds to the alpha-1 receptors distributed in the resistance arterioles of the subglottic laryngeal mucosa. This activates the Gq protein, increasing intracellular calcium in the smooth muscle cells of the vessels and causing powerful and rapid local vasoconstriction.

2. Resolution of Subglottic Edema and Exudation: By decreasing local capillary flow due to vasoconstriction, rhinosinusal and subglottic capillary hydrostatic pressure decreases netly, stopping plasma extravasation and fluid exudation into the interstitial tissue at its roots:

Nebulization of Adrenaline Arteriolar capillary vasoconstriction ↓ Capillary hydrostatic pressure and edema

3. Postsynaptic Beta-2 Stimulation (Bronchodilation and Cellular Stabilization): Stimulates beta-2 receptors in bronchial smooth muscle and local mast cells. This activates protein Gs/adenylate cyclase, increasing intracellular cAMP, which relaxes the airways and stops the degranulation of histamine and inflammatory cytokines by local mast cells.

Pharmacokinetics

High Resolution Pharmacokinetics

• Onset of Action: Immediate, less than 1-5 minutes after nebulization.
• Duration of Effect: Short, approximately 1 to 2 hours. When local sympathetic stimulation ceases, reactive vasodilation occurs that can reproduce basal laryngeal edema (rebound effect), requiring continuous monitoring of the patient.
• Systemic Absorption: Moderate systemic absorption occurs through the distal respiratory tree and the gastrointestinal mucosa of swallowed saliva, which can induce sinus tachycardia, mild hypertension and generalized tremors in the patient temporarily.

Indicators and dose

Clinical Indications and Off-Label Uses

• Moderate to Severe Acute Stridulous Laryngitis (Laryngeal Croup): Emergency management in infants and children with persistent inspiratory stridor at rest, intercostal indrawing and progressive acute respiratory distress.
• Acute Glottis Edema or Anaphylaxis with Upper Airway Obstruction: Inhaled rescue therapy adjuvant to the immediate intramuscular injection of systemic adrenaline.
• Post-extubation Laryngeal or Tracheal Edema: Analgesic and anti-inflammatory management in pediatric or adult intensive care units.
• Bleeding from the oropharyngeal cavity or nasal cavity immediately postoperative (off-label): Local application of tamponades impregnated with adrenaline as a direct capillary hemostatic agent (epistaxis, post-adenoidectomy).

Dosage and Clinical Adjustment

Nebulization Scheme in Children (Laryngeal Croup):

• Dose of Adrenaline L-isomer standard (1:1000, 1 mg/mL):
  • Children over 4 years of age or weighing 10 kg: 5 mL of pure adrenaline (5 ampoules) without prior dilution, or diluted with sterile physiological solution to a volume of 6 mL, administered by nebulizer with a face mask and oxygen flow at 6-8 L/min.
  • Infants under 1 year of age or weight < 10 kg: 0.5 mL/kg of the standard solution 1:1000 (maximum dose of 5 mL) completed with sterile physiological solution for nebulization.
• Repetition Frequency: In severe refractory cases, nebulization can be repeated every 30-60 minutes under strict monitoring of the infant's heart rate (suspend or space out if the rate exceeds 180-200 bpm).

Adjustment in Renal or Hepatic Failure: Does not require modifications to the topical dose.

Security

Absolute and Relative Contraindications

Absolute Contraindications

• Known hypersensitivity to adrenaline or sulfites in the injectable ampoule.
• Airway obstruction due to solid foreign body: Nebulization can delay surgical approach or emergency rigid bronchoscopy.

Relative Contraindications

• Chronic anatomical subglottic stenosis or laryngeal vascular malformations.
• Hypertrophic obstructive cardiomyopathy, ischemic heart disease, underlying ventricular arrhythmias or history of severe refractory sinus tachycardia.
• Decompensated hyperthyroidism.

Adverse Effects (ADR) and Specific Toxicity

• Frequent (1%-10%): Moderate sinus tachycardia (transient increase in heart rate by 10-15%), facial flushing, general perioral pallor, acute nervousness, fine distal hand tremor, transient sleep insomnia.
• Uncommon (0.1%-1%): Supraventricular arrhythmias or benign ventricular extrasystoles, mild self-limited hypertensive crisis.
• Rare (<0.1%): Ischemia of the laryngeal mucosa in cases of excessive repetitive nebulization, acute lung edema due to cardiovascular hemodynamic overload (associated with accidental overdose).

Observation Alert: The Laryngeal "Rebound Effect"

Due to the short duration of nebulized adrenaline (≈ 1-2 hours), as the drug is cleared from the laryngeal mucosa, the vessels may undergo reflex rebound vasodilation. Subglottic edema may reappear abruptly with the same or greater severity than the initial condition. Any pediatric patient receiving nebulized adrenaline for moderate to severe laryngeal croup must remain under strict medical observation in the emergency department for a minimum period of 3 to 4 hours after completing the nebulization, verifying the absence of respiratory stridor at rest before authorizing discharge home.

Drug Interactions of Clinical Relevance

• Inhalation Halogenated Anesthetics (Halothane, Isoflurane): They strongly sensitize the myocardium to the effects of catecholamines, multiplying the risk of malignant ventricular arrhythmias if co-administered with adrenaline.
• Non-selective beta-adrenergic blockers (Propranolol): They cause extreme peripheral vasoconstriction of a hypertensive type mediated by the stimulation of free alpha receptors without beta-2 vasodilatory opposition.

Safety in Pregnancy and Breastfeeding

• Pregnancy: FDA Category C. Use only if the clinical benefit justifies the risk, considering that systemic adrenaline can reduce uteroplacental blood flow due to vasoconstriction of the uterine arteries.
• Breastfeeding: Compatible. It is excreted in breast milk temporarily, but due to its poor digestive absorption and rapid stomach degradation by the infant's gastric enzymes, it does not represent a risk.