Use of endotracheal epinephrine for refractory unanticipated post-intubation bronchospasm

Summary

Epinephrine is a commonly used agent for a variety of indications and clinical scenarios within the emergency department. It is commonly administered during cardiopulmonary arrest and serves as an option when there is a loss/lack of access. A female patient presented with respiratory depression secondary to opioid overdose, requiring emergent intubation. Shortly after intubation, she developed severe bronchospasm unresponsive to standard therapies including inhaled beta-agonists, intravenous corticosteroids, intramuscular epinephrine and sedation. As a last-resort intervention, 0.5 mg of epinephrine 1:10 000 in 10 mL normal saline was administered via the endotracheal tube, resulting in immediate clinical improvement in oxygen saturation and airway pressures. The purpose of this report is to describe the utilisation of 0.5 mg of epinephrine 1:10 000 in 10 mL normal saline given endotracheally for unanticipated post-intubation bronchospasm. The findings of this case support the idea that the endotracheal administration may be beneficial in the intubated patient with severe bronchospasm that is refractory to more traditional treatments.

Background

Epinephrine is an endogenous catecholamine neurotransmitter that regulates the sympathetic nervous system.¹ Exogenous forms are used extensively for their vasoconstrictive and bronchodilator effects. The Food and Drug Administration-approved indications include the treatment of anaphylaxis and other severe immediate hypersensitivity reactions, hypotension associated with septic shock and mydriasis during intraocular surgery.² Several off-label indications are recommended by evidence-based guidelines and consensus statements published by national societies including severe acute asthma exacerbations, symptomatic bradycardia, hypotension associated with septic and cardiogenic shock and general inotropic support in the post-cardiac arrest setting.3,7

Common routes of administration for epinephrine include the intravenous (IV) and intramuscular (IM) routes. The preferred route of administration is often driven by the indication for which the medication is being given. In advanced cardiopulmonary care, epinephrine should be administered via the IV or intraosseous (IO) route when treating cardiac arrest.⁸ In the setting of severe acute asthma attacks, epinephrine can be given via the IV route in patients whose symptoms are refractory to first-line therapies including short-acting beta-agonists, inhaled anticholinergics, IV corticosteroids and magnesium.⁹ Epinephrine has also been used to arrest severe stridor in cases of croup or off label for angioedema.⁹ When unable to obtain IV or IO access, epinephrine can be administered by instillation into an endotracheal tube (ETT). Although IV administration is the preferred route of administration, a study conducted on patients in the neonatal intensive care unit showed that inhalation can be used in intensive resuscitation, as no significant difference was noted between IV and inhalational route in terms of outcome.¹⁰ Studies in animal models have shown substantial absorption of epinephrine at the tracheal tissue with variable effects on haemodynamics relative to the IV route.^{11 12} These early studies suggested that epinephrine administered via the endotracheal route needed to have a tenfold increase in the dose to produce similar blood concentrations of epinephrine. Later studies have suggested that dose increases on the magnitude of one hundred times that of the IV dose are required to obtain desirable and equivalent cardiovascular effects. The American Heart Association (AHA) guidelines currently recommend dosing epinephrine at two to two and a half times the recommended IV dose in the setting of adult cardiopulmonary arrest.⁸

Bronchospasm is a manifestation of hyper-reactive airway disease, characterised by the abrupt contraction of the smooth muscles within the bronchial walls. It is important to note that bronchospasm can occur at various stages of anaesthesia, including induction, maintenance and emergence. While the overall incidence is relatively low, certain risk factors, such as a history of asthma, smoking or recent respiratory infections, can increase the likelihood of bronchospasm during anaesthesia. The incidence of bronchospasm during general anaesthesia is approximately 0.2%, but this rate increases to around 6% in patients with asthma undergoing general endotracheal anaesthesia and up to 9% in those experiencing perioperative bronchospasm following ETT insertion. Notably, 28% of anaesthesia-related brain damage is attributed to respiratory events, with 11% directly linked to bronchospasms. Post-intubation bronchospasms can be effectively assessed or prevented through a comprehensive preoperative examination, which may involve identifying poorly controlled airway hyperactivity, evaluating the severity of asthma and considering the type of procedure and patient positioning. Treatment strategies include administering 100% oxygen to enhance oxygenation and bypassing dead space ventilation. Mechanical ventilation techniques, such as reducing tidal volume and applying positive end-expiratory pressure, aim to mitigate high peak airway pressure and prevent barotrauma. Additionally, increasing sedation and deepening anaesthesia can alleviate bronchospasms induced by ETT placement or airway manipulation. This can be achieved by augmenting the concentration of inhalational anaesthetics to diminish respiratory hyper-reactivity. Studies have demonstrated that propofol effectively reduces tachykinin-induced airway constriction.^{13 14}

This report details the use of endotracheal administered epinephrine to a patient exhibiting increased airway resistance secondary to endotracheal intubation-induced bronchospasm. A literature search was conducted to identify any existing articles that have reported epinephrine given by the endotracheal route for this indication. This current report highlights a unique use and method of administration for epinephrine that could be beneficial in patients experiencing refractory bronchospasms.

Case presentation

A young female in her early 40s with a medical history of asthma, anxiety, opiate dependence, major depressive disorder, bipolar disorder, chronic pain syndrome and chronic urinary tract infections was brought to the emergency department (ED) by emergency medical services. The patient was found unconscious in respiratory distress secondary to a suspected drug overdose. During transport, the patient received 2 mg of naloxone intranasally and 1 mg intravenously. This helped increase the respiratory rate, but the patient remained confused and was unable to provide a relevant history on arrival.

On arrival, her vitals were as follows: blood pressure, 166/96 mmHg; heart rate, 106 beats per minute; and respiratory rate, 69 breaths per minute. Despite 15 liters per minute of oxygen via a non-rebreather mask, her oxygen saturation (SpO2) remained at 88%. A physical exam revealed a patient in severe distress, diaphoretic and altered mental status with a Glasgow Coma Scale score of 13. Auscultation of her lungs was evident for loud crackling sounds heard from across the room and significant use of accessory muscles.

Due to acute hypoxic respiratory failure after being in the ED for 20 mins, rapid sequence intubation was performed with etomidate 20 mg IV and succinylcholine 200 mg IV, from a calculated weight of 72 kg. Pre-oxygenation to SpO2 of 100% achieved with bag-valve-mask for 5 min. However, the patient exhibited no paralysis and resisted stimuli due to IV infiltration. On examination, the IV line appeared to have infiltrated. Two additional IV lines were established, and 100 mg of rocuronium was administered. The patient was subsequently successfully paralysed and intubated with minimal initial airway resistance to ventilation, and accurate positioning was confirmed through colourimetric and inline capnography.

Investigations

Labs shortly prior to intubation were significant for a sodium of 129 mmol/L and potassium of 4.9 mmol/L. Arterial blood gas showed a PO2 of 67 mmHg, pCO2 of 56 mmHg and a pH of 7.25. Shortly after being connected to the ventilator circuit, the ventilator began alarming due to elevated peak pressure levels, and oxygen saturation dropped. A chest radiograph was performed to verify ETT placement and exclude the possibility of a pneumothorax. Flash pulmonary oedema, potentially due to acute opioid withdrawal or naloxone administration, was suspected in the setting of elevated blood pressure and was started on nitroglycerin infusion at a rate of 100 mcg per minute. Repeat arterial blood showed a pH of 7.21, PO2 of 58 mmHg and PCO2 of 74 mmHg.

Treatment

The patient was disconnected from the ventilator, and manual bag ventilation was attempted, with notable high resistance and moderate secretions. Suctioning was unsuccessful, and the patient’s oxygen saturation dropped to 66%. Bronchospasm from a drug reaction was suspected. Despite administering 0.3 mg epinephrine IM, diphenhydramine 50 mg IV, methylprednisolone 125 mg IV and terbutaline 0.25 mg subcutaneous, the patient’s condition did not improve. Propofol was initiated at a rate of 20 mcg/kg/min, to no avail.

Due to continued bronchospasms, airway resistance and hypoxia, the patient continued to decompensate, by slowly going into a peri-arrest state with dropping heart rates. 0.5 mg of epinephrine 1:10 000 in 10 mL normal saline was administered via ETT. This had a near-immediate effect of decreasing airway resistance, improved bag ventilation and a rise in oxygen saturation to 71%. Within 1 min, an additional 0.5 mg of epinephrine 1:10 000 in 10 mL normal saline was administered again through the same route. This had a similar desired effect, her oxygen saturation increased to 96% and she was able to be reconnected to the ventilator. Peak pressures are now in low 30 cm of water pressure (cm H₂O). An epinephrine continuous infusion was started at a rate of 10 mcg/min. The patient remained stable on the ventilator for about 30 min, before high pressure alarms sounded off again, with a SpO2 of 82%. Another dose of 0.5 mg of epinephrine via ETT was administered. Saturation improved to 95%, and decreased peak pressures were noted. Epinephrine infusion was increased to 20 mcg/min, and the patient was admitted to the intensive care unit (ICU) for further management. Please refer to table 1 for a timeline.

Table 1. Emergency department timeline.

Time (min)	Event/intervention	Notes
T0	EMS contact	The patient was found unresponsive, in severe respiratory distress
T+5	Intranasal and IV naloxone	Partial improvement in mental status
T+20	Arrival to the ED	HR, ~130 bpm; RR, ~40; SpO₂, <85% on NRB
T+30	Intubation	Etomidate+rocuronium
T+35	Propofol infusion started	For sedation and deeper anaesthesia
T+40	Mechanical ventilator alarm	Significant hypoxia with diffuse wheezing and rhonchi
T+36–45	Albuterol, IV steroids, IV magnesium	Initiation of standard asthma protocol
T+40	IM epinephrine 0.3 mg	Minimal response
T+45	IM terbutaline	No significant improvement
T+50	Second dose of IM epinephrine	Still refractory bronchospasm
T+55–80	Endotracheal epinephrine 1.5 mg (1:10 000)	Rapid bronchodilation and clinical improvement
T+60–70	Stabilisation	SpO₂ >90%, improved ventilator parameters

ED, emergency department; EMS, emergency medical service; HR, heart rate; IM, intramuscular; IV, intravenous; NRB, non-rebreather; RR, respiratory rate; SpO2, peripheral oxygen saturation.

Outcomes and follow-up

The patient continued to stabilise and was eventually weaned off medication and sedation. Lab work was notable for a positive urine toxicology screen of cocaine, opiates and amphetamines. Other lab works were unremarkable. She was subsequently extubated, and on history taking, it was noted that she was non-compliant with her medications, except for her rescue albuterol inhaler. She continued to remain stable and was discharged approximately 36 hours after intubation.

Discussion

Where this case deviated and why

We present a case of a patient with multiple treatment-refractory bronchospasms successfully alleviated through the administration of epinephrine via the endotracheal route. Patients with a history of asthma are at increased risk of post-intubation complications, including bronchospasm, haemodynamic instability and complex airway management.¹⁵ Notably, our patient initially exhibited no clinical or auscultatory signs of bronchospasm, presenting instead with respiratory depression secondary to suspected opioid overdose.

This case deviated from guideline-based asthma management, which typically prioritises inhaled therapies as first-line treatment. However, the patient’s altered mental status, absence of adequate spontaneous ventilation and rapidly declining oxygenation precluded the use of inhaled agents. Parenteral therapies were initiated but proved ineffective. Endotracheal administration of epinephrine was pursued as a last resort measure due to its immediate availability, potential for rapid mucosal absorption and presumed direct action on bronchial smooth muscle.

While inhaled bronchodilators are known to reduce the incidence of intubation-induced bronchospasm in perioperative settings, such interventions are often impractical in critically ill or peri-arrest patients. In this case, endotracheal epinephrine markedly and rapidly reduced airway resistance and oxygenation, highlighting its potential utility as a rescue therapy when conventional routes fail.

Standard management of bronchospasm

Several studies have investigated the appropriate management of patients experiencing intubation-induced bronchospasms. Deepening the level of sedation by providing IV boluses of propofol and/or ketamine has been demonstrated as an effective treatment for bronchospasms.^{13 14} The patient was determined to have adequate levels of sedation at the time of intubation and was promptly started on a continuous IV infusion of propofol to maintain light sedation as the effects of etomidate wore off. Anticholinergic agents such as glycopyrrolate, atropine and inhaled ipratropium have been proven effective in managing bronchospasms but were not administered in this case. The reason is that the patient was critically ill with continuously dropping vitals and required an intervention that would provide immediate relief. Inhaled beta-agonists have been shown to have similar efficacy to IV beta-agonists, but ease of administration is diminished compared with the IM and IV preparations. Parenteral beta-2 (β2) agonists such as epinephrine or terbutaline can be used in acute severe asthma exacerbations to induce bronchorelaxation but are not superior to inhaled beta-2 agonists.¹⁶ Additionally, IV agents have been associated with a higher risk of cardiovascular complications compared with inhaled agents.¹⁷ Both IM epinephrine and terbutaline were administered in this case with little to no effect on the perceived airway resistance and evident hypoxia.

While endotracheal epinephrine is traditionally reserved for scenarios such as asystole or severe anaphylaxis, nebulised epinephrine has also been described as an adjunctive therapy in adults with post-intubation stridor, upper airway oedema or refractory bronchospasm. Although more commonly associated with paediatric croup, nebulised racemic or L-epinephrine has been employed in adult patients in the ICU and operative settings, particularly after prolonged or traumatic intubation.¹⁸ Several case reports and small series support its utility in rapidly reducing laryngeal oedema, improving airflow and delaying or averting the need for reintubation. For instance, nebulised epinephrine has been proven beneficial in post-extubation stridor among critically ill adults, potentially avoiding reintubation when administered early during symptoms.^{19 20} In ED settings, racemic epinephrine has been used for acute upper airway obstruction, often with good clinical effect.²¹ Although robust randomised data are lacking, its safety profile and rapid onset make it viable in the proper clinical context.^{22 23} Other agents that have been studied, such as the inhaled volatile anaesthetics including halothane, isoflurane and sevoflurane, alleviate bronchoconstriction in status asthmaticus by directly relaxing airway smooth muscle through decreasing intracellular calcium concentration or calcium sensitivity, reducing airway hyperresponsiveness and attenuating histamine-induced bronchospasm.²⁴ A case report in 1985 described two patients with acute severe asthma, unresponsive to standard treatments and halothane, who showed rapid improvement in airway pressures, blood gases and clinical status after inhaling diethyl ether.²⁵ This approach has been abandoned due to the availability of other agents and side effects associated with ether, including flammability, irritation and central nervous system depression. In refractory cases unresponsive to conventional therapies, they have demonstrated clinical and physiologic improvement within 1 to 2 hours of administration.

Implications of endotracheal epinephrine use

Epinephrine is a dose-dependent sympathomimetic catecholamine that affects alpha (α) and beta (β) adrenergic receptors through a G-protein-linked second messenger system. At small doses, epinephrine has a greater affinity in favouring the β-receptors and α-receptors at higher doses or concentrations.²⁶ In cases of bronchospasm, the desired effect of β2-receptor activation produces bronchodilation. Endotracheal administration of epinephrine has been demonstrated as an alternative route of administration in cardiopulmonary arrest when IV or IO access is not available.¹¹ Administration of epinephrine by the endotracheal route has not been widely studied in the setting of intubation-induced bronchospasms in patients with asthma. A case report in the New England Journal of Medicine described the use of epinephrine in the perioperative setting, which was administered endotracheally for bronchospasms induced by using the inappropriate concentration of lidocaine.²⁷ The patient’s respiratory parameters returned to baseline, highlighting the potential efficacy of this administration route. Given the dose-dependent nature of epinephrine targeted therapy via endotracheal route, it could show benefits in preventing undesirable or systemic effects. However, broader data on this use in the ICU or ED settings remains scarce.

The underlying mechanism attributing to this increased efficacy with the endotracheal route is unclear. While IV and IM routes are common for epinephrine delivery, the inhalation route offers direct access to pulmonary tissues, potentially enhancing drug efficacy in bronchospasm scenarios. This method ensures rapid interaction with β2-adrenergic receptors in the bronchial smooth muscle, promoting swift bronchodilation.10,12 Alternatively, one may speculate that a patient in such extremes may not circulate enough β2 agonist effect to the endobronchial tissues where it is needed. Topical application of epinephrine to endobronchial tissues, as having been shown effective for stridor and croup, may also be superior to IM or IV administration. These benefits may have drawbacks as well, and in cases of anaphylaxis or angioedema where airway oedema is prevalent, it might interfere with the absorption of the medication. Further study is needed to understand the true mechanism by which this patient benefited from this drug via this route. This case was an example of the rapid effect that endotracheal epinephrine was able to provide in the event of bronchospasms.

Strengths of this case report include a thorough depiction of events that occurred during the care for the patient, as well as an extensive review of the literature surrounding the management of laryngospasms and bronchospasms. Additionally, this study supports the findings of previous trials indicating that a higher dose of epinephrine is required to obtain similar effects to epinephrine administered via the IV route. In our case, a total of 1.5 mg of 1:10 000 of epinephrine was given. In events of cardiac arrest, a dosage of 2 to 2.5 mg every 3 to 5 min should be given till IV access can be obtained. It remains unclear what may have led to this patient’s bronchospasm, but the writers believe that it is very clear what fixed it. While the literature has established that utility of the endotracheal route is limited relative to more optimal routes, there may be a unique role of endotracheal administration of epinephrine in specific patients and situations.

LEARNING POINTS.

• This case report highlights the use of epinephrine administered via the endotracheal route to treat severe bronchospasms after emergent endotracheal intubation of a patient with refractory respiratory distress.

• Endotracheal tube administration of epinephrine offers a viable alternative in managing severe bronchospasms, especially when conventional routes are impractical or ineffective.

• Epinephrine has a direct action on bronchial tissues that can lead to rapid bronchodilation, potentially improving patient outcomes in critical situations.