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Adenosine in reactive airway disease

Adenosine

A 44-year old woman presents via EMS with a chief complaint of a racing heartbeat. She is placed on a cardiac monitor, which displays a heart rate of 192, and a subsequent EKG reveals she is in SVT. She also complains of chest discomfort and shortness of breath. Her blood pressure is stable, and you decide to treat her with adenosine. As you take a more thorough past medical history, you learn your patient has a history of asthma. One of the EM residents mentions that he thought adenosine should not be given to patients with reactive airway disease.

So, you decide to check the package insert which reads:

“Adenosine should be used with caution in patients with obstructive lung disease not associated with bronchoconstriction (e.g. emphysema, bronchitis, etc.) and should be avoided in patients with bronchoconstriction or bronchospasm (e.g. asthma). Adenosine should be discontinued in any patient who develops severe respiratory difficulties.” 1

You recall that patients with reactive airway disease are also generally excluded from pharmacologic stress tests using other agents that trigger adenosine receptors, such as regadenoson. However, is this reason enough not to use adenosine in patients with reactive airway disease?

Likely Mechanism

Adenosine has a short half-life of approximately 10 seconds. As an anti-arrhythmic, it works by binding to adenosine type 1A (A1A) receptors, leading to decreased conduction velocity across the AV node and interruption of reentry pathways. Hopefully, this results in restoration of a normal sinus rhythm.

Unfortunately, adenosine also binds to other targets triggering various cellular responses that may cause adverse reactions. Reactions are usually transient and can include hypotension, chest tightness, flushing, and dyspnea. Problems occur when adverse reactions persist longer than the expected duration of the drug.

Several theories exist for adenosine-induced bronchospasm, including:

  • Release of mast cell mediators, such as histamine and tryptase
    • An early study showed that inhaled adenosine use in patients with asthma caused bronchoconstriction and increased levels of tryptase and histamine in the bronchoalveolar fluid. 2
  • Stimulation of postganglionic vagal nerve endings
    • In a rat model, intravenous (IV) adenosine stimulated vagal pulmonary C fibers via the activation of A1 receptors. 3
    • Two studies attribute adenosine-related dyspnea to vagal fiber stimulation in the setting of patients without asthma. 4,5
  • Release of serotonin and lipoxygenase products (animal studies). 6,7
  • Stimulation of carotid chemoreceptors

Just COPD and Asthma?

Multiple case reports and small studies show an association between adenosine and bronchospasm. The majority of these cases were in adult patients receiving higher-than-normal adenosine doses for pharmacologic stress tests. However, cases have also been reported in the pediatric population. Aside from these cases, there is limited evidence tying standard-dose adenosine to the risk of bronchoconstriction, as illustrated in the following case reports.

Case Respiratory Status Adenosine Treatment Complication Reversal, treatment, and outcome

54 y/o male

Narrow complex tachycardia 8

  • COPD treated with theophylline
  • 6 mg followed by 12 mg 4 minutes later
  • Converted to sinus tachycardia after 2nd dose
  • Dyspnea
  • Cyanotic
  • O2 sat 59%
  • Required intubation
  • Albuterol
  • Atropine
  • Parenteral steroid

Extubated on day 8

65 y/o female

Narrow complex tachycardia 9

  • Nonsmoker
  • No history of COPD or asthma
  • 6 mg
  • Converted to sinus rhythm
  • Dyspnea
  • Wheezing
  • Cough
  • Oxygen
  • Aminophylline 100 mg

Discharged on day 3

29 y/o male

Tachycardia with LBBB 10

  • Nonsmoker
  • No history of COPD or asthma
  • 6 mg, 12 mg, 12 mg
  • Converted after 3rd dose, but recurred during bronchospasm
  • Mild cough
  • Dyspnea
  • O2 sat 83%
  • Diffuse bronchospasm
  • Oxygen
  • Inhaled and IV steroids
  • Aminophylline

No cardiac or respiratory symptoms during follow up 40 days after discharge

Dyspnea versus Bronchospasm

One important note to take away from these case reports is the differentiation between dyspnea and bronchospasm. Dyspnea is more commonly defined as a subjective sensation of breathing discomfort. Bronchospasm is a change in lung function, and not diagnosed on the basis of subjective symptoms as reported by the patient. In patients who experience exercise-induced bronchospasm, spirometry is generally conducted to measure the change in their forced expiratory volume (FEV) and FEV1/FVC ratio. Unfortunately, in emergent situations, this cannot be readily measured.

Surrogate markers for bronchoconstriction may include oxygen saturation and persistent wheezing accompanied with dyspnea. Patients who develop bronchospasm may have a cough as an early sign of impending clinical deterioration. 10

Reversal of Bronchospasm

Multiple treatment options are available when patients experience bronchoconstriction post-adenosine administration. Dyspnea caused by adenosine should be short-lived and should spontaneously resolve. If symptoms persist for more than a few minutes, it is reasonable to start therapy.

Common agents used in published case reports include oxygen, bronchodilators (e.g. albuterol), and steroids (e.g. methylprednisolone, hydrocortisone, prednisolone, inhaled beclometasone, etc.). IV steroids is an option in patients experiencing true bronchospasm and not just transient dyspnea because it is easier to administer (if intravenous access is available) and does not rely as heavily on the patient’s ability to cooperate with the treatment. 11 However, it may have a delayed effect. If inhaled steroids are available and feasible to administer, then that should be given to the patient.

In some of the case reports detailed above, aminophylline was used in addition to inhaled beta-agonists to reverse the bronchoconstrictive effects of adenosine. This makes it difficult to tease out the isolated efficacy of aminophylline itself. Aminophylline works by causing bronchodilation through the inhibition of phosphodiesterase and by antagonizing the effects of adenosine at the receptor level. Because adenosine has such a short half-life, it seems reasonable that aminophylline’s effect may be less due to the adenosine receptor antagonism than its bronchodilatory effects. However, aminophylline comes with complex pharmacokinetic properties and drug-drug interactions must be considered.

Older studies have shown that anticholinergics such as ipratropium may have protective effects against bronchoconstriction triggered by adenosine. 12

Case Resolution

In our patient presented above, we decided to give 6 mg of adenosine. The risk of adenosine-induced bronchospasm is extremely rare. We explained the symptoms she may feel transiently after administration of adenosine and that these should resolve shortly thereafter. We also discussed the risks and benefits of treatment, mainly the rare risk of prolonged bronchospasm with the urgent need to convert the arrhythmia to normal sinus rhythm. We asked her to advise us if she experiences worsening breathing difficulty or has increased cough afterwards. She was closely observed for 30 minutes after adenosine administration and she did not experience prolonged dyspnea or bronchoconstriction within this time period. She converted to sinus tachycardia shortly after the administration of adenosine and the shortness of breath from earlier also resolved thereafter.

Take Home Points

  • Adenosine is a reasonable option to treat SVT even in patients with reactive airway disease as long as the patient does not have active bronchospasm and can be monitored closely after administration.
  • Weak evidence from case reports suggests that adenosine may be associated with bronchoconstriction at the lower doses used for SVT, even in patients without reactive airway disease. However, the incidence of adenosine-induced bronchospasm is extremely rare and is rarely clinically significant.
  • It is important to distinguish between transient dyspnea and true bronchospasm in these patients. Watch out for symptoms such as cough or wheezing when monitoring patients after they have received adenosine.
  • Treatment of adenosine-induced bronchoconstriction includes albuterol and steroids. Aminophylline may be considered as adjunct therapy but dosing and guidance for its use is not well-established.

 

1.
Adenocard Package Insert. Astellas Pharma. https://www.astellas.us/docs/adenocard.pdf.
2.
Polosa R, Ng W, Crimi N, et al. Release of mast-cell-derived mediators after endobronchial adenosine challenge in asthma. Am J Respir Crit Care Med. 1995;151(3 Pt 1):624-629. [PubMed]
3.
Hong J, Ho C, Kwong K, Lee L. Activation of pulmonary C fibres by adenosine in anaesthetized rats: role of adenosine A1 receptors. J Physiol. 1998;508 ( Pt 1):109-118. [PubMed]
4.
Burki N, Alam M, Lee L. The pulmonary effects of intravenous adenosine in asthmatic subjects. Respir Res. 2006;7:139. [PubMed]
5.
Burki N, Dale W, Lee L. Intravenous adenosine and dyspnea in humans. J Appl Physiol (1985). 2005;98(1):180-185. [PubMed]
6.
Van S, Joos G, Kips J, Drajesk J, Carpentier P, Pauwels R. The effect of ABT-761, a novel 5-lipoxygenase inhibitor, on exercise- and adenosine-induced bronchoconstriction in asthmatic subjects. Am J Respir Crit Care Med. 1997;155(3):875-880. [PubMed]
7.
Hannon J, Tigani B, Williams I, Mazzoni L, Fozard J. Mechanism of airway hyperresponsiveness to adenosine induced by allergen challenge in actively sensitized Brown Norway rats. Br J Pharmacol. 2001;132(7):1509-1523. [PubMed]
8.
Burkhart K. Respiratory failure following adenosine administration. Am J Emerg Med. 1993;11(3):249-250. [PubMed]
9.
Martinez-Sabater H, Cruzado-Quevedo J, Muñoz-Gimeno L, Hernandez-Cascales J. Can adenosine cause asthma-like symptoms in patients with cardiac arrhythmias receiving atenolol? Int J Clin Pharmacol Ther. 2012;50(1):47-48. [PubMed]
10.
Coli S, Mantovani F, Ferro J, Gonzi G, Zardini M, Ardissino D. Adenosine-induced severe bronchospasm in a patient without pulmonary disease. Am J Emerg Med. 2012;30(9):2082.e3-5. [PubMed]
11.
Woods B, Sladen R. Perioperative considerations for the patient with asthma and bronchospasm. Br J Anaesth. 2009;103 Suppl 1:i57-65. [PubMed]
12.
Crimi N, Palermo F, Oliveri R, Polosa R, Settinieri I, Mistretta A. Protective effects of inhaled ipratropium bromide on bronchoconstriction induced by adenosine and methacholine in asthma. Eur Respir J. 1992;5(5):560-565. [PubMed]

ALiEM Copyedit

Nice flow, easy to read, nice use of clinical case and literature summary. Is image available to clarify mechanism of adenosine effects for visual learner?

  1. Changed minor grammatical issues.
  2. Under Likely Mechanism \"adenosine binds to other receptors\" made me ask if all of these complications are actually receptor mediated?
  3. First patient lists \"intubation\" as complication and treatment, seems redundant.
  4. Would remove palpitations for second patient, symptoms aren\'t listed for other patients and most tachycardic patients will have palpitations.
  5. Would remove \"wide complex\" from patient 3 as by definition RBBB is wide complex so redundant.
  6. SVT is listed as an abbreviation for the table, but isn\'t in the table.
  7. Under Dyspnea vs Bronchospasm, \"not diagnosed on the basis of symptoms\" but bronchospam is often diagnosed on the basis of cough and wheeze. Not sure if this needs clarification.
  8. Under \"Reversal of Bronchospasm\" you say that \"dyspnea . . . should be short lived and spontaneously resolve\". I believe this, but the papers you mention all discuss severe cases. Is there any data on the number of cases that are short lived and spontaneously resolve?
  9. Why IV steroids better? Faster, more effective, easier?
  10. Probably don\'t need to mention the flush, it\'s not discussed elsewhere and is assumed.
  11. Might reframe discussion of risk and benefit in case resolution as opportunity for verbal informed consent.
  12. Though not relevant to bronchospasm, most readers will want to know if she converted, it frames the story.
  13. Under Take Home Points #2, might further emphasize that this is extremely rare and even more so rarely clinically significant.
Matthew Zuckerman, MD
ALiEM-AAEM Social Media and Digital Scholarship Fellow; Assistant Professor of Emergency Medicine, University of Colorado, Anschutz Medical Campus

Thank you for the copyedit!

I did a search for images and can\'t find a good one that is free to use but I\'ll keep searching or try my hand at creating an image.

  1. The edits look great.
  2. I believe most of the proposed mechanisms are receptor-mediated but I changed the wording for a better fit.
  3. Fixed to remove redundancy.
  4. Fixed.
  5. Fixed.
  6. I believe that case where I mentioned SVT has been removed because the doses used were lower than usual. I don\'t see the abbreviations in the draft posted anymore.
  7. Clarified to say bronchospasm is not on the based on the subjective symptoms reported by the patient.
  8. I think this is where I tried to delineate the difference between the two. Transient symptoms such as dyspnea may occur in patients receiving adenosine. However, prolonged symptoms such as bronchospasm are rare and the cases I\'ve listed are in patients most likely with prolonged dyspnea due to bronchospasm. I\'ve added more details in regards to bronchospasm and how it may be measured.
  9. I added additional details to this. The cases usually used systemic corticosteroids and I think these are more convenient to administer especially if intravenous access is available.
  10. Removed that part of the sentence.
  11. I added more details to the case resolution to include a discussion with the patient.
  12. I added more details to the case resolution to include a discussion with the patient.
  13. Done.
Marian Gaviola, PharmD
PGY-2 Critical Care Pharmacy Resident

Expert Peer Review

Dr. Gaviola,

Thank you for this well-written, insightful and focused clinical pearl on what is undoubtedly an overlooked potential complication in the ED. Overall, I think you are in pretty good hands with your copy-editors, and the content is all there.

Please consider some of the following suggestions:

  1. Did the patient in your case have any pertinent home medications worth noting (think those that might otherwise influence the initial dose of adenosine used)? If not, consider stating that fact.
  2. I think the first case with the COPD patient is interesting given the fact that he was on theophylline (albeit with a low serum level), yet the traditional adenosine dosing regimen was used and was perceivably efficacious. It may be worth briefly discussing your own interpretation as to the significance (or lack thereof) of theophylline in this case. In light of this, do you think adenosine was the culprit in causing the respiratory distress?
  3. Given the proposed mechanism of vagal nerve-mediated bronchospasm from adenosine, is there any literature to support reversal with inhaled anticholinergics as an alternative to or in conjunction with other bronchodilators?
  4. From a logistical/pragmatic standpoint, it may be a challenge initiating prompt treatment of adenosine-induced bronchospasm with intravenous aminophylline in the ED. Consider adding your own viewpoint on the practicality of this as an initial therapeutic option as compared to the others. When you commit to treatment of adenosine-induced bronchospasm with albuterol, would you at that point also recommend requesting aminophylline at the bedside as a backup?
  5. Is there any evidence available regarding pretreatment options for patients requiring adenosine but who are deemed to be high risk for bronchospastic complications? Further, is there any evidence for this approach in the patient presenting in SVT with active bronchospasm?
  6. Following the above point, consider adding a statement reflecting your personal recommendation for treatment in the bronchospastic asthmatic in SVT.

Thank you again for the opportunity to review this worthy submission. Please feel free to contact me for any questions/clarifications.

Adam Spaulding, PharmD, BCPS
Emergency Medicine Pharmacist, Pharmacy Residency Program Director, Waterbury Hospital Health Center; Adjunct Assistant Professor - UCONN School of Pharmacy; Contributor to Emergency Medicine PharmD Blog

Dr. Spaulding,

Thank you for the comments!

  1. The patient was not on medications we thought could significantly affect the adenosine dose given. However, it is important to note that it may be prudent to change the initial and subsequent doses of adenosine depending on the patient\'s home medication list. Dr. Hayes provided a very good review on this that can be found here. In short, patients on methylxanthines such as theophylline may require higher doses of adenosine while patients on carbamazepine or dipyridamole may need to have lower starting doses. Dipyridamole inhibits the cellular uptake of adenosine which can enhance adenosine\'s effects.
  2. The first case presented would fit the subgroup of patients who may benefit from higher initial doses of adenosine. The first 6-mg dose failed but the patient eventually converted after the 2nd dose, using 12mg. I think the borderline low level of theophylline may have caused the patient to have preexisting bronchospasm due to his uncontrolled airway disease. A couple of things probably happened at the same time: the preexisting bronchospasm put him at higher risk of developing the bronchospasm but the theophylline could have been antagonizing that effect. Without the theophylline, the first dose may have been effective at converting his heart rhythm but would have most likely led to a quicker need for intubation. Of note, the patient\'s shortness of breath started the previous day so it\'s unlikely that adenosine was the sole cause of his pulmonary failure.
  3. A few of the case reports I encountered did use ipratropium as part of their therapy. Also, older trials have actually been done. I’ll update my post to include more information!
  4. Thank you for bringing up this important point. It would be challenging to start aminophylline in the ED. I don’t believe it would be feasible to start this as first line therapy. Albuterol would be the easiest to administer. One of the cases presented resolved without the use of aminophylline. Adenosine’s half-life is so short that the bronchospasm is really due to downstream effects. However, aminophylline might be able to help as a nonselective PDE inhibitor. Patients may resolve without the use of aminophylline so I wouldn’t routinely use it but would always keep it in the back of my mind in case the patient’s symptoms don’t improve with the use of albuterol and other therapies.
  5. I’ve seen some evidence using ipratropium for pretreatment. It seems that more recently, the use of bronchodilators have focused on pretreatment in patients undergoing pharmacologic stress tests which uses much higher doses of adenosine. If a patient is actively having a bronchospasm, then pretreatment is a reasonable choice. So is choosing another agent to convert the patient’s rhythm. I think it would depend heavily on how the patient presented. If the patient’s bronchospasm is severe, then I would opt to use something else because my worry is the pretreatment may not be enough to protect the patient and would cause further complications.
  6. I will clarify this point!
Marian Gaviola, PharmD
PGY-2 Critical Care Pharmacy Resident

Expert Peer Review

This was a thorough review of a rare adverse reaction to adenosine that clinicians should absolutely be aware of. However, I\'m not exactly sure what to do in order to minimize this event since it is not dose dependent and history of COPD/asthma doesn\'t seem to predict ADR.

I would like to suggest that the order in which the proposed mechanisms of adenosine induced dyspnea/bronchospasm be listed in chronological order so the reader can understand the current line of research. My understanding is the leading theory would suggest that if bronchospasm does happen, it\'s difficult to contribute it solely to adenosine since some researchers suggest adenosine likely causes dyspnea but not bronchospasm (vagal pulmonary C fiber research).

As the authors stated in reference to treatment, dyspnea is usually short lived as a result of the extremely short half-life of the drug, but if symptoms persist treatment should initiated. I would suggest that other causes of dyspnea be investigated (since as presented the likelihood is this event very low), IV steroids will work later (in a few hours), and that aminophylline has complex pharmacokinetic dosing and drug-drug interaction considerations.

Craig Cocchio, PharmD, BCPS
Clinical Assistant Professor, Emergency Medicine, Residency Program Director, Editor-in-Chief of Emergency Medicine PharmD Blog
Marian Gaviola, PharmD

Marian Gaviola, PharmD

PGY-2 Critical Care Pharmacy Resident
University of Vermont Medical Center
Marian Gaviola, PharmD

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Meghan Groth, PharmD, BCPS

Meghan Groth, PharmD, BCPS

Emergency Medicine Pharmacy Clinician
University of Vermont Medical Center
Contributor for Emergency Medicine PharmD Blog
Meghan Groth, PharmD, BCPS

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