Not too long ago, I had an interfacility transport for a patient with anaphylaxis who was not responding to conventional treatment (epi, steroids, etc.). It turned out the patient was not in anaphylaxis but, rather, was experiencing angioedema due to an NSAID they had started taking the day prior. While we know that early administration of epi is a staple in anaphylaxis, knowing that there are other things that can cause angioedema may increase your accuracy in arriving at the correct diagnosis and treatment.
Angioedema is a manifestation of increased capillary permeability, leading to non-pitting swelling in large erythematous areas in the skin and subcutaneous tissues. Anytime we hear the term swelling, we know that something is increasing the capillary permeability and allowing fluid to enter the third space. So now the question is....
What is increasing capillary permeability?
Both can present similarly in their extremes, but the treatment regimen differs quite a bit. Bradykinin-mediated angioedema does not respond to epinephrine, antihistamines, or corticosteroids. Likewise, histamine-mediated angioedema does not respond to TXA, FFP, and C1-inhibitor concentrate.
Therefore, a clinician's knowledge and understanding of the two may come in handy when a patient is not responding to one or the other's treatment regimens, such as in my case.
The obvious intimidation factor when presented with angioedema is airway compromise, so let's start there
Rapid identification of potential airway compromise is crucial, as bradykinin or histamine-mediated angioedema can lead to severe airway obstruction, particularly if the tongue, larynx, or other upper airway structures are involved.
Is The Larynx Involved?
Without a fiberoptic bronchoscope (FOB) to examine whether the swelling involves the larynx, it can be difficult to know how far the edema extends. I have noticed that, typically, bradykinin-mediated angioedema only involves the tongue, and once you get around that, the airway is not too bad. However, poking around to "check for extension" can drastically make the situation worse by irritating the mucosa.
Check out this video by Dr. Mellick where they scope a patient with angioedema due to lisinopril.
Deciding how swollen the larynx is in the pre-hospital setting will largely relay findings such as hoarseness, stridor, and the patient's inability to control their secretions. If they can't swallow secretions, there is a good chance the larynx is edematous as well. The most skilled and experienced person to perform the intubation should be the one performing the procedure, and the equipment to perform a surgical airway should always be ready.
Video vs FBO
I came across this paper while doing some research for this blog. It compared fiberoptic bronchoscope (FOB) intubation with video laryngoscopy (VL) and surprisingly found VL was faster and just as good as FOB. In some of the cases I reviewed, this probably really depends on the degree in with the epiglottis is swollen. Check out this swelling in this video.
In the few cases I have had to intubate a patient with severe angioedema, the hyper-angulated blade with a rigid style was definitely needed. Due to the angle of the blade, you are getting a peek around the tongue and not actually displacing the tissue.
Utilizing a bougie or even rigid stylet can cause issues because they will not hold their form when pressure is applied against the tongue.
Always Assume Anaphylaxis??
In speaking with Dr. Cynthia Griffin, she expressed that in the ED, it is always safer to start treating this as anaphylaxis if you do not have a very clear reason to expect it is either hereditary angioedema (HAE) or bradykinin mediated. If it is truly anaphylaxis, ensuring timely administration of epinephrine is extremely important. So, to start breaking down these triggers, let's start off with the histamine-mediated flavor.
This type of angioedema is mediated by the release of histamine from mast cells and basophils. The IgE antibody recognizes the presence of the antigen, and mast cell degranulation takes place.
There is usually a clear trigger (peanuts, shell fish, new medication, etc.). However, Mast Cell Activation Syndrome (MCAS) is prevalent in about 17% of individuals. Suspicion for mast cell degranulation should always be considered when at least 2 organ systems are involved.
Treatment
Epinephrine: Administered in cases of severe life-threatening reactions, such as anaphylaxis, to counteract the effects of histamine and improve airway patency, blood pressure, and cardiac output.
Antihistamines: To block the effects of histamine (e.g., diphenhydramine).
Corticosteroids reduce inflammation and immune response (e.g., prednisone).
Bradykinin-Mediated Angioedema
This type is usually related to conditions like hereditary angioedema (HAE) or angioedema induced by ACE inhibitors. Bradykinin-mediated angioedema does not respond to histamine blockers or corticosteroids.
In the prehospital setting, the treatment of bradykinin-mediated angioedema, such as that seen with hereditary angioedema (HAE) or ACE inhibitor-induced angioedema, focuses primarily on airway management and the administration of specific medications if available:
Treatment
Fresh Frozen Plasma (FFP):
While FFP is generally not available in the prehospital setting, it is becoming increasingly prevalent among helicopter emergency medical services (HEMS) programs.
Fresh frozen plasma (FFP) has been used as a treatment option for patients with Hereditary Angioedema (HAE) because it contains C1-esterase inhibitor and may be used in emergencies when other therapies aren't immediately available.
Tranexamic Acid (TXA):
TXA inhibits the conversion of plasminogen to plasmin, a key enzyme involved in fibrinolysis (the breakdown of blood clots). By inhibiting plasmin formation, TXA indirectly reduces the activation of kallikrein, an enzyme that contributes to the production of bradykinin from its precursor. By reducing kallikrein activity, TXA helps lower the levels of bradykinin, thus decreasing the excessive vascular permeability and swelling associated with bradykinin-mediated angioedema.
Dose: Administer 1 gram of TXA IV over 10 minutes if available. TXA has been used off-label in some cases of bradykinin-mediated angioedema, especially when specific treatments (e.g., C1-INH) are not available.
Key Takeaways
Angioedema Differentiation: If the patient does not have a clear indicator that their angioedema is not bradykinin mediated, such as HAE, it is probably safer to treat for anaphylaxis.
Histamine-Mediated Angioedema: Responds to antihistamines, corticosteroids, and epinephrine. Often linked to allergic reactions.
Bradykinin-Mediated Angioedema: Does not respond to standard allergic reaction treatments. Focuses on airway management and specific medications like TXA.
Airway Management: Early recognition of airway compromise and preparation for advanced airway interventions (stridor, hoarseness, uncontrolled secretions) is critical.
Equipment: When using video laryngoscopy, consider employing a hyper-angulated blade, especially in severe cases, to improve visualization and facilitate intubation.
References
Bernstein, J. A., Cremonesi, P., Hoffmann, T. K., & Hollingsworth, J. (2017). Angioedema in the emergency department: A practical guide to differential diagnosis and management. International Journal of Emergency Medicine, 10(1), 15. https://doi.org/10.1186/s12245-017-0152-7
Cicardi, M., Banerji, A., Bracho, F., Malbrán, A., Rosenkranz, B., Riedl, M., & Bork, K. (2014). Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema. New England Journal of Medicine, 363(6), 532-541. https://doi.org/10.1056/NEJMoa0906393
Ishoo E, Shah UK, Grillone GA, Stram JR, Fuleihan NS. Predicting airway risk in angioedema: staging system based on presentation. Otolaryngol Head Neck Surg. 1999 Sep;121(3):263-8. doi: 10.1016/S0194-5998(99)70182-8. PMID: 10471868.
Karagiannis, C. P., & Bors, A. D. (2022). Acute management of bradykinin‐mediated angioedema: A systematic review. Allergy, 77(6), 1553-1564. https://doi.org/10.1111/all.15304
Maurer, M., Magerl, M., Ansotegui, I., Aygören-Pürsün, E., Betschel, S., Bork, K., ... & Zanichelli, A. (2018). The international WAO/EAACI guideline for the management of hereditary angioedema – The 2017 revision and update. Allergy, 73(8), 1575-1596. https://doi.org/10.1111/all.13384
Wood A, Choromanski D, Orlewicz M. Intubation of patients with angioedema: A retrospective study of different methods over three year period. Int J Crit Illn Inj Sci. 2013 Apr;3(2):108-12. doi: 10.4103/2229-5151.114267. PMID: 23961454; PMCID: PMC3743334.
Zuraw, B. L., Bork, K., Binkley, K. E., Banerji, A., Christiansen, S. C., Castaldo, A. J., ... & Bernstein, J. A. (2013). Hereditary angioedema with normal C1 inhibitor function: Consensus of an international expert panel. Allergy, Asthma & Clinical Immunology, 9(1), 29. https://doi.org/10.1186/1710-1492-9-29
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