Swelling out of the Blue - Angioedema in the ED
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Angioedema is like urticaria in that both are transient swelling of well-demarcated areas. However, angioedema involves swelling of deeper tissues, producing nonpitting edema of the dermis and subcutaneous layers. It is most often seen in the eyelids and lips, and sometimes in the mouth and throat. While it is not pruritic it may be painful.
Angioedema (AE) may be broadly divided into histamine or bradykinin mediated processes
Allergic AE involves significant release of histamine. It is mast cell or immunoglobulin E [IgE]-mediated
Bradykinin-mediated AE has distinct pathophysiologic subtypes:
ACEi-AE = impaired breakdown of bradykinin
Hereditary AE (HAE) = deficiency of functional C1 inhibitor -> allows plasma kallikrein activation -> overproduction of bradykinin
HAE has 3 broad subtypes: deficiency of C1E, decreased function of C1E, estrogen induced failure of C1E
Other non-allergic types include:
Acquired = idiotypic autoantibodies directed against C1q; often associated with lymphoproliferative disorders
Pseudoallergic = mimics an acute allergic reaction but is not mediated by IgE – pathophysiology depends on the drug trigger
Top drugs/classes: bupropion, vaccinations, SSRIs, COX2 inhibitors, Ang2 antagonists, NSAIDs, statins, PPIs, excessive alcohol, opioids, contrast
One that EM providers definitely need to be ready for: post-tPA! Look for unilateral tongue swelling on the side contralateral to the involved hemisphere.
Idiopathic = often associated with chronic urticaria
Incidence and Impact
In the US, angioedema accounts for approximately 100,000 ER visits annually (1). Across the world, 35% of prescriptions written for hypertension are for ACE-inhibitors (>40 million people). With a reported incidence of angioedema in 0.1–0.7% of those patients on ACEI, there are approximately 40,000 cases of ACEI-associated angioedema worldwide annually (2).
Though it can occur within days to weeks after starting therapy, ACEI-associated angioedema may occur after years of stable therapy. One should be suspicious of ACEI as the cause of angioedema in anyone on an ACEI. The onset of angioedema can sometimes be triggered by an unrelated trauma or stress. There is a higher incidence among women, African Americans, and in patients that have a preexisting NSAID allergy (2).
The incidence of post-tPA AE is anywhere from 0.4%-7.9% and it occurs within 5 minutes to 3 hours after administration. There are some reports that it may be more common in those patients on ACEI (3,4). Extra care should be taken to avoid trauma during intubation as the recent administration of tPA could lead to an exceptionally bloody airway.
A Closer Look at ACEi-Angioedema
As mentioned above, ACEI angioedema is due to excessive accumulation of bradykinin. During treatment with ACE inhibitors, the alternative enzymatic pathways for metabolism of bradykinin become critical. Because bradykinin increases vascular permeability at the postcapillary venules accumulation of this and substance P results in rapid edema. Genetic variants probably underlie the susceptibility of different individuals (5): those with lower activity of alternative clearance pathways are likely those at an increased risk of bradykinin accumulation. Some studies have speculated that dipeptidyl peptidase IV polymorphisms specifically were responsible, but the evidence is limited.
The attempts to utilize HAE treatments for ACEI-AE have so far not succeeded (6, 7)
Presentation of Bradykinin-Mediated Angioedema
If the patient’s angioedema is not associated with urticaria then it doesn’t meet the definition of anaphylaxis. The pathophysiology of this reaction does not involve the substantial releases of histamine, and the resultant swelling is nonpruritic and does not produce a rash. Other than swelling, chief complaints that may represent angioedema include dysphagia, dyspnea, change in voice, drooling, stridor, diarrhea, abdominal pain.
The following can help differentiate ACEI angioedema from histamine-mediated allergic angioedema (although it will have more features in common with other forms of bradykinin-induced angioedema).
Starts with focal swelling (isolated swelling of tongue or lips, often asymmetric)
Evolves over hours (slower progression than histamine-mediated angioedema)
Absence of urticaria, itching, and other skin changes
Won’t respond in the classic way to antihistamines, steroids, or epinephrine
HAE specifically is more likely to involve swelling of the hands & feet and have been precipitated by stress (trauma, dental surgery – board favorite clues)
A thorough history should include familial or personal history of similar episodes, current medications, exposure to known allergens or physical stimuli (including trauma), and timing of the episode (as you really need to know how fast things are evolving!) Be aware that as many as 25% of cases of HAE occur de novo, without any family history. Although not helpful for emergency management, to help our colleagues on this patient’s future care team, you can draw a complement C4 level (low levels screen for hereditary or acquired types) and a tryptase level (histaminergic type).
Treatment
Treatment changes between the different types of angioedema. Although most still typically administer the standard treatments for anaphylaxis in each, they are not be as effective for HAE and ACEI AE.
Pharmacological Treatments for Histamine-mediated Types (anaphylaxis)
Remove the offending agents!
Primary agents used for the treatment of anaphylaxis are:
Epinephrine (adult dose 0.3 mg IM q 5-15min for up to 3 doses escalating to a drip if needed)
Steroids (methylprednisone 1-2mg/kg)
H1/H2 blockers (25-50mg diphenhydramine +/- famotidine)
Albuterol or racemic epinephrine can be used for wheezing or stridor
Pharmacological Treatments for Bradykinin-mediated Types
“As with management of acute angioedema in patients with C1-inhibitor deficiency, administration of antihistamines, corticosteroids, or epinephrine is not associated with benefit and is not recommended”
– International consensus on hereditary and acquired angioedema, Lang 2012
…which is exactly what we do for histamine-mediated anaphylaxis. So what to do for this type? In situations where the exact cause of the patient’s angioedema, one can consider these therapies. But first, in all cases of angioedema, one should assess and manage the airway (more on that below).
Recent years have seen the development of multiple products for bradykinin-mediated AE.
FFP (9)
Why? Because FFP contains enzymes which metabolize bradykinin (including C1E), it is not incredibly expensive, but most importantly because we can get it quickly
Why not use it? FFP could, in theory, make things worse as it contains plasma prekallikrein, Factor XII, and HMWK which have the potential to fuel the fire
TXA (1g IV over 10 minutes), the newest addition, is based on a single study from France with 33 patients – but it’s even cheaper than FFP and unlikely to cause significant harm (10)
Specific to HAE – the following information is specific to the UCMC campus, and their use clinically will likely require approval by Pharmacy.
Berinert (plasma-derived C1-INH, FDA approved for use in C1E deficiency) is UC’s formulary agent of choice for hereditary angioedema – be aware that cost to health centers is estimated to be $6000–$12,000 (and higher for the patients). Dose at 20IU/kg IV.
Ecallantide (kallikrein inhibitor) = “brown bagged”. Patients will fill this medication from their pharmacy and we label it and keep it for them in the pharmacy. We can then administer their own medication when they come into the hospital with a hereditary angioedema attack. Monitoring is mainly due to the risk of anaphylaxis after administration. Dose at 30mg SC, which will end up being 3 injections of 10mg.
Icatibant (bradykinin receptor antagonist) isn’t stocked. Patients do come in for monitoring after administering icatibant for their hereditary angioedema attacks at home. If the patient were to worsen or not receive their own supply, we would then administer Berinert.
Cinryze (FDA approved as a prophylactic C1-INH therapy) we do not stock, most of the data with this agent is in outpatient populations. Berinert is more efficacious and quicker acting in an acute situation.
Airway Management
A crucial decision point in the management of any type of angioedema is if you will need early, aggressive airway intervention due to a rapidly devolving clinical course. 4% of patients with AAE ultimately require intubation (2). It is smart to perform diagnostic nasopharyngoscopy early on in any patient with signs or symptoms of oropharyngeal involvement. A significant number of patients without externally visible AE may still have significant supraglottic involvement so even though you may only be planning to do a diagnostic scope, be prepared to place a definitive airway if you find a scary scenario.
Ishoo Classification for Monitoring Severity of Upper Airway Swelling. Ishoo, et al (11)
High-risk patients may be best identified by those with significant voice changes or hoarseness to indicate larynx involvement (Ishoo class 4) (11), inability to manage secretions, or rapidly progressing symptoms. You must anticipate that this will be a difficult airway. Remember the algorithm: have the most experienced operator on hand and prepare a double set up!
Topicalization prior to intubation
All attempt should be made to properly prepare patients prior to any attempts at nasopharyngoscopy and intubation.
Lidocaine – Lidocaine in jelly (2%) or aqueous (4%) formulations can be used to anesthetize the patient’s nasal mucosa as well as naso- and oropharyngeal mucosa. An atomizer is useful to spray a fine mist of lidocaine on the patient’s oral and pharyngeal mucosa. Nebulized lidocaine can be considered as well, though the particle size created may be too fine to appropriately anesthetize the upper airway structures. Remember that secretions are going to dilute any topical you use so, if you have time, don’t forgo first giving…
Glycopyrrolate: an antimuscarinic, anticholinergic drying agent. It is effective at reducing sialorrhea and bronchorrhea and because it is vagolytic, it can also reduce the bronchospasm in response to laryngoscopy. Maximal drying effects occur ~10-20 minutes after IV push (0.2mg).
Vasoconstrict the nose with oxymetazoline while you are waiting for the drying agent – even if you are planning on trying oral intubation first, this will mean your nose is prepared if you end up needing it.
Ketamine is an ideal induction agent in patients with angioedema as the patient’s respiratory drive should remain unaffected. The location of the patient’s edema will likely guide the means of intubation (should there be more significant oral or lingual swelling a nasal fiberoptic approach will likely be most successful, should there be primarily glottic edema, oral fiberoptic with a Williams airway or oral video laryngoscopy may be possible). For patients with severe swelling noted prior to nasopharyngoscopy, an awake look (i.e. non-paralyzed but anesthetized patient) with a “double set up” (neck prepared for cricothyrotomy) is often appropriate. If during the course of laryngoscopy, the patient’s vocal cords are able to be visualized but are closed or opening and closing to the extent that it would exclude passage of an endotracheal tube, paralytics can be pushed with constant visualization of the vocal cords. Also, when the vocal cords are first visualized, one can administer additional topical lidocaine directly to the glottic and subglottic structures via an atomizer or the fiberoptic endoscope.
One last pearl!
“Patients with abdominal pain, who present with hypovolemic shock and are taking medications that can predispose to angioedema, may have this complication if their hemoglobin level is elevated compared with their previous levels. An abdominal computed tomography scan, if it does not identify any other significant etiology, will increase the probability that ACEI-induced visceral angioedema is the diagnosis when there is nonspecific bowel wall thickening or edema.” Hypovolemic Shock Caused by Angiotensin-Converting Enzyme Inhibitor-Induced Visceral Angioedema: A Case Series and A Simple Method to Diagnose this Complication in the Emergency Department, J Emerg Med, 2018; 54(3)
References
Kelly, M., Donnelly, J. P., McAnnally, J. R., & Wang, H. E. (2013). National estimates of emergency department visits for angioedema and allergic reactions in the United States. Allergy and asthma proceedings, 34(2), 150–154.
Banerji, A., Blumenthal, K. G., Lai, K. H., & Zhou, L. (2017). Epidemiology of ACE Inhibitor Angioedema Utilizing a Large Electronic Health Record. The journal of allergy and clinical immunology. In practice, 5(3), 744–749.
Lekoubou A, Philippeau F, Derex L, et al. Audit report and systematic review of orolingual angioedema in post-acute stroke thrombolysis. Neurol Res. 2014;36(7):687-694.
Wang YX, Li YQ, Chen Y, et al. Analysis of related factors of orolingual angioedema after rt-PA intravenous thrombolytic therapy. Eur Rev Med Pharmacol Sci. 2018;22(5):1478-1484.
Campo P, Fernandez TD, Canto G, Mayorga C. Angioedema induced by angiotensin-converting enzyme inhibitors. Curr Opin Allergy Clin Immunol. 2013;13(4):337-344. doi:10.1097/ACI.0b013e328362b835
Anand Swaminathan, "Icatibant Doesn’t Improve Outcomes in ACE-I Induced Angioedema", REBEL EM blog, June 22, 2017. Available at: https://rebelem.com/icatibant-doesnt-improve-outcomes-in-ace-i-induced-angioedema/.
Davis, T. Angioedema - Icatibant Rant. July 27, 2017. https://journalfeed.org/article-a-day/2017/angioedema-icatibant-rant
Lang DM, Aberer W, Bernstein JA, et al. International consensus on hereditary and acquired angioedema. Ann Allergy Asthma Immunol. 2012;109(6):395-402. doi:10.1016/j.anai.2012.10.008
Chaaya, G., Afridi, F., Faiz, A., Ashraf, A., Ali, M., & Castiglioni, A. (2017). When Nothing Else Works: Fresh Frozen Plasma in the Treatment of Progressive, Refractory Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema. Cureus, 9(1), e972.
Beauchêne C, Martins-Héricher J, Denis D, Martin L, Maillard H. Intérêt de l’acide tranexamique en traitement d’urgence de première intention des crises d’angiœdème bradykinique sous IEC [Tranexamic acid as first-line emergency treatment for episodes of bradykinin-mediated angioedema induced by ACE inhibitors]. Rev Med Interne. 2018;39(10):772-776.
Ishoo, E., Shah, U. K., Grillone, G. A., Stram, J. R., & Fuleihan, N. S. (1999). Predicting airway risk in angioedema: staging system based on presentation. Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery, 121(3), 263–268.
Moellman JJ, Bernstein JA, Lindsell C, Banerji A, Busse PJ, Camargo CA Jr, Collins SP, Craig TJ, Lumry WR, Nowak R, Pines JM, Raja AS, Riedl M, Ward MJ, Zuraw BL, Diercks D, Hiestand B, Campbell RL, Schneider S, Sinert R; American College of Allergy, Asthma & Immunology (ACAAI); Society for Academic Emergency Medicine (SAEM). (2014). A consensus parameter for the evaluation and management of angioedema in the emergency department. Acad Emerg Med, (4), 469-84
Authorship
Authored by Marlena Wosiski-Kuhn, MD,
Dr. Wosisiki-Kuhn is a PGY-1 University of Cincinnati Department of Emergency Medicine
Peer Review and Editing by Jeffery Hill, MD MEd
Dr. Hill is an Associate Professor Emergency Medicine, Assistant Residency Director, Editor-in-Chief TamingtheSRU
