It’s a Monday morning, and you’re just too excited for the start of the week. Your first patient of the day rolls up to the front of the unit, just as you put your things down. Your trusty triage nurse walks up to you vitals in hand, and says “Doc, we’ve got a 65-year-old male, with history of hypertension and face and lip swelling starting about 1 hour ago.”
The patient has slightly elevated blood pressure, and obvious facial swelling, but he is protecting his airway. Other vital signs are within normal limits. He tells you he has history of HTN and DM, and takes HCTZ, metformin, and one other medication for his blood pressure that he cannot recall. He has been taking these medications for years, and there have not been any recent changes. He has no history of trauma, no known allergies, and ate his usual toast for breakfast this morning.
His complete exam shows facial and perioral edema, with edematous, non-tender lips, and no uvular, tonsillar, or pharyngeal edema. Dentition is intact. His lung sounds are clear, and the remainder of the physical exam is otherwise unremarkable.1. What's your differential?
- Hereditary Angioedema
- Ace-inhibitor-related angioedema
- Facial/Dental trauma
- Cellulitis or facial/dental abscess
- Superior Vena Cava Syndrome
2. What is the most likely diagnosis?
This patient has no history or other physical signs of trauma. He is also afebrile, without tenderness to palpation, overlying erythema, or any other infectious signs or symptoms. Angioedema, in one of its many forms is the most likely culprit.
3. What is the pathogenesis of angioedema?
To think of it simply, angioedema is mediated by interactions that are triggered either by histamine or bradykinin.
Histamine is released by mast cell degranulation. Mast cells become sensitized by IgE antibodies that form in response to an antigen. When they come in contact with that antigen again, they degranulate and release histamine. This results in vasodilation (which leads to edema) and also bronchoconstriction, pruritis, vasodilation (which leads to edema), and stimulation of gastric acid secretion.
Bradykinin is formed as the end product of the kallikrein-kinin system. Kallikrein helps form activated Factor XII, which activates the classic complement pathway. It also helps with bradykinin formation. Bradykinin acts on endothelial cell receptors resulting in increased permeability and vasodilation, and ultimately edema. Specific proteases, which include ACE (angiotensin-I-converting enzyme), are responsible for metabolizing bradykinin.(1)
4. What kind of things can cause angioedema?
- Hereditary Angioedema (HAE)
- Type I and Type II HAE are caused by genetic mutations that cause a deficiency in functional C1-esterase inhibitor (C1-INH)(2)
- C1-INH is involved in inhibition of the classic complement cascade and kinin pathway
- HAE with normal C1-INH also exists, although the pathophysiology isn’t well understood
- Acquired Angioedema
- This is angioedema that is also related to a C1-INH deficiency, however, it is not genetic
- It is rare, and occurs later in life (typically after age 40)
- This is often related to an underlying disease, most commonly lymphoproliferative, autoimmune, or monoclonal gammopathies(1,2)
- Allergic Angioedema
- This is a type I immediate hypersensitivity response – IgE mediated mast cell degranulation, the release of histamine, and other mediators from mast cells and basophils(2)
- This is the most common form of angioedema
- It is often accompanied by urticaria, and concurrent anaphylaxis can also occur
- ACE-Inhibitor (ACE-I) and Drug-Induced Angioedema
- Incidence can occur most commonly in the first few weeks of treatment with an ACE-inhibitor, but has no time limit and can occur even after years of use(1)
- It occurs in about 0.1-0.7% of patients on ACE-I, and there is three times higher risk in African Americans vs. Caucasians(1)
- Other drugs such as NSAIDS, statins, contrast agents, SSRIs, PPIs, and TPA have also been implicated in angioedema(3)
5. What is the most important part of treatment/resuscitation of your patient ?
As always, don’t ever forget your airway, breathing, and circulation. Given the strong possibility of development of oropharyngeal involvement and airway edema, ensuring a patent airway is critical.
Remember that supraglottic airway devices like oropharyngeal airways or laryngeal mask airways have limited success, and can often fail, in these patients, as there is often swelling of the vocal cords and the glottis.(2)
Awake, fiberoptic nasotracheal intubation is the preferred technique in the setting of acute oropharyngeal edema.(4) Standard rapid-sequence intubation RSI) with induction and paralysis can result in sagging of edematous epiglottis and oral tissues,qhich may obstruct your view. RSI should be done with caution, if attempted.(2) Regardless of airway management method, you should always be prepared for an emergency cricothyroidotomy.
6. How are you going to treat your patient?
Again, ensuring a patent airway is key. Supplemental oxygen should be considered in any patient with angioedema involving the head and neck and hypoxemia, or for pre-oxygenation/de-nitrogenation if intubation is being considered.(1) Obtain IV access ands, give crystalloid as needed for hypotension or suspected fluid shifts.
Flexible fiberoptic laryngoscopy should be used for any patient with head and neck involvement or upper airway complaints, if available. This will help determine the extent of swelling, especially in the base of the tongue and the larynx.(5)
If there are any signs of anaphylaxis (urticaria, bronchospasm, or hypotension), epinephrine should be given immediately and can be repeated every five minutes as needed. Glucagon can also be considered in patients on B-blockers who may not be as responsive to epinephrine.(1,5) Corticosteroids, H1 and H2 blockers should be used in conjunction with epinephrine.
When a histamine-mediated cause cannot be ruled out corticosteroids, H1, and H2 blockers are often a mainstay of treatment. While these have no proven benefit in ACE-Inhibitor induced angioedema, a favorable side effect profile and low risk of harm make them considerable therapies for our patient.
One of the only readily available therapies that has some reported benefit in ACE-Inhibitor induced angioedema and theoretical benefit in hereditary angioedema is Fresh Frozen Plasma (FFP).(1,5 However, administration of FFP comes with the risk of infectious transmission, fluid overload, and hypersensitivity.(1) Worsening of hereditary angioedema is also a possible risk, and FFP should be used with caution for this indication.(5)
Targeted treatment is also a consideration for patients with known hereditary angioedema. C1-INH concentrate (Berinert), a kallikrein inhibitor (Ecallantide), and a bradykinin-2 receptor agonist (Icatibant) have all been FDA approved for use in the US. While some of these treatments have also been shown to have possible benefit in ACE Inhibitor- induced angioedema, there is not enough data to support their use in this population.(5)
8. What is your patient's disposition?
While there is no clear consensus on ultimate disposition for patients with angioedema, clinical presentation should be used to guide your decision. The Ishoo criteria are clinical and laryngoscopic criteria based on involvement of oropharyngeal and airway edema that may predict the risk for airway compromise. A patient’s disposition depends on the extent of involvement. The criteria set was determined based on a retrospective review of 93 episodes of angioedema in 80 patients from 1985-1995.(6) Keep in mind that while this tool may be helpful in making your clinical decision, it requires laryngoscopy and, more importantly, has not yet been validated.
Patients with only facial, lip, or soft palate edema can often be observed in the emergency department (anywhere from 2-6 hours) to ensure that it is not progressive.(7) Based on their clinical status, patients can then either be discharged home with appropriate follow up or admitted to an inpatient ward or observation unit. For patients with ACE-Inhibitor induced angioedema, the ACE-I should be discontinued and alternative blood pressure control or immediate follow up should be ensured. For those with life threatening attacks of angioedema, angiotensin receptor blockers should also be avoided.(7)
In any patient with tongue or laryngeal involvement, disposition to a critical care unit should be considered, given the possible need for definitive airway management.
(1) Wilkerson G. Angioedema in the Emergency Department: An Evidence Based Review. Emergency Medicine Practice [Internet] 2012;14(11):1-24. Available from: http//www.ebmedicine.net/
(2) Fischer D. Abukhdeir H. Understanding and Managing Angioedema in the Emergency Department. Emergency Medicine Reports 2016;37(23): 1-16.
(3) Salih I. Thomas S. Causes and management of Drug Induced Angioedema. Prescriber 2006;17(7):14-18.
(4) Nadel ES, Brown DF. Angioedema. Journal of Emergency Medicine1998;16:477-479.
(5) Moellman J, Bernstein J, Lindsell C. A Consensus Parameter for the Evaluation and Management of Angioedema in the Emergency Department. Academic Emergency Medicine 2014;21(4):469-484.
(6) Ishoo E. Shah UK. Stram JR. Fuleihan NS. Predicting airway risk in angioedema: staging system based on presentation. Otolaryngology Head and Neck Surgery 1999;121(3):263-268.
(7) Bernstein J. Cremonesi P. Hoffman T. Hollingsworth J. Angioedema in the emergency department: A practical guide to differential diagnosis and management. International Journal of Emergency Medicine [Internet] 2017;10:15, doi: 10.1186/s12245-017-0141-z
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