New Treatments for Angioedema

An in-depth look at the latest medications for this emergency

Few procedures in emergency medicine are as potentially disastrous as the management of a difficult airway. The patient with a gun-shot wound to the jaw, the tracheal crush injury, the diabetic with Ludwig’s, and the case of severe angioedema all occur regularly in the airway nightmares of emergency physicians (EPs). Within the realm of difficult airways, it is important to understand the causes of and treatments for angioedema, including several new medications that could help your next angioedema patient.

Angioedema involves swelling of non-dependent subcutaneous or submucosal tissue. There are two main, mechanisms by which angioedema occurs: mast cell-mediated and bradykinin-mediated (Figure 1 below). One important difference between the two is the presence of urticaria and pruritus. In mast cell mediated angioedema, as seen in allergic reactions, urticaria and pruritus are almost always present, whereas in bradykinin-mediated angioedema, seen in ACE-inhibitor (ACEI) induced and hereditary angioedema, urticaria and pruritus are absent. The final common pathway for both mechanisms is vasodilation and increased vascular permeability leading to fluid extravasation. The lips, tongue, uvula, throat, hands, feet, and genitalia are most often affected because they contain looser connective tissue. The GI tract can also be involved, especially in bradykinin-mediated angioedema, causing nausea, vomiting, diarrhea, and abdominal pain. Since angioedema is self-limited, the goal of the EP is to first assess, stabilize, and secure the airway if needed, and to reduce the edema if possible.

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It is important to review the underlying pathophysiology of mast cell and bradykinin-mediated angioedema in order to understand why the treatments for the two types of angioedema are so vastly different. Whereas mast cell-mediated processes respond to steroids, antihistamines, and epinephrine, bradykinin-mediated angioedema is unlikely to respond to these treatments. Broadly speaking, bradykinin-mediated angioedema occurs either due to excess production of bradykinin, or decreased break-down of bradykinin. The mechanisms are complex and interrelated with many other signaling pathways, but are simplified here in Figure 2 below.

ACE-Inhibitor Induced Angioedema
ACEIs are the number one drug-related cause of angioedema, accounting for 20-40% of all ED angioedema visits, and occurring in around 0.3-0.7% of patients taking ACEIs [^1]. It occurs because break-down of bradykinin by ACE is inhibited. Excess bradykinin binds to B2 receptors, causing vasodilation and angioedema. Half of cases occur within the first week of taking the ACEI, but angioedema can occur even after years of taking the drug. Angioedema typically peaks within the first minutes to hours of onset and then resolves over 2-5 days. If the ACEI is not discontinued, then the patient will typically have recurrent and more severe episodes. Even after stopping the ACEI, patients can have recurrent episodes of angioedema for several months following the initial have an effect.

Treatment
Icatibant, C1-INH, or FFP have all been used for ACE-I angioedema [^2,3]. There are case reports of the successful use of FFP in ACEI induced angioedema [^1,4]. FFP contains the ACE enzyme, which breaks down bradykinin. However, there is some risk of worsening the edema because FFP also contains high molecular weight kininogen, the bradykinin precursor [^5]. A small, phase II, randomized, controlled trial of icatibant published in the NEJM showed that patients treated with icatibant had improvement of their symptoms within two hours of administration, and resolution within about eight hours, compared to 27 hours for the group receiving prednisolone and clementine [^6]. However, in the March 2016 EM:RAP, Gentry Wilkerson, an angioedema researcher reported unpublished data on their phase III trial that showed no benefit to icatibant [^7]. Ecallantide does not perform well and is not recommended [^3]. None of the medications have FDA approval for treatment of ACI-induced angioedema.

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Hereditary Angioedema (HAE)
HAE occurs because of excess production of bradykinin. There are a number of mutations associated with HAE, the most common of which result in a dysfunction or lack of C1 inhibitor (C1-INH), formerly known as C1 esterase inhibitor [^8]. C1-INH inhibits the kallikrein enzyme responsible for bradykinin formation. The first presentation of HAE usually occurs during the childhood or teenage years. Laryngeal obstruction and asphyxiation is the leading cause of death in patients with HAE, so definitive airway management should be a priority [^8]. There is data showing that early treatment will lead to earlier resolution of symptoms [^9].

Treatment
C1-INH, icatibant, and ecallantide are all considered first line therapies for HAE-induced airway edema. If none of them are available, then FFP can be used. However there are concerns that FFP can paradoxically cause worsening of the angioedema [^9]. C1-INH and icatibant can both be self-administered by patients or caregivers at home.

Acquired Angioedema (C1INH-AAE)
This occurs in patients who have B cell lymphoproliferative disorders leading to C1-INH deficiency or dysregulation, and excess bradykinin production. In contrast to HAE, acquired angioedema usually occurs in middle aged or older adults [^9].

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Treatment: C1-INH, icatibant, and ecallantide can all be used. C1-INH concentrate is the medication recommended most [^10].

Mechanisms of Action and Dosing:

• Icatibant – Binds and antagonizes the bradykinin B2 receptor. The dose is 30mg slow SQ administration in the abdomen. A second dose can be given 6 hours later if needed.
• Ecallantide – Inhibits kallikrein, the enzyme that converts kininogen to bradykinin. 3 doses of 20mg each given at different sites SQ. The dose can be repeated in 1 hour if needed.
• C1 inhibitor concentrate – Inhibits kallikrein. The dose 20 units/kg IV over 10 minutes. A second dose can be given 30min to 2 hours later if needed.
• Fresh Frozen Plasma or solvent/detergent (S/D) treated plasma – Contains angiotensin converting enzyme, which breaks down bradykinin. A typical dose is 2 units IV, with resolution of symptoms expected 2-4 hours later.

Cost
The cost of one dose of C1-INH, icatibant, or ecallantide are all in the range of $5,000-$10,000. Given the high cost and the relatively infrequent need for these medications, many smaller hospitals will likely not stock them. Physicians should always focus on managing the airway first. Particularly for ACEI-induced angioedema, it is not clear that any of the medications are effective so supportive care is most important.

Ten Airway Tips and Tricks
Patients with bradykinin-mediated angioedema may worsen gradually or precipitously, so they should have an airway evaluation right away and have frequent re-examinations. Stridor or any respiratory distress should prompt a consideration of intubation. If you have time, and the patient is not emergently decompensating, here are some tips to increase your chance of successful airway management:

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1. If you are not sure if the angioedema is bradykinin mediated, such as in someone with a first episode of angioedema, treat with 0.3mg of IM epinephrine for adults (an epi-pen) in case it is a mast cell-mediated process. Remember that if the patient has any urticaria, then the cause is mast cell-mediated and it should respond to epinephrine, steroids, and antihistamines.
2. Ask the patient or check their wallet for a card describing which medications have worked in the past for their angioedema, and give the medication if your hospital carries it.
3. If you are not sure if the cause is ACE-inhibitor induced or HAE, give icatibant, as it is effective for both.
4. If you have ENT or anesthesia available, call them.
5. Prepare for a cricothyroidotomy (mentally and equipment-wise). Identify the landmarks and prep the neck.
6. Have a nasal fiberoptic intubation setup ready, with the tube loaded on the scope (or it can be inserted into the nare before introducing the scope), and the nares pre-treated with a vasoconstrictive agent and numbing medication.
7. Keep a bougie at the ready.
8. Use a smaller tube than usual since you can anticipate it may be difficult to pass due to edema.
9. Use a video laryngoscope if you have one. If the tongue is swollen it may be difficult or impossible to push it out of the way with direct laryngoscopy.
10. If the patient is breathing spontaneously, avoid paralytics if possible and allow the patient to continue breathing during intubation. An agent such as IV ketamine will maintain the patient’s ventilations while you visualize the cords and pass the tube.

REFERENCES

1. Guyer AC, Banerji A. ACE inhibitor-induced angioedema. Up to Date Web site. uptodate.com. Published 06/04/2015. Updated 2015. Accessed 07/15, 2016.
2. Culley CM, DiBridge JN, Wilson GL,Jr. Off-label use of agents for management of serious or life-threatening angiotensin converting enzyme inhibitor-induced angioedema. Ann Pharmacother. 2016;50(1):47-59.
3. Scalese MJ, Reinaker TS. Pharmacologic management of angioedema induced by angiotensin-converting enzyme inhibitors. Am J Health Syst Pharm. 2016;73(12):873-879. doi: 10.2146/ajhp150482 [doi].
4. Hassen GW, Kalantari H, Parraga M, et al. Fresh frozen plasma for progressive and refractory angiotensin-converting enzyme inhibitor-induced angioedema. J Emerg Med. 2013;44(4):764-772.
5. Adebayo O, Wilkerson RG. Angiotensin-converting enzyme inhibitor-induced angioedema worsened with fresh frozen plasma. Am J Emerg Med. 2016. doi: S0735-6757(16)30339-4 [pii].
6. Bas M, Greve J, Stelter K, et al. A randomized trial of icatibant in ACE-inhibitor-induced angioedema. N Engl J Med. 2015;372(5):418-425. doi: 10.1056/NEJMoa1312524 [doi].
7. EM:RAP. Emergency medicine reviews and PErspective. www.emrap.org. Published 2016. Updated 2016. Accessed 08/08, 2016.
8. Zuraw B, Bingham CO. An overview of angioedema: Clinical features, diagnosis, and management. Up To Date Web site. uptodate.com. Published 07/21/2015. Updated 2015. Accessed 07/15, 2016.
9. Christiansen SC, Zuraw BL. Hereditary angioedema: Management of laryngeal attacks. Am J Rhinol Allergy. 2011;25(6):379-382.
10. Cicardi M. Acquired C1 inhibitor deficiency: Management and prognosis. Up to Date Web site. uptodate.com. Published 04/11/2016. Updated 2016. Accessed 07/15, 2016.