Management of angioedema without urticaria in the emergency department

Figures & data

Table I. Classification of angioedema (modified from Caballero et al. (49)).

1. Histamine-mediated angioedema
Allergic	IgE-mediated mast cell activation (type I hypersensitivity reaction)
Non-allergic	Non-IgE-mediated mast cell activation
Idiopathic	Unknown trigger, response to antihistamine therapy
2. Bradykinin-mediated angioedema
With C1-INH deficiency	Hereditary	Type I (antigenic deficiency)
Type II (functional deficiency)
Acquired
Without C1-INH deficiency	Hereditary (associated with estrogens)	With F12 gene mutation
Without F12 gene mutation (unknown)
ACEi-induced
Idiopathic	Unknown trigger, no genetic abnormality, response to bradykinin antagonist
3. Non-histamine non-bradykinin angioedema
ASA, NSAIDs intolerance

C1-INH = C1-inhibitor; ACEi = angiotensin converting enzyme inhibitor; ASA = acetyl-salicylic acid; NSAIDs = non-steroidal anti-inflammatory drugs.

Figure 1. Schematic diagram showing type I hypersensitivity reactions.

Figure 2. The contact system, showing the generation and degradation of bradykinin (reproduced with permission from: Caballero T, et al. J Investig Allergol Clin Immunol. 2011;21:333–47). ACE = angiotensin-converting enzyme; APP = aminopeptidase P; B1R = bradykinin B1 receptor; B2R = bradykinin B2 receptor; C1-INH = C1 esterase inhibitor; HMWK = high-molecular-weight kininogen; LMWK = low-molecular-weight kininogen; tPA = tissue plasminogen activator; UK = urokinase.

Table II. Differential features of bradykinin and histamine-mediated angioedema.

Angioedema features	Bradykinin-mediated angioedema	Histamine-mediated angioedema
Clinical features	Non-erythematous, non-pruritic	Erythemathous, pruritic
Time of onset/Duration	Slower onset/48–96 hours (up to 5 days)	Rapid onset/24–48 hours
Cutaneous rash	Without urticaria, sometimes erythema marginatum	Commonly associates urticaria
Response to treatment	Unresponsive to antihistamines, corticoids, and epinephrine	Responsive to antihistamines, corticoids, and epinephrine
	Response to pdhC1-inhibitor/icatibant/ecallantide	–
Personal or family history	Personal or familiar history of HAE (25% de novo mutations)	Frequent personal or familiar history of atopy (but not always)

HAE = hereditary angioedema.

Figure 3. The picture shows an erythema marginatum preceding an angioedema acute attack in a patient with type I HAE. The erythematous rash with circular polycyclic border and a clear center should not be confused with urticaria.

Table III. Staging system of airway obstruction risk from Ishoo et al. (58).

Stage	Anatomic site of presentation	Required ICU admission
I	Face, Lip	0%
II	Soft palate	0%
III	Tongue	67%
IV	Laryngeal	100%

Figure 4. Algorithm for management of acute angioedema in the emergency department. Note: Non-responders are considered when there is not an improvement 30–60 minutes after antihistamines, steroids, and/or epinephrine treatment. *Doses and treatment in each type of angioedema as described in Table IV. In those cases that a patient with ACEi treatment presents the first attack of angioedema, and the localization or the history of the evolution of the angioedema does not seem to be related to ACEi, first it is preferred to treat with antihistamines, steroids, and epinephrine to confirm that it is a histamine-mediated angioedema or it is a bradykinin angioedema. **In those cases that patient has presented previous episodes of angioedema without response to antihistamines, steroids, and epinephrine, or in those cases that suspicion of ACEi induced angioedema is elevated, they should be treated directly as a bradykinin-mediated angioedema as shown in Table IV. Indications for treatment of acute episodes depend on the severity and location of the angioedema episodes. One should treat all episodes of glottic edema, those that affect the cervicofacial or pharyngolaryngeal region, and also abdominal episodes. Peripheral episodes should be treated based on the impact on the patient's quality of life. HAE = hereditary angioedema; ACEI = angiotensin-converting enzyme inhibitors; ICU = intensive care unit.

Table IV. Treatment profile in each type of angioedema.

Type of angioedema	Treatment and dosage
1. Histamine-mediated angioedema	Epinephrine: Adults: 0.3–0.5 mg (1:1000). IM, in the thigh Children: 0.01 mg/kg (1:1000). IM, in the thigh Repeated every 5–15 min as needed
	Dexchlorpheniramine: Adults: 5 mg (1 vial) IV Children: 0.15–0.3 mg/kg IV
	Diphenhydramine: 1.25 mg/kg/6 hours
	Corticosteroids: Hydrocortisone: 200 mg in adults; 10–15 mg/kg/dose in children IV Methylprednisolone: 1–2 mg/kg in adults and in children IV
2. Bradykinin-mediated angioedema	Plasma-derived C1 INH: Berinert^®: 20 U/kg body weight IV Cinryze^®: 1000 U IV (only in children > 12 years and adults)
	Bradykinin receptor antagonist (icatibant acetate): Firazyr^®: 30 mg SC in abdominal site. It could be repeated at 6 hours and 24 hours. It is the preferred drug in case of ACEi angioedema
	Kallikrein inhibitor (ecallantide): Kalbitor^®: 30 mg injected in three vials of 10 mg/mL SC in abdominal site (approved by FDA; not approved by EMA)
	Recombinant C1 inhibitor: Ruconest^®, Rhucin^®: 50 U/kg IV (only in adult patients)
	Tranexamic acid: Amchafibrin^®: 15 mg/kg/4 h IV
3. Non-histamine- and non-bradykinin-mediated	The same as in 1.

IM = intramuscular; IV = intravenously; SC = subcutaneously.

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