24.2.1 What Is the Pathophysiology of Angioedema?
Angioedema is defined as the abrupt onset of non-pitting swelling of the skin, mucous membranes, and deep subcutaneous tissues, including the linings of the upper respiratory and intestinal tracts.1 Angioedema develops because of a local increase in permeability of the submucosal or subcutaneous capillary vessels, causing local plasma extravasation. This is exacerbated by the release of vasoactive substances such as histamines, prostaglandins, bradykinins, and cytokines.2 Angioedema can be divided into hereditary angioedema (HAE) and acquired angioedema.
Hereditary angioedema is extremely rare, affecting 1 in 50,000 people.2 It develops due to a C1 esterase inhibitor deficiency, which is inherited in an autosomal dominant pattern. This deficiency results in an abnormal increase in the activation of C1 and subsequently excessive formation of the enzyme kallikrein. The excess kallikrein transforms kininogen into kinins, including bradykinin. Bradykinin is highly vasoactive and produces the characteristic tissue swelling.2 HAE is commonly precipitated by trauma and stress, and can recur. If the patient has known HAE, then treatment with fresh frozen plasma (FFP) is beneficial, as it contains C1 esterase inhibitor. In some centers, vapor-heated C1 inhibitor concentrate is available and is proving beneficial in recurrent attacks of HAE.2
Acquired angioedema is due to faulty activation of the complement and kallikrein–kinin systems. It comprises several types, including the traditional IgE-mediated allergic response, precipitated by exposure to an allergen (such as peanuts, antibiotics, and shellfish). Anaphylaxis is characterized by an acute onset and not only causes angioedema of the upper airways but also has a more systemic effect causing wheeze secondary to bronchoconstriction and hypotension secondary to vasodilation and third spacing.3 Anaphylaxis (or anaphylactoid) reactions can cause angioedema through other mechanisms such as direct mast cell degranulation (opiates, radio-contrast media) or by altering arachidonic acid metabolism (benzoates, angiotensin-converting enzyme inhibitors [ACEIs], and nonsteroidal anti-inflammatory agents [NSAIDs]).4,5
The development of angioedema secondary to ACEIs is of particular interest.4,5 In addition to inhibiting the conversion of angiotensin I to angiotensin II, the suppression of ACE results in a decrease in the breakdown of bradykinin and substance P. As outlined earlier, this can result in severe tissue swelling.1 ACEI-induced angioedema has a predilection for the head and neck,2 rendering it a particular challenge in airway management. It appears that this drug effect is associated specifically with the class of drugs known as ACEIs,2 although recently, angioedema has been demonstrated to occur with the angiotensin II receptor blockers (ARBs) as well.6,7 Treatment with IV steroids, antihistamines, and subcutaneous epinephrine (0.3 mg) may be beneficial in allergy-induced angioedema, but has been shown to be ineffective in HAE and of limited use in ACEI and ARB-induced angioedema.7,8 There is no role for FFP in ACEI or ARB-induced angioedema.
ACEI-induced angioedema affects more women than men in the United States and is most common among 40- to 50-year-olds. Close to half of those affected with angioedema are African American.9 According to the literature, the incidence of ACEI-induced angioedema ranges from 0.1% to 0.2% of all patients taking this class of drugs.1,2,10 However, ACEI-induced angioedema is the most common cause of angioedema seen in US EDs, accounting for 17% to 38% of all angioedema cases.11 In the omapatrilat (a new ACEI) versus enalapril (OCTAVE) trial, the investigators found that there was an increased incidence of the disorder in African American patients, those older than 65, and those with a history of drug rash or seasonal allergies.10 Approximately 50% of all ACEI-induced angioedema cases occur within 1 week of starting the medication, with the remainder occurring anywhere from weeks to years after starting the drug.2
24.2.2 What Is the General Clinical Course of the Disorder?
Patients with HAE usually report trauma, often minor (eg, dental visit), followed by tissue swelling. They can present with swelling in such widespread anatomic areas as the face, hands, arms, legs, GI tract, and genitalia, but often respond to treatment. In one large series, 10% of the patients with HAE required definitive airway intervention because of upper airway edema. The onset of IgE-mediated anaphylaxis is rapid and often life threatening if not treated appropriately.2 The clinical course of ACEI-induced angioedema is often subacute but always extremely unpredictable, and life-threatening presentations requiring airway interventions do occur and are reported in up to 20% of these patients.2 According to the literature, between 0 and 22.2% of patients with angioedema will require intubation.9 It is extremely difficult to predict which patients who present with a stable airway will progress to a requirement for airway intervention. Researchers from Boston9 retrospectively analyzed cases of ACEI-related angioedema and determined that increasing age and oral cavity/oropharyngeal involvement predicted the need for airway intervention. These predictors had a sensitivity of 65.2% and specificity of 83.7%.
Since the clinical course of angioedema, especially ACEI-induced, is very unpredictable, it is recommended that these patients be admitted to an environment where they can be closely monitored for at least 24 hours.
24.2.3 What Investigations Might One Employ to Aid in the Diagnosis and Evaluate the Severity of the Disorder?
The severity of airway compromise on presentation will determine the extent of initial investigations of these patients, and thus the workup for HAE is typically undertaken after the acute episode has resolved. The unpredictable clinical course of this disorder demands that each of these patients be triaged as emergencies to a resuscitation area of the ED and attended to immediately by nursing and physician staff. Evaluation and management are carried out concurrently, as is appropriate in patients with life-threatening conditions. As a result, early airway intervention is strongly advised. It is often obvious that the airway is in immediate jeopardy and this should trigger calling for assistance and implementing a strategy to secure the airway, from either above or below (surgically). The decision for airway intervention will be based largely on the clinical signs of respiratory distress: air hunger, agitation, hypoxia, and especially muffled voice, difficulty swallowing saliva, and stridor.
If one has the luxury of time and possess the skill, severity may be assessed by flexible nasopharyngoscopy.12 It is prudent to prepare for this procedure as though one were intending to perform an awake endoscopic-guided nasal intubation. This assumes that one has anesthetized the nasopharyngeal passage and inserted a nasotracheal tube through which the endoscope is passed in case the findings mandate intubation. It is preferable that the scope used for this procedure be of sufficient length and stiffness to guide an endotracheal tube into the trachea.12 Repeated nasopharyngoscopic evaluation at regular intervals may be indicated in the event immediate endotracheal intubation is not necessary. Additionally, as with all upper airway emergencies, it is prudent to be prepared to undertake an immediate surgical airway in the event that diagnostic maneuvers trigger complete upper airway obstruction. This is often referred to as a double set-up in the context of airway management.
A portable cross-table soft tissue x-ray of the airway is seldom useful and it should be emphasized that this investigation must not delay care if the airway is compromised and must not mean that the patient has to leave the resuscitation area. These patients are always reluctant to lay flat for studies, such as CT scanning and MRI evaluations to be performed. This hesitancy ought to alert the practitioner that the degree of airway obstruction is significant, rendering such studies contraindicated. Arterial blood gases and other laboratory investigations are generally not helpful in the management of these patients.