Angioedema

OVERVIEW

• Angioedema is a clinical diagnosis characterized by the abrupt onset of non-pitting, non-pruritic swelling that involves the reticular dermis, subcutaneous, and submucosal layers
• Angioedema may be life-threatening, depending on the underlying cause and the body location affected
• Airway involvement is usually the immediate life-threat
• The possibility of anaphylaxis must be considered

CAUSE

• Hereditary angioedema (HAE) (type 1 and type 2)
  • C1 esterase inhibitor deficiency (functionally abnormal C1-INH leads to bradykinin over-production)
  • affects 1/50,000 people
  • 50% present with recurrent episodes of angioedema by age 10 years
  • type 1 has low antigen and functional levels of C1-INH
  • type 2 has normal antigen levels but low functional levels of c1-INH
  • HAE without C1-INH deficiency has also been described
• Acquired
  • Medications
    • ACE Inhibitors (ACEI)
      • up to 1% incidence
      • angioedema is a class effect and is not dose dependent – symptoms can occur any time from a few hours up to 10 years after the initial dose (Winters et al, 2013)
      • more common in African Americans and patients on immunosuppressants
      • note that angioedema can occur in patients switched to an angiotensin receptor blocker
    • NSAIDS
      • usually localised to the face +/- uritcaria
    • Opiates
    • Dextrans
  • Acquired C1 esterase inhibitor deficiency
    • due to an underlying lymphoproliferative disorder and/or an antibody directed against C1-INH
  • Food
  • Latex
  • Local trauma
  • Hymenoptera envenomations and other insect stings
• Idiopathic (most cases are thought to be histamine-mediated)

PATHOGENESIS

Angioedema may be histamine-mediated or non-histamine-mediated:

• histamine-mediated angioedema may co-exist with urticaria and is mast-cell mediated
  • e.g. anaphylaxis, allergies, some drug reactions
• non-histaminergic (bradykinin-mediated) angioedema tens to be more severe, more prolonged and less responsive to adrenaline
  • includes ACEI-related angioedema and both herediatry and acquired C1 esterase inhibitor deficiency

CLINICAL FEATURES

• abrupt onset of non-pitting, non-pruritic swelling
  • well demarcated
  • usually asymmetric
  • located in non-dependent areas
  • transient (up to 7 days duration)
• angioedema may be isolated or co-exist with urticaria
• areas affected
  • asymmetric swelling of the lips and face
  • tongue, the floor of the mouth, neck, and eyelids
  • may affect extremities, genitalia or viscera (e.g. intensitines)
• Features of significant airway involvement:
  • Dyspnea, dysphagia, dysphonia, odynophagia, stridor, hoarseness, and drooling
  • Can progress to complete airway obstruction and death
• Features of gastrointestinal involvement:
  • abdominal pain, nausea, vomiting, altered bowel habit
  • may mimic an acute surgical abdomen
• previous episodes
• identify triggers
  • exposures (may not be new, e.g. 40% of ACEI-related angioedema occurs months to years after initiation)
  • HAE pateints may have prodroma symptoms
    • e.g. erythema marginatum, an erythematous serpentine but nonpruritic and non-raised rash (do not confuse with urticaria)
  • family history

See Table 4 of Moellman et al (2014) for a comparison of historical features of different causes of angioedema

INVESTIGATIONS

There are no point-of-care tests that can guide management in the emergency situation, but investigations may help guide longterm management

Bedside

• Fiberoptic laryngoscopy (significant airway swelling can occur in rare cases even in the absence of clinical features suggesting significant airway involvement)

Laboratory

• identify underlying cause
  • C1 esterase inhibitor (C1-INH) assays (low/ abnormal in HAE)
  • C4 levels (low in HAE attacks, usually normal between attacks)
  • serial tryptase levels (may be elevated in anaphylaxis/ mast cell-mediated angioedema)

Imaging

• CT abdomen may show evidence of angioedema in patients presenting with abdominal pain:
  • may involve GI and GU tracts
  • Angioedema of the visceral organs is often accompanied by adjacent fluid
  • involvement may be multifocal or asymmetric (not always be diffuse or concentric)
• CT neckprimarily has a role in excluding conditions that may mimic angioedema (e.g. soft tissue infection)
  • glossomegaly is common
  • shows the extent of airway involvement

MANAGEMENT

Resuscitation

• Airway obstruction is the potential life-threat in most patients with angioedema
  • if stable and cooperative, awake fiberoptic intubation (AFOI) with anaesthetist and ENT involvement is preferred
    • awake intubation in a spontaneous breathing patient avoids loss of pharyngeal tone and can be performed in an upright position, both of which lessen the likelihood of airway compromise
    • even with advanced fiberoptic or video techniques it may be impossible to pass and endotracheal tube through the glottis due to swelling
    • be aware that failed attempts at intubation may worsen airway compromise
  • if unstable with hypoxia and progressive airway obstruction, then laryngoscopy with a ‘double setup’ emergency surgical airway should be attempted
    • video laryngoscopy (e.g. C-Mac) and use of a bougie are preferred
    • supraglottic airway devices (SAD, e.g. LMA) are more likely to fail due to able supraglottic soft-tissue swelling and airway obstruction
    • emergency surgical airway may be difficult due to distortion of anatomy and subcutaneous edema (extended vertical incision may be required initially)
  • the decision to intubate is based on careful observation, fiberoptic examination (when possible) and clinical judgement, and should be performed by a senior clinician
    • patients with features suggestive of airway involvement (e.g. dyspnea, dysphagia, dysphonia, odynophagia, stridor, hoarseness, and drooling) should have fiberoptic examination performed to check for upper airway edema (unless requiring emergency intubation)
    • no ACEI-related angioedema patient with a normal larynx on fiberoptic examination has progressed to required emergency intubation (Winters et al, 2013)
• Hypovolaemic shock may also occur due to vasodilation and increased vascular permeability
  • fluid resucitation
  • vasopressors

Specific therapy

• FFP
  • possible therapy for ACEI-related angioedema (case reports), thought to be beneficial in most cases
  • FFP contains ACE (kininase II), which degrades bradykinin
  • risk of viral transmission, allergic reactions, and volume overload and a possibility of worsening symptoms in HAE (by providing additional substrate, kininogen)
• Therapies for HAE attacks
  • these include:
    • icatibant — a bradykinin 2 receptor inhibitor
    • ecallantide — a kallikrein inhibitor (kallikrein is the enzyme that produces bradykinin from high-molecular-weight kininogen (HMWK))
    • C1-INH concentrate — C1 esterase inhibitor blocks the pathways that produceHMWK (the C1-INH concentrate may be plasma-derived or recombinant)
  • limited data for role in non-HAE patients (e.g. ACEI-related angioedema)
    • Several case reports describe the potential use of icatibant in the treatment of ACEI-related angioedema
• role of adrenaline, steroids and antihistamines
  • unlikely to be be effective for ACEI-related angioedema
    • this a bradykinin-mediated condition, not related to mast cell degranulation
    • many ACEI-related angioedema cases can be managed by observation alone, without pharmacotherapy or intubation
    • most ACEI-related angioedema cases resolve over 24-48h
    • the apparent effectiveness of therapies may be confounded by spontaneous resolution of the angioedema
  • should be adminstered if the underlying cause of angioedema is uncertain (i.e. anaphylaxis is possible)

Supportive care and monitoring

• note that pulse oximetry and capnography are late markers of airway compromise, and should not be used in isolation to guide airway management

Disposition

• all angioedema patients with potential airway involvement should be observed in a high visibility area until marked resolution has occurred
• this often requires admission to an HDU/ICU
• admission to hospital, rather than in ED, is preferred in the following situations (Winters et al, 2013):
  • previous history of angioedema
  • tongue edema
  • pharyngeal edema (palate, uvula)
  • laryngeal edema (true vocal cords, false vocal cords, arytenoids, aryepiglottic folds, epiglottis; the term upper airway oedema is probably more useful)
  • lack of improvement during the ED course
• patients with isolated angioedema of the face or lips and be usually be observed in ED for 4 to 8 hours for progression of symptoms, then discharged

Follow up

• follow up with allergist/ immunologist
• stop ACEI
• advise to return if symptoms recur
• patients with HAE
  • may be given targeted therapy for self-administration (requires training of patient and family)
  • may be started on antifibrinolyitics and anabolic steroids for prophylaxis
  • those on C1-INH or ecallantide should have adrenaline in case of anaphylaxis to these agents

References and links

LITFL

• Rorschach test revealed (CT head and neck of a patient with angioedema)
• Traumatic angioedema

Journal articles

• Farkas H. Management of upper airway edema caused by hereditary angioedema. Allergy Asthma Clin Immunol. 2010 Jul 28;6(1):19. doi: 10.1186/1710-1492-6-19. PMC2920238.
• Ishigami K, Averill SL, Pollard JH, McDonald JM, Sato Y. Radiologic manifestations of angioedema. Insights Imaging. 2014 Jun;5(3):365-74. doi: 10.1007/s13244-014-0329-1.PMC4035492.
• Lewis LM. Angioedema: etiology, pathophysiology, current and emerging therapies. J Emerg Med. 2013 Nov;45(5):789-96. doi: 10.1016/j.jemermed.2013.03.045. Epub 2013 Aug 29. PMID: 23992848.
• 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). A consensus parameter for the evaluation and management of angioedema in the emergency department. Acad Emerg Med. 2014 Apr;21(4):469-84. PMC4100605.
• Pedrosa M, Prieto-García A, Sala-Cunill A; Spanish Group for the Study of Bradykinin-Mediated Angioedema (SGBA) and the Spanish Committee of Cutaneous Allergy (CCA). Management of angioedema without urticaria in the emergency department. Ann Med. 2014 Dec;46(8):607-18. PMID: 25580506.