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ANGIOEDEMABradley Davis, DO
Mercy Hospital and Medical Center
Chicago, IL
Disclosure Statement
■ No conflicts/disclosures
Lecture Objectives
■ Define and discuss prevalence of angioedema
■ Gain understanding of risk factors and common demographical
features
■ Recognize angioedema as a sign with a differential
■ Review relevant literature regarding treatment options
■ Introduce airway strategies for angioedema patients
Angioedema
Bradykinin-Mediated Histamine-Mediated
Hereditary Non-Hereditary Treatment
Treatment Strategies with Literature Review
Airway Options
Nurs Open. 2019 Jan; 6(1): 126–135.
Published online 2018 Aug 28. doi: 10.1002/nop2.194
Definition
■ Angioedema: localized edema involving the deep dermis or
subcutaneous/submucosal tissues caused by dilatation and
increased capillary permeability
Prevelance
■ Roughly 100,000 ED visits per year for angioedema
■ Hereditary angioedema effects between 1 in 10,000 and 1 in 50,000
people
■ ACE Inhibitor-mediated account for 30% of angioedema cases
Angioedema
Bradykinin-Mediated Histamine-Mediated
Hereditary Non-Hereditary Treatment
Treatment Strategies with Literature Review
Airway Options
Lets Divide By Mechanism
■ 1.) Histamine (also called mast cell-mediated)
■ 2.) Bradykinin Mediated
■ 3.) Idiopathic
Histamine Mediated
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4989802/
Indian J Anaesth. 2016 Aug; 60(8): 534–541.
doi: 10.4103/0019-5049.187776
Mast Cell-Mediated
■ This is the mechanism we all deal with routinely
■ Peanut + IgE + Mast Cell -> Histamine ->leaky vasculature -> ok I got
this one
– Block the histamine receptors and constrict the vessels with epi
– Not the focus of this lecture
Bradykinin-Mediated
■ Pathway/model not as well understood
■ More complicated than initially thought
– As evidenced some futile meds that should work
– Weird distribution of symptoms
– Hereditary type with intact enzyme!?
Bradykinin Mediated - 2014
Bradykinin Mediated 2019Now a
circle with
lots more
arrows
Front Immunol. 2019; 10: 2046.
Published online 2019 Aug
27. doi: 10.3389/fimmu.2019.02046
Why Does It Matter?
■ Treatments are different
■ Histamine-Mediated responds to steroids, epinephrine and
antihistamines
■ Bradykinin-Mediated does not respond to the above
measures – may benefit from other treatments
Angioedema
Bradykinin-Mediated Histamine-Mediated
Hereditary Non-Hereditary Treatment
Treatment Strategies with Literature Review
Airway Options
Differentiating the Mechanisms at the Bedside
■ Histamine-mediated angioedema typically accompanied by
urticaria and pruritis
■ May have GI involvement
■ Can progress to hypotension
■ Responsive to epinephrine
■ May elicit history of atopy
Differentiating the Mechanisms at the Bedside
■ Bradykinin mediated
– Often asymmetry (half of the tongue or lip), one
extremity
– No urticaria
– Does not respond to epinephrine – can give trial dose
– Slower in onset
So You’re Thinking Bradykinin Angioedema
■ What kind?
Most Common Forms
■ Hereditary Angioedema
■ Medication Associated Angioedema
■ Acquired Angioedema
■ Idiopathic
What I’m calling
“Non-
Hereditary”
Hereditary Angioedema
■ Autosomal Dominant with near 100% penetrance
■ C1 Inhibitor deficiency leading to build up of bradykinin
■ 1:30,000 to 1:80,000 in general population
Hereditary Angioedema
■ Typically presents in children
■ Increases in severity in puberty
■ Triggered by stress, infection, trauma – patients learn a prodrome
■ Involves the gut or an extremity in almost 100% of attacks
– Rarely involve the larynx (50% lifetime risk)
■ Can have attacks every 10-20 days!
Allergy Asthma Clin Immunol. 2018; 14(Suppl 2): 59.
Published online 2018 Sep 12. doi: 10.1186/s13223-018-
0288-z
Acquired Angioedema
■ Thought to be autoantibodies against C1 INH
■ 1:100,000 to 1:500,000
■ Seen in elderly patients
– Often with lymphoma or autoimmune diseases
Medication-Associated Angioedema
■ The list is a mile long – memorize a few
– ACE/ARB
– NSAIDS
– ASA
– Alteplase
– DPP-4 inhibitors
– Oral contraceptive pills
ACE Inhibitor Angioedema
■ More common in elderly, females, smokers
■ More common in black population
■ 0.1% to 0.7% of patients taking ACE
■ 1.5% to 10% cross over to ARB
■ Can develop at anytime (even years after initiation)
Lets Get to the Good Stuff
Treatment
■ Airway, Airway, Airway
THE END
Management
■ Airway management remains backbone of ED care
■ Newer agents may provide benefit in certain situations
Airway Management
■ No great evidence for when/who to intubate
■ Use your typical indications
– Stridor
– Inability to handle secretions
– Dyspnea
– Involvement of posterior structures
■ When in doubt, use sphincter tone as guide
Ishoo Criteria
■ Attempted to classify clinical findings into 4 stages
■ Never externally validated
■ Requires laryngoscopy
Beware the Angioedema Airway
■ LMA probably won’t work
■ Manipulating airway might make edema worse
■ Paralysis might cause immediate obstruction
■ Good chance BVM won’t work
Get Help
■ Now is the time to call your friends
■ Need someone with scope skills and someone with knife
skills
Double Setup
■ Set up for cric with one provider
■ Attempt awake nasotracheal intubation via second provider
■ If tongue allows, can try awake video
Value of Nasolaryngoscopy
■ https://www.youtube.com/watch?v=REjCjIiTreA
Adjunct Medications
■ What about the fancy stuff?
– Ecallantide – kallikrein inhibitor
– Icatabant – B2 Bradykinin competitive inhibitor
– FFP – contains C1 INH and ACE
– TXA – blocks plasminogen -> plasmin
Hereditary or Acquired Angioedema
■ Consensus Guidelines via AAAI (2013)
– Early administration of icatibant, ecallantide or concentrated C1 Inhibitor
– Acquired typically responds better to FFP than other types
– Extremity or bowel: supportive care
What about for ACE-I?
■ French retrospective chart review
■ 33 patients with “severe” ACE angioedema”
■ 27 treated with TXA alone
■ None required intubation
■ No fatalities
■ Ecallantide vs placebo for ACE-I angioedema
■ Most patients were classified as mild to moderate
■ “The addition of ecallantide to standard therapy does not
appear to improve angioedema compared with placebo in
ED patients with ACEIA.”
■ Anaphylaxis in 3.5% (different study)
■ 20 patients received FFP
■ Matched to controls
– 60% vs 35% required intubation p = 0.05
– Other cases reported show temporal improvement in symptoms with FFP administration
– Some negative case reports: paradoxical worsening
Icatabant
■ Looked great with NEJM study in 2015 (phase II clinical
trial)
■ Two negative studies in 2017
– No difference compared to placebo in time to DC or
resolution of symptoms
2016 Pubmed search + case report
Looked mostly at mean time to symptom improvement vs
“historical patients”
Cases showing improvement in 20-88 minutes vs 33 hours
What to do with all that great evidence?
■ Ecallantide – no benefit with 3% risk of anaphylaxis
■ Icatabant – no benefit with $5,000 – $20,000 price tag
■ FFP – case reports with some improvement, cheap, blood
product, gotta thaw
■ TXA – retrospective study, cheap, available, pretty safe
■ C1 INH – case reports, expensive, not widely available
Goldilocks Situation with Maybe Meds?
■ Patient types
– 1.) Behind already -> crash airway +/- cric
■ no time for maybe meds
– 2.) Urgent intubation -> gather resources, double setup
■ TXA? Likely not waiting for FFP
– 3.) Bad but watching -> ICU obs type
■ Probably best indication for maybe meds?
– 4.) Looks fine ->observe ->home
■ Not worried enough to give maybe meds
Area Ripe for Further Study
■ RCT’s difficult to conduct given spectrum of illness but could provide valuable
information
■ TXA?
■ C1-INH concentrate for ACEi?
■ Lanadelumab for ACEi?