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?