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I have completed bits of my EM training from India. Currently I am boarded with credentials from Christian Medical College, Vellore and also from the prestigious Royal College of Emergency Medicine, UK.  I am currently working in London as an A&E doctor, trying to appreciate the differences in the practise and culture of Emergency Medicine across different healthcare systems. I have always been an avid FOAMed supporter because FOAMed played an indispensable role during the days of my initial training. Through this blog, I aspire to disseminate knowledge and stay up to date with the EM literature. 

Monday, February 6, 2017

Angioedema - Bradykinin v/s Histamine

Angioedema is a Non-Pitting edema of reticular, dermal, subcutaneous and submucosal layers commonly affecting tongue, lips and upper airway (occasionally genitilia, abdomen, extremities)


  • Mast Cell/IgE mediated - Type I hypersensitivity reaction
  • Urticaria in common and a trigger is often present, acute onset
  • Responds to Anaphylaxis medications
  • HAE (Hereditary Angioedema)
  • AAE (Acquired Angioedema)
  • Pseudo allergic 
  • Idiopathic 
  • ACEi related Angioedema 

Pathophys based classification
1. Histamine Mediated (Released from Mast cells or basophils)
Allergic or immunologic cause
2. Bradykinin Mediated
Hereditary or Acquired or ACE inhibitor induced edema
3. Idiopathic Angioedema 

Urticaria or Itching means histamine mediated reaction
Bradykinin affects more of deeper structures - not a/w itching but associated with pain and swelling

Dysphagia, Change in voice, Abdominal pain, lump in throat, stridor, dyspnea 


1. Hereditary Angioedema  (HAE) - Accumulation of Bradykinin

  • Autosomal Dominant (ask for family history). Can have airway or extremity swellings
  • May present with recurrent abdominal pains due to mucosal swelling, urticaria is rare

  1. Type I: due to C1 inhibitor (C1-INH) deficiency - increased bradykinin - 85%
  2. Type II: Defective C1 inhibitor - need to test functionality 15-20%
  3. Type III: due to defective factor XII (Normal levels and fiction of C1-I) - Rare

HAE often present with Erythema Marginatum - serpeginous erythematous rash but not pathognomic

  • Triggers for HAE: Trauma, Medical Procedures, Stress, OCPs, Infection
  • Clinical diagnosis but also show reduced C4 levels
  • HAE does not respond to Anaphylaxis medications

2. Acquired Angioedema (Accumulation of Bradykinin)
Antibodies against C1 inhibitor  
AutoAb lead to reduction in C1-INH
Type 1- lymphoproliferative disorders (a/w lymphomas)
Type 2 - Autoimmune

Labs - Decreased levels of C1q (HAE - Normal C1q levels)

3. Pseudo allergic - not IgE mediated but mimics allergic AE
NSAIDs/Opioids/IV Contrast

4. Idiopathic - Unclear cause but common type of AE
All labs are normal
Chronic Urticaria can be a feature  

5. ACE inhibitor induced Angioedema - Accumulation of Bradykinin
  • More prevalent in African Americans, Females, Elderly 
  • ACEi interfere with bradykinin metabolism, therefore bradykinin mediated 
  • Can present as "isolated genital swelling" or "peritonitic abdomen"
  • Can develop with first dose or after years
  • Other meds that can cause - Sitagliptin, CCBs, ARBs, Alteplase (tPA), COX inhibitors
  • Patients who are on ACE inhibitor and get tPA are more likely to get tPA
  • Can be unilateral as well!! (Look at the image above)
  • ACEi Angioedema does not respond to Anaphylaxis medications
Recently I heard about a case where physicians did not give FFPs but intubated a patient with unilateral oral edema and also got a neck CT done. This patient was on ACEi for 6 years. FFP is a reasonable treatment option and must be considered prior to intubation. 

Consider sending a C4 level for undifferentiated angioedema (even if they are on ACEi, ACEi can unmask underlying Angioedema)

  • Lip Abscess
  • Panniculitis 
  • Ludwig's Angina 


Supportive Care
  • Only a few of them require intubation
  • Majority resolve with observation and treatment. AIRWAY is our concern. 
  • Be concerned for potential airway compromise - Stridor, drooling, respiratory distress, change in voice 
  • Be prepared for a difficult airway (Fiberoptic, Surgical)

Allergic Angioedema (Think and treat like Anaphylaxis)
  • Epinephrine 0.3-0.5mg IM 1:1000
  • Epinephrine drip/Steroids/Antihistaminics
  • Fluids
Anaphylaxis cocktail does not help but often tried 
1) Traditional Rx - FFP (acute and chronic Rx), Antifibrinolytics (chronic), Androgens such as Danazol (chronic Rx)

Rationale for FFP: FFP contain C1-INH, other complement factors and kinin (dose 1-4 units for HAE). Few case reports mention worsening of angioedema. 

2) Newer Therapies
  • C1 INH concentrates (Berinert, Cinrynze) - For acute treatment 
  • Ecallantide (Plasma kallikrein inhibitors) - 30mg SQ, very expensive 
  • Icatibant (Bradykinin B2 receptor antagonists) - 30mg SQ

ACEi Angioedema
  • Anaphylaxis cocktail does not help but often tried 
  • Discontinue ACEi
  • Inconsistent data on ACEi induced Angioedema treatment 

Rationale for FFPsin ACEi Angioedema:

  • FFP's supply Kininase II which functions similar to ACE and degrades bradykinin
  • Inexpensive, easily available, improves symptoms
  • Risks - Volume overload, ?Possible worsening of Angioedema

Admit if
  • Past h/o angioedema
  • Tongue/pharynx/laryngeal edema
  • Lack of improvement in ED

Take Home
  • Strongly consider FFPs prior to intubation in any patient with Bradykinin induced Angioedema
  • Don't be surprised if Anaphylactic cocktail does not work for Bradykinin related reactions
  • Get ENT/Anesthesia involved early. This is not the time to learn intubation!

  • TemiƱo, Viviana M., and R. Stokes Peebles. "The spectrum and treatment of angioedema." The American journal of medicine 121.4 (2008): 282-286.
  • Lewis, Lawrence M. "Angioedema: etiology, pathophysiology, current and emerging therapies." The Journal of emergency medicine 45.5 (2013): 789-796.
  • Winters, Michael E., et al. "Emergency department management of patients with ACE-inhibitor angioedema." The Journal of emergency medicine 45.5 (2013): 775-780.


     Lakshay Chanana
     Speciality Doctor
     Northwick Park Hospital
     Department of Emergency Medicine



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