Tuesday, October 16, 2012

One Way to Get a Fat Lip -Crickey!

The Gist:  ACE-inhibitor (ACE-I) induced angioedema (ACE-I AE) is a serious and common adverse effect that may be under-called.  ACE-I AE requires careful attention to the patient's airway.  If you're not scared of ACE-I AE, listen to this PHARM podcast.  Obtain a patient's current medication history (don't rely on just the patient's memory or the most recent EHR list) and communicate instances of ACE-I AE with the patient's primary doctor.

The Case:  A 34 year old male presented to the ED complaining of a bee sting to his lower lip.  The patient stated he was outside cleaning his pool when he noticed his lip swelling.  He did not see a stinging insect, but states he must have been stung as there are often bees and wasps in the yard.  He had no pain or dyspnea.
  • No known environmental or medical allergies.
  • Past Medical History:  Hypertension, high cholesterol, sleep apnea, and borderline "sugar problems." Didn't know medications but after running through options with the patient, we found that one ends in -astatin, and another ends in -pril.
  • Vital signs are stable and within normal limits.  
  • Physical exam significant for a massively edematous lower lip, more predominant on the right than the left.  No notable area of puncture or sting. Oropharynx without notable edema, patient is a Mallampati 3.  
We observed the patient and saw the swelling subside. We stopped his ACE-I, called his primary physician and counseled the patient on ACE-I AE and he did just fine.  

On Sunday, I tallied the number of cases of ACE-I AE I've seen recently.  I've seen an average of one case per week since mid-May at institutions from Massachusetts to Florida, something I discovered when a recent case prompted me to do the math.  I've collected quite the case series, perhaps because I look for it (availability bias?).  

Hold up, is ACE-I angioedema really that common?
  • This week the Archives of Internal Medicine published (online) a database study on the incidence of ACE-I angioedema between 2001-2010 capturing cases that presented to a provider.
    • ACE-I AE Incidence of 1.79 (1.73-1.85) per 1000 people with a Hazard Ratio 4.38 per 1000 person years
    • Of the Angiotensin Receptor Blockers (ARBs, end with -artan), losartan carried the highest risk (first to become generic)
    • Greatest risk within 90 days of initiation (66% of reported events)
  • Yes, according to an article published in Emergency Medicine News in July.  Apparently between two Philadelphia hospitals (at 82,000 visits/year) had 91 cases in one year, of which 60 patients were admitted.
  • After the article in Emergency Medicine News came out in July, there was some Twitter discussion regarding whether ACE-I AE is really the silent epidemic that the article claimed.  Given my anecdotal experience, I naturally fell on the side of "yes, it really is."  
    • One common thing I've noticed from the patients presenting to the ED (or in a few cases to the family practice clinic) is that they give pretty convincing stories for alternative exposures, as evidenced by the "bee sting" above.  Another patient came in with a "shellfish reaction."  She ate crab the day before and woke up with a massive lip.  She left her medications at home, but after having her daughter raid the medicine cabinet, we discovered the offending lisinopril. 
A quick ACE-I AE refresher:
  • Can occur at any point during ACE-I therapy (1st dose or 600th dose) and sometimes with ARBS.  AE is due to the ACE-I interference with the degradation of bradykinin.
  • Typically features edema of the mucosal and subcutaneous tissues of the face, lips, and upper airway but can extend to subglottic tissue (1).  ACE-I may also cause uvulitis, which can cause a patient to feel as if they're choking.
  • Often asymmetrical (tip from Dr. Andy Neill) and is typically non-pruritic and not associated with urticaria.
  • Most cases resolve spontaneously within 2 days (peak swelling within minutes to hours) (1).
    • Note:  this isn't always the case.  I had a patient remain nasally intubated in the ICU for over a week without improvement in her massive tongue swelling.
  • Mainstay of treatment:  monitor airway and STOP the ACE-I
  • May cause intra-abdominal pathology.  The Poison Review reviews an article on visceral angioedema.  More than 50% occur within first few days of ACE-I therapy (1)
  • Has been associated with penile angioedema 
Why is ACE-I AE a big deal?
  • Airway, airway, airway!  Listen to this podcast from the PHARM featuring Dr. Jordan Schooler's frightening experience with a surgical airway on an ACE-I AE patient as an intern.  
    • The tongue and soft tissue of the airway can become so edematous that the patient's airway may become completely compromised (and this progression isn't necessarily predictable).    Standard endotracheal intubation is often not feasible in these cases, resulting in a need for nasal fiberoptic intubation or a cricothyroidotomy.  
    • This slide set is a case from the PHARM by Dr. Peter Sherren details another ACE-I AE airway experience.
    • These pieces of FOAM changed my management of ACE-I AE in that I'm now much more conservative with disposition and observation periods.  I have been seen lurking by these patients rooms and I keep them within my general sight line as I dart around the ED. 
  • These reactions are not amenable to the standard allergic reaction/anaphylaxis cocktail of histamine blockaders, glucocorticoids, and epinephrine.  See University of Maryland's pearl on treatment.  Most pharmaceutical interventions have minimal evidence, mostly derived from hereditary angioedema and from case reports.
    • Fresh frozen plasma (FFP)
    • Icantibant, a bradykinin receptor antagonist (case series).  Apparently this is thrombogenic

    • Ecallantide (inhibits plasma kallikrien to prevent conversion to bradykinin)
    • C-1 inhibitor.    
  • Patients are susceptible to recurrence if an ACE-I is not resume these medications if there is inadequate communication between the treating physician, the patient, and the patient's primary care physician.  
    • Call the patient's primary physician know that they were treated at the ED for ACE-I AE.  Many ED notes aren't able to be accessed by PCPs and patients may assume that their PCP knows precisely why they were seen in the ED.  Take guess work out of the equation by contacting the PCP's office.
    • Tell the patient to list ACE-I as an allergy.  
    • If possible, make sure they don't go home with their ACE-I.
  • The incidence and severity of ACE-I AE has caused physicians to petition the FDA for a black box warning.  This was denied after a petition in 2002 (notably, a decade has passed since then and, as an idiosyncratic reaction, many more cases have presented).  ACE-I are a core measure for diabetics and in heart failure, is this a double edged sword? 
1.  Guyer A, Banerji A. ACE inhibitor-induced angioedema.  UpToDate.  Updated June 2012.


  1. ACE-i AE is often oddly asymmetrical - ie one side of the tongue much more than the other which often makes me think of it.

  2. We are just finishing a prospective, duble blinded study with Ecallantide in ACE i angioedema - we have 46 patients to date with an n=50 - results to hopefully be published in the next 6 months.

    Although FFP has been touted as a possible therapy, many allergists state it can worsen the angioedema due to the bradykinin substrates in the FFP.

    This week, we (Department of Emergency Medicine at University of Cincinnati and the Division of Allergy and Immunology) will be hosting a meeting to develop ED consensus guidelines for the treatment of acute angioedema. Several prominent allergists as well as ED physicians (Camargo, Pines, Moellman, Collins, Nowak, Ward and Raja) will attempt to develop guidelines to address issues such as "when is fiberoptics necessary for evaluation " and "what is the best approach to the airway" in such individuals.

    I will keep you informed.

    Joseph Moellman, M.D.
    Associate Professor of Emergency Medicine
    University of Cincinnati

    1. I look forward to both the ecallantide in ACE-I AE study and the guidelines for ACE-I AE. Thanks for keeping me abreast of these happenings!

  3. Hi Lauren! Thanks so much for your blog. Been a faithful reader for a while, and while only a paramedic (16 years in a very busy major urban EMS system) with hopes of moving into practice as a PA, this certainly is an excellent FOAMed resource for me!

    For this post in particular, I had a question that I haven't been able to find any good evidence for, although I suspect that there is some pathological similarities: While you can have ACE-I AE, have you heard of any patients presenting with an ACE-I anaphylaxis?I had an old student of mine who now works as a paramedic himself for a fire department call and described patient that he just treated for syncope following a sting from a yellow jacket to the top of the head while working in the yard. The yellow jacket was confirmed as two other insects were found in the man's t-shirt as his chest was exposed. The paramedic stated that the patient presented with clear breath sounds, a slight flush but without pronounced urticaria, no oral/tongue swelling but a chief complaint of syncope, a BP of 60/40ish, and had been started on lisinopril within the last couple of weeks. I had just read this post, had heard the PHARM podcast and was just thinking how similar these sounded. Thoughts?

    Thanks for your time,


  4. Hey, I'm certainly not an expert on this subject. It sounds like that case was probably secondary to envenomation. However, in looking to answer your question, I did find case reports in pubmed of potentially exacerbated hypersensitivity to Hymenoptera, etc in individuals on ACE-inhibitors. These were collated in this report http://www.theannals.com/content/40/4/699.short but it certainly doesn't show causality, only potential association. Sorry I don't have a better answer for you!

  5. Thank you so much, Lauren! I really appreciate your time and effort!