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

#UCSFtoxIcatibant appears very useful for ACE-I induced angioedema. When is cheaper and more available, probably standard of care
— Derrick Lung (@ToxHead) September 17, 2012

Jim Roberts: Drugs don't work for ACE-I angioedema. Fresh frozen plasma possible alternative to Icatibant. #NACCT12
— Leon Gussow (@poisonreview) October 2, 2012

• Ecallantide (inhibits plasma kallikrien to prevent conversion to bradykinin)
• C-1 inhibitor.    

10 confirmed and 7 possible cases of C1 esterase inhibitor thrombotic events have been reported to FDA's AERS database. ncbi.nlm.nih.gov/pubmed/23033229
— Bryan D. Hayes (@PharmERToxGuy) October 10, 2012

• 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? 

References:

1.  Guyer A, Banerji A. ACE inhibitor-induced angioedema.  UpToDate.  Updated June 2012.