Ace-Inhibitor Induced Angioedema:What You Probably Didn't Learn

in Paramedical Training

By Kristin Spencer, MS, NRP

If I were to ask you to list the treatmentmodality for angioedema, your list would probablyinclude oxygen therapy, I.V., cardiac monitoring,pulse oximetry, capnography, IM epinephrine,corticosteroids, diphenhydramine and in some cases,rapid sequence intubation. In most cases of an allergy-induced angioedema, your answer would be spot-on.Angiotensin-converting enzyme inhibitor-relatedangioedema (ACEI-RA) is a different beast, however.Before I discuss why ACEI-RA is less than responsiveto the standard pharmacological agents listed above, theepidemiology and pathophysiology of ACEI-RA will becovered.

More than 40 million people worldwide areprescribed ACE inhibitors, and chances are several ofyour previous patients have been taking them for heartfailure or hypertension.1 ACE inhibitors are the drugsthat end in the familiar "prils," lisinopril, captopril,and enalapril, for example. Like any prescriptionmedication, there are potential side effects from ACEinhibitors, angioedema being one of the most serious.

Angioedema is estimated to occur in 0.1% to 0.7%of patients on ACE inhibitor therapy. Of those whopresent to the emergency department with angioedema,35% of those are attributed to ACEI.1 Additionally,one study concluded that African-Americans are threetimes more likely to develop ACEI-RA within sixmonths of starting ACE inhibitor therapy.2 The mostcommon signs and symptoms of ACEI-RA are mildand may not even be reported by the patient; in othercases, the situation can be life-threatening. Accordingto Almazroua, et. al (2013), the most common sign ofACEI-RA is asymmetric (and isolated) swelling of thelips and face, although cases of isolated swelling hasbeen documented in the small bowel, genitals, uvula,tongue, and floor of the mouth. Urticaria is usuallyabsent.3 Unlike other types of allergic reactions thatcan occur rapidly and aggressively, several studieshave shown ACEI-RA can occur with those who havebeen taking ACE inhibitors for weeks, months—evenyears. 2.4

Most cases of angioedema is mediated by IgEantibodies—the endogenous antibodies that attackseemingly innocuous allergens (antigens) in those withType I sensitivity reactions. Insect stings, seafood,pollen, and some medications are frequently associatedwith IgE-mediated allergic reactions. IgE antibodieshave a high affinity for mast cells and basophils andwhen bonded together, results in the formation andsubsequent release of chemical mediators.

Of course, the chemical mediator closely examinedin paramedic curriculum was, and is, histamine.Histamine causes its effects by binding to HI and H2receptors that cause contraction of smooth musclesof the aii-way and GI tract, increased vascularpermeability, vasodilation, enhanced mucus production,pruritus, and gastric acid secretion. Translated, ahistaminergic-mediated angioedema means yourpatient with allergy sensitivities could present witha runny nose, conjunctivitis, nausea and vomiting,diarrhea, bronchoconstriction, increased bronchialmucous secretions, generalized swelling, urticarial/weals, and hypotension- a multi-systemic reaction.1-3Again, angioedema induced by histamine will respondto conventional therapies like antihistamines andcorticosteroids, pharmacological agents commonlyemphasized in most paramedic curriculums.

Interestingly, ACEI-RA is not IgE mediated;the physiology of the condition is caused by thelevels of the blood vessel-dilating bradykinin in thebody, a peptide. Bradykinin counterbalances thevasoconstrictive workings of the renin-angiotensin-aldosterone system, and is thought to be a primarymediator in non-allergic angioedemas.

There are two kinds of bradykinin receptors:BI and B2. When bradykinin binds with thesereceptors, increased vascular permeability andisolated, non-pitting edema occurs. Glossitis isfrequently seen.5-6 Given the pathophysiology behindACEI-RA, you can now understand why conventionalinterventions for angioedema probably will not workwith these specific cases.1-2 So, what do you do? Do

FALL 2015 Missouri EMS Connectioi 43

you not treat the angioedema? Of course you do.Most cases of angioedema are not caused by ACEinhibitors and, it may be difficult to make a precisecorrelation between the two. However, if you're aperson who would prefer a specific treatment algorithmfor ACEI-RA or a definitive diagnostic test, you will besorely disappointed.

When assessing a patient with upper airwayobstruction/edema, conduct a fastidious, yet rapidexam- early identification regarding its etiology isextremely time-sensitive, especially when dealing withACEI-RA. For purposes of this discussion, the upperairway is defined as the conduit from the nose andmouth to the larynx.

You've probably heard the mantra to avoidthe perils and pitfalls of approaching your patientwith tunnel vision, and this bears repeating. Notall cases of angioedema are secondary to shellfish,hymenoptera stings or penicillin, so keeping a broadlist of differentials is important. You must consider thelikely causes of upper airway obstructions consideringage, medical history, recent events, and physicalexamination. For example, you would not diagnose ayoung patient with a history of fever, dysphagia, sorethroat, and drooling as ACEI-RA.

There are multiple causations for upper airwayswelling-some are progressive and potentially lethal,while some more benign. Through your physicalexamination and history-taking, you can rule out someof the more common differentials:

• Burns• Epiglottitis• Laryngotracheobronchitis (croup)• Massive maxillofacial trauma• Acute laryngeal injury• Ludwig's Angina• Laryngeal stenosis• Laryngeal tumors

Understanding the underlying cause of commonupper airway obstructions and identifying life threats isparamount, as treatment modalities differ. You wouldnot treat a patient with massive maxillofacial injuriesas you would a patient presenting with anaphylaxis,epiglottitis, or croup. Although the end point maybe the same in most airway management challenges(e.g. oral intubation), patients with ACEI-RA may benon-intubatable through the oral cavity; glossitis maybe severe enough to make the mouth impenetrablewith an OPA, endotracheal tube, LMA®, Combitube®,or King Airway*. (As a side note, although

44 | Missouri EMS Connection

glossitis may look outlandish, the larynx may notbe affected and the patient can still move air.) If thepatient needs ventilatory assistance, perform BVMventilations while simultaneously watching the riseand fall of your patient's chest to ensure adequatetidal volume. Observe Sp02, the patient's color,mental status, heart rate, and ETC02—your patientmay respond surprisingly well. It would be difficultto justify performing, say, a surgical airway whenassisted ventilations prove beneficial. Sometimes theleast invasive practices are preferred over invasiveprocedures that may have catastrophic consequences.

If you determine BVM ventilations are ineffectual,intubate through the orotracheal route. If you cannotinsert an ETT through the orotracheal route, considerthe nasotracheal route. Although becoming a lost artand at times forgotten as a viable option, a scenariomay arise when using the nasotracheal route may beyour only option in securing a definitive airway.

Arguably controversial and not instituted in someregions and states, rapid sequence induction (RSI) isan option and should be included in every paramedic'streatment toolbox. If necessary and viable, RSI canbe very beneficial in cases of ACEI -RA when youhave a conscious patient showing signs of imminentairway closure (e.g., stridor, hoarse voice, reports ofdysphagia) or respiratory failure. If you anticipate adifficult intubation due to anatomic changes, preparetwo or three different sizes of ETTs. If the larynxis edematous, you may not successfully pass a tubenormally appropriate for the stature of your patient. Ifyou are able to visualize the glottic opening, but areunsuccessful with direct laryngoscopy, consider usingfiberoptic intubation if available.

In extreme cases, a cricothyroidotomy may berequired when all other attempts have failed. Accordingto Yatako and Mehta (2008), orotracheal intubationis successful in 97% of airway management cases,leaving only 3% of patients requiring immediatecricothyroidotomy.7 Don't let these numbers lure youinto thinking "I will never get that patient." You mayget "that" patient, and should always be prepared toperform this procedure if the worst case scenario fallsin your lap. Practice surgical airways frequently.

Once you have determined, through ruling outvarious differentials, that ACEI-RI is the probableetiology for your patient's angioedema, examine theairway and act accordingly based on the patient'spresentation. Your ultimate treatment goal is more thanmanaging the airway through basic or advanced airwaydevices; attempts to abate airway swelling through

FALL 2015

pharmacological agents is also vital.Case studies show great promise in treating ACEI

patients with fresh frozen plasma (FFP, Class II) orbradykinin blockers (e.g., icatibant, Class II).1-2-5-8However, neither is carried in ambulances. Nor isthere a precise antidote to treat ACEI-RA.1-5 Basedon that harsh reality, paramedics are forced to relyon conventional therapies including epinephrine,corticosteroids, and antihistamines. According to someclinicians, evidence-based treatment recommendationsfor ACEI-RA are:

Supplemental oxygen• Securing the airway, assist ventilations if

neededPharmacologically-assisted intubation (RSI)

• Nasotracheal intubation if orotrachealintubation impossibleCapnography, pulse oximetry

• I.V. and fluids, if necessaryAlthough controversial, treatment still involvesthe consideration of HI and H2 blockers (e.g.,ranitidine, cimetidine/class indeterminate)Corticosteroids (e.g., prednisone,methylprednisolone/class indeterminate)Cardiac monitoringRacemic EpinephrineEpinephrine 1:1,000, 0.3-0.5 IM, repeat if needed

Examining the list above, you may question whyhistaminic antagonists and epinephrine are includedas part of the suggested treatment plan for ACEI-RAgiven histamine release is not the triggering agent.Epinephrine is administered primarily for its alphaone properties; the vasoconstrictive actions mayreduce swelling in the affected areas, although severalcase studies have shown less than impressive resultswhen using epinephrine for bradykinin-mediatedangioedema.2"4 Histamine blockers are generally usedif the source of the angioedema is either histaminic-induced or unknown. It is reasonable to administer HIand H2 blockers for angioedemas of unknown etiology,because there are relatively few, benign side effects.4It is important to note that in a small study publishedin the New England Journal of Medicine (2013), Bass,cl al. found that patients with ACE-inhibitor-inducedangioedema recovered nearly three times faster with theadministration of a bradykinin blocker than those givena standard glucocorticoid/antihistamine treatment.6

Although ACEI-RA is rarely examined in eitherinitial or ongoing paramedical training, airwaymanagement is. If your patient shows signs of airway

FALL 2015

closure or indicators that airway compromise isimminent, be aggressive in securing the airway beforeit becomes impossible. Although basic maneuverssuch as the insertion of an NPA and BVM ventilationsmay prove successful, watch your patient closely todetermine how he/she is trending. Complete airwayobstruction secondary to laryngeal edema may occurrapidly and unexpectedly. Immediate intubation,either the oral or nasal route, RSI, or in extreme casescricothyrotomy, may be required. With those suspectedof ACEI-RA this fundamental training may very wellbe the most important intervention we can make forthese patients—after all, it always comes down to yourABCs.#

About the AuthorKristin Spencer, MS, NRP, has been in EMS since 1994. She holds a B.S.in Criminology from Old Dominion University and a B.S. in Journalismfrom OSU-Tulsa. She earned her Master's in CriminalJustice withhonors from Missouri Southern State University (MSSU) in 2011. Kristinhas been the EMS Director for Crowder College since 2005. In 2011, shewas selected as Crowder's Outstanding Instructor. She is the MissouriState Coordinator for Advanced Medical Life Support, has publishedarticles in JEMS, and is a Missouri POST certified instructor. She alsoteaches classes and seminars in CriminalJustice at MSSU.

References1. Chandler, A., and Benerji, A. Ace inhibitor induced angioede

ma. Retrieved Sept. 13, 2015 from http://www.uptodate.com/contents/ace-inhibitor-induced-angioedema.

2. Wilkerson, G.R. (2012) Angioedema in the emergency department: an evidence based review. Retrieved April 21, 2015 I mmhttps://umem.org/files/intl/Angioedema%20-%20Final%20copy.pdf.

3. Almazroua, F., Rosenbbaum, S., Vile, G., and Winters, M.(2013). Emergency department management of patients withACE-inhibitor angioedema. Journal of Emergency Medicine,45(5), 775-780.

4. Flattery, M. (2011). When ACE inhibitors cause angioedema.Retrieved April 21, 2015 from http://www.americannurset.o-day.com/when-ace-inhibitors-cause-angioedema/.

5. Winters, M. (2006, July 10J. Clinical Practice Guideline: InitialEvaluation and Management of Patients Presenting with AcuteUrticaria or Angioedema. Retrieved May 3, 2015, from http://www.aaem.org/em-resources/position-statements/2006/clini-cal-practice-guidelines

6. Bas, M., et al. A Randomized Trial of Icatibant in ACE-Inhibi-tor-Induced Angioedema. Retrieved June 26, 2015, from http://www.nejm.org/doi/full/10.1056/NEJMoa 1312524

7. Busse RJ. and Buckland, M.S. (2013, April). Non-histaminergicangioedema: focus on bradykinin-mediated angioedema.Clinical and Experimental Allergy, 43(4), 385-94.

8. Yatako, J., and Mehta, A. (2008). Upper airway obstruction.Retrieved June 24, 2015 from hltps://www.acponline.org/eBi-zATPRO/images...books/.../CCM37.pdf

Missouri EMS Connectioi 45

ADVERTISER'SA i r E v a c L i f e t e a m 1 8A i r M e t h o d s 4 7A m e r i c a n R e s p o n s e V e h i c l e s 4 8Barnes-Jewish Hospital Trauma Center 21Barnes-Jewish Stroke & Cerebrovascular Center 23B o o n e H o s p i t a l C e n t e r 4 2D e m e r A m b u l a n c e s 1 3E M S B i l l i n g S e r v i c e s I n c 3 1L i f e fl i g h t E a g l e 3 4M a r y v i l l e U n i v e r s i t y 4 6M e r c y L i f e L i n e 2 2M i s s o u r i P o i s o n C e n t e r 2M M S - A M e d i c a l S u p p l y C o m p a n y 2 6O m n i E M S B i l l i n g 2 0S e n t i n e l E m e r g e n c y S o l u t i o n s 4 0SSM Cardinal Glennon Children's Medical Center 8St. Louis Children's Hospital - Emergency & Trauma Svcs.. 4S t . L o u i s U n i v e r s i t y H o s p i t a l 1 5UMKC School of Medicine - EMS Education Program 38Z O L L 6

YOUR CAREER.EVERYONE'SHEALTH.If you are a licensed paramedic, have beenemployed as such for two years, and want to takeyour career to the next level, Maryville University'sCommunity Paramedic certificate may be for you.

THE CERTIFICATE PROGRAM:

• Consists of 4 required courses, 3 online with anin-person practicum

• Requires 135 hours of clinical practice

• Enhances practical knowledge and proactivelyprepares you for the current turbulence of thehealthcare system

• Emphasizes your crucial role in the health caresystem, including public health

• Reinforces the importance of community healthand clinical care

About the Missouri EMS ConnectionThe Missouri EMS Connection is sponsored by the Missouri EMS

Association (MEMSA). It is published quarterly. To obtain a previouscopy, or for advertising deadlines and rates, contact Publication Editor -Mary Napier at maiy@napiercommunications.coni or 785-783-5494.

All materials published in the magazine are the property ofMEMSA. No articles in this publication may be reprinted without theexpress consent of the editor. To obtain consent, contact the editor.

To submit materials for publication in this magazine, e-mailsubmissions to the editor. MEMSA reserves the right to refuse asubmission for publication. Complete article and photo guidelines areavailable at wvvw.memsa.org.

Download a media kit at www.meiPublication Editor Mary Napier at

marv@napJercommunications.com.Winter 2015 Ad Deadline: Dec 12015

MMARYVILLEU N I V E R S I T Y

F O R M O R E I N F O R M AT I O N

Dr. Bonnie Stegman314.529.6595

bstegman@maryvi l le.edu

Learn more by visiting

m a r y v i l l e . e d u / p a r a m e d i c

46 Missouri EMS Connection FALL 2015