Wednesday, April 1, 2015

Can Agents for Hereditary Angioedema Be Used to Avoid Intubation in Patients Presenting with a Compromised Airway?

A middle-aged male with no known history of hereditary angioedema (HAE) and a questionable medication history presents to your ED with oropharyngeal angioedema. He has received the usual cocktail of intramuscular epinephrine along with an intravenous antihistamine, H2-receptor antagonist, and corticosteroid with no improvement in symptoms. The EM resident asks you for the correct dose of C1-esterase inhibitor (C1-INH). Oh, and it is needed STAT because the decision has been made to perform rapid sequence intubation on the patient…and in the meantime, can you also help draw up the RSI medications?

What would you do in this scenario? It may be instinct to rattle off the agent and dosing recommendation, click “verify” and then call the central pharmacy to tell them that you need the C1-INH in the next 30 seconds while preparing the medications needed for RSI at the same time. We all know that’s not how it works, especially in a larger institution. But even if we could obtain it in a very short time frame, is that really the right place to focus our efforts? At this point, the RSI medications have been drawn up, the respiratory therapist is at the head of the bed pre-oxygenating the patient, and the attending physician is talking about intubation strategies with the EM resident. It is clear that this patient needs to be intubated, no matter how soon the drug is received.

There are a few targeted therapies available on the market for acute attacks of HAE, which include plasma-derived C1-INH, recombinant C1-INH, ecallantide, and icatibant. Of note, fresh frozen plasma has also been studied for treatment of acute HAE attacks, but its use remains controversial.1 The reported time to symptom relief for each of these agents varies, as trials describe different endpoints and have used various methods to measure these endpoints (i.e. time to first symptom relief, time to 50% symptom relief, or time to complete symptom resolution).2-4 Regardless, we do know that if protection of the airway is of concern, this will not be reversed with prompt administration of these agents. It is important to remember that these drugs do not immediately reverse the edema. Instead, their mechanisms of action prevent further edema from developing.5 If the airway is close to or has already become compromised, then perhaps the clinical utility of these drugs is futile at that particular point in time, since airway management becomes the priority.6

Icatibant was recently studied for ACE-inhibitor induced angioedema in a multicenter, double-blind, randomized trial.7 Patients received either icatibant 30 mg SC (n = 13) or prednisolone 500 mg IV plus clemastine 2 mg (n = 14). All patients achieved complete resolution of edema and those who received icatibant achieved complete resolution more quickly (8 hours versus 27.1 hours, p = 0.002). More patients in the icatibant group achieved complete resolution of symptoms within 4 hours of treatment (5 of 13 versus 0 of 14, p = 0.02). Three patients in the conventional therapy group required further rescue treatment with icatibant and more steroids and one patient required tracheotomy. Despite these results, it is important to note that the median time to onset of symptom relief reported in this study was two hours in the icatibant group.

C1-INH has also recently been studied in a historical control case series of ACE-inhibitor induced angioedema in adult patients.8 Patients received plasma-derived C1-INH 1000 units (n = 10) compared to historical controls who received a conventional corticosteroid/antihistamine treatment (n = 47). None of the patients who received C1-INH required intubation, while five of the patients who received conventional treatment required airway protection. Time to complete resolution of symptoms was 10.1 hours in the C1-INH group versus 33.1 hours in the standard treatment group. While this looks like a tempting option and may be beneficial in decreasing the duration of intubation and mechanical ventilation, it is important to realize that the mean time to first improvement of symptoms was 88 minutes in the C1-INH group.

While neither of these two studies necessarily suggests using these agents as a last resort in the attempt to stave off intubation, nor do any of the studies in acute attacks of HAE, there is potential for misuse of these medications.

In the case of the above patient scenario, it does not seem appropriate to treat with an HAE agent at this particular point in time, since the drug has not been demonstrated to prevent intubation in patients presenting with airway compromise. After protecting the airway via intubation, I would not empirically administer any of these agents. Instead, I would advocate for providers to consult with allergy and immunology specialists to help direct further care. I suspect that most institutions do not have all of these medications available on formulary, if any at all. While it is not always about the cost, it is important to realize that these agents may cost upwards of $4,000 to 10,000 or more per dose and certain agents may not be an appropriate choice for all patients. While these medications may be acute treatment options for HAE and a treatment prospect for ACE-inhibitor induced angioedema, we must not forget that they do not instantaneously reverse edema and may not prevent intubation in a patient who may already be exhibiting airway compromise.


Sheena Merwine, Pharm.D. (@MerwinePharmD)
PGY2 Critical Care Pharmacy Resident
Duke University Hospital, Durham NC

Reviewed by: Craig Cocchio, Pharm.D., BCPS and Nadia Awad, Pharm.D., BCPS


1. Prematta M, Gibbs J, Pratt E, et al. Fresh frozen plasma for the treatment of hereditary angioedema. Ann Allergy Asthma Immunol 2007; 98:383-8.

2. Craig T, Levy R, Wasserman R, et al. Efficacy of human C1 esterase inhibitor concentrate compared to placebo in acute hereditary angioedema attacks. J Allergy Clin Immunol 2009; 124(4):801-8.

3. Lumry W, Li H, Levy R, et al. Randomized placebo-controlled trial of the bradykinin B2 receptor antagonist icatibant for the treatment of acute attacks of hereditary angioedema: the FAST-3 trial. Ann Allergy Asthma Immunol 2011; 107(6):529-37.

4. Riedl M, Bernstein J, Li H, et al. Recombinant human C1-esterase inhibitor relieves symptoms of hereditary angioedema attacks: phase 3, randomized, placebo-controlled trial. Ann Allergy Asthma Immunol 2014; 112:163-9.

5. Zuraw B. Hereditary angioedema. N Engl J Med 2008; 359(10):1027-36.

6. Moellman J, Bernstein J, Lindsell C, et al. A consensus parameter for the evaluation and management of angioedema in the emergency department. Acad Emerg Med 2014; 21:469-84.

7. Bas M, Greve J, Stelter K, et al. A randomized trial of icatibant in ACE-inhibitor induced angioedema. N Engl J Med 2015; 372(5): 418-25.

8. Greve J, Bas M, Hoffmann T, et al. Effect of C1-esterase Inhibitor in angiotensin-converting enzyme inhibitor-induced angioedema. Laryngoscope 2015 Jan 13 [Epub ahead of print].

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