Angioedema In The Emergency Department: An Evidence-Based Review

Table of Contents

 

1. Abstract
2. Case Presentations
3. Introduction
4. Critical Appraisal Of The Literature
5. Etiology And Pathophysiology
   1. Mediators Of Angioedema
      1. Bradykinin
      2. Histamine
   2. Causes Of Angioedema
      1. Hereditary Angioedema
      2. Acquired Angioedema
      3. Immunologic/Allergic Angioedema
      4. ACE Inhibitor-Induced Angioedema
      5. Physically Induced Angioedema
      6. Idiopathic Angioedema
6. Differential Diagnosis
7. Prehospital Care
8. Emergency Department Evaluation
   1. Initial Stabilization
   2. History
   3. Physical Examination
9. Diagnostic Studies
10. Treatment
    1. Pharmacologic Treatment
       1. Epinephrine
       2. Glucagon
       3. Terbutaline
       4. Antihistamines
       5. Steroids
       6. Fresh Frozen Plasma
       7. C1 Inhibitor Concentrate
          • Berinert® (CSL Behring; Marburg, Germany)
          • Cinryze® (ViroPharma, Inc.; Exton, PA)
          • Rhucin® (Pharming; Leiden, The Netherlands)
          • Ecallantide (Kalbitor®/DX-88; Dyax; Burlington, MA)
          • Icatibant (Firazyr®/HOE-140; Shire Human Genetic Therapies, Inc.; Lexington, MA)
       8. Prophylactic Medications
          • Androgens
          • Antifibrinolytic Agents
11. Controversies And Cutting Edge
    1. Controversies In Treatment
    2. Use Of Angiotensin Receptor Blockers
12. Disposition
13. Summary
14. Risk Management Pitfalls For Angioedema
15. Time- And Cost-Effective Strategies
16. Case Conclusions
17. Clinical Pathway For The Management Of Patients With Angioedema
18. Tables and Figures
    1. Table 1. Complement Profile Testing For Different Causes Of Angioedema
    2. Table 2. Comparison Of New Medications For Treatment Of Angiodema
    3. Table 3. Ishoo Staging Of Angioedema
    4. Figure 1. Interaction Of Kallikrein-Kinin System, Coagulation Pathway, And Common Complement Pathway
19. References

Abstract

Angioedema is the end result of a variety of pathophysiological processes resulting in transient, localized, nonpitting swelling of the subcutaneous layer of the skin or submucosal layer of the respiratory or gastrointestinal tracts. It is now generally accepted that the swelling is mediated by either histamine or bradykinin. Angioedema may result in severe upper airway compromise or—less commonly recognized—compromise in the gastrointestinal tract often associated with severe abdominal pain. A variety of new therapeutic options are becoming available for use in the United States that have the potential to greatly impact the management and outcomes for those with severe clinical manifestations. This review assesses the evidence on the causes and treatments of angioedema in the emergency department and reviews the new therapeutic options available for treatment of angioedema based on their effectiveness, price, and availability.

Case Presentations

In the middle of an unusually slow evening shift, a 52-year-old black male presents to the ED from walk-in triage with a complaint of lip swelling. He states that he noticed a tingling in his lips shortly after waking that morning, but it wasn’t until he brushed his teeth that he noticed how large his lips had become. He decided to come to the hospital almost 12 hours later only after family members insisted that he get “checked out.” He denies any recent trauma, infection, or known exposures to possible allergens. He denies any pain or itching. His past medical history is significant for hypertension and borderline diabetes. He is unable to remember the name of the medication that he takes for his blood pressure, but he says he has been taking it for years. His vital signs are: heart rate, 74 beats per minute; blood pressure, 156/82 mm Hg; respiratory rate, 16 breaths per minute; temperature, 36.8°C; and oxygen saturation, 98% on room air. He is comfortable and in no apparent distress. It would be impossible to miss the rather impressive size of his lips. The upper lip looks to be about 10 times the normal size and the lower lip is only somewhat less enlarged. You are able to examine his oropharynx and find no further swelling of the uvula or posterior pharynx. The rest of his examination is unremarkable. Your nurse checks the airway cart out of concern that the patient will need to be immediately intubated. Your medical student asks the following logical questions:

• What is the cause of his lip swelling?
• Is there a diagnostic test to determine the cause?
• What is the appropriate treatment?
• Should the patient be intubated immediately to protect his airway?

The next week, you see a 19-year-old white female who is brought in by EMS for severe diffuse abdominal pain. She states that the pain began 8 hours earlier. She has had nausea with multiple episodes of vomiting. She denies fever, recent antibiotics, foreign travel, or sick contacts. She does state that she has had similar presentations multiple times in the past but never this pronounced. She denies any past medical history other than recurrent abdominal pain similar to how she is currently presenting. She was recently started on oral contraceptives, but she denies being sexually active. Her vital signs are: heart rate, 112 beats per minute; blood pressure, 92/64 mm Hg; respiratory rate, 22 breaths per minute; temperature, 36.9°C; and oxygen saturation, 100% on room air. She is obviously uncomfortable and actively retching. Her physical exam is remarkable for a soft but markedly distended abdomen with evidence of shifting dullness. She is diffusely tender to palpation without guarding or rebound. A pelvic exam is unremarkable. After reviewing her vital signs and performing her physical exam, you are much more concerned about this patient. You pull over the portable ultrasound to take a look and are immediately impressed by a large amount of free fluid in the abdomen. You ask yourself several questions:

• What is the cause of her recurrent abdominal pain?
• Does she need an abdominal CT scan, and, if yes, does it need to be with contrast?
• Does she need emergent surgical consultation?
• Other than treating the pain, is there any medication that is indicated?

Introduction

Angioedema is the clinical manifestation of transient, localized, nonpitting swelling of the subcutaneous layer of the skin or submucosal layer of the respiratory or gastrointestinal tracts. The first widely recognized description of angioedema was by Heinrich Quincke in 1882. In honor of his contribution, it is sometimes referred to as Quincke edema.

Angioedema is not a disease; rather, it is a physical manifestation of a variety of pathophysiological processes. These processes have the end result of either mast cell degranulation or formation of bradykinin. The incidence of angioedema, overall, is not known. For patients taking angiotensin-converting enzyme (ACE) inhibitors, the incidence is between 0.1% and 0.7%. The prevalence of the various forms of hereditary angioedema is estimated to be between 1 in 10,000 and 1 in 50,000.¹

The emergency clinician must understand the various causes of angioedema and tailor the treatment of the patient based on the likely etiology. In this issue of Emergency Medicine Practice, the various causes of angioedema are discussed as well as different diagnostic and treatment strategies.

Critical Appraisal Of The Literature

A literature search was performed using PubMed from 1964 to present, using the search term angioedema and limited to English-language articles that were systematic reviews, meta-analyses, multicenter studies, clinical trials, or randomized clinical trials. Using this approach, 269 articles were found and assessed for review. In addition, 1502 case reports were identified in the search; however, it was determined that they would add little to the evidence provided by the better-quality resources, and, therefore, these case reports were not systematically reviewed.

A search of the National Guidelines Clearinghouse (www.guideline.gov) produced no additional practice guidelines focused on angioedema. There was 1 guideline for urticaria that resulted when a search for angioedema was performed.² A review of the Cochrane Database of Systemic Reviews failed to find any completed reviews. There is a protocol in place for a review of “angiotensin-converting enzyme inhibitor-induced angioedema in patients with primary hypertension,” but it has not been completed.

Risk Management Pitfalls For Angioedema

1. “The patient had been on an ACE inhibitor for years. I assumed the angioedema was due to another cause, so I did not tell the patient to stop taking it.”

   ACE inhibitor-induced angioedema can develop at any time, although most cases are reported to occur in the weeks following initiation of treatment. There are multiple cases of angioedema developing after years of being on the ACE inhibitor. If a patient is on an ACE inhibitor and develops angioedema, the patient should be told to stop taking that medication immediately.

2. “The patient had no family history of hereditary angioedema, so I thought it must be due to some other cause.”

   Not all patients with hereditary angioedema have a family history of the disease. While the disease is due to a genetic defect and is therefore considered hereditary, up to 25% of these mutations occur de novo. An investigation for hereditary angioedema should be undertaken in patients with recurrent angioedema even if there is no family history.

3. “I didn’t give this patient epinephrine because I thought this was angioedema and not anaphylaxis.”

   It is important to remember that angioedema is a physical manifestation of a disease process. This may include allergic reactions and anaphylaxis. If the patient is having an anaphylactic reaction and epinephrine is indicated, then the presence of angioedema does not change the need for epinephrine.

4. “The patient’s swelling only involved the lips, so I sent him home after an hour of observation.”

   Patients with angioedema should be observed in the ED for a minimum of 4 to 6 hours before there is any consideration for discharge. The swelling of angioedema may present with a benign initial evaluation but then significantly worsen in a short period of time.

5. “The patient wasn’t on an ACE inhibitor or an ARB, there was no family history, and there was no sign of an allergic reaction. I didn’t think she needed follow-up.”

   It is important to remember that there are multiple causes of angioedema. One possible cause, although rare, is acquired angioedema. This is usually associated with a lymphoproliferative or autoimmune disease. Angioedema may be the presenting complaint for some of these patients. For recurrent angioedema without an obvious cause, an investigation into possible malignancy or autoimmune disease should be initiated.

6. “I knew the patient had a history of hereditary angioedema, but she presented with a rigid, tender abdomen and elevated WBC, so I thought emergency surgery was indicated.” Angioedema affects not only the subcutaneous tissue but also the submucosal layer of the gastrointestinal tract. Patients with hereditary angioedema often have recurrent abdominal pain. The presentation may be so profound that unnecessary surgical exploration may be undertaken. An elevated WBC count is unlikely to be helpful in differentiating an acute infectious abdominal process from abdominal angioedema. These patients present a diagnostic challenge to the treating physician.
7. “The tongue swelling was getting worse, but I thought I could wait to secure the airway.”

   The airway is of paramount importance in any patient presenting with swelling that involves the head or neck. It is better to err on the side of caution and secure the airway before the edema prevents the use of normal airway devices. At times, the progression of swelling can be rapid. A case of death from asphyxiation within 20 minutes of onset of laryngeal edema has been reported. Once there is significant swelling, the airway may only be secured with either fiber-optic means or by using a surgical technique.

8. “I had given steroids, diphenhydramine, cimetidine, and epinephrine. The patient didn’t get better, so I didn’t think that there was any other therapeutic option.”

   The FDA has approved many new therapeutic options over the past few years. It is important for the emergency clinician to stay current on available medications and their indications and to establish a protocol on the use of these new agents, proactively, with other services.

9. “This patient with hereditary angioedema was complaining of shortness of breath. I didn’t see any sign of swelling after observing her for 4 hours, so I thought she was OK to be discharged.”

   Some patients with hereditary angioedema are placed on antifibrinolytic agents such as sigma-aminocaproic acid and tranexamic acid as prophylaxis against angioedema episodes. There is an increased risk of thromboembolic events with the use of these medications. Alternative diagnoses unrelated to angioedema should be considered in these patients.

10. “I didn’t think that the patient needed any further medications because her angioedema and urticaria resolved in the ED.”

    Patients with allergic/immunologic angioedema who respond to initial therapy and are able to be discharged should be sent home with a prescription for at least 3 days of steroids and instructions to continue antihistamines. Despite initial improvement, there is always a concern for a second episode. This is due to a biphasic nature of up to 20% of allergic reactions. The second phase may be delayed as much as 72 hours after the initial presentation.

Tables and Figures

References

Evidence-based medicine requires a critical appraisal of the literature based upon study methodology and number of subjects. Not all references are equally robust. The findings of a large, prospective, randomized, and blinded trial should carry more weight than a case report.

To help the reader judge the strength of each reference, pertinent information about the study will be included in bold type following the reference, where available. In addition, the most informative references cited in this paper, as determined by the authors, are noted by an asterisk (*) next to the number of the reference.

1. Zuraw BL. Clinical practice. Hereditary angioedema. N Engl J Med. 2008;359(10):1027-1036. (Review)
2. Grattan CE, Humphreys F. Guidelines for evaluation and management of urticaria in adults and children. Br J Dermatol. 2007;157(6):1116-1123. (Consensus statement)
3. Maurer M, Bader M, Bas M, et al. New topics in bradykinin research. Allergy. 2011;66(11):1397-1406. (Review)
4. Blanch A, Roche O, Urrutia I, et al. First case of homozygous C1 inhibitor deficiency. J Allergy Clin Immunol. 2006;118(6):1330-1335. (Review)
5. Nussberger J, Cugno M, Cicardi M. Bradykinin-mediated angioedema. N Engl J Med. 2002;347(8):621-622. (Prospective cohort study; 14 patients)
6. Cicardi M, Johnston DT. Hereditary and acquired complement component 1 esterase inhibitor deficiency: a review for the hematologist. Acta Haematol. 2012;127(4):208-220. (Review)
7. Warin RP, Cunliffe WJ, Greaves MW, et al. Recurrent angioedema: familial and oestrogen-induced. Br J Dermatol. 1986;115(6):731-734. (Case series; 2 patients)
8. Bork K, Barnstedt SE, Koch P, et al. Hereditary angioedema with normal C1-inhibitor activity in women. Lancet. 2000;356(9225):213-217. (Case series; 24 patients)
9. Binkley KE, Davis A III. Clinical, biochemical, and genetic characterization of a novel estrogen-dependent inherited form of angioedema. J Allergy Clin Immunol. 2000;106(3):546-550. (Case series; 7 patients)
10. Gupta S, Yu F, Klaustermeyer WB. New-variant hereditary angioedema in three brothers with normal C1 esterase inhibitor level and function. Allergy. 2004;59(5):557-558. (Case series; 3 patients)
11. Bork K, Gul D, Dewald G. Hereditary angio-oedema with normal C1 inhibitor in a family with affected women and men. Br J Dermatol. 2006;154(3):542-545. (Case series; 8 patients)
12. Bork K, Gul D, Hardt J, et al. Hereditary angioedema with normal C1 inhibitor: clinical symptoms and course. Am J Med. 2007;120(11):987-992. (Retrospective analysis of case reports; 138 patients)
13. Bork K, Frank J, Grundt B, et al. Treatment of acute edema attacks in hereditary angioedema with a bradykinin receptor-2 antagonist (icatibant). J Allergy Clin Immunol. 2007;119(6):1497-1503. (Prospective uncontrolled intervention; 15 patients)
14. Dewald G, Bork K. Missense mutations in the coagulation factor XII (Hageman factor) gene in hereditary angioedema with normal C1 inhibitor. Biochem Biophys Res Commun. 2006;343(4):1286-1289. (Case-control DNA analysis; 20 patients)
15. Cichon S, Martin L, Hennies HC, et al. Increased activity of coagulation factor XII (Hageman factor) causes hereditary angioedema type III. Am J Hum Genet. 2006;79(6):1098-1104. (Case control DNA analysis; 2 families and case- controlled enzymatic activity analysis; unknown number of patients)
16. Prieto A, Tornero P, Rubio M, et al. Missense mutation Thr309Lys in the coagulation factor XII gene in a Spanish family with hereditary angioedema type III. Allergy. 2009;64(2):284-286. (Case report with DNA analysis; 4 patients)
17. Caldwell J, Ruddy S, Schur P, et al. Acquired C1 inhibitor deficiency In lymphosarcoma. Clin Immunol Immunopathol. 1972;1:39-52. (Case series; 2 patients)
18. Jackson J, Sim RB, Whelan A, et al. An IgG autoantibody which inactivates C1-inhibitor. Nature. 1986;323(6090):722-724. (Case report)
19. Chevailler A, Arlaud G, Ponard D, et al. C-1-inhibitor binding monoclonal immunoglobins in three patients with acquired angioneurotic edema. J Allergy Clin Immunol. 1996;97(4):998-1008. (Case series; 3 patients)
20. D’Incan M, Tridon A, Ponard D, et al. Acquired angioedema with C1 inhibitor deficiency: is the distinction between type I and type II still relevant? Dermatology. 1999;199(3):227-230. (Case series; 2 patients)
21. Sampson HA, Munoz-Furlong A, Campbell RL, et al. Second symposium on the definition and management of anaphylaxis: summary report--second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network Symposium. Ann Emerg Med. 2006;47(4):373-380. (Consensus statement)
22. Wilkin JK, Hammond JJ, Kirkendall WM. The captopril-induced eruption. A possible mechanism: cutaneous kinin potentiation. Arch Dermatol. 1980;116(8):902-905. (Case series; 7 patients)
23. Nussberger J, Cugno M, Amstutz C, et al. Plasma bradykinin in angio-oedema. Lancet. 1998;351(9117):1693-1697. (Case control; 27 patients)
24. Blais C Jr, Rouleau JL, Brown NJ, et al. Serum metabolism of bradykinin and des-Arg9-bradykinin in patients with angiotensin-converting enzyme inhibitor-associated angioedema. Immunopharmacology. 1999;43(2-3):293-302. (Case control biochemical analysis; 20 patients)
25. Adam A, Cugno M, Molinaro G, et al. Aminopeptidase P in individuals with a history of angio-oedema on ACE inhibitors. Lancet. 2002;359(9323):2088-2089. (Case control enzyme kinetic analysis; 39 patients)
26. Brown NJ, Byiers S, Carr D, et al. Dipeptidyl peptidase-IV inhibitor use associated with increased risk of ACE inhibitor-associated angioedema. Hypertension. 2009;54(3):516-523. (Retrospective cohort analysis of pooled data from premarketing phase 3 studies of vildagliptin; 27 patients)
27. Byrd JB, Touzin K, Sile S, et al. Dipeptidyl peptidase IV in angiotensin-converting enzyme inhibitor associated angioedema. Hypertension. 2008;51(1):141-147. (Case control; 50 patients)
28. Kostis JB, Packer M, Black HR et al. Omapatrilat and enalapril in patients with hypertension: the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial. Am J Hypertens. 2004;17(2):103-111. (Multicenter randomized double-blind active-controlled; 25,302 patients)
29. Kostis JB, Kim HJ, Rusnak J, et al. Incidence and characteristics of angioedema associated with enalapril. Arch Intern Med. 2005;165(14):1637-1642. (Retrospective cohort study; 86 patients)
30. Miller DR, Oliveria SA, Berlowitz DR et al. Angioedema incidence in US veterans initiating angiotensin-converting enzyme inhibitors. Hypertension. 2008;51(6):1624-1630. (Retrospective cohort study; 869 patients)
31. Woo KS, Norris RM, Nicholls G. Racial difference in incidence of cough with angiotensin-converting enzyme inhibitors (a tale of two cities). Am J Cardiol. 1995;75(14):967-968. (Case control; 160 patients)
32. Morimoto T, Gandhi TK, Fiskio JM, et al. An evaluation of risk factors for adverse drug events associated with angiotensin-converting enzyme inhibitors. J Eval Clin Pract. 2004;10(4):499-509. (Retrospective cohort study; 422 patients)
33. Byrd JB, Adam A, Brown NJ. Angiotensin-converting enzyme inhibitor-associated angioedema. Immunol Allergy Clin North Am. 2006;26(4):725-737. (Review)
34. Bas M, Adams V, Suvorava T, et al. Nonallergic angioedema: role of bradykinin. Allergy. 2007;62(8):842-856. (Review)
35. Lawlor F, Black AK, Breathnach AS, et al. Vibratory angioedema: lesion induction, clinical features, laboratory and ultrastructural findings and response to therapy. Br J Dermatol. 1989;120(1):93-99. (Case report)
36. Rose RF, Bhushan M, King CM, et al. Solar angioedema: an uncommonly recognized condition? Photodermatol Photoimmunol Photomed. 2005;21(5):226-228. (Case series; 2 patients)
37. Bentley B II. Cold-induced urticaria and angioedema: diagnosis and management. Am J Emerg Med. 1993;11(1):43-46. (Case report)
38. Frigas E, Nzeako UC. Angioedema. Pathogenesis, differential diagnosis, and treatment. Clin Rev Allergy Immunol. 2002;23(2):217-231. (Review)
39. Bork K, Barnstedt SE. Laryngeal edema and death from asphyxiation after tooth extraction in four patients with hereditary angioedema. J Am Dent Assoc. 2003;134(8):1088-1094. (Case series; 4 patients)
40. Decloedt E, Freercks R, Maartens G. Cerebral angioedema associated with enlapril. Br J Clin Pharmacol. 2009;68(2):271-273. (Case report)
41. Bork K, Meng G, Staubach P, et al. Hereditary angioedema: new findings concerning symptoms, affected organs, and course. Am J Med. 2006;119(3):267-274. (Retrospective cohort study; 221 patients)
42. Agostoni A, Aygoren-Pursun E, Binkley KE, et al. Hereditary and acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond. J Allergy Clin Immunol. 2004;114(3 Suppl):S51-S131. (Consensus statement)
43. Khan DA. Hereditary angioedema: historical aspects, classification, pathophysiology, clinical presentation, and laboratory diagnosis. Allergy Asthma Proc. 2011;32(1):1-10. (Review)
44. Yucelten D, Kus S. Chicken-wire erythema, but not urticaria, as the presenting sign of hereditary angioedema. Eur J Dermatol. 2006;16(2):197-198. (Case report)
45. Tarzi MD, Hickey A, Forster T, et al. An evaluation of tests used for the diagnosis and monitoring of C1 inhibitor deficiency: normal serum C4 does not exclude hereditary angio-oedema. Clin Exp Immunol. 2007;149(3):513-516. (Case series; 49 patients)
46. Markovic SN, Inwards DJ, Phyliky RP. Acquired C1 esterase inhibitor deficiency. Ann Intern Med. 2000;133(10):839. (Case series; 22 patients)
47. Alsenz, J, Bork K, et al. Autoantibody-mediated acquired deficiency of C1 inhibitor. N Engl J Med. 1987;316(22):1360-1366. (Case series; 2 patients)
48. Geha RS, Quinti I, Austen KF, et al. Acquired C1-inhibitor deficiency associated with antiidiotypic antibody to monoclonal immunoglobulins. N Engl J Med. 1985;312(9):534-540. (Case series; 4 patients)
49. Bas M, Hoffmann TK, Bier H, et al. Increased C-reactive protein in ACE inhibitor-induced angioedema. Br J Clin Pharmacol. 2005;59(2):233-238. (Retrospective cohort study; 25 patients)
50. Taki M, Watanabe H, Hasegawa T, et al. Angioedema: 6 years experience with 14 cases. Auris Nasus Larynx. 2010;37(2):199-204. (Case series; 14 patients)
51. Temino VM, Peebles RS Jr. The spectrum and treatment of angioedema. Am J Med. 2008;121(4):282-286. (Review)
52. Scheirey CD, Scholz FJ, Shortsleeve MJ, et al. Angiotensin-converting enzyme inhibitor-induced small-bowel angioedema: clinical and imaging findings in 20 patients. AJR Am J Roentgenol. 2011;197(2):393-398. (Case series; 20 patients)
53. Calbo L, Quattrocchi P, Ferlazzo B. Abdominal attack of hereditary angioedema associated with marked leucocytosis. A case report. Ital J Gastroenterol. 1992;24(8):464-465. (Case report)
54. Sofia S, Casali A, Bolondi L. Sonographic findings in abdominal hereditary angioedema. J Clin Ultrasound. 1999;27(9):537-540. (Case series; 2 patients)
55. Al-Khudari S, Loochtan MJ, Peterson E, et al. Management of angiotensin-converting enzyme inhibitor-induced angioedema. Laryngoscope. 2011;121(11):2327-2334. (Prospective cohort observational study; 40 patients)
56. Bork K, Hardt J, Schicketanz KH, et al. Clinical studies of sudden upper airway obstruction in patients with hereditary angioedema due to C1 esterase inhibitor deficiency. Arch Intern Med. 2003;163(10):1229-1235. (Retrospective cohort study; 123 patients)
57. Simons FE, Roberts JR, Gu X, Simons KJ. Epinephrine absorption in children with a history of anaphylaxis. J Allergy Clin Immunol. 1998;101(1 Pt 1):33-37. (Prospective randomized blinded parallel-group study; 17 patients)
58. Simons FE, Gu X, Simons KJ. Epinephrine absorption in adults: intramuscular versus subcutaneous injection. J Allergy Clin Immunol. 2001;108(5):871-873. (Prospective randomized blinded placebo-controlled 6-way crossover study; 13 patients)
59. Poland GA, Borrud A, Jacobson RM, et al. Determination of deltoid fat pad thickness. Implications for needle length in adult immunization. JAMA. 1997;277(21):1709-1711. (Prospective cohort study; 220 patients)
60. Johnston SL, Unsworth J, Gompels MM. Adrenaline given outside the context of life threatening allergic reactions. BMJ. 2003;326(7389):589-590. (Case series; 2 patients)
61. ECC Committee, Subcommittee, and Task Forces of the American Heart Association. 2005 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 10.6: anaphylaxis. Circulation. 2005;112(24 Suppl):IV1-IV203. (Guideline)
62. Bramante RM, Rand M. Images in clinical medicine. Angioedema. N Engl J Med. 2011;365(2):e4. (Case report)
63. Richman MJ, Talan DA, Lumry WR. Treatment of laryngeal hereditary angioedema. J Emerg Med. 2012;42(1):44-47. (Case report)
64. Albert KS, Hallmark MR, Sakmar E, et al. Pharmacokinetics of diphenhydramine in man. J Pharmacokinet Biopharm. 1975;3(3):159-170. (Pharmacokinetic study; 2 patients)
65. Kaplan AP. Clinical practice. Chronic urticaria and angioedema. N Engl J Med. 2002;346(3):175-179. (Review)
66. Runge JW, Martinez JC, Caravati EM, et al. Histamine antagonists in the treatment of acute allergic reactions. Ann Emerg Med. 1992;21(3):237-242. (Prospective randomized double-blind placebo-controlled trial; 39 patients)
67. * Lin RY, Curry A, Pesola GR, et al. Improved outcomes in patients with acute allergic syndromes who are treated with combined H1 and H2 antagonists. Ann Emerg Med. 2000;36(5):462-468. (Prospective randomized double-blind placebo-controlled trial; 91 patients)
68. Pickering RJ, Good RA, Kelly JR, et al. Replacement therapy in hereditary angioedema. Successful treatment of two patients with fresh frozen plasma. Lancet. 1969;1(7590):326--330. (Case series; 2 patients)
69. Hill BJ, Thomas SH, McCabe C. Fresh frozen plasma for acute exacerbations of hereditary angioedema. Am J Emerg Med. 2004;22(7):633. (Case report)
70. Pekdemir M, Ersel M, Aksay E, et al. Effective treatment of hereditary angioedema with fresh frozen plasma in an emergency department. J Emerg Med. 2007;33(2):137-139. (Case series; 3 patients)
71. Warrier MR, Copilevitz CA, Dykewicz MS, et al. Fresh frozen plasma in the treatment of resistant angiotensin-converting enzyme inhibitor angioedema. Ann Allergy Asthma Immunol. 2004;92(5):573-575. (Case report)
72. Bolton MR, Dooley-Hash SL. Angiotensin-converting Enzyme Inhibitor Angioedema. J Emerg Med. 2011. (Case report)
73. Jaffe CJ, Atkinson JP, Gelfand JA, et al. Hereditary angioedema: the use of fresh frozen plasma for prophylaxis in patients undergoing oral surgery. J Allergy Clin Immunol. 1975;55(6):386-393. (Prospective uncontrolled intervention; 7 patients)
74. Longhurst HJ. Emergency treatment of acute attacks in hereditary angioedema due to C1 inhibitor deficiency: what is the evidence? Int J Clin Pract. 2005;59(5):594-599. (Review)
75. * Prematta M, Gibbs JG, Pratt EL, et al. Fresh frozen plasma for the treatment of hereditary angioedema. Ann Allergy Asthma Immunol. 2007;98(4):383-388. (Abstract: chart review and literature search)
76. Epstein TG, Bernstein JA. Current and emerging management options for hereditary angioedema in the US. Drugs. 2008;68(18):2561-2573. (Review)
77. Brackertz D, Kueppers F. Hereditary angioneurotic oedema. Lancet. 1973;2(7830):680.
78. Martinez-Saguer I, Rusicke E, Aygoren-Pursun E et al. Pharmacokinetic analysis of human plasma-derived pasteurized C1-inhibitor concentrate in adults and children with hereditary angioedema: a prospective study. Transfusion. 2010;50(2):354-360. (Prospective single-center pharmacokinetic study; 6 children, 34 adults)
79. Nielsen EW, Gramstad S. Angioedema from angiotensin-converting enzyme (ACE) inhibitor treated with complement 1 (C1) inhibitor concentrate. Acta Anaesthesiol Scand. 2006;50(1):120-122. (Case report)
80. * Bork K, Barnstedt SE. Treatment of 193 episodes of laryngeal edema with C1 inhibitor concentrate in patients with hereditary angioedema. Arch Intern Med. 2001;161(5):714-718. (Prospective uncontrolled intervention; 42 patients)
81. Craig TJ, Levy RJ, Wasserman RL, et al. Efficacy of human C1 esterase inhibitor concentrate compared with placebo in acute hereditary angioedema attacks. J Allergy Clin Immunol. 2009;124(4):801-808. (Prospective randomized double-blind placebo controlled intervention trial; 125 patients)
82. Craig TJ, Bewtra AK, Bahna SL, et al. C1 esterase inhibitor concentrate in 1085 Hereditary Angioedema attacks--final results of the I.M.P.A.C.T.2 study. Allergy. 2011;66(12):1604-1611. (Prospective open-label intervention trial; 57 patients)
83. Baker J, Sheffer A, Christensen J, et al. Cinryze Replacement Therapy In Hereditary Angioedema and Pregnancy. J Allergy Clin Immunol. 2009;123(2):S106. (Abstract: Prospective uncontrolled intervention; 7 patients)
84. Zuraw BL, Busse PJ, White M, et al. Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema. N Engl J Med. 2010;363(6):513-522. (Part 1, double-blind placebo-controlled intervention trial; 68 patients; Part 2, double-blind placebo-controlled crossover intervention trial; 22 patients)
85. Riedl MA, Hurewitz DS, Levy R, et al. Nanofiltered C1 esterase inhibitor (human) for the treatment of acute attacks of hereditary angioedema: an open-label trial. Ann Allergy Asthma Immunol. 2012;108(1):49-53. (Prospective open- label intervention trial; 113 patients)
86. Cocchio C, Marzella N. Cinryze, a human plasma-derived C1 esterase inhibitor for prophylaxis of hereditary angioedema. P T. 2009;34(6):293-328. (Review)
87. Choi G, Soeters MR, Farkas H, et al. Recombinant human C1-inhibitor in the treatment of acute angioedema attacks. Transfusion. 2007;47(6):1028-1032. (Prospective uncontrolled intervention; 9 patients)
88. Zuraw B, Cicardi M, Levy RJ, et al. Recombinant human C1-inhibitor for the treatment of acute angioedema attacks in patients with hereditary angioedema. J Allergy Clin Immunol. 2010;126(4):821-827. (2 independent prospective randomized double-blind placebo-controlled intervention trials; 70 patients)
89. Schneider L, Lumry W, Vegh A, et al. Critical role of kallikrein in hereditary angioedema pathogenesis: a clinical trial of ecallantide, a novel kallikrein inhibitor. J Allergy Clin Immunol. 2007;120(2):416-422. (Prospective randomized double-blind placebo-controlled ascending-dose intervention trial; 48 patients)
90. Lumry W, Li H, Schneider L, et al. Results of a repeat-dosing study of intravenous and subcutaneous administration of ecallantide (DX-88), a recombinant plasma kallikrein inhibitor, in patients with hereditary angioedema. Ann Allergy Asthma Immunol. 2007;98(Supp 1):A29. (Abstract: Prospective uncontrolled tiered-dosing intervention trial; 77 patients)
91. Levy R, McNeil D, Li H, et al. Results of a 2-stage, phase 3 pivotal trial, EDEMA3: a study of subcutaneous DX-88 (ecallantide), a plasma kallikrein inhibitor, in patients with hereditary angioedema (HAE). J Allergy Clin Immunol. 2008;121(2):S103. (Abstract: 2-stage prospective intervention trial; Stage 1, placebo-controlled, 72 patients; Stage 2, open-label, 67 patients)
92. * Levy RJ, Lumry WR, McNeil DL, et al. EDEMA4: a phase 3, double-blind study of subcutaneous ecallantide treatment for acute attacks of hereditary angioedema. Ann Allergy Asthma Immunol. 2010;104(6):523-529. (Prospective randomized double-blind placebo-controlled intervention trial; 96 patients)
93. Cicardi M, Banerji A, Bracho F, et al. Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema. N Engl J Med. 2010;363(6):532-541. (2 independent prospective randomized double-blind controlled intervention trials; 56 and 74 patients)
94. * Lumry WR, Li HH, Levy RJ, et al. Results from FAST-3: a phase 3 randomized, double-blind, placebo-controlled, multicenter study of subcutaneous icatibant in patients with acute hereditary angioedema (HAE) attacks. J Allergy Clin Immunol. 2011;127(2):AB1. (Abstract: Prospective randomized double-blind placebo-controlled intervention trial; 88 patients)
95. Schmidt PW, Hirschl MM, Trautinger F. Treatment of angiotensin-converting enzyme inhibitor-related angioedema with the bradykinin B2 receptor antagonist icatibant. J Am Acad Dermatol. 2010;63(5):913-914. (Case report)
96. * Bas M, Greve J, Stelter K, et al. Therapeutic efficacy of icatibant in angioedema induced by angiotensin-converting enzyme inhibitors: a case series. Ann Emerg Med. 2010;56(3):278-282. (Prospective; intervention with historical patients as control trial; 8 patients)
97. Martello JL, Woytowish MR, Chambers H. Ecallantide for treatment of acute attacks of hereditary angioedema. Am J Health Syst Pharm. 2012;69(8):651-657. (Review)
98. Heymann WR. Acquired angioedema. J Am Acad Dermatol. 1997;36(4):611-615. (Review)
99. Greaves M, Lawlor F. Angioedema: manifestations and management. J Am Acad Dermatol. 1991;25(1 Pt 2):155-161. (Review)
100. Drouet C, Desormeaux A, Robillard J, et al. Metallopeptidase activities in hereditary angioedema: effect of androgen prophylaxis on plasma aminopeptidase P. J Allergy Clin Immunol. 2008;121(2):429-433. (Prospective cohort enzymatic assay trial; 216 patients)
101. Ott HW, Mattle V, Hadziomerovic D, et al. Treatment of hereditary angioneurotic oedema (HANE) with tibolone. Clin Endocrinol (Oxf). 2007;66(2):180-184. (Prospective, uncontrolled, open-label intervention trial; 8 patients)
102. Zingale LC, Castelli R, Zanichelli A, et al. Acquired deficiency of the inhibitor of the first complement component: presentation, diagnosis, course, and conventional management. Immunol Allergy Clin North Am. 2006;26(4):669-690. (Review)
103. Smit DV, Cameron PA, Rainer TH. Anaphylaxis presentations to an emergency department in Hong Kong: incidence and predictors of biphasic reactions. J Emerg Med. 2005;28(4):381-388. (Retrospective chart review; 282 patients)
104. Stark BJ, Sullivan TJ. Biphasic and protracted anaphylaxis. J Allergy Clin Immunol. 1986;78(1 Pt 1):76-83. (Prospective observation study)
105. * Haymore BR, Yoon J, Mikita CP, et al. Risk of angioedema with angiotensin receptor blockers in patients with prior angioedema associated with angiotensin-converting enzyme inhibitors: a meta-analysis. Ann Allergy Asthma Immunol. 2008;101(5):495-499. (Meta-analysis)
106. Makani H, Messerli FH, Romero J, et al. Meta-analysis of randomized trials of angioedema as an adverse event of renin-angiotensin system inhibitors. Am J Cardiol. 2012;110(3):383-391. (Meta-analysis)
107. * Ishoo E, Shah UK, Grillone GA, et al. Predicting airway risk in angioedema: staging system based on presentation. Otolaryngol Head Neck Surg. 1999;121(3):263-268. (Retrospective chart review; 80 patients)
108. * Bentsianov BL, Parhiscar A, Azer M, et al. The role of fiberoptic nasopharyngoscopy in the management of the acute airway in angioneurotic edema. w 2000;110(12):2016-2019. (Retrospective chart review; 70 patients)