From American Academy of Emergency Medicine
Clinical Practice Guideline
Posted 03/06/2007
Position Statements
AAEM statements are not to be construed as dictating an exclusive course of action nor are they intended to replace the medical judgment of healthcare professionals. The unique circumstances of individual patients and environments are to be taken into account in any diagnosis and treatment plan. AAEM statements reflect clinical and scientific advances as of the date of their publication and are subject to change.
Clinical Practice Guideline: Initial Evaluation and Management of Patients Presenting with Acute Urticaria or Angioedema
Reviewed and approved by the AAEM Clinical Practice Guidelines Committee
Scope of Application
This guideline is intended for use by physicians working in community and hospital-based emergency departments.
Inclusion Criteria
This clinical guideline is intended for patients presenting with a chief complaint of acute urticaria and/or angioedema.
Exclusion Criteria
Excluded from this clinical guideline are patients with chronic urticaria.
Methodology
A MEDLINE search for articles published between January 1996 and April 2006 was performed for urticaria and angioedema. Key words consisted of urticaria, angioedema, angio-neurotic edema, antihistamines, corticosteroids, nasopharyngolaryngoscopy, angiotensin converting enzyme inhibitor, angiotensin receptor blocker, and hereditary angioedema. The bibliographies of individual articles were also searched for additional references, some of which were published prior to 1996. Articles were reviewed and analyzed by the lead author and then scored for strength according to the following levels of evidence:
I Evidence obtained from at least one properly designed, randomized controlled trial
II-i Evidence obtained from well designed controlled trials without randomization
II-ii Evidence obtained from well designed cohort or case-control analytic studies, preferably more than one center or research group
II-iii Evidence obtained from multiple time series with or without intervention. Dramatic results in uncontrolled experiments could also be regarded as this type of evidence
III Opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees
IV Evidence inadequate owing to problems of methodology (e.g. sample size, or length or comprehensiveness of follow up or conflicts of evidence)
Recommendations were then made according to the following grading system:
A. There is good evidence to support the use of the procedure
B. There is fair evidence to support the use of the procedure
C. There is poor evidence to support the use of the procedure
D. There is fair evidence to support the rejection of the procedure
E. There is good evidence to support the rejection of the procedure
Introduction
Up to 25% of the United States population will experience an episode of urticaria or angioedema during their lifetime.[1,2]Each year, over one million patients present to a physician for evaluation and treatment of urticaria and/or angioedema.[3] Many of these patients arrive at local emergency departments seeking treatment. For emergency physicians, the evaluation and management of patients with urticaria or angioedema can be challenging. Both disorders can be caused by a number of immunologic and non-immunologic mechanisms. As a result, the list of potential etiologies is extensive. Aside from the history and physical examination, there is little that the emergency physician can rely on to aid in discovering a cause. With the exception of hereditary angioedema, routine laboratory studies such as a complete blood count, basic metabolic panel, electrolytes, liver function tests, or urinalysis have been shown to be of no utility in the evaluation of acute urticaria and angioedema. Management is often dependent upon the etiology and severity of clinical presentation. For some causes, treatment, as well as patient disposition, remains controversial. In order to provide effective and efficient care, it is imperative to understand current concepts and controversies in the management of urticaria and angioedema.
This clinical guideline focuses on the evaluation and treatment of emergency department patients with acute urticaria and/or angioedema. Specific emphasis is placed on the importance of the history of present illness, the role of laboratory testing, angiotensin converting enzyme (ACE) inhibitor angioedema, indications for antihistamines and corticosteroids, indications for nasopharyngolaryngoscopy, and patient disposition.
Are the lesions consistent with urticaria or angioedema?
Urticaria is described as generalized, erythematous, pruritic papules that are localized to the papillary dermis.[4] Lesions are typically discrete with raised borders, round or oval in shape, range in size from several millimeters to a few centimeters, and blanch with pressure.[2,4] Occasionally, urticarial lesions may appear irregular, serpiginous, or gyrate.[2]
Mechanisms of urticaria can be classified into one of four categories: immune-mediated, complement-mediated, non-immune mediated, and autoimmune-mediated.[4] Regardless of the etiology, all mechanisms cause degranulation of the dermal mast cell. Mast cell release of preformed mediators results in endothelial activation, vasodilatation, and increased vascular permeability. Vasoactive mediators implicated in urticaria include histamine, prostaglandin D 2 , cysteinyl leukotrienes C 4 and D 4 , platelet activating factor, anaphylotoxins, histamine releasing factor, cytokines, and chemokines.[2,4,5] Immune-mediated urticaria results from the cross-linking of IgE located on the surface of mast cells and basophils. Examples of immune-mediated urticaria include medications (penicillin), foods, and hymenoptera venom.[4] Complement-mediated urticaria is caused by the direct activation of mast cells by complement proteins, most notably the anaphylatoxins C3a, C4a, and C5a. Antibody-antigen complexes, seen in serum sickness and transfusion reactions, directly activate the complement cascade and can result in urticaria. Non-immune mediated urticaria results from the direct activation of mast cells by non-IgE mechanisms. Examples of non-immune mediated etiologies include physical stimuli, alcohol, radiocontrast dye, and medications such as opiates, vancomycin, non-steroidal anti-inflammatory drugs, and aspirin.[4] Degranulation of mast cells by circulating auto-antibodies defines autoimmune-mediated urticaria.
Angioedema commonly accompanies urticaria. Approximately 50% of patients present with both urticaria and angioedema.[6] Clinically, angioedema is characterized by the abrupt onset of non-pitting, non-pruritic swelling that involves the reticular dermis, subcutaneous, and submucosal layers.[5,7,8] Lesions are typically asymmetric in distribution, well defined, and located in non-dependent areas. Common locations include the face, especially the lips and periorbital area; the extremities; genitalia; and abdominal viscera.[5] In contrast to urticaria, angioedema typically lasts anywhere from 24 to 96 hours. There is no fundamental difference between the lesions of urticaria and angioedema.[5] Both result from local vasodilatation and increased vascular permeability.
Etiologies of angioedema are divided into mast cell mediated and non-mast cell mediated. Patients with mast cell mediated angioedema present with urticaria and angioedema. The mechanisms are identical to that of isolated urticaria and are discussed above. Isolated angioedema, which occurs in approximately 10% of patients, is due to non-mast cell mediated mechanisms. The two most common mechanisms of non-mast cell mediated angioedema are abnormalities in the bradykinin pathway and abnormalities of the complement system.[6] ACE inhibitor angioedema and hereditary angioedema are examples of etiologies that present with isolated angioedema.
Patient Management Recommendations:
Strength of Evidence: III
Recommendation Grade: A
What are the key elements of the history of present illness in patients with acute urticaria and/or angioedema?
History is the most important component of the evaluation of patients with urticaria and/or angioedema.[4] The history should begin with an assessment of symptom duration. Six weeks has arbitrarily been chosen to divide patients between acute and chronic urticaria/angioedema. Time distinction is important, as etiologies and the evaluation of acute and chronic urticaria/angioedema are different. In contrast to chronic urticaria, acute urticaria and/or angioedema are more likely to have an identifiable etiology. The most common causes of acute urticaria and/or angioedema are medications, foods, infections, insect venom, contact allergens (latex sensitivity), and radiocontrast media.[2,8,9] Medications known to cause urticaria and/or angioedema include antibiotics (penicillins, sulfonamides, vancomycin), ACE inhibitors, angiotensin receptor blockers (ARB), non-steroidal anti-inflammatory drugs (NSAID), aspirin, opiates and narcotics, ß-blockers, and hormonal treatments (contraceptives and hormone-replacement therapy).[10-14] Urticaria and angioedema are also associated with numerous vitamin supplements and herbal products. Patients should be directly questioned regarding alternative medicine treatments, as most will not consider these products to be medications.[10] Common food allergens that cause urticaria and angioedema include nuts, eggs, milk, fish (scombroid), and shellfish.[9] Viral infections are a common cause of acute urticaria.[2] Although controversial, other infections reported to cause urticaria and/or angioedema include sinus infections, dental abscesses, cholecystitis, andHelicobacter pylori gastric infections.
Additional etiologies of acute urticaria and/or angioedema include physical and environmental triggers. Dermatographism, in which mast cell degranulation is caused by minor skin trauma, is the most common physical trigger.[10] Environmental triggers include exposure to heat, cold, sun, and water. Similar to alternative medicine treatments, patients should be asked about the use of topical products. Herbal soaps, lotions, hair dyes, nail products, detergents, and toiletries can cause urticaria and, in rare cases, angioedema.[10] Endocrine disorders (thyroid), paraneoplastic syndromes, and autoimmune conditions more commonly cause chronic urticaria and are usually suggested by findings from the review of systems.
Following symptom duration, determine the duration of individual lesions. Urticarial lesions last less than 24 hours and resolve without skin change.[8] For lesions that last longer than 24 hours, alternative diagnoses should be considered. One of the most important alternative diagnoses to consider is urticarial vasculitis. The lesions of urticarial vasculitis are painful rather than pruritic, do not blanch, are located predominantly in the lower extremities, and typically leave a permanent pigmentary change.[2] Skin biopsy is required for a definitive diagnosis of vasculitis. Other disorders to consider in the patient with urticarial lesions that exceed 24 hours are erythema multiforme minor, discoid lupus, morbilliform drug eruption, dermatitis herpetiformis, and bullous pemphigoid.[9] Angioedema characteristically lasts 1 to 3 days. For patients with lesions that last longer than 96 hours consider dermatomyositis, superior vena cava syndrome, photodermatitis, Crohn's disease of the mouth and lips, facial cellulitis, Ascher syndrome (recurrent swelling of the eyelids), and Melkersson-Rosenthal syndrome (granulomatous swelling of the lips).[5]
In patients with isolated angioedema, consider medications and abnormalities of C1 esterase inhibitor (C1INH). Abnormalities in C1INH can either be acquired or hereditary. Hereditary angioedema (HAE) is an autosomal dominant disorder characterized by recurrent bouts of angioedema primarily affecting the extremities, gastrointestinal tract, and genitalia. Suspect HAE in the patient with a family history of first degree relatives with similar symptoms. Medications known to cause isolated angioedema include ACE inhibitors, ARBs, NSAIDS, fibrinolytics, and estrogen.[5]
Patient Management Recommendations:
Strength of Evidence: III
Recommendation Grade: A
Are routine laboratory studies indicated in the evaluation of acute urticaria and angioedema?
Unless hereditary angioedema is suspected from the history and physical examination, there is no role for laboratory studies in the evaluation of acute urticaria and/or angioedema.[15] Acute urticaria or angioedema is self-limited. Laboratory testing is deferred until at least 6 weeks of persistent symptoms.[10] For patients whose symptoms are longer than 6 weeks in duration, it is recommended to obtain a complete blood count, urinalysis, erythrocyte sedimentation rate, and liver function tests. However, the utility of these labs, even in patients with chronic symptoms, remains controversial. In a recent comprehensive meta-analysis that included over 6400 patients with chronic urticaria or angioedema, screening laboratory analysis detected unsuspected diagnoses in only 1.6% of patients.[16]
Patient Management Recommendations:
Strength of Evidence: III
Recommendation Grade: B
What is the role of ACE inhibitors in isolated angioedema?
Introduced in 1981 for the treatment of hypertension and congestive heart failure, ACE inhibitors have become one of the most largely prescribed medications worldwide.[5,17] Currently, as many as 40 million patients are taking an ACE inhibitor.[18] Angioedema is a well-recognized side effect of these medications. The reported incidence of ACE inhibitor angioedema ranges from 0.1% to 1.0%.[19] For African Americans, the risk is 4.5 times higher than Caucasians.[18,20] It is important to recognize that ACE inhibitor angioedema is a class effect and is not dose-dependent.[5] Symptoms can occur anywhere from a few hours up to 10 years after the initial dose. In fact, up to 40% of patients with ACE inhibitor angioedema present months to years after their initial dose.[19] Unfortunately, many physicians remain unaware of the delayed onset of ACE inhibitor angioedema.[17] A recent study demonstrated an average delay of 10 months between the initial episode of angioedema and the eventual withdrawal of the medication.[21] Continuing an ACE inhibitor after an initial episode of angioedema increases patient morbidity.[22]
The pathophysiology of ACE inhibitor angioedema remains controversial. Most theories center on the decreased degradation of bradykinin, a potent vasodilator that increases vascular permeability. Only a small percentage of patients, however, develop angioedema while taking an ACE inhibitor. It is likely that other humoral factors such as nitric oxide, interleukin-1, and tumor necrosis factor are involved.[19,23] Defects in C1INH, carboxyalkyldipeptide N, and urinary kallikrein have also been proposed as mechanisms for ACE inhibitor angioedema.[19,24]
Clinically, ACE inhibitor angioedema presents without urticaria. Up to 68% of cases of isolated angioedema are due to an ACE inhibitor.[25-28] Edema is often localized to the head, neck, lips, mouth, tongue, larynx, pharynx, and subglottal regions.[5] In rare cases, involvement of the abdominal viscera can occur, resulting in sudden abdominal pain, nausea, vomiting, and diarrhea.[5,19]
Treatment of patients with ACE inhibitor angioedema focuses on discontinuation of the drug, airway management, and supportive care. Careful airway management is crucial. Immediately intubate patients with stridor, accessory muscle use, or drooling of saliva. Additional indications for intubation, based upon retrospective series, include tongue edema and edema of the floor of the mouth.[25,26,29] For patients presenting with angioedema and complaints of odynophagia, hoarseness, voice change, or dyspnea, fiberoptic nasopharyngolaryngoscopy (NPL) can be an invaluable tool. Any patient with laryngeal edema by NPL requires admission to the intensive care unit (ICU) for airway monitoring. The role of medications in ACE inhibitor angioedema is controversial. Epinephrine, antihistamines, and corticosteroids can be given to these patients; however, there are no controlled studies that demonstrate the efficacy of the medications in this setting.[8,18,30]
Patient Management Recommendations:
Strength of Evidence: II-iii
Recommendation Grade: B
Do ARBs cause angioedema?
Introduced in 1995, angiotensin receptor antagonists (ARB) are gaining widespread use in the treatment of hypertension, heart failure, and renal disease. ARBs primarily act by blocking the angiotensin type I receptor, which mediates the vasoconstrictive effects of angiotensin II.[19] Since the mechanism of action is different from ACE inhibitors, ARBs, theoretically, should not be associated with the same side effects. Angioedema, however, does occur with ARBs. There is increasing evidence that ARBs also activate angiotensin type II receptors, producing vasodilatation and increased vascular permeability through nitric oxide pathways.[19]
The true incidence of ARB angioedema remains unknown; however, it does appear to be less than angioedema caused by ACE inhibitors.[19] Patients with ARB angioedema often have a prior history of ACE inhibitor angioedema. Warner et al, found that 32% of patients with angioedema due to an ARB had a prior episode of angioedema attributed to an ACE inhibitor.[31] ARBs should not be considered a safe alternative for patients who have experienced ACE inhibitor angioedema.[19] The management of patients with ARB angioedema is identical to that of patients with ACE inhibitor angioedema.
Patient Management Recommendations:
Strength of Evidence: II-iii
Recommendation Grade: B
What is the role of fiberoptic NPL in the evaluation of patients with angioedema?
Emergency physicians recognize that angioedema involving the upper airway can be life-threatening. Fiberoptic NPL provides the emergency physician the ability to evaluate the severity of laryngeal compromise. Laryngeal edema is considered an ominous finding indicative of severe disease. All patients with laryngeal edema require admission to the ICU. Based upon recent studies, patients who complain of dyspnea, hoarseness, voice change, odynophagia, or have stridor on examination are likely to have laryngeal edema.[32,33] These patients should undergo NPL. For emergency physicians without access to a nasopharynoscope, otolaryngology consultation for NPL should be obtained. Based on current literature, no patient with a normal larynx on NPL has progressed to require emergent airway intervention.[32]
Patient Management Recommendations:
Strength of Evidence: II-iii
Recommendation Grade: B
What medications are first-line treatment for the patient with acute urticaria and angioedema?
Emergency department treatment of the patient with acute urticaria and/or angioedema centers on antihistamines and corticosteroids. For patients presenting with anaphylaxis, respiratory distress, or severe laryngeal edema, administer epinephrine intramuscular or subcutaneously in a dose of 0.3 mg every 10 minutes (0.3 ml of 1:1000 dilution).[15]
H1-blocking antihistamines are the cornerstone of therapy in patients with acute urticaria and angioedema. In addition to relieving pruritus, these agents reduce the number, size, and duration of lesions.[34] First-generation H1 antihistamines such as diphenhydramine and hydroxyzine are effective; however, sedation is a significant side effect. As a result, second-generation H1 antagonists (loratadine, cetirizine, desloratadine, fexofenadine) are considered the agents of choice for outpatient therapy.[4] These medications have poor central nervous system penetration, thereby producing less sedation. There are currently no controlled trials that demonstrate the superiority of any first- or second-generation H1 antagonist.[35] Many dermatologists prescribe a combination of two H1 antagonists; a non-sedating agent during the day combined with a sedating H1 antihistamine at night. This regimen has not been proven in randomized, placebo-controlled trials.[34] Doxepin hydrochloride, a tricyclic antidepressant with potent H1 and H2 antagonist properties, is recommended as an alternative to treatment with antihistamines. This medication, however, has significant side effects of severe sedation, dry mouth, and weight gain. For these reasons, it should not be considered first line treatment for acute urticaria and angioedema.
For patients whose symptoms are not controlled with an H1 antagonist, the addition of an H2 antagonist may be beneficial.[2] Approximately 15% of histamine receptors in the skin are of the H2 subtype. The combination of H1 and H2 antagonists has been demonstrated to be beneficial to patients with urticaria.[2] H2 antagonists used alone, however, are not effective.
Corticosteroids are indicated for patients with anaphylaxis, laryngeal edema, and severe symptoms unresponsive to antihistamines.[10] Corticosteroids exhibit an anti-inflammatory effect by preventing the formation of leukotrienes and prostaglandins.[10] In addition, these agents also suppress multiple facets of the cellular and humoral immune system.[10] Recommended doses for patients with severe symptoms range from 0.5 - 1.0 mg/kg/day, with or without a taper.[4] Antileukotrienes do not have a role in the management of patients with acute urticaria and angioedema.
Patient Management Recommendations:
Strength of Evidence: I
Recommendation Grade: A
What medications must be avoided in patients with acute urticaria and angioedema?
Regardless of whether an etiology is discovered, patients should avoid drugs that exacerbate urticaria or angioedema. Aspirin, NSAIDs, and opiates should be discontinued, as these medications can worsen urticaria.[8,9] ACE inhibitors must be stopped in anyone presenting with isolated angioedema. As discussed, emergency physicians should not switch patients with ACE inhibitor angioedema to an ARB. In addition to medications, patients should avoid alcohol, as this can also aggravate symptoms.
Patient Management Recommendations:
Strength of Evidence: III
Recommendation Grade: B
What is the treatment for patients with HAE?
HAE is a rare, autosomal dominant disorder affecting approximately 1:50,000 individuals.[5,36] HAE occurs as a result of either an inherited or acquired abnormality in C1INH. Currently, there are three types of HAE. Type I accounts for 80% to 85% of cases and is due to decreased production of C1INH. Type II comprises 15% to 20% of cases and occurs as a result of a functionally impaired C1INH. Type I and Type II HAE occur in all races with no sex predilection. Type III has only recently been described where both C1INH levels and function are normal. To date, Type III has only been reported in women and the clinical significance is unknown.[37] Interestingly, there is an increased frequency of autoimmune diseases in patients with HAE. Depending on the study, up to 12% of patients with HAE have an autoimmune disorder.[38] Systemic lupus erythematosus, thyroiditis, glomerulonephritis, and inflammatory bowel disorders are reported to occur with greater frequency in patients with HAE.[36]
Patients with HAE typically first manifest symptoms during the second decade of life.[36] The majority of patients are able to identify a potential trigger. Common triggers include minor trauma, dental procedures, vigorous exercise, emotional stress, infections, oral contraceptive use, and alcohol consumption.[5,36,39] Attacks of HAE typically last 2 to 5 days before spontaneously resolving.[36] The main sites of edema include the face, extremities, and genitalia.[5] Gastrointestinal involvement can occur presenting with severe cramps, nausea, vomiting, and diarrhea. Episodes of gastrointestinal tract HAE usually last 12 to 24 hours.[36,40]
Diagnosis of HAE requires laboratory investigation. During acute attacks, complement proteins C4 and C2 are consumed, thereby producing low levels. A C4 level below 50% suggests the diagnosis. If C4 levels are low, a quantitative and functional measurement of C1INH activity is performed. A normal C4 level during an acute episode essentially rules out HAE.[5] For the emergency physician, C4 and C1INH levels are not routine laboratory requests. If HAE is suspected from the history and physical examination, the emergency physician should obtain a C4 level. The result will not return during the patient's emergency department visit. Therefore, promptly refer patients to an immunologist or dermatologist for clinical and laboratory follow up. C1INH levels are performed as part of the outpatient evaluation. Interestingly, up to 25% of patients with HAE have no family history of disease.[36] Thus, a negative family history should not be used to exclude HAE when clinical suspicion is high.
Acute episodes of HAE typically do not respond to antihistamines, corticosteroids, or epinephrine.[5,36,41] As stated, symptoms spontaneously resolve in the majority of cases. For patients with severe attacks, the treatment of choice is C1INH concentrate. However, C1INH concentrate is not available in the United States . There are several reports on the successful use of fresh frozen plasma (FFP) for acute exacerbations of HAE.[41] FFP contains C1INH, as well as other complement proteins. There is a theoretical concern that episodes may be worsened by FFP. As such, many physicians recommend that FFP not be used in patients with HAE. A recent review of the literature, however, found no case reports of HAE exacerbated by the administration of FFP.[41] Androgens, as well as antifibrinolytics, have been used for prophylaxis against attacks; however, they have no role in the acute management of HAE.
Patient Management Recommendations:
Strength of Evidence: III
Recommendation Grade: B
Which patients with angioedema require admission?
Disposition of the patient with angioedema can be challenging for the emergency physician. As discussed, any patient with laryngeal edema by NPL should be admitted to the ICU for airway monitoring. In addition, ICU admission is also indicated for non-intubated patients with tongue edema or edema of the floor of the mouth. Indications for non-ICU admission include patients who present with severe symptoms (without laryngeal edema), unreliable patients, or those with disease progression in the emergency department. Patients with isolated cutaneous swelling may be observed in the emergency department and discharged home. Although 6 hours is the recommended period of observation, there is currently no literature to support this recommendation.
Patient Management Recommendations:
Strength of Evidence: II-iii
Recommendation Grade: B
Flow chart (PDF)
