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A Consensus Parameter for the Evaluation and Management of Angioedema in the Emergency Department

2014; Wiley; Volume: 21; Issue: 4 Linguagem: Inglês

10.1111/acem.12341

1553-2712

Joseph J. Moellman, Jonathan A. Bernstein, Christopher J. Lindsell, Aleena Banerji, Paula Busse, Carlos A. Camargo, Sean P. Collins, Timothy Craig, William Lumry, Richard M. Nowak, Jesse M. Pines, Ali S. Raja, Marc A. Riedl, Michael J. Ward, Bruce L. Zuraw, Deborah Diercks, Brian Hiestand, Ronna L. Campbell, Sandra M. Schneider, Richard Sinert,

Autoimmune Bullous Skin Diseases

Despite its relatively common occurrence and life-threatening potential, the management of angioedema in the emergency department (ED) is lacking in terms of a structured approach. It is paramount to distinguish the different etiologies of angioedema from one another and more specifically differentiate histaminergic-mediated angioedema from bradykinin-mediated angioedema, especially in lieu of the more novel treatments that have recently become available for bradykinin-mediated angioedema. With this background in mind, this consensus parameter for the evaluation and management of angioedema attempts to provide a working framework for emergency physicians (EPs) in approaching the patient with angioedema in terms of diagnosis and management in the ED. This consensus parameter was developed from a collaborative effort among a group of EPs and leading allergists with expertise in angioedema. After rigorous debate, review of the literature, and expert opinion, the following consensus guideline document was created. The document has been endorsed by the American College of Allergy, Asthma & Immunology (ACAAI) and the Society for Academic Emergency Medicine (SAEM). A pesar de su ocurrencia relativamente común y su potencial riesgo vital, el manejo del paciente con angioedema en el servicio de urgencias está falto de una aproximación estructurada. Es primordial distinguir las diferentes etiologías del angioedema y más específicamente diferenciar el angioedema mediado por histamina del mediado por bradicinina, especialmente en relación con los tratamientos que recientemente están disponibles para el angioedema mediado por bradicinina. Con este escenario en mente, este parámetro consenso para la evaluación y el manejo del angiodema intenta proporcionar un marco de trabajo para los urgenciólogos en la aproximación del paciente con angiodema en términos de diagnóstico y tratamiento en el servicio de urgencias. Este esquema consenso fue desarrollado a través de un esfuerzo de colaboración entre un grupo de urgenciólogos y alergólogos expertos líderes en angiodema. Tras un riguroso debate, una revisión de la literatura y la opinión de los expertos, se creó el siguiente documento de guía clínica de consenso. En reconocimiento a la importancia de este tema, este documento de consenso ha sido respaldado por el American College of Allergy, Asthma, and Immunology (ACAAI) y la Society for Academic Emergency Medicine (SAEM). Angioedema is a physical sign secondary to swelling of the subcutaneous or submucosal tissues and is due to enhanced vascular permeability, which allows movement of fluid from the vascular space into the interstitial space. Angioedema is nonpitting, non–gravity-dependent, and transient (lasting up to 7 days). It is critical to distinguish angioedema from edema, which is pitting, dependent, and persistent. Angioedema may be life-threatening, depending in large part on its underlying cause and body location. Thus, the clinical approach to a patient presenting in the emergency department (ED) with angioedema should include a consideration of potential causes. This article is meant to provide the emergency physician (EP) with a practical framework for classifying angioedema and to outline management based on this classification. Most ED visits for angioedema will involve allergic or idiopathic angioedema, with or without concomitant urticaria or evidence of anaphylaxis. These forms of angioedema are typically mediated by histamine, and their management is usually familiar to ED staff. The key challenge in the management of angioedema in the ED, however, is recognizing and treating potential nonhistaminergic (bradykinin-mediated) angioedema. Unlike histamine-mediated angioedema, bradykinin-mediated angioedema is not associated with urticaria, does not respond to antihistamines or corticosteroids, and is poorly responsive to epinephrine. Bradykinin-mediated angioedema tends to be more severe, longer lasting, and much more likely to involve concurrent abdominal symptoms than histamine-mediated angioedema. When angioedema develops, it often leads to an urgent (unscheduled) office or ED visit. Population-based data are lacking, but it is likely that patients with new-onset or recurring angioedema will go to the ED. Although anecdotal, this behavior fits that of pediatric patients with anaphylaxis; data suggest that roughly three-fourths of these children are managed in the ED.1 Few studies have examined the epidemiology of ED visits for angioedema. To date, all studies have relied on the International Classification of Diseases, 9th Edition, Clinical Modification (ICD-9-CM) code 995.1 to identify cases. Using this approach is limited, as the sensitivity and specificity of ICD-9-CM criteria to identify angioedema are currently unknown. Findings by Clark and Camargo,2 who demonstrated the low sensitivity and clinically relevant bias that comes from using ICD-9-CM anaphylaxis codes as the only source of case identification, further emphasize the need to overcome these methodologic issues to generate more accurate epidemiologic data on angioedema. Based on data from the National Hospital Ambulatory Medical Care Survey (NHAMCS), there are as many as 80,000 to 112,000 ED visits for angioedema annually.3, 4 The hospitalization rate for angioedema was 4.0 per 100,000 in 2005, making this condition the "dominant allergic disorder that results in hospitalization in the United States."5 About 18% of ED visits coded as angioedema result in hospitalization.4 However, understanding the true epidemiology of angioedema is hampered by persistent confusion among clinicians about the case definition, and more specifically, the distinction between different groups of allergic reactions that might present to the ED including: 1) anaphylaxis with angioedema, 2) an isolated angioedema disorder, or 3) other related conditions such as chronic urticaria with angioedema. This consensus parameter focuses on the presentation of isolated angioedema disorders to the ED. Angioedema disorders are the result of either bradykinin- or histamine-mediated responses.6 Many different factors are associated with the bradykinin-mediated angioedema disorders, most notably hereditary conditions and specific types induced by medication. Up to 50% of hereditary angioedema (HAE) patients in the United States experiencing attacks have been reported to require ED visits, with the majority of these patients requiring hospitalization.4 A chart review conducted at five academic EDs revealed that 30% of adult ED patients with angioedema had angiotensin-converting enzyme (ACE) inhibitor-induced angioedema, with 18% of these being admitted to observation units, 12% being admitted to inpatient units, and 11% being admitted to intensive care units (ICUs).7 Bluestein and colleagues8 also found that 30% of angioedema cases in the ED were induced by ACE inhibitors, although they noted a lower admission rate of 14% in their community setting. The possibility of medication-induced angioedema in children should also not be ignored. Although rare, in one study of 42 cases of pediatric angioedema, 7% (n = 3) presented with upper airway obstruction and were taking either an ACE inhibitor or a calcium channel blocker.9 It is difficult, if not sometimes impossible, to establish a precise cause of swelling in a patient presenting with angioedema in the ED. Therefore, it is recommended that patients be categorized using the following classification (Table 1): 1) anaphylaxis, 2) histaminergic angioedema without anaphylaxis (including both allergic and idiopathic angioedema), and 3) nonhistaminergic angioedema (including both HAE and ACE inhibitor–induced angioedema). Because the pathophysiology of these groups is different, the clinical manifestations and optimal treatments also differ. Unlike histamine-mediated angioedema, bradykinin-mediated angioedema does not respond to antihistamines or corticosteroids and is only poorly responsive to epinephrine. Bradykinin-mediated angioedema tends to be more severe, longer-lasting, and much more likely to involve the abdominal viscera than histamine-mediated angioedema.10 Bradykinin-mediated angioedema also frequently involves the upper airway, with a significant risk of death due to asphyxiation.11 Table 2 illustrates the general approach to classifying and managing angioedema in the ED. Details of the evaluation and management are expounded below. Employing a simple classification scheme for angioedema can help in developing an efficient and effective approach to assessing and managing patients presenting with angioedema. The first step in managing any patient in the ED is to sufficiently manage the airway and breathing, as well as to support circulatory function if necessary. Once the patient is stabilized, a focused history and physical should be obtained to separate bradykinin-mediated (ACE inhibitor–induced, HAE) from histamine-mediated. Subsequent distinctions between the underlying causes of angioedema can then be made to ensure appropriate longitudinal management and follow-up care. If the patient is on an ACE inhibitor, stop the medication and provide airway management support. If the patient has a known history of HAE, treat according to HAE guidelines using one of the recommended "on demand" therapies (Table 4).37 If the patient has signs of anaphylaxis (i.e., hypotension, vomiting, vasculature instability), administer epinephrine and treat according to anaphylaxis guidelines.48 The growing body of evidence describing the underlying mechanisms resulting in angioedema presenting to the ED provides the foundation necessary to care for these patients. Likewise, with the recent development and availability of novel pharmaceutical agents to treat bradykinin-mediated angioedema, it has become paramount that EPs be able to distinguish between histamine-mediated and bradykinin-mediated etiologies. In the following sections, we discuss recommendations for the evaluation, management, and follow-up of the angioedema patient presenting to the ED. These recommendations were developed collaboratively among a group of allergists and EPs with expertise in this area. This consensus parameter was developed following a rigorous process to maximize use of available evidence. The workgroup included experts in the specialties of emergency medicine (EM) and allergy and immunology. The chairs (JJM, JAB) invited workgroup members to participate in the parameter development. The charge to the workgroup was to use a systematic literature review, in conjunction with consensus expert opinion and workgroup-identified supplementary documents, to develop practice parameters that provide a comprehensive approach for an assessment and management of angioedema in the ED. A search of the medical literature was performed for a variety of terms that were considered to be relevant to this practice parameter. Literature searches were performed on PubMed, Google Scholar, and the Cochrane Database of Systematic Reviews. All reference types were included in the results. References identified as being relevant were searched for further relevant sources, and those were searched. In addition, members of the workgroup were asked for references that may have been missed by this initial search. Published clinical studies were rated by category of evidence and used to establish the strength of the recommendations (Table 3). However, a formal evidence evaluation system such as the GRADE scheme was not used. Each individual element of the recommendations was derived by an allergist–EP team pair. Elements were then combined into a parameter during an in-person conference. The approach taken was to generate a practical, evidence-based tool that could be used by EPs to guide their practice. The consensus parameter includes an executive summary of recommendations. Each recommendation is supported by a discussion of the literature. Finally, participants identified areas where lack of evidence suggests a role for future research, as well as possible barriers to implementation of the parameter. The parameter was appraised by external reviewers identified by the workgroup as experts in the field of EM and allergy and immunology. Based on this process, this parameter represents an evidence-based, broadly accepted consensus document. Angioedema can be classified as either bradykinin-mediated or histamine-mediated angioedema. Angioedema secondary to ACE inhibitors is a common side effect of this class of drugs and occurs when decreased metabolism of bradykinin leads to excess accumulation. HAE type I and type II are forms of angioedema due to a functionally abnormal C1-inhibitor (C1-INH) gene that results in the overproduction of bradykinin. HAE with normal C1-INH function with or without a genetic defect has been well-described, but to date only indirect anecdotal evidence supports bradykinin as the mediator. Acquired C1-INH deficiency clinically resembles HAE, but the low C1-INH is from consumption of the protein due to an underlying lymphoproliferative disorder and/or an antibody directed against C1-INH, resulting in the overproduction of bradykinin. Most idiopathic angioedema is thought to be histamine-mediated and is frequently responsive to H1 antagonists, epinephrine, and corticosteroids; however, refractory cases may be secondary to bradykinin. In patients with idiopathic angioedema unresponsive to H1 antagonists, epinephrine, and corticosteroids, without a family history of angioedema, in the absence of direct evidence for bradykinin as the primary mediator of swelling, it would be premature to recommend the use of therapies approved for HAE. Different types of angioedema have various historical features that are helpful for determining the putative cause. The physical examination of the angioedema patient should focus initially on vital signs and proceed to a targeted, focused examination of the airway, integumentary, and abdominal regions. There are no point-of-care or laboratory-based tests available in the ED to provide immediate guidance on treatment to the EP. However, C4 and tryptase levels should be considered to assist in the diagnosis of HAE and angioedema associated with anaphylaxis, respectively. Results of these labs when drawn during an angioedema attack are particularly useful during follow-up with a primary care physician, allergist, or angioedema specialist and on return of the patient to the ED. All patients with head and neck angioedema with any lingual involvement, as well as those with upper airway complaints, may benefit from flexible fiberoptic laryngoscopy, if immediately available, to determine the extent of involvement of the base of the tongue and the larynx. This is necessary to determine the possible need for airway management and the appropriate disposition of the patient. Radiographic techniques for assessment of the airway in patients presenting with acute angioedema have limited utility, and the unavoidable delay and reduced medical observation caused by these procedures may impose unnecessary risk. General monitoring of angioedema patients in the ED should be performed in a similar manner to the approach taken for patients with other respiratory or airway complaints, which includes close monitoring of oxygen saturation, cardiac status, and clinical signs and symptoms. Maneuvers such as supplemental oxygen, nasal trumpets, and bag–valve–mask ventilation may be useful temporizing measures for the angioedema patient with mild airway involvement, but are not a substitute for intubation if there is any concern about airway compromise. The decision to intubate or perform a more aggressive procedure should be based on the physician's assessment of the patient's prior history, airway anatomy, other comorbidities, and objective nasopharyngeal findings. When invasive airway management is indicated, maneuvers may involve the placement of an endotracheal tube, which requires patient sedation and analgesia to ameliorate significant discomfort. Once the decision to intubate is made, a rescue plan should be in place that involves having alternative airway devices available as rescue devices, as well as the means to perform a cricothyrotomy if necessary. Treatment of angioedema depends on historical features of the patient and, if available, his or her preexisting diagnosis. If angioedema presents with signs of anaphylaxis (urticaria, asthma, hypotension), epinephrine is recommended. Standard treatment for histamine-mediated angioedema includes H1 and H2 antagonists and corticosteroids and may require epinephrine in life-threatening situations. While generally not effective for bradykinin-mediated angioedema, these treatments are not contraindicated, and if a putative cause of angioedema is unknown, epinephrine followed by H1 antagonists and corticosteroids should be given. The only potential acute treatment currently readily available for the treatment of ACE-induced or other bradykinin-mediated angioedema in the ED is fresh-frozen plasma (FFP), which has a risk of viral transmission, allergic reactions, and volume overload and a possibility of worsening symptoms in HAE. Several targeted therapies are now FDA-approved in the United States for the treatment of acute HAE attacks. These novel therapies, including icatibant, ecallantide, and C1-INH concentrate, are effective for the treatment of HAE attacks and may have benefit in ACE inhibitor–induced angioedema, but data are limited to support these treatments for non-HAE patients. There is a paucity of data to guide disposition decisions for hospitalization versus discharge home for angioedema patients. The Ishoo criteria12 provide one potential way for a physician to assess risk and admission decisions; however, these criteria have not yet been validated. Histamine-mediated angioedema is often associated with urticaria and with swelling episodes that typically resolve within 24 to 48 hours. Causes include drugs, foods, latex, and insect stings. Bradykinin-mediated angioedema is not mediated by IgE antibodies and is not associated with urticaria. Swelling attacks in bradykinin-mediated angioedema typically last 2 to 5 days and are characteristically unresponsive to antihistamines and/or corticosteroids.6, 13-15 Angioedema is a well-known side effect associated with use of ACE inhibitors. About 0.1% to 0.7% of patients treated with these agents are estimated to develop angioedema, characterized mostly by edema of the lips and tongue.16, 17 African Americans and patients on immunosuppressants tend to be at higher risk.18 The rate of development of angioedema has been shown to be the highest during the first 30 days of initiation of ACE inhibitor therapy and thereafter declines in incidence. However, there is still an increased rate of ACE inhibitor-induced angioedema even in patients taking ACE therapy for longer than 1 year.19 The treatment of choice is discontinuing all ACE inhibitors. Even after discontinuing the ACE inhibitor, patients may be at increased risk of a subsequent angioedema attack for many weeks. In patients who do not discontinue the ACE inhibitor, the average time to the next angioedema event is 10 months.20 The mediator of angioedema is bradykinin. It is notable that other drugs affecting the renin-angiotensin system such as angiotensin receptor blockers and renin antagonists have been shown to cause angioedema, but secondary to a different unknown mechanism. Other non–histamine-mediated drug reactions include angioedema associated with inhibition of cyclooxygenase, leading to an accumulation of leukotriene mediators as seen with reactions to nonsteroidal anti-inflammatory drugs (NSAIDs).21 Patients with this condition usually manifest with urticaria and facial swelling upon exposure to the drug, but can present with swelling only.22 Hereditary angioedema is a rare form of angioedema that affects approximately 1 in 50,000 in the general population.23 Angioedema of this type usually begins in childhood or young adulthood and may worsen at puberty.24 Fifty percent of patients manifest recurrent episodes of swelling or abdominal pain by the age of 10 years.25 The underlying cause is a mutation of the gene encoding the C1-INH, which is inherited in an autosomal dominant pattern with relatively high penetrance. Two subtypes are recognized. Type I, which comprises 85% of cases, has low antigenic and functional C1-INH levels. Patients with normal or high antigenic C1-INH levels but abnormal C1-INH function are referred to as Type II.22, 24, 25 Type II HAE is caused by synthesis of a dysfunctional C1-INH protein.24-26 HAE due to C1-INH deficiency has been shown to be mediated by bradykinin.27 Many patients experience prodromal symptoms prior to an attack. A prominent prodromal symptom is erythema marginatum. This is an erythematous serpentine but nonpruritic and nonraised rash that should not be confused with urticaria.28 Hereditary angioedema in patients with normal complement levels and anormal C1-INH, but a well-defined family history of angioedema, is believed to be an autosomal dominant condition with low penetrance.17, 29 Patients tend to present at a slightly older age compared to HAE due to C1-INH deficiency. It is reported more frequently in women, and attacks are characteristically more common in the facial region, especially tongue swelling. When affected, men tend to have less severe and less frequent attacks. Taking estrogen-containing therapies increases attack frequency in most patients.29, 30 A minority of these patients has a mutation in the gene encoding coagulation factor XII, but the underlying cause of angioedema is unknown.17, 30 Bradykinin is presumed to be the mediator of swelling in these patients, since most appear to respond to the same medications used to treat HAE with C1-INH deficiency but not to H1 antagonists, corticosteroids, or epinephrine.17, 22 Acquired angioedema with C1-INH deficiency clinically resembles HAE due to C1-INH deficiency, but is not familial and tends to present in individuals over 40 years of age. Acquired C1-INH deficiency results from excessive C1-INH catabolism, which in approximately 15% of these cases is due to an underlying lymphoproliferative disorder and/or an autoantibody directed against C1-INH.17, 31-33 The most common underlying disorders are lymphoreticular disorders (ranging from monoclonal gammopathy of unknown significance to lymphomas), but a variety of other malignancies and autoimmune disorders have been linked to the disease. In all cases, the mediator of swelling is bradykinin. Most patients with idiopathic angioedema are responsive to H1 antagonists, epinephrine, and corticosteroids; however, there is a small group of patients with idiopathic angioedema who do not respond to H1 antagonists, and refractory cases may be secondary to bradykinin. There is limited and weak evidence that the mediator of swelling is bradykinin in this small subset of patients. Figure 1 summarizes how elements of the history and physical examination should help to establish the working diagnosis. Table 4 summarizes the historical characteristics of different types of angioedema. Although these characteristics do not directly distinguish one type of angioedema from another, they can help guide the EP toward the best possible treatment course. Although patients with either bradykinin- or histamine-mediated angioedema may have normal hemodynamic parameters, a number of patients may exhibit profound hypotension, tachycardia, and respiratory failure secondary to fluid shifts and airway edema. Due to vasodilation and increased vascular permeability, both bradykinin- and histamine-mediated angioedema have the potential to cause hypovolemic shock due to the shift of fluids in various bodily compartments. More importantly, asphyxiation secondary to airway edema is the leading cause of death in such patients, and thus it is essential to recognize subtle aspects of stridor and voice change in such patients immediately.12 A focused, detailed oropharyngeal examination is essential in evaluating patients with either bradykinin- or histamine-mediated angioedema, specifically noting any edema in the lips, tongue, soft palate, or posterior pharynx since many treatment algorithms are determined by the specific region of the oropharynx affected. In particular, any presence of stridor or hoarseness must be noted because further diagnostic tests may be necessary, such as nasopharyngoscopy.12 Although oropharyngeal involvement can occur with either bradykinin- or histamine-mediated angioedema, it is more commonly seen in bradykinin-mediated angioedema. Over half of the patients with HAE have at least one episode of laryngeal edema during their lifetime. In the past, 30% of deaths in patients with HAE were due to laryngeal edema.11, 34 In patients with ACE inhibitor–induced angioedema, the head and neck is the site most commonly affected. The characteristic physical examination finding in bradykinin-mediated angioedema is a firm, nonpruritic swelling resulting from the accumulation of fluid in the reticular dermis and subcutaneous or submucosal tissue. The lesions are sometimes tender to palpation and are nonpitting. Histamine-mediated angioedema involves the deeper dermis and tends to be more commonly associated with urticarial lesions that are discrete, pruritic erythematous papules in the epidermis that blanch with pressure. Both lesions arise from local vasodilatation and increased vascular permeability. Although it is uncommon to have urticarial lesions in bradykinin-mediated angioedema, some studies suggest that up to 50% of patients with histamine-mediated angioedema may present with both angioedema and urticarial lesions.22, 35, 36 In HAE, the most common sites of edema include the arms, legs, hands, and feet.22 Patients with bradykinin- or histamine-mediated angioedema may present with gastrointestinal symptoms. However, a patient presentation consistent with an "acute surgical abdomen" on examination, with severe tenderness, guarding, and rebound tenderness due to bowel wall edema, is much more characteristic of HAE patients. Cases of unnecessary abdominal surgery have been documented in HAE patients.22 Almost all patients with HAE Types I and II have persistently low serum C4 levels; C4 is an excellent screening tool for C1-INH deficiency states.13, 22, 37 C4 levels combined with C1-INH level and C1-INH function (<50% using the chromogenic assay or <68% using the quidel assay) can be used to differentiate between Type I and Type II HAE and HAE that is not mediated by C1-INH deficiency.38 If C4 is normal during an attack in a patient not on androgens or C1-INH replacement, proceeding to C1-INH analysis is unnecessary.14 Currently, the C4 test is not recommended for patients younger than 1 year because of its unreliability in this age group. C1-INH and C4 concentrations increase to adult levels between 2 and 3 years of age.39 The chromogenic functional C1-INH assay appears to be superior to the ELISA-based (quidel) C1-INH functional assay.37 Serum tryptase levels are sometimes considered in differentiating various causes of angioedema. Tryptase is normal in HAE I and II and may be elevated in cases of anaphylaxis or other mast cell–mediated disorders manifesting with angioedema. An elevated tryptase level can be helpful in ruling out HAE although a normal tryptase level provides no discriminatory information. Laboratory testing is of little use to the ED evaluation and management of the patient with angioedema. Measurement of C4 and tryptase levels to discriminate between bradykinin- and histamine-mediated angioedema, respectively, typically takes longer to process and provide results than the time frame in which management decisions must be made in the ED. By the time testing is complete, it is known whether or not the patient has responded to H1 antagonists, corticosteroids, and epinephrine, and thus the likely mechanism for the attack can be surmised. Laboratory testing at the time of an attack, however, can be useful for the long-term management of patients with angioedema. For example, in 2% to 4% of cases of HAE, the C4 level is normal in between attacks but is low in virtually 100% during acute angioedema attacks, and in these patients subsequent measurements of the antigenic and functional C1-INH level are helpful to evaluate for HAE Type I versus Type II.22, 37, 38 Measuring the C4 level is an effective screening test to rule out HAE Type I and Type II, and initiating this in the ED will ensure that the patient has results available during follow-up and subsequent ED visits.22 It is not useful to screen with a CH50 or C3 complement level.38 It is prudent to obtain a C4 level in a patient with angioedema when no obvious etiology is found, especially if the angioedema appears to be mediated by bradykinin.39 It is important that C4 is sent to the laboratory in a timely fashion, as degradation and artificially low C4 levels may be reported if there is a significant delay in transfer or poor handling.37 In the perioral region and neck, angioedema can involve any number of mucosal sites from the lips to the larynx, and the involvement of these sites is random and can be noncontiguous.12, 40-46 Angioedema of the upper aerodigestive tract can be life-threatening if it causes airway compromise that is not recognized and treated. A major question for EPs is how and in whom to evaluate the airway beyond what can be seen on physical examination.12, 40-46 Current studies are of small sample size but suggest that any presentation of head and neck angioedema can have associated swelling of the larynx, base of the tongue, or both. We recommend that those patients with involvement of the tongue, soft palate, or floor of the mouth should have direct visualization, if immediately available, of