Docstoc

Clinical Practice Guideline Initial Evaluation and Management of

Document Sample
Clinical Practice Guideline Initial Evaluation and Management of Powered By Docstoc
					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
Author:        Michael Winters, MD

Reviewed and approved by the AAEM Clinical Practice Guidelines Committee
Co-chairs:    Mary Palmer, MD
             Steven Rosenbaum, MD

Reviewers:     Lisa Mills, MD
               Mary Palmer, MD
               Steven Rosenbaum, MD
               Guy Sanders, MD

Reviewed and approved by the AAEM Board of Directors
07//10/06

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.




                                                                                               2
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 D2, cysteinyl leukotrienes C4 and D4, 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.




                                                                                           3
Patient Management Recommendations:
       1. Lesions should be consistent with the definitions of urticaria or
          angioedema.

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, β-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, and Helicobacter 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]



                                                                                             4
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:
       1. Review medications, foods, and exposure to insect venom, contact
          allergens, and radiocontrast media in patients with acute urticaria and/or
          angioedema.
       2. Consider medications (namely ACE inhibitors), hereditary angioedema,
          and acquired abnormalities in C1INH in patients with isolated
          angioedema.
       3. Consider alternative diagnoses in patients with presumed urticaria whose
          lesions last longer than 24 hours.

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:
       1. Routine laboratory studies are not indicated in the evaluation of patients
          with acute urticaria and angioedema.

Strength of Evidence: III
Recommendation Grade: B




                                                                                           5
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:
       1. Discontinue ACE inhibitors in any patient presenting with isolated
          angioedema.
       2. Intubate patients presenting with respiratory distress, stridor, drooling,
          tongue edema, or significant edema of the floor of the mouth.




                                                                                         6
       3. Antihistamines and corticosteroids can be given; although, there is no
          evidence supporting their efficacy.

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:
       1. Patients with a history of ACE inhibitor angioedema should not be
          prescribed an ARB.
       2. Treatment of ARB angioedema is identical to that of ACE inhibitor
          angioedema.

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:




                                                                                         7
       1. Perform NPL on patients presenting with dyspnea, hoarseness, voice
          change, or odynophagia.
       2. Admit all patients with laryngeal edema to the ICU.

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:
       1. Administer intramuscular or subcutaneous epinephrine to patients with
          respiratory distress.



                                                                                            8
       2. Administer an H1 antagonist to patients with acute urticaria and
          angioedema.
       3. For patients whose symptoms are not controlled with an H1 antagonist,
          add an H2 antagonist to the treatment regimen.
       4. Patients with severe symptoms, laryngeal edema, or anaphylaxis should
          receive corticosteroids.

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:
       1. Alcohol, NSAIDS, aspirin, opiates, and ACE inhibitors should be avoided
          in patients with acute urticaria and/or angioedema.

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]



                                                                                           9
        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:
       1. Obtain a C4 level in patients with suspected HAE.
       2. Consider FFP for acute, severe episodes of HAE.

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:
       1. Admit intubated patients and those with laryngeal edema, edema of the
          floor of the mouth, or tongue edema to the ICU.




                                                                                        10
       2. Patients who are unreliable, or those who have disease progression while in
          the ED, should be admitted to a non-ICU bed provided there is no
          laryngeal edema.
       3. Patients with isolated cutaneous swelling can be observed for 6 hours in the
          emergency department and, if there is no disease progression, discharged
          home.

Strength of Evidence: II-iii
Recommendation Grade: B




                                                                                   11
                                                                                               Treatment
                                                                                    - IV, O2, monitor
                                                                                    - Epinephrine SC or IM
                                             Angioedema                             - Intubate patients with stridor,
                                                                                      drooling, tongue edema, or
                                                                                      edema of the floor of the
                                                                            Yes
                                        Does the patient have signs                   mouth
                                         of respiratory distress?                   - Antihistamines
                                                                                    - Corticosteroids



                                                    No
                    Angioedema + Urticaria?                            Isolated Angioedema?



                             Consider:                                         Consider:
                    -Medications (PCN)                                -Medications
                    -Foods                                              -ACE-i / ARB
                    -Insect venom                                       -NSAIDs
                    -Contact allergens (latex)                          -estrogens
                    -Radiocontrast media                              -Hereditary angioedema
                    -Infections (viral)                               -Acquired C1INH def.


                                                      Evaluation
                                              -Clinical diagnosis
                                              -Routine labs not indicated
                                              -Perform NPL on any
                                              patient with:
                                                -dyspnea
                                                -hoarseness
                                                -odynophagia
                                                -laryngeal irritation



                Treatment                                                                   Treatment
-H1 antagonists primary treatment                                           -Discontinue meds (ACE-i)
-H2 antagonists can be added for non-                                       -Antihistamines and corticosteroids can be
responders                                                                  given, but have not been proven to be
-Corticosteroids for severe symptoms                                        efficacious
                                                                            -HAE: consider FFP for severe episodes



                                                    Disposition
                                 -Admit to ICU → intubated pts; any pt with
                                 laryngeal edema by NPL, tongue edema, or
                                 edema of the floor of the mouth
                                 -Admit to non-ICU bed → severe symptoms
                                 without laryngeal edema; unreliable pt, or
                                 symptom progression in ED
                                 -ED observation with discharge → isolated
                                 cutaneous swelling without laryngeal edema +
                                 hemodynamically stable + reliable pt with
                                 available 24 hour follow up
                                                                                                            12
1.    Mathews, K.P., Urticaria and angioedema. J Allergy Clin Immunol, 1983. 72(1):
      p. 1-14.
2.    Dibbern, D.A., Jr. and S.C. Dreskin, Urticaria and angioedema: an overview.
      Immunol Allergy Clin North Am, 2004. 24(2): p. 141-62, v.
3.    Henderson, R.L., Jr., A.B. Fleischer, Jr., and S.R. Feldman, Allergists and
      dermatologists have far more expertise in caring for patients with urticaria than
      other specialists. J Am Acad Dermatol, 2000. 43(6): p. 1084-91.
4.    Baxi, S. and C. Dinakar, Urticaria and angioedema. Immunol Allergy Clin North
      Am, 2005. 25(2): p. 353-67, vii.
5.    Kaplan, A.P. and M.W. Greaves, Angioedema. J Am Acad Dermatol, 2005. 53(3):
      p. 373-88; quiz 389-92.
6.    Champion, R.H., et al., Urticaria and angio-oedema. A review of 554 patients. Br J
      Dermatol, 1969. 81(8): p. 588-97.
7.    Muller, B.A., Urticaria and angioedema: a practical approach. Am Fam
      Physician, 2004. 69(5): p. 1123-8.
8.    Varadarajulu, S., Urticaria and angioedema. Controlling acute episodes, coping
      with chronic cases. Postgrad Med, 2005. 117(5): p. 25-31.
9.    Krishnaswamy, G. and G. Youngberg, Acute and chronic urticaria. Challenges and
      considerations for primary care physicians. Postgrad Med, 2001. 109(2): p. 107-8,
      111-4, 119-23.
10.   Dibbern, D.A., Jr., Urticaria: selected highlights and recent advances. Med Clin
      North Am, 2006. 90(1): p. 187-209.
11.   Bhalla, M. and G.P. Thami, Delayed diagnosis of angiotensin-converting enzyme
      (ACE) inhibitor induced angioedema and urticaria. Clin Exp Dermatol, 2003.
      28(3): p. 333-4.
12.   Grattan, C.E., The urticaria spectrum: recognition of clinical patterns can help
      management. Clin Exp Dermatol, 2004. 29(3): p. 217-21.
13.   Howard, P.J. and M.R. Lee, Beware beta-adrenergic blockers in patients with
      severe urticaria! Scott Med J, 1988. 33(5): p. 344-5.
14.   Sanchez-Borges, M., A. Capriles-Hulett, and F. Caballero-Fonseca, Cutaneous
      reactions to aspirin and nonsteroidal antiinflammatory drugs. Clin Rev Allergy
      Immunol, 2003. 24(2): p. 125-36.
15.   Grattan, C., S. Powell, and F. Humphreys, Management and diagnostic guidelines
      for urticaria and angio-oedema. Br J Dermatol, 2001. 144(4): p. 708-14.
16.   Kozel, M.M., et al., Laboratory tests and identified diagnoses in patients with
      physical and chronic urticaria and angioedema: A systematic review. J Am Acad
      Dermatol, 2003. 48(3): p. 409-16.
17.   Lombardi, C., et al., Are physicians aware of the side effects of angiotensin-
      converting enzyme inhibitors?: a questionnaire survey in different medical
      categories. Chest, 2005. 128(2): p. 976-9.
18.   Agostoni, A. and M. Cicardi, Drug-induced angioedema without urticaria. Drug
      Saf, 2001. 24(8): p. 599-606.
19.   Howes, L.G. and D. Tran, Can angiotensin receptor antagonists be used safely in
      patients with previous ACE inhibitor-induced angioedema? Drug Saf, 2002. 25(2):
      p. 73-6.



                                                                                     13
20.   Brown, N.J., et al., Black Americans have an increased rate of angiotensin
      converting enzyme inhibitor-associated angioedema. Clin Pharmacol Ther, 1996.
      60(1): p. 8-13.
21.   Cicardi, M., et al., Angioedema associated with angiotensin-converting enzyme
      inhibitor use: outcome after switching to a different treatment. Arch Intern Med,
      2004. 164(8): p. 910-3.
22.   Brown, N.J., M. Snowden, and M.R. Griffin, Recurrent angiotensin-converting
      enzyme inhibitor--associated angioedema. JAMA, 1997. 278(3): p. 232-3.
23.   Regoli, D., Neurohumoral regulation of precapillary vessels: the kallikrein-kinin
      system. J Cardiovasc Pharmacol, 1984. 6 Suppl 2: p. S401-12.
24.   Mathews, K.P., et al., Familial carboxypeptidase N deficiency. Ann Intern Med,
      1980. 93(3): p. 443-5.
25.   Agah, R., V. Bandi, and K.K. Guntupalli, Angioedema: the role of ACE inhibitors
      and factors associated with poor clinical outcome. Intensive Care Med, 1997.
      23(7): p. 793-6.
26.   Chiu, A.G., et al., Angiotensin-converting enzyme inhibitor-induced angioedema: a
      multicenter review and an algorithm for airway management. Ann Otol Rhinol
      Laryngol, 2001. 110(9): p. 834-40.
27.   Gunkel, A.R., et al., Angioneurotic edema as a reaction to angiotensin-converting
      enzyme inhibitors. Am J Otolaryngol, 1996. 17(2): p. 87-91.
28.   Megerian, C.A., J.E. Arnold, and M. Berger, Angioedema: 5 years' experience,
      with a review of the disorder's presentation and treatment. Laryngoscope, 1992.
      102(3): p. 256-60.
29.   Sondhi, D., M. Lippmann, and G. Murali, Airway compromise due to angiotensin-
      converting enzyme inhibitor-induced angioedema: clinical experience at a large
      community teaching hospital. Chest, 2004. 126(2): p. 400-4.
30.   Vleeming, W., et al., ACE inhibitor-induced angioedema. Incidence, prevention
      and management. Drug Saf, 1998. 18(3): p. 171-88.
31.   Warner, K.K., J.A. Visconti, and M.M. Tschampel, Angiotensin II receptor
      blockers in patients with ACE inhibitor-induced angioedema. Ann Pharmacother,
      2000. 34(4): p. 526-8.
32.   Bentsianov, B.L., et al., The role of fiberoptic nasopharyngoscopy in the
      management of the acute airway in angioneurotic edema. Laryngoscope, 2000.
      110(12): p. 2016-9.
33.   Ishoo, E., et al., Predicting airway risk in angioedema: staging system based on
      presentation. Otolaryngol Head Neck Surg, 1999. 121(3): p. 263-8.
34.   Simons, F.E., Advances in H1-antihistamines. N Engl J Med, 2004. 351(21): p.
      2203-17.
35.   Lee, E.E. and H.I. Maibach, Treatment of urticaria. An evidence-based evaluation
      of antihistamines. Am J Clin Dermatol, 2001. 2(1): p. 27-32.
36.   Nzeako, U.C., E. Frigas, and W.J. Tremaine, Hereditary angioedema: a broad
      review for clinicians. Arch Intern Med, 2001. 161(20): p. 2417-29.
37.   Bork, K., et al., Hereditary angioedema with normal C1-inhibitor activity in
      women. Lancet, 2000. 356(9225): p. 213-7.




                                                                                     14
38.   Brickman, C.M., et al., Immunoregulatory disorders associated with hereditary
      angioedema. I. Clinical manifestations of autoimmune disease. J Allergy Clin
      Immunol, 1986. 77(5): p. 749-57.
39.   Borum, M.L. and D.E. Howard, Hereditary angioedema. Complex symptoms can
      make diagnosis difficult. Postgrad Med, 1998. 103(4): p. 251, 255-6.
40.   Heymann, W.R., Acquired angioedema. J Am Acad Dermatol, 1997. 36(4): p. 611-
      5.
41.   Hill, B.J., S.H. Thomas, and C. McCabe, Fresh frozen plasma for acute
      exacerbations of hereditary angioedema. Am J Emerg Med, 2004. 22(7): p. 633.


                                                                    7/10/06




                                                                                 15
16