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Concise Definitive Review

Jonathan E. Sevransky, MD, Series Editor

Angioedema
Daniel LoVerde, DO, MS1; Daniel Clark Files, MD1;
Guha Krishnaswamy, MD, FACP, FCCP, FAAAI, FACAAI1,2

Objectives: Angioedema is a potentially life-threatening occur- Conclusions: Angioedema is a life-threatening syndrome with mul-
rence that is encountered by critical care providers. The mecha- tiple subtypes, each with a distinct pathophysiology. We present
nistic understanding of angioedema syndromes has improved in an evidence-based approach to the diagnosis and suggested
recent years, and novel medications are available that improve management of various subtypes of angioedema. Securing the
outcomes from these syndromes. This clinically focused review airway remains the most important intervention, followed by
will describe the underlying genetics, pathophysiology, classifica- administration of both established and more novel pharmacologic
tion and treatment of angioedema syndromes, with an emphasis interventions based on disease pathology. (Crit Care Med 2017;
on the novel pharmacologic agents that have recently become 45:725–735)
available for acute treatment. Key Words: acquired angioedema; bradykinin B2 receptor
Data Sources: A MEDLINE search was conducted with the MeSH antagonists; hereditary angioedema types I and II; hereditary
terms angioedema, acquired angioedema, hereditary angioedema type angioedema type III; kallikrein-kinin system
III, and angiotensin converting enzyme inhibitor-induced angioedema.
Study Selection: Selected publications describing angioedema,
clinical trials, diagnosis, management, and genetics were retrieved

A
(reviews, guidelines, clinical trials, case series), and their bibliogra- ngioedema is a nonpitting, nondependent, asym-
phies were also reviewed to identify relevant publications. metric form of swelling that stems from increased
Data Extraction: Data from the relevant publications were vasodilation and vascular permeability resulting in
reviewed, summarized and the information synthesized. extravasation of fluid into the subcutaneous and submucosal
Data Synthesis: The data obtained were used to describe the cur- interstitium (Fig. 1). This process is often self-limited but can
rent state of diagnosis and management of various angioedema become life threatening (1–4). The last 2 decades have seen
syndromes. enormous advances in the diagnosis, classification, and man-
agement of angioedema, and these will be summarized in this
review with an emphasis on critical care management.
A MEDLINE search was conducted with the MeSH terms
1
Division of Pulmonary, Critical Care, Allergy and Immunology, Department
of Medicine, Wake Forest Baptist Medical Center, Winston-Salem, NC. angioedema, acquired angioedema, hereditary angioedema
2
Division of Allergy and Clinical Immunology, Department of Medicine, (HAE) type III, and angiotensin converting enzyme inhibi-
W.G. (Bill) Hefner VA Medical Center, Salisbury, NC. tor (ACEI)-induced angioedema. Selected publications in the
This work was completed at Wake Forest Baptist Medical Center. English-literature describing angioedema, clinical trials, diag-
Supplemental digital content is available for this article. Direct URL cita- nosis, management, and genetics were retrieved (reviews, guide-
tions appear in the printed text and are provided in the HTML and PDF lines, clinical trials, case series), and their bibliographies were also
versions of this article on the journal’s website (http://journals.lww.com/
ccmjournal). reviewed to identify relevant publications. Studies were evaluated
Dr. Files disclosed other support (he conducts industry sponsored critical based on the methodologies used, double-blinded randomized
care studies as a site Principal Investigator for the following companies: trials given greater weight than case series or reviews. This is
Ferring, Leading Biosciences and Nestle). His institution received funding noted in appropriate areas in figure and text. Selected sources are
from the Francis Family Foundation, American Thoracic Society Founda-
tion, and National Institutes of Health. Dr. Krishnaswamy disclosed other included in Supplemental Table 1 (Supplemental Digital Content
support from CSL Behring Corporation Immunodeficiency research grant 1, http://links.lww.com/CCM/C388), which includes major trials
support. They make a hereditary angioedema product (purified C1 ester- and current data justifying the use of various medications.
ase inhibitor), but this did not have any impact on the current article. Dr.
LoVerde has disclosed that he does not have any potential conflicts of
interest.
APPROACH TO ANGIOEDEMA IN THE ICU
For information regarding this article, E-mail: gkrishna@wakehealth.edu;
guha.krishnaswamy2@va.gov Angioedema of a fulminant nature can lead to rapid evolution
Copyright © 2017 by the Society of Critical Care Medicine and Wolters of airway obstruction requiring immediate evaluation and tri-
Kluwer Health, Inc. All Rights Reserved. age. When approaching a patient with presumed angioedema
DOI: 10.1097/CCM.0000000000002281 in the ICU, the following questions must be considered.

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LoVerde et al

Figure 1. Mechanisms of bradykinin-mediated angioedema and allergic/histamine-mediated angioedema. Black boxes demonstrate pathway inhibitors.
(A) Bradykinin-mediated angioedema: Complement-1 inhibitor (C1-INH) is a prime inhibitor of the complement C1 (1), plasmin and the factor XII (2),
and kallikrein-kinin-mediated (3) activation pathways. In the absence of C1-INH, there is excess generation of bradykinin, due to activation of kallikrein
by factor XII and plasmin with subsequent generation of high-molecular weight kininogen, the substrate for bradykinin. Bradykinin binds to B2 receptor
on subcutaneous and submucosal vasculature culminating in edema. Additional degradation products of bradykinin (including des-Arg9 bradykinin) may
be active. Mechanism of action of commercially available therapies including purified or recombinant C1 esterase inhibitors, ecallantide, and icatibant
are shown (black boxes). These pathway inhibitors are marked by interrupted arrows. The role of drugs (sacubitril, enalapril, and vitagliptin) in generating
bradykinin by inhibiting degradation and resulting in angioedema is also indicated. Bradykinin-mediated angioedema is resistant to glucocorticoids, epi-
nephrine, and antihistamines with few exceptions. (B) Allergic/histaminergic angioedema: Results from mast cell degranulation and release of histamine,
leukotrienes, and proteases such as tryptase as well as inflammatory cytokines. Antigen presenting cell (APC) or B lymphocyte present allergen to T cells
resulting in elaboration of type 2 (Th2) T-helper cell secreting interleukin (IL)-4 and IL-5. These regulate IgE biosynthesis and eosinophil recruitment,
respectively. IgE occupying its receptor binds to allergen and allows mast cell degranulation leading to mediator release. These events result in urticaria
and angioedema and are exquisitely responsive to glucocorticoids, epinephrine, and antihistamines. BK2 = bradykinin 2, HAE = hereditary angioedema,
HMW = high-molecular-weight kininogen, IgE = immunoglobulin E.

How Is Angioedema Managed Acutely in the ICU? two nanofiltered plasma-derived formulations (Berinert and
Immediate Management. Airway, breathing, and circulation Cinryze). Cinryze has been approved by the USFDA for long-
must be meticulously maintained. Antihistamines (H1 and H2 term prophylaxis, whereas Berinert has been approved for
receptor blockade), epinephrine, and glucocorticoids (5–7) the treatment of acute attacks of HAE (30). These medica-
are uniformly effective in allergic/histaminergic angioedema. tions can be given through either central venous catheters
Glucocorticoids are not immediately effective for angioedema or peripheral venous access devices. Self-dosing is avail-
as a manifestation of anaphylactic reactions; epinephrine is able for all the complement-1 inhibitor (C1-INH) prod-
the drug of choice and needs to be administered immediately. ucts (on demand therapy) and may require placement of an
Corticosteroids, antihistamines, and epinephrine are usually implanted vascular access device if peripheral access is lim-
ineffective for HAE or ACEI-angioedema and are not recom- ited. Plasma-derived nanofiltered C1-INH is administered IV
mended for acute therapy (8). Figure 2 provides our suggested and has been shown to be effective in the acute management
algorithm for evaluation and management. of HAE attacks based on several clinical trials (31–36). Rarely,
Specific Management. Currently, there are four United anaphylaxis (5), hypercoagulability, and thrombotic compli-
States Food and Drug Administration (USFDA) approved cations have occurred (37). Conestat alfa or Ruconest is a
medications (Table 1) available to treat HAE. These include recombinant form of C1-INH administered IV (38–41). It is
two exogenous C1 inhibitors, the bradykinin-receptor antag- purified from the skim milk of transgenic rabbits. Of note,
onist, Icatibant (Firazyr), and the plasma kallikrein inhibitor patients sensitized to rabbits may develop anaphylaxis. Skin
Ecallantide (Kalbitor). or serum testing for rabbit epithelium-specific immuno-
Exogenous C1 inhibitor comes in two formulations: a globulin E is essential before administering this medication.
recombinant form from transgenic rabbits (Ruconest) and Headache, nausea, diarrhea, angioedema, sneezing, erythema

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Concise Definitive Review

Figure 2. This algorithm demonstrates suggested pathophysiologic based management pathways for acute angioedema in the ICU. If airway obstruction
is imminent or manifest, then acute airway management takes immediate precedence. 1) In general, it is important to quickly determine if the patient has
any of the conditions causing pseudoangioedema. 2) If the patient has true angioedema, the presence of urticaria/hives will suggest histamine-induced
or allergic angioedema, usually responsive to epinephrine, antihistamines, and glucocorticoids. 3) If isolated angioedema (usually bradykinin-mediated)
of the airway or elsewhere is present, then determination needs to be made if the patient has hereditary angioedema (HAE) (prior history of HAE, family
history), acquired angioedema (AAE) (due to autoantibody, paraprotein, or lymphoreticular neoplasia), iatrogenic disease (typically angiotensin converting
enzyme inhibitors or other drugs), and by exclusion, idiopathic angioedema. Some patients with AAE and idiopathic angioedema may respond to epineph-
rine, antihistamines, and glucocorticoids. Appropriate management is suggested in this algorithm. C1-INH = complement-1 inhibitor.

marginatum, vertigo, and back pain may occur in a minority Does the Patient Have True Angioedema or a
of patients (38). Condition That Mimics Angioedema?
Ecallantide (Kalbitor) is a recombinant plasma kalli- There are several conditions that may be mistaken for angio-
krein inhibitor that prevents the cleavage of high-molecular edema in the ICU and need to be excluded (49). Examples
weight kininogen, thus reducing the synthesis of bradykinin include anasarca syndromes (such as nephrotic syndrome or
and its serum levels (30). The efficacy of this medication protein losing enteropathies), myxedema, and pseudoangio-
to abort acute angioedema episodes was shown in several edema disorders such as superior vena cava syndrome (49–51).
clinical trials (25,42–44). Self-dosing is not allowed, and the Macroglossia arising from acromegaly, amyloidosis, or hypo-
medication has to be administered by trained personnel. thyroidism may be mistaken for angioedema. In factitious
Icatibant (Firazyr) is a selective, competitive bradykinin B2 angioedema, laryngoscopy demonstrates an absence of vocal
receptor antagonist; several clinical trials have demonstrated cord swelling (51–53). The Melkersson-Rosenthal syndrome is
the efficacy of this medication in aborting acute angioedema characterized by repeated facial nerve palsy, facial or lip edema,
(30, 44–47). The medication can be self-administered as a sin- a fissured tongue, and noncaseating granulomas on biopsy (54).
gle subcutaneous 30-mg dose (5).
Fresh frozen plasma can be used for treatment of HAE but If the Patient Has True Angioedema-What Type Is It?
volume overload, theoretical concerns regarding worsening of Table 2 presents an approach to the classification of angio-
angioedema, and the potential for transmission of infectious edema and includes four categories: angioedema with urti-
agents limit its use (48). caria, angioedema without urticaria, idiopathic angioedema,
Supplemental Table 1 (Supplemental Digital Content 1, and angioedema mimics.
http://links.lww.com/CCM/C388) includes selected sources The presence of urticaria strongly suggests allergic or hista-
including landmark trials, reviews, and case series data mine-mediated angioedema. Bradykinin-mediated angioedema
that justify the use of different pharmacotherapy in each has several subtypes; the prototypic disease is HAE. In general,
angioedema subtype. The results of each study are briefly patients with HAE, acquired and iatrogenic (ACEI-related)
summarized. angioedema, do not develop hives or urticaria, rather edema

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LoVerde et al

TABLE 1. Medications for Acute Attacks of Hereditary Angioedema


Category Product (References) Dosage Indication Adverse Effects

C1-INH Plasma-derived nanofiltered 20 U/kg > 12 yr old Anaphylaxis


C1-INH (Berinert)a (80–86)
Recombinant C1-INH 50 U/kg (< 84 kg) > 18 yr old Anaphylaxis in r­ abbit-allergic
(Conestat alpha/Ruconest)b 4,200 U IV (> 84 kg) patientc
(87–90)
Kallikrein inhibitor Ecallantide (Kalbitor)d 30 mg subcutaneous into > 12 yr old Anaphylaxis
(36, 91–94) abdominal skin
3 doses of 10 mg (1 mL)
Bradykinin receptor Icatibant (Firazyr)e 30 mg subcutaneous > 18 yr old Injection site reaction
antagonist (22, 36, 94–97) Administer in upper arm
Thigh and/or abdomen
FFP FFP (98) 2 U and can repeat every At any age Can worsen adverse effect
2 hr (suggested) Volume overload
Infection transmission
C1-INH = complement-1 inhibitor, FFP = fresh frozen plasma.
a
Plasma derived C1-INH: Second dose can be given 30–120 min after the first dose; Berinert is U.S. Food and Drug Administration-approved for acute use and
Cinryze for prophylaxis.
b
Recombinant C1-INH: Second dose is rarely needed.
C
Assay for rabbit-immunoglobulin E and do not infuse if positive due to risk of serious reactions.
d
Kalbitor: Administered by subcutaneous injection by healthcare professional. Can repeat dose within 24 hr, if required.
e
Icatibant: Administered by subcutaneous injection. If needed, additional dose can be given every 6 hr (no more than three total doses in 24 hr.)

itself is the most prominent feature (Fig. 1). Patients with HAE The Bradykinin-Mediated Angioedema. Subtypes
may develop a nonpruritic, erythematous eruption known as include HAE types I and II, HAE with normal C1-INH,
“erythema marginatum,” but these lesions do not resemble urti- drug-induced angioedema (such as ACEI-induced angio-
caria (55). Table 3 reviews the typical features and laboratory edema), as well as some forms of acquired and idiopathic
abnormalities observed in the various subtypes of angioedema. It angioedema. Proper classification of these disorders are
is to be emphasized that the immediate diagnosis of angioedema based on: 1) absolute level (< 50% of normal level) and
is clinical. Laboratory reports sometimes are only available days 2) function level of C1 INH and/or C1q (Table 3). These
or weeks later and would not influence emergent management. conditions are often resistant to standard therapies such
as epinephrine, glucocorticoids, or antihistamines (Fig. 2)
What Are the Differences Between Allergic/ and are discussed below.
Histamine-Mediated and Bradykinin-Mediated
Angioedema? What Are the Subtypes of Nonallergic, Bradykinin-
In terms of pathogenesis, angioedema may resultant from either Mediated Angioedema?
an excess of histamine (allergic angioedema) or bradykinin syn- HAE is an autosomal dominant disease that results from a defi-
thesis. The pathophysiology is illustrated in Figure 1 and this is ciency in C1-INH production leading to excessive generation
extremely important, as it has profound therapeutic implications. of bradykinin.
Allergic or Histaminergic Angioedema. This is the most Three subtypes of HAE have been described: type I, type
common form of angioedema and almost always occurs with II, and HAE with normal C1-INH these can be differentiated
urticaria (wheals) (20). Allergic angioedema is caused by the clinically and by laboratory testing (Tables 2 and 3) (5, 94, 95).
degranulation of mast cells or basophils with release of media- C1-INH is a member of the serpin (serine protease inhibi-
tors such as histamine, leukotrienes, proteases, and cytokines tor) superfamily and functions as a “suicide inhibitor,” form-
(56–58). Vasodilatation, vascular leakage, mucus hypersecre- ing stoichiometric complexes with its target protease. C1-INH
tion, and inflammation ensue with resultant manifestations. is a 110-kDa glycoprotein comprising 478 amino acids and
The clinical manifestations can begin within several minutes, a 22-residue signal peptide (96). The gene for C1-INH is
or up to 2 hours after the inciting event, occasionally evolv- located on chromosome 11(p11.2-q13) and has been termed
ing into anaphylaxis (7, 20). Some of these episodes may result SERPING1 (73, 94, 97). HAE type I is an autosomal dominant
from specific food allergens, latex exposure, medications, or disease with complete penetrance caused by mutations of the
following exercise (6, 7). Other urticarial syndromes associated SERPING1 gene. Seventy-five percent of the patients have a
with angioedema are listed in Table 2 (6, 7, 20, 59–61). These family history with the remaining 25% representing de novo
conditions are very sensitive to standard therapies such as epi- mutations (96). HAE type II is caused by a missense muta-
nephrine, glucocorticoids, or antihistamines. tion that interferes with the ability of the mutated molecule

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Concise Definitive Review

Classification of Angioedema and


TABLE 2. to inhibit the proteases. Most patients with HAE I and II are
Angioedema Mimics heterozygous for the mutation (74, 96).
The prevalence of HAE in the United States has been approxi-
1. Angioedema with urticaria (histamine- or immune-mediated)a mated at one in 50,000 persons with the disease accounting
  Allergy to food, latex, venom, or medication for about 30,000 emergency department visits per year (5, 74,
  Acute and chronic spontaneous urticaria 96). Nonpruritic, nonpitting subcutaneous, and submucosal
edema occurs frequently, often affecting the face and orophar-
  Other urticaria/angioedema syndromes associated with
angioedema ynx (including tongue, palate, and uvula), legs, arms, buttocks,
and genitalia, and can be painful or disabling. Swelling slowly
  Cold urticaria
increases over a day and resolves over 48–72 hours. Involvement
  Urticarial vasculitis
of the oropharynx, larynx, and tongue can lead to partial or com-
   Exercise-induced urticaria or anaphylaxis plete airway obstruction, whereas bowel edema can lead to severe
   Episodic eosinophilia with angioedema (cytokine-driven) abdominal pain and diarrhea or culminate in intestinal obstruc-
  Vibration-induced urticaria tion or vascular collapse (75–80). Triggers are highly variable and
include trauma, stress, infection, and food although numerous
   Reaction to nonsteroidal agents (nonsteroidal anti-inflammatory
drugs/leukotriene-driven) attacks are cryptogenic. Type I HAE results from abnormally
2. Angioedema without urticaria (bradykinin-mediated)b
low antigenic and functional levels of C1-INH and accounts for
approximately 85% of cases (5, 81, 94). Type II HAE accounts
  HAE due to C1-INH deficiency
for roughly 15% of HAE and is associated with normal antigenic
   Type I (defective C1-INH level and function) C1-INH levels but reduced functional activity (5, 94, 96). The
   Type II (normal C1-INH level but defective function) management is multidisciplinary and will be discussed later.
  HAE with normal C1-INH (formerly type III) HAE with normal C1-INH (formerly HAE Type III) is more
   With factor XII mutation (normal C1-INH levels)
common in females; it results in increased activity of factor XII,
driving enhanced activity of both the contact pathway and fibri-
   HAE-unknown (normal C1-INH levels)
nolytic pathway. It manifests as recurrent cutaneous and mucosal
  Acquired angioedema with C1-INH deficiency swelling in the absence of urticaria with hemorrhage at edema
   Associated with lymphoproliferative disordersc sites (94). Testing shows normal levels of C1-INH and C4 (30,
   Associated with autoantibodyd 62–64, 82–84, 95). Hormone replacement therapy or oral con-
   Associated with autoimmune disease such as lupus
traception often causes worsening of this type of angioedema.
The disease has an autosomal dominant pattern of inheritance
  Angioedema due to medications
with a low penetrance. A minority (25%) of these patients have
   Angiotensin converting enzyme inhibitor mutations in the factor XII gene and are referred to as “HAE-XII,”
   Dipeptidyl peptidase 4 inhibitors whereas the others are referred to as “HAE-unknown” (Tables 2
   Direct renin inhibitor aliskiren and 3) (5, 64, 94). Anecdotal reports suggest that icatibant (65–
   Recombinant tissue plasminogen activator
67), ecallantide (68), and plasma-derived nanofiltered C1-INH
infusions (69) may be beneficial for acute attacks. Discontinuing
   Combination of angiotensin converting enzyme and mechanistic
target of rapamycin inhibitors (sirolimus and everolimus)
hormone replacement therapy or oral contraceptives, as well as
the use of progestins and tranexamic acid, have been effective
3. Angioedema of unknown cause (idiopathic)
prophylactic measures in these patients (62).
 Histaminergic Iatrogenic angioedema is most commonly due to ACEI-
 Nonhistaminergica angioedema, presents often with orofacial edema in 0.7% of
4. Angioedema mimics patients taking these medications and can be fatal (70). ACEI-
  Munchausen stridor/factitious angioedema
angioedema results from inhibition of ACE which results in
reduced degradation and resultant accumulation of bradykinin
  Superior vena cava syndrome
(70–72, 96). ACEI-angioedema has been documented to occur
  Anasarca due to hepatic or renal disease in patients up to 6 months after the last dose of the drug and
 Myxedema can also occur years after starting an ACEI. It is more frequent
  Melkersson-Rosenthal syndrome in females, African-Americans, smokers, and patients being
C1-INH = complement-1 inhibitor, HAE = hereditary angioedema.
treated for heart failure. Patients with prior history of drug rash,
a
Usually sensitive to epinephrine, antihistamines, and glucocorticoids. seasonal allergy, and angioedema seem to be more prone to the
b
Usually resistant to epinephrine, antihistamines, and glucocorticoids. The role complication (70–72, 96). Angiotensin receptor blockers are less
of bradykinin in the mechanisms behind acquired angioedema and idiopathic
angioedema is less clear.
likely to precipitate angioedema and can be used cautiously if
c
Lymphoproliferative disorders described include chronic lymphocytic necessary (96). Recently, there have been reports of angioedema
leukemia, non-Hodgkins lymphoma, Waldenstrom’s macroglobulinemia, with dipeptidyl peptidase 4 inhibitors, the direct renin inhibi-
follicular, and splenic marginal zone lymphoma.
d
Autoantibodies against complement-1 inhibitor (C1-INH) are detectable as tor aliskiren, recombinant tissue plasminogen activator, with
immunoglobulins which prevent C1-INH function or binding to target. combinations of ACEI and mechanistic target of rapamycin

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LoVerde et al

TABLE 3. Clinical and Laboratory Abnormalities and Management of Patients With


Angioedema
Disease Description Laboratory Test Treatment (References)

HAE type 1 (AD) Onset < 20 yr; angioedema affects the Low C4, low C1-INH antigen, Corticosteroids, antihistamines,
85% of HAE face, oropharynx (including tongue, low C1-INH function, normal and epinephrine are ineffective.
palate, and uvula), legs, arms, buttocks, C1q; no paraprotein or MGUS Treatment with C1-INH (purified
and genitalia. Over 300 mutations SERPING1 gene mutations or recombinant), kallikrein, or
(missense, nonsense, frameshift, present. bradykinin-receptor inhibitor
large deletions/insertions, or splicing preferred. Anabolic steroids can
defects are seen) have been described be used for prophylaxis in certain
in the SERPING1 gene located populations (25,42–47).
on chromosome 11 (p11.2-q13);
autosomal dominant disease with 75%
having a family history and 25% being
de novo mutations.
HAE type 2 (AD) Onset < 20 yr; angioedema affects the Low C4, normal C1-INH antigen, As for HAE type 1 (25,42–47).
15% of HAE face, oropharynx (including tongue, low C1-INH function, normal
palate, and uvula), legs, arms, buttocks, C1q; no paraprotein or MGUS.
and genitalia. Fifteen percent of SERPING1 gene mutations
HAE cases demonstrate a missense present.
mutation interfering with the ability
of mutant C1-INH to inhibit target
proteases.
HAE with normal More common in females. Hormone Normal C4, normal C1-INH As for HAE type 1. Stop estrogens
C1-INH dependent; recurrent swelling in the antigen, normal C1-INH (20,54–61).
absence of urticaria with hemorrhage function, normal C1q; no
at edema sites. paraprotein or MGUS; factor
XII gene mutation in a fraction
(25%). Remainder are of
uncertain etiology.
Acquired Onset > age 40 yr. Underlying MGUS, Low C4, low C1-INH antigen, Treat underlying disease.
angioedema B-cell clonal disorders/ low C1-INH function, low C1q. Antifibrinolytic drugs, anabolic
paraproteinemia, lymphoreticular MGUS or autoantibody against steroids, C1-INH (purified or
neoplasia, or autoimmune disorders C1-INH is detectable. recombinant), kallikrein, or
(such as systemic lupus). Can be a bradykinin-receptor inhibitor have
primary autoantibody as well. been used (62–72).
Iatrogenic Due to ACEI, dipeptidyl peptidase Normal C4, normal C1-INH Stop medication. C1-INH (purified
angioedema 4 inhibitors, the direct renin antigen, normal C1-INH or recombinant) or bradykinin-
inhibitor aliskiren, recombinant function, normal C1q; no receptor inhibitor have been used
tissue plasminogen activator, and paraprotein or MGUS; higher in refractory disease (73–84).
combinations of ACEI and mechanistic frequency of atopic disease
target of rapamycin inhibitors (proposed).
(sirolimus and everolimus).
Allergic/ Can occur at any age but usually Normal C4, normal C1-INH Corticosteroids, antihistamines, and
histamine younger patients; any gender; antigen, normal C1-INH epinephrine are very effective
mediated associated with urticaria; may progress function, normal C1q; no (25, 33–41).
angioedema to anaphylaxis; onset minutes to hours paraprotein or MGUS; allergy
after contacting potential allergen. demonstrable to food, latex,
medication, or venom.
Idiopathic Diagnosis after exclusion of above Normal C4, normal C1-INH Corticosteroids and antihistamines
angioedema diagnoses; both histaminergic and antigen, normal C1-INH may be effective. C1-INH
nonhistaminergic varieties have been function, normal C1q; no (purified or recombinant),
described; absence of allergy, HAE, or paraprotein or MGUS. kallikrein, or bradykinin-receptor
medications. inhibitor have been used
anecdotally (85–93).
ACEI = angiotensin converting enzyme inhibitor, C1-INH = complement-1 inhibitor, HAE = hereditary angioedema, MGUS = monoclonal gammopathy of
uncertain significance.
Bolded laboratory tests are abnormal results that suggest the diagnosis of that particular disease in appropriate clinical settings. Levels of complement-1 inhibitor
and C1q of < 50% reported laboratory normal values are considered significant.

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Concise Definitive Review

inhibitors (sirolimus and everolimus) (71). The first step in the tongue or larynx, stridor within 4 hours of onset of symp-
management of drug-induced angioedema is discontinuing the toms, and drooling are considered risk factors for early intu-
suspected medication. Antihistamines and glucocorticoids can bation or tracheostomy (100, 101). African-American females
be initiated but are often ineffective in life-threatening angio- with ACEI-angioedema seem particularly susceptible to severe
edema. Nanofiltered C1-INH infusion (85–88), ecallantide (89, angioedema requiring tracheostomy (102). In difficult cases,
90), and icatibant (86, 91–93) have shown variable efficacy. fiberoptic-guided intubation as well as consultation with an
Acquired angioedema presents after the fourth decade, and a anesthesiologist or otolaryngologist may help in securing the
family history of angioedema is usually absent. More than half airway rapidly though this may not be available in all hospi-
the patients have an underlying autoimmune or hematological tals or healthcare settings (103). A recent study used simulated
disorder, which might include monoclonal gammopathy includ- angioedema in cadavers that allowed training of critical care
ing monoclonal gammopathy of uncertain significance, B-cell personnel in airway management in difficult cases (104). The
clonal disorders/lymphoreticular neoplasia (chronic lympho- most experienced airway provider should manage this situation
cytic leukemia, non-Hodgkin’s lymphoma, Waldenstrom’s mac- with the most advanced airway equipment available (Fig. 2).
roglobulinemia, follicular, splenic marginal zone lymphoma), Ventilator Management. Laryngeal edema, macroglossia, and
or autoimmune disorders (systemic lupus erythematosus). In other fixed upper airway obstructions caused by angioedema are
some cases, an autoantibody against C1-INH is detectable as bypassed by either endotracheal intubation or the placement of
an immunoglobulin either preventing C1-INH function or a surgical airway. In patients with bradykinin-mediated early
binding C1-INH. Orofacial edema is commonly seen; however, administration of C1-INH may prevent progression of angio-
patients can present with abdominal pain or with peripheral and edema minimizing or avoiding airway occlusion. In patients with
genital edema. Plasma-derived C1-INH infusions (9, 98), ecal- difficult airways, massive angioedema, or macroglossia, early con-
lantide (10), and icatibant (11–13) have been used anecdotally. sultation with otolaryngologists or physicians trained in crico-
Treatment of the primary disorder with rituximab (14–17) or thyroidotomy or tracheostomy is essential (105, 106). Ventilator
etanercept (18) can lead to remission. management after the upper airway is secure should include
Idiopathic angioedema is a diagnosis of exclusion and two prevention of ventilator induced lung injury in addition to other
forms have been described, nonhistaminergic and histaminer- evidence-based ventilator management bundles (105, 107).
gic. In this condition, a family history is absent and C1-INH Angioedema typically resolves within 72 hours; therefore, plans
levels are normal. The histaminergic variety responds to anti- for liberation should be made if no other precluding factors exist.
histamines, epinephrine, and glucocorticoids, but a larger A cuff-leak should be present prior to liberation attempts,
dose of antihistamines (up to four times usual dose) may be and all available advanced airway equipment as well as the
required to suppress the angioedema in some patients (19). most experienced airway providers should be at the bed-
The nonhistaminergic variant of idiopathic angioedema might side (105). The patient should be extubated over an airway
be difficult to treat; plasma-derived C1-INH infusion (21, 22), exchange device capable of delivering supplemental oxygen, in
ecallantide (22–24), and icatibant (26–29) have led to anec- case the patient needs to be emergently reintubated. If after 72
dotal improvement. hours, upper airway occlusion persists, alternative diagnoses
should be considered. The placement of an emergent surgi-
What Are the Unique Critical Care Implications of cal airway (cricothyroidotomy or tracheostomy) should be the
Angioedema? last resort but should not be delayed such that hypoxemia is
Airway Emergencies. Assessing and securing of the airway is prolonged. These procedures should be performed by the most
of crucial importance in the management of angioedema as experienced practitioner trained to do so, with surgical backup
airway involvement can lead to life-threatening hypoxemia immediately available (106).
if untreated. Early infusion with purified or recombinant Vascular Emergencies. Stroke and angina can complicate
C1-INH may prevent progression of laryngeal and oropharyn- HAE resulting either from hypoxemia or hypovolemia (108).
geal edema in bradykinin-mediated angioedema. Intubation Additionally, the use of thrombolytic therapy is becoming more
needs to be considered early and often once airway compro- common practice and should be mentioned as a potential trig-
mise is detected. Later into the disease, intubation becomes ger for bradykinin-mediated angioedema. Orolingual edema
difficult and if intubation fails then emergent tracheostomy or as well as hypotension have complicated alteplase treatment
cricothyroidotomy may be required. Supraglottic airways are for stroke (109). There have been reports of C1-INH infusions
not likely to be effective as they will not bypass the obstruc- for angioedema complicating thrombolytic therapy resulting
tion and may lead to worsening edema secondary to laryngeal in resolution of swelling within 2 hours, thereby retarding pro-
trauma. gression to stridor or intubation (110). In one study, 2.2% of
In one U.S. study of 367 acute episodes of angioedema patients developed orolingual edema after alteplase treatment
reported from three hospitals, intubation occurred in 3.3% of for stroke (111). This complication was more frequent (16%)
cases and tracheostomy or cricothyroidotomy in 0.3% (99). if the patients were also being treated with an ACEI. Massive
Although acuity is high in angioedema patients admitted to the macroglossia can also occur, in some cases requiring endo-
ICU, several small U.S. studies suggest that mortality is quite scopic-guided intubation, nasotracheal intubation, or trache-
low (< 2%). Involvement of the anterior tongue, base of the ostomy (103, 112, 113).

Critical Care Medicine www.ccmjournal.org 731


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LoVerde et al

Genitourinary Emergencies. Genital edema has been is essential. Advanced diagnostic testing, consultations with spe-
described with hereditary or ACEI-angioedema and can cialists, and administration of newer advanced therapies are all
present with severe pain and/or genital swelling (114–117). appropriate. However, nothing should delay the establishment of
Epididymitis or orchitis and other testicular emergencies such a secure airway (by the most experienced practitioner).
as testicular strangulation may enter into the differential diag-
nosis. Treatment with C1-INH replacement is usually effective.
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Concise Definitive Review

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