CONTENTS

overview of angioedema

• Diagnosis of angioedema (vs other airway obstructive syndromes)
• Differentiating histamine-mediated versus bradykinin-mediated angioedema
• Airway management
  • Intubation
  • Extubation

histamine-mediated angioedema

• (This is essentially anaphylaxis!)
• (Treat this as anaphylaxis.)

bradykinin-mediated angioedema

• Pathophysiology
• Causes
• Evaluation
• Treatment

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diagnosis of angioedema

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clinical features of angioedema

• Swelling of mucus membranes (e.g., eyelids, tongue, lips, pharynx, larynx, intestines).
• The anatomic distribution varies, depending on the etiology.
• Usually, angioedema may be diagnosed based on swelling of observable anatomy (e.g., lips, tongue).

for a patient with upper airway obstruction (e.g., stridor) & no visible mucus membrane swelling 

• Differential diagnosis is broad here, for example: (28291095)
  • Angioedema can cause localized swelling of the airway (e.g., larynx).
  • Infection (e.g, deep neck space infection).
  • Foreign body.
  • Superior vena cava syndrome.
  • Macroglossia (e.g., due to acromegaly, amyloid, or hypothyroidism)
  • Functional or factitious stridor.
• Nasolaryngoscopy or bronchoscopy is the preferred test:
  • (a) Identify the location of the airway obstruction.
  • (b) Define airway anatomy.
  • (c) Allow planning of therapeutic strategy (e.g., whether or not the patient's airway is amenable to orotracheal intubation).
  • (d) In the case of bronchoscopy, this may be converted into bronchoscopic intubation if necessary.
• CT scan of the neck may be useful in some situations:
  • [1] If the patient has already been intubated, then consider a CT scan of the neck to exclude infectious foci, which may require drainage. Fiberoptic airway examination may be difficult or impossible in the intubated patient.
  • [2] For patients who are stable and able to lie flat, a neck CT scan may occasionally be useful.

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differentiating histamine-mediated vs bradykinin-mediated angioedema

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Angioedema may be divided into histamine-mediated versus bradykinin-mediated etiologies. This is a critical differentiation, because the treatment for these two entities is entirely different. Histamine-mediated angioedema is essentially equivalent to anaphylaxis (so it is treated the same way you would treat anaphylaxis). Alternatively, bradykinin-mediated angioedema requires specific therapies discussed later on in this chapter.

differentiating histamine-mediated versus bradykinin-mediated angioedema

• [1/5] Potential triggers. However, note that both types of angioedema may be triggered by stress. Furthermore, there is often no obvious trigger. (39654054)
  • Histamine-mediated:
    • Allergic trigger (e.g., medications, foods, insects).
  • Bradykinin-mediated:
    • Trauma.
    • Infections.
    • Estrogens (e.g., pregnancy). (39654054)
• [2/5] Distribution:
  • Histamine-mediated: 
    • Diffuse, symmetric distribution of edema.
    • More often involves the lips & eyes.
    • Eyelids in 4%.
    • Lips in 30%.
    • Tongue in 33%.
    • Larynx in only 3%.
    • Extremities in 11%. (29721614)
  • Bradykinin-mediated: 
    • Often focal and asymmetric.
    • Often primarily involves the tongue.
    • Eyelids in 2%.
    • Lips in 24%.
    • Tongue in 42%.
    • Larynx in 17%.
    • Extremities in 4%. (29721614)
• [3/5] Tempo (rapidity of onset & episode duration):
  • Histamine-mediated:
    • Fast onset (may evolve over minutes to hours).
    • Shorter duration (an episode usually lasts for only hours). (35350995)
  • Bradykinin-mediated:
    • Slow onset (evolves slowly, often over ~24-36 hours).
    • Slow duration (episode may last for ~3-5 days). (39654054)
• [4/5] Associated skin findings:
  • Histamine-mediated: 
    • Urticaria or flushing may occur.
    • Pruritus may occur (which can be generalized).
  • Bradykinin-mediated: 
    • No urticaria nor pruritus.
    • (Hereditary angioedema may cause erythema marginatum = erythematous rings on the torso that aren't pruritic).
• [5/5] Involvement of other organs:
  • Histamine-mediated: Other organs are often involved involved:
    • Hypotension.
    • Wheeze is a strong indicator of histamine involvement.
    • GI symptoms (e.g., nausea/vomiting, diarrhea).
  • Bradykinin-mediated:
    • This usually doesn't involve other organs.
    • Bradykinin-induced angioedema can involve the bowel, but bowel symptoms often aren't synchronous with upper airway symptoms (but rather, patients may present with isolated abdominal symptoms).  

approach to sorting out the etiology of angioedema

• History and examination are generally sufficient to sort this out.
• If the diagnosis remains unclear, a diagnostic/therapeutic challenge of epinephrine may be reasonable. Anaphylaxis is histamine-mediated, so it will almost always respond rapidly to aggressive treatment (with epinephrine, antihistamine, and steroid, as discussed below). In contrast, bradykinin-mediated angioedema won't respond to these treatments.

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airway management

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intubation

heliox

• Heliox may also be considered as a stop-gap measure to stabilize the patient sufficiently to organize the material and people required for intubation.

indications for intubation

• Precise indications are unclear. High-quality evidence is impossible to obtain for the following reasons:
  • (#1) Physicians cannot be blinded to clinical features when they decide whether to intubate a patient.
  • (#2) Intubation is generally used as an outcome variable, but this may simply be a measurement of the decision algorithms that physicians employ when deciding whether to intubate (#1).
  • (#3) Truly determining which patients absolutely require intubation would require a decision to randomly assign patients and never intubate some patients and see which patients die, which is obviously impossible.
• Potential indications for intubation are as follows:
  • (1) Stridor, dyspnea – especially if worsening & not responding to therapy.
  • (2) Inability to handle secretions.
  • (3) Progressive deterioration of edema (intubation may become more difficult over time if edema worsens).
  • (4) Nasolaryngoscopy shows significant laryngeal edema or impending closure of the posterior pharynx. When in doubt, nasolaryngoscopy may help reveal whether there is significant laryngeal edema. The true threat to the airway is the larynx and posterior tongue – not the lips and anterior tongue.

intubation is fraught with hazard

• Airway manipulation may worsen swelling.
• Laryngeal edema will often preclude the use of a laryngeal mask airway.
• In severe angioedema, orotracheal intubation may simply be impossible.
• For patients with anaphylaxis (histamine-mediated angioedema), there is a high risk of hemodynamic collapse following intubation: start epinephrine & give fluid beforehand.

general intubation principles

• Any airway attempt must involve a clinician who is skilled, ready, and willing to perform a cricothyrotomy (scalpel-finger-bougie cricothyrotomy). The ideal strategy is a “double setup” wherein one clinician attempts to intubate via the oropharynx and a second clinician is prepared to perform cricothyrotomy if needed.
• Paralysis may precipitate a CICO emergency (“Can't Intubate, Can't Oxygenate”). So rapid sequence intubation can be deadly. Consequently, an awake fiberoptic intubation is preferred.
• The exact details of intubation will depend on patient specifics and available resources.

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extubation 

patient-specific factors to consider

• How severe was the swelling encountered during the initial intubation?
• Has the patient received medical treatment for angioedema? (e.g., steroid/antihistamine/epinephrine for allergic angioedema, or C1-esterase concentrates for C1-esterase deficiency)

general approach

• If there is externally visible swelling (e.g., of tongue/lips), wait until this has substantially improved prior to considering extubation.
• Especially if there is no external swelling, direct examination of the larynx can be helpful. Under deep sedation, very gently insert a hyperangulated video laryngoscope blade over the endotracheal tube. This should allow for direct visualization of the airway, including the epiglottis. The primary determinant of readiness to extubate is visual confirmation that laryngeal edema has improved. (30480175)
• The presence or absence of cuff leak may provide some adjunctive information.

extubation procedure

• Consider extubation over an airway exchange catheter:
  • Leave the airway exchange catheter in place temporarily to ensure that the airway is patent.
  • If stridor occurs, re-intubation can be performed immediately over the exchange catheter.
• Staff and materials should be available to perform reintubation or cricothyrotomy if necessary.

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histamine-mediated angioedema

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• The treatment and investigation of histamine-mediated angioedema is essentially identical to that of anaphylaxis.
• According to the WHO 2020 definition of anaphylaxis, patients with acute histamine-mediated angioedema are actually classified as having anaphylaxis (making these two conditions one and the same!).
• More on anaphylaxis therapy is here.

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pathophysiology of bradykinin-mediated angioedema

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common pathway for bradykinin-mediated angioedema pathogenesis 

• Bradykinin-mediated angioedema involves a vicious spiral involving plasmin, XIIa, and kallikrein, as shown below. These proteins enzymatically activate one another, leading to an explosion of kallekrine activity.
• Kallekrine leads to the generation of bradykinin, a nonapeptide that causes increased capillary wall permeability, resulting in tissue edema. Bradykinin has a short half-life (~34 seconds), so sustained bradykinin elevation must always reflect ongoing, active bradykinin generation. (37394257)
• This vicious spiral results from an imbalance between kallekrines and kallekrine inhibitors. There are different causes of this imbalance (e.g., congenital C1-esterase inhibitor, ACE-inhibitor use). However, all forms of bradykinin angioedema seem to share this common spiral of activity.

clinical implications

• A vicious-spiral physiology explains why people who are predisposed to develop angioedema (e.g., hereditary angioedema) may be fine for long periods of time and then suddenly develop severe, dangerous angioedema. Likewise, this explains the mystery of how patients can take ACE inhibitors for years and then suddenly develop angioedema.
• The most effective therapies will intervene in the vicious-spiral loop (e.g., aminocaproic acid, C1-esterase inhibitor).
• Icatibant lies downstream of the vicious spiral, so it is unable to break the vicious spiral. Consequently, icatibant would be predicted to have reduced efficacy.

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causes of bradykinin-mediated angioedema

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Types of bradykinin-mediated angioedema are listed below. The acute therapy for all of these disorders is similar, so if your diagnosis is slightly incorrect, that will be OK. Sorting out the different types of bradykinin-mediated angioedema can be done later on, after the dust has settled. 

medication-induced

• ACEi-inhibitors:
  • Most often due to ACE inhibitors, but may also be due to angiotensin-receptor inhibitors.
  • It can occur years after starting an ACE inhibitor.
  • Risk appears to be higher among Black patients (5% vs. 0.5%). (37394257)
  • Careful history may often elicit prior episodes of angioedema, which may have been less severe.
• thrombolysis (e.g., tPA).
• Dipeptidyl peptidase-IV inhibitor (i.e., gliptins for diabetes). Dipeptidyl peptidase IV is an enzyme involved in the degradation of bradykinin, similar to ACE.
• Aliskiren (direct renin inhibitor).
• Sirolimus, tacrolimus, everolimus.
• Estrogens: Estrogens can enhance bradykinin signaling. This can exacerbate bradykinin-induced angioedema due to various etiologies (e.g., hereditary angioedema). (35988876)

hereditary angioedema

• Hereditary angioedema due to C1-inhibitor deficiency (onset generally <20 years old).
  • Type 1 (85%): Low C1-esterase protein level.
  • Type 2 (15%): Normal C1-inhibitor level, but the protein is dysfunctional.
• Hereditary angioedema with normal C1-inhibitor function (formerly Type 3):
  • May result from a factor XII mutation (which increases conversion of prekallikrein into kallikrein) or an unknown mutation.
  • Clinically, associated with predominantly tongue edema. (40380367)

acquired angioedema (AAE)

• This is very rare (less common than hereditary angioedema) and typically presents after the age of 40. (28405953)
• Type I:
  • Associated with lymphoproliferative disorders (including chronic lymphocytic leukemia, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, follicular, and splenic marginal zone lymphoma, monoclonal gammopathy of uncertain significance).
  • Due to increased consumption of C1-inhibitor. Anti-idiotype antibodies drive the chronic overactivation of the classic complement pathway, leading to excessive consumption of C1-inhibitor. (40380367)
• Type II:
  • May occur in lupus.
  • Due to autoantibodies against C1-inhibitor, which cause inactivation of C1-inhibitor.

idiopathic angioedema

• Idiopathic angioedema is defined as patients with recurrent angioedema without urticaria, with no explanation despite a thorough evaluation. Two types exist, which may need to be differentiated based on therapeutic trials of antihistamine therapy: (40380367)
• Idiopathic histaminergic angioedema:
  • Patients respond to high-dose antihistamines (up to four times the standard dose), leukotriene receptor antagonists, and/or steroids.
  • (This is listed here for completeness' sake, although it is obviously not bradykinin-mediated.)
• Idiopathic nonhistaminergic angioedema:
  • This is often defined empirically, based on failure to respond to suppressive anti-histaminergic therapies as listed directly above.
  • Icatibant, encallantide, and C1-inhibitor may sometimes be effective.
  • Tranexamic acid is often useful (especially as a preventative therapy). (40380367)

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evaluation of bradykinin-mediated angioedema

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history

• Prior episodes? Hereditary angioedema will typically begin during adolescence.
• Medication history?
• Family history? Family history of angioedema suggests hereditary angioedema (but absence doesn't exclude it, because mutations can occur de novo).

angioedema labs

• C4 level:
  • C4 level may be used as a screening test for hereditary angioedema. Sensitivity is greater during an acute attack (96%) as compared to between attacks (81%). (37394257)
  • Hereditary angioedema-I (low C1-INH): Low.
  • Hereditary angioedema-II (defective C1-INH): Low.
  • Hereditary angioedema with normal C1-INH (often XII abn'l): Normal.
  • Acquired angioedema: Low.
  • ACE-i angioedema: Normal.
  • Idiopathic angioedema: Normal.
• C1-Inhibitor antigen level:
  • Hereditary angioedema-I (low C1-INH): Low (<30%). (40380367)
  • Hereditary angioedema-II (defective C1-INH): Normal.
  • Hereditary angioedema with normal C1-INH (often XII abn'l): Normal.
  • Acquired angioedema: Low or normal.
  • ACE-i angioedema: Normal.
  • Idiopathic angioedema: Normal.
• C1-Inhibitor function:
  • Hereditary angioedema-I (low C1-INH): Low (<30%). (40380367)
  • Hereditary angioedema-II (defective C1-INH): Low (<30%). (40380367)
  • Hereditary angioedema with normal C1-INH (often XII abn'l): Normal.
  • Acquired angioedema: Low.
  • ACE-i angioedema: Normal.
  • Idiopathic angioedema: Normal.
• C1q:
  • Hereditary angioedema-I (low C1-INH): Normal.
  • Hereditary angioedema-II (defective C1-INH): Normal.
  • Hereditary angioedema with normal C1-INH (often XII abn'l): Normal.
  • Acquired angioedema: Low in 75% of patients. (35988876)
  • ACE-i angioedema: Normal.
  • Idiopathic angioedema: Normal.
• Paraprotein:
  • Hereditary angioedema-I (low C1-INH): No.
  • Hereditary angioedema-II (defective C1-INH): No.
  • Hereditary angioedema with normal C1-INH (often XII abn'l): No.
  • Acquired angioedema: Usually present.
  • ACE-i angioedema: Normal.
  • Idiopathic angioedema: Normal.
• Tryptase level:
  • Tryptase level may be used to evaluate for anaphylaxis if this is a concern.
  • (Further discussion of tryptase level is here.)

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treatment of bradykinin-mediated angioedema

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airway management

• Airway management is generally the same for all types of angioedema (discussed above).
• Bradykinin-mediated angioedema often evolves more gradually than histamine-mediated angioedema, so there may be more time to watch the process of disease evolution.

medical therapy: why it is important

• Regardless of intubation status, medical therapy is important:
  • For a patient who isn't intubated: Medical therapy may avert the need for intubation.
  • For a patient who is intubated: Medical therapy may accelerate resolution and reduce the need for prolonged intubation. Remember, every day on the ventilator exposes the patient to a myriad of risks (e.g., ventilator-associated pneumonia, deconditioning, DVT/PE).

🏆 fibrinolytic inhibitors (tranexamic acid or aminocaproic acid)

• Physiology: Fibrinolytic inhibitors block the conversion of plasminogen into plasmin, which is a critical step involved in amplification of kallikrein activation. Theoretically, these agents should be beneficial in any form of bradykinin-mediated angioedema.
• Evidence:
  • Hereditary angioedema: Tranexamic acid and aminocaproic acid have been used for the treatment of hereditary angioedema for decades, more frequently for prevention than for acute management. (27672078, 20101876) Fibrinolytic inhibitors appear to be effective for all types of hereditary angioedema. (35988876)
  • Acquired angioedema: Multiple studies suggest that tranexamic acid is a safe and effective therapy. (35988876)
  • Idiopathic nonhistaminergic angioedema: Tranexamic acid is often used, especially as a suppressive therapy. (40380367)
  • ACEi-related angioedema: IV tranexamic acid is supported by some case reports as well as a large case series (which reported avoidance of intubation in all 31 patients who weren't already intubated prior to receiving tranexamic acid). (29735174, 33164754, 35105472, 33164754, 37525579, 34692327)
• Logistics:
  • These agents are universally available, relatively inexpensive, and generally safe.
• Dosing & contraindications:
  • Dosing of these agents is discussed here.
  • Please note that a single dose is generally inadequate (e.g., a one-time dose of 1 gram of tranexamic acid). Ongoing treatment over time is often required to fully suppress the episode of angioedema. Bradykinin-induced angioedema evolves and resolves over a time frame of days, so treatment for a couple of hours may fail.
• Bottom line:
  • Tranexamic acid or aminocaproic acid are safe, inexpensive, widely available, and likely effective for a broad range of patients with bradykinin-induced angioedema.
  • These are rational front-line agents for most patients with bradykinin-induced angioedema.  Notable exceptions include:
    • [1] Patients with C1 esterase deficiency (in whom C1-esterase concentrate is preferred).
    • [2] Stroke patients with post-thrombolytic angioedema.
  • The choice of tranexamic acid versus aminocaproic acid depends on availability and practitioner preference.

C1-inhibitor concentrate

• Physiology:
  • C1-inhibitor inhibits XIIa and kallikrein, perhaps the two most important enzymes involved in bradykinin generation. Based on its ability to inhibit multiple enzymes that are centrally involved in the spiral of kallikrein activation, this drug is predicted to be useful in treating bradykinin-induced angioedema.
  • C1-inhibitor is the definitive therapy for the management of hereditary forms of angioedema due to a deficiency of C1-inhibitor.
• Evidence:
  • Congenital angioedema with deficient C1-inhibitor activity (Type I and II): C1-inhibitor is generally acknowledged as front-line therapy. It works extremely well.
  • Congenital angioedema without deficient C1-inhibitor activity (Type III): Efficacy of C1-inhibitor is variable, possibly depending on the specific underlying genetic mutation.
  • ACEi-induced angioedema: Retrospective case series of C1-inhibitor use in patients with ACE-inhibitor-induced angioedema have arrived at mixed conclusions: some patients appeared to respond to therapy, whereas others still required intubation despite C1-inhibitor therapy. (32727672, 31843319, 33588931, 27502825, 27886906)
  • Thrombolytic-induced angioedema: Some case studies suggest that it may be useful.
• Logistics: C1-inhibitor is often unavailable in smaller hospitals. The primary limitation of C1-inhibitor is its cost, which is approximately $10,000 for 1,500 units. This is certainly a significant amount of money, but it's still less than the cost of intubation and mechanical ventilation for 2-3 days in the ICU.
• Dose:
  • Berinert: 20 units/kg, generally rounding to the nearest 500-unit vial, most often ~1500 units (preferred, FDA approved for acute exacerbations of hereditary angioedema).
  • Ruconest: 50 units/kg (contraindicated if rabbit allergy).
  • Cinryze: 1000 units (not preferred; FDA approved for long-term prophylaxis).
• Bottom line:
  • C1-inhibitor concentrate is a silver bullet for patients with known C1-inhibitor deficiency.
  • For other types of bradykinin-mediated angioedema, the cost of C1-inhibitor may be difficult to justify.

icatibant

• Physiology: Icatibant is a bradykinin blocker that functions downstream to the vicious spiral of bradykinin generation. Consequently, icatibant is unable to interrupt the vicious cycle that is fundamentally the root cause of this disease process. Theoretically, this may predict that icatibant would be less effective than other agents.
• Evidence:
  • Hereditary angioedema: Evidence supporting icatibant appears robust (based on the FAST-1, FAST-2, and FAST-3 RCTs).
  • ACE-I angioedema: Icatibant initially appeared to be effective in a 2015 RCT. (25629740) However, more recent RCTs have yielded neutral results. (27913306) A 2019 meta-analysis of three RCTs found no statistically significant results. (31290163)
• Logistics: Extremely expensive and not widely available.

ecallantide

• Physiology: Inhibits kallikrein, which is a critical enzyme in the generation of angioedema.
• Evidence:
  • Ecallantide carries a ~3% risk of causing anaphylaxis. (31316698)
  • Hereditary angioedema: Ecallantide is approved for use in acute episodes.
  • ACE-inhibitor-induced angioedema: RCTs have found that ecallantide may only be minimally effective. (25601538, 25182544) It isn't recommended for ACE-inhibitor-induced angioedema. (37394257)
• Logistics: Expensive and not widely available.

fresh frozen plasma (FFP) 

• Physiology: Patients with ACEi-induced angioedema have deficient activity of angiotensin converting enzyme (ACE), whereas patients with hereditary angioedema have deficient C1-inhibitor activity. Fresh frozen plasma contains both of these enzymes, so it may help normalize anti-bradykinin mechanisms in these situations. Fresh-frozen plasma also contains substrates of the kallikrein system (e.g., high-molecular-weight kininogen), which theoretically could exacerbate angioedema.
• Evidence:
  • Case reports generally suggest that FFP may be beneficial in ACEi-induced angioedema, although two recent reports described deterioration despite FFP administration. (27401592, 31892783) A retrospective cohort study found that patients treated with FFP were less likely to require intubation. (26953061) Similarly, case reports describe the use of FFP to prevent or treat exacerbation of hereditary angioedema. (31316698)
  • Risk of harm: FFP carries some known risks, including volume overload, TRALI (transfusion-related acute lung injury), and transmission of bloodborne pathogens. Although these risks are low, they do exist.
• Logistics: Widely available and relatively inexpensive.
• Dose: Two units initially. May use an additional two units subsequently PRN.
• Bottom line: Whether FFP is beneficial remains unclear.

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questions & discussion

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