Angioedema

Bradykinin

Question: What are some examples of bradykinin-mediated angioedema?

Answer: Examples of bradykinin-mediated angioedema include:

• ACE-inhibitor-induced angioedema
• Hereditary Angioedema (HAE)
• Acquired Angioedema (AAE)
• Estrogen-dependent angioedema
• Certain forms of idiopathic angioedema

Question: Why are antihistamines and corticosteroids generally ineffective in treating bradykinin-mediated angioedema?

Answer: Antihistamines are ineffective because bradykinin-mediated angioedema is not driven by histamine. Corticosteroids have limited or no value in these cases because they do not address the underlying bradykinin-related pathology.

Question: How can fresh frozen plasma (FFP) be used in the treatment of bradykinin-mediated angioedema?

Answer: FFP contains C1-INH, which can be helpful in treating some cases of bradykinin-mediated angioedema. However, FFP may also contain substances that could worsen angioedema attacks. If FFP is used, be prepared for potential airway management interventions.

Question: What role do antifibrinolytic agents play in treating bradykinin-mediated angioedema?

Answer: Antifibrinolytic agents, such as aminocaproic acid or tranexamic acid, may be helpful in treating HAE, C1-INH-AAE, and certain cases of idiopathic angioedema. However, they are not indicated for InH-AAE. Their exact mechanism is not fully understood but is thought to relate to the inhibition of plasmin and effects on bradykinin metabolism.

Question: How is C1-INH concentrate used to treat HAE attacks?

Answer: C1-INH concentrate is used to treat acute HAE attacks by infusing 20 U/kg of the agent. Nanofiltered C1-INH concentrate has been shown to reduce the duration of attacks and, when used prophylactically, can decrease the frequency of attacks. It is currently approved by the FDA primarily for prophylaxis.

Question: What are the benefits of using ecallantide for acute HAE attacks?

Answer: Ecallantide is a potent, reversible inhibitor of plasma kallikrein, which suppresses bradykinin generation. This helps manage acute HAE attacks by reducing the excessive bradykinin that causes swelling, inflammation, and pain.

Question: How does icatibant work in the treatment of HAE?

Answer: Icatibant is a bradykinin B2 receptor antagonist that helps manage acute HAE attacks by blocking the action of bradykinin. It is administered subcutaneously via prefilled syringes and can be self-injected by patients.

Question: What are the key management recommendations for patients with HAE?

Answer: Key recommendations for managing HAE include:

• Ensure patients have access to specific medications such as C1 inhibitors, icatibant, or ecallantide.
• Train patients to keep medication on hand and to self-administer if needed.
• Advise patients to treat any recognized attack promptly and to seek hospital care if laryngeal symptoms persist after initial treatment.

Question: What are the treatment options for bradykinin-mediated angioedema?

Answer: For bradykinin-mediated angioedema, administer one of the following targeted therapies:

• Purified C1-INH concentrate (plasma-derived or recombinant)
• Kallikrein inhibitor (e.g., ecallantide)
• Bradykinin-B2 receptor antagonist (e.g., icatibant)
• If ACE inhibitor-induced etiology is suspected, fresh frozen plasma (FFP) can be used as a second-line treatment.

Question: Why are epinephrine, glucocorticoids, and antihistamines generally not effective in acute hereditary angioedema attacks?

Answer: Epinephrine, glucocorticoids, and antihistamines are generally not effective in acute hereditary angioedema attacks because this condition is typically driven by bradykinin rather than histamine. If these treatments have been administered and there is a poor response, targeted therapies for bradykinin-mediated angioedema should be considered.

Anaphylaxis Treatment Guidelines

1. Immediate Actions:

   • Establish and maintain airway.
   • Administer oxygen and intravenous fluids (1-2L).
   • Place the patient flat or in Trendelenburg position if hypotensive.
   • Remove the trigger, if possible.

2. Epinephrine:

   • First-Line Treatment: The only medication that reverses airflow obstruction and prevents cardiovascular collapse.
   • Dosing:
     • IM: 0.3-0.5 mg (1:1000 dilution, 1 mg/mL) in the mid-outer thigh.
     • IV: 0.1-0.3 mg (1:10,000 dilution, 0.1 mg/mL).
     • May repeat every 5-15 minutes. If more than 3 doses are required, consider a continuous infusion at 1-10 mcg/min.
   • Beta Blocker Resistance: If the patient is on beta blockers and resistant to epinephrine, administer glucagon 1-5 mg bolus followed by a continuous infusion at 5-15 mcg/min.

3. Adjunctive Agents:

   • Albuterol: Administer nebulized treatments (stacked nebs x3) as needed for wheezing, cough, or shortness of breath.
   • H1 Antihistamines: Diphenhydramine 25-50 mg IV/IM for pruritus or urticaria. Note: Does not treat airway obstruction or hypotension.
   • H2 Antihistamines: Famotidine 20 mg IV over 2 minutes.
   • Glucocorticoids: Methylprednisolone 125 mg IV. May be beneficial for severe symptoms, known asthma, or significant bronchospasm, though it does not prevent biphasic reactions.

4. Discharge and Follow-Up:

   • Discharge with an EpiPen and refer to an allergist.
   • For history of anaphylaxis to stinging insects, refer for skin testing. If positive, consider subcutaneous venom immunotherapy to reduce the risk of subsequent anaphylaxis from 50-60% to 2-3%.

5. Dosing Summary:

• Epinephrine:
  • IV: 0.1-0.3 mg at 1:10,000 dilution.
  • IM/SQ: 0.3-0.5 mg at 1:1000 dilution.
• Repeat every 5-15 minutes. If more than 3 doses are required, consider a continuous infusion at 1-10 mcg/min.
• Glucocorticoids: Methylprednisolone 125 mg IV, administered once daily for 2 days.
• Diphenhydramine: 50 mg IV/IM.
• Glucagon: For beta-blocker resistance, 1-5 mg bolus followed by a continuous infusion at 5-15 mcg/min.
• Albuterol: For bronchospasm.

ies have shown cyclosporine and various other immunomodulatory drugs, including omalizumab, [59, 60] to be effective for many recalcitrant cases of chronic idiopathic urticaria and angioedema. [61, 46] However, a major limitation of omalizumab treatment is high cost. The beneift of these immunomodulators has not been well studied in angioedema without urticaria. [62] Corticosteroid use in histamine-mediated angioedema should be limited to severe cases. Outpatient treatment should avoid long-term corticosteroid use.

Question:

Answer: Histaminergic angioedema (IH-AAE) can be either immunoglobulin E (IgE)-dependent, such as allergic reactions to food or drugs, or IgE-independent, such as reactions to radiocontrast media. NSAID-related angioedema and most cases of idiopathic angioedema are also treated using similar measures.

Question: What is the first-line treatment for most cases of histaminergic angioedema?

Answer: The first-line treatment for most cases of histaminergic angioedema is the use of second-generation antihistamines (e.g., cetirizine, desloratadine, fexofenadine, levocetirizine, and loratadine). These antihistamines can be used in higher doses, up to four times the standard dosage, to reduce the severity or frequency of attacks.

Question: How do current treatment guidelines recommend managing histaminergic angioedema with second-generation antihistamines?

Answer: Current guidelines support using higher dosages of second-generation antihistamines as the treatment of choice for histaminergic angioedema. This approach is preferred over corticosteroids or other immune modulators, although this recommendation is based primarily on expert opinion with limited clinical evidence.

Question: Are there differences in efficacy among various second-generation antihistamines?

Answer: Some studies suggest that cetirizine 10 mg may be more effective than fexofenadine 180 mg, and levocetirizine 5 mg may be more effective than desloratadine. However, there is variability in findings regarding the sedative effects of these antihistamines, with some studies showing greater sedation with cetirizine compared to others.

Question: What additional treatments are available for moderate-to-severe histaminergic angioedema?

Answer: For moderate-to-severe cases, diphenhydramine 50 mg administered intramuscularly (IM) or intravenously (IV) can be helpful. Hydrocortisone 200 mg IV or methylprednisolone 40-60 mg IV may also reduce the possibility of relapse.

Question: What steps should be taken if a patient with histaminergic angioedema experiences laryngeal swelling and airway obstruction?

Answer: In cases of laryngeal swelling and airway obstruction, close monitoring of the airway is essential. Administer epinephrine (1:1000) IM at a dose of 0.01 mg/kg or 0.3 mg, repeated every 10-15 minutes if necessary. Intubation or tracheostomy may be required, and patients should be admitted for at least 24 hours of observation.

Question: Are there any additional pharmacologic options for treating histaminergic angioedema?

Answer:

• Leukotriene Antagonists: Theoretical benefits have been suggested, but clinical evidence for their effectiveness in urticaria or angioedema is lacking.
• First-Generation Antihistamines: These can be used as add-on therapy when second-generation antihistamines are insufficient. They may be combined with H2 antihistamines and are often given at bedtime to manage sedative effects.
• Doxepin: A tricyclic antidepressant with potent H1-blocking activity, used off-label for recalcitrant angioedema that does not respond to standard antihistamines.
• Immunomodulatory Drugs: Cyclosporine and omalizumab have shown effectiveness in chronic idiopathic urticaria and angioedema. However, omalizumab is costly, and the benefits in angioedema without urticaria are not well studied.

Question: When should corticosteroids be used in histaminergic angioedema?

Answer: Corticosteroids should be reserved for severe cases of histaminergic angioedema. They should not be used long-term for outpatient treatment due to potential side effects.

Understanding Anaphylaxis vs. Angioedema: Symptoms and Treatment Approaches

1. How can you differentiate between anaphylaxis and angioedema in patients?

• Answer: Anaphylaxis often presents with a clear trigger (e.g., bee sting or shellfish ingestion) and features systemic effects such as flushed skin, hypotension, tachycardia, and multiple organ involvement (e.g., upper airway swelling, lung pathologies). Angioedema, on the other hand, might have a similar presentation but is usually localized. There are two types: histamine-induced angioedema, which can present similarly to anaphylaxis with diffuse erythema and swelling, and bradykinin-induced angioedema, which often presents with localized swelling of the lips, tongue, and oral structures without the systemic symptoms seen in anaphylaxis.

2. What are the key differences in symptoms between histamine-induced angioedema and bradykinin-induced angioedema?

• Answer: Histamine-induced angioedema often presents with diffuse erythema, urticaria, pruritus, and systemic symptoms including respiratory and gastrointestinal involvement. Bradykinin-induced angioedema typically shows localized swelling of the lips, tongue, and oral structures, without systemic symptoms or skin manifestations. Bradykinin-induced patients may also present with hypertension due to respiratory distress.

3. How should you approach treatment for histamine-induced angioedema?

• Answer: Treatment for histamine-induced angioedema generally involves administering epinephrine, antihistamines (such as Benadryl), and corticosteroids (like Prednisone). Beta-agonists may be used if there is wheezing or pulmonary involvement. High-flow oxygen with heliox may help in severe cases to improve airway patency.

4. What is the recommended treatment for bradykinin-induced angioedema?

• Answer: For bradykinin-induced angioedema, especially when related to ACE inhibitors, antihistamines and corticosteroids are not usually effective. Instead, Fresh Frozen Plasma (FFP) and Tranexamic Acid (TXA) are considered. FFP can be helpful, though evidence is mixed, and TXA may reduce bradykinin release. C1 esterase inhibitors may be used in hereditary angioedema but are costly and less effective in non-hereditary cases.

5. When is it appropriate to administer epinephrine in cases of suspected anaphylaxis or angioedema?

• Answer: Epinephrine should be administered early if anaphylaxis is suspected or if there is significant airway swelling or systemic symptoms. In cases where there is a rapid progression of symptoms or severe respiratory distress, IM epinephrine is preferred due to its quick action, with IV epinephrine considered if needed.

6. What should be considered regarding airway management in patients with severe angioedema?

• Answer: For severe cases, especially with potential airway compromise, a nasopharyngeal laryngoscopy (NPL) should be performed to assess the airway. In cases where there is significant swelling of the hypopharynx or vocal cords, preparation for intubation should be made. For patients with less severe symptoms, NPL can be used to monitor the airway and decide on further actions based on the findings.

7. How should you manage airway compromise in patients with angioedema?

• Answer: In cases of airway compromise, the focus should be on securing the airway promptly. If the patient’s airway is deteriorating or is at risk, intubation may be necessary. Nasopharyngeal laryngoscopy can help assess the situation, but if the airway is threatened, immediate intubation or even surgical airway intervention may be required. The goal is to stabilize the airway as quickly as possible to prevent respiratory failure.