eMedicine Specialties > Pediatrics: General Medicine > Allergy & Immunology

Angioedema: Treatment & Medication

Author: Shih-Wen Huang, MD, Medical Director of Allergy Service, Professor, Department of Pediatrics, Division of Immunology and Infectious Diseases, University of Florida College of Medicine
Contributor Information and Disclosures

Updated: Oct 21, 2009

Treatment

Medical Care

• Preventive measures
• Ideally, episodes of swelling should be prevented with long-term or short-term prophylaxis.
• Once an angioedema episode occurs, mediators that increase vascular permeability have already been released, and intervention measures can only (possibly) reduce the severity or duration of the attack. Therefore, treatment is aimed at preventing attacks.
• Successful pharmacologic approaches have included prevention of the activation of kinin-releasing enzymes or increasing the blood level of normal C1INH. Androgens and antifibrinolytic agents are frequently used to achieve this purpose. C1INH concentrate for prophylaxis, especially before surgery, has been used.
• Treatment of an episode of acute angioedema
• Minor episodes of subepithelial swelling need no treatment, but the patient with edema of the face and neck should be closely observed for spread of edema and signs of airway involvement. When hoarseness or other signs of a compromised airway occur, an otolaryngologist should be consulted for possible tracheostomy. This procedure is usually not needed but is sometimes a life-saving measure.
• The use of C1INH for an acute attack of hereditary angioedema (HAE) has been reported.
• Another treatment that may be beneficial is an oropharyngeal spray of a 1:1000 dilution of racemic epinephrine (0.2-0.3 mL). However, one study indicated that fewer than 27% of patients with hereditary angioedema felt the epinephrine injection was effective during acute attack.⁷
• Cautious sedation with antihistamines may be beneficial. These patients may be frightened when airway symptoms or difficulty in swallowing occurs because they have witnessed affected relatives die during such episodes.
• When an episode of abdominal colic occurs, symptomatic treatment with narcotics may be required to relieve pain. These patients may become addicted.
• When a major loss of fluid from the vascular compartment occurs, replacement with physiologic intravenous fluid may aid in recovery. The degree of hemoconcentration may boost hematocrit (Hct) or leukocyte counts.
• Ultrasonography of the abdomen may be useful when differential diagnosis is needed.
•  Treatment strategies for angioedema
• HAE1 and HAE2: C1INH concentrate administration is preferred for acute treatment and has recently received US Food and Drug Administration (FDA) approval in the United States. Androgens such as danazol and oxandrolone are used for possible prevention of episodes. Hypotension accompanied by abdominal symptoms may require fluid replacement therapy. The combination of meperidine (Demerol) and prochlorperazine (Compazine) suppositories (and possibly dicyclomine to relieve abdominal pain and vomiting) is useful.
• A study was conducted to evaluate effects of short-term and long-term danazol treatment on healthy volunteers and patients with hereditary angioedema (10 females and 7 males).⁹ Short-term danazol treatment in healthy volunteers was associated with a reduction in high-density lipoprotein cholesterol levels without a significant effect on endothelial function or coagulation parameters. In contrast, patients with hereditary angioedema treated for more than 2 years with danazol had increased activation of coagulation, but no significant difference in high-density lipoprotein cholesterol levels or carotid intima-media thickness (CIMT) was noted when compared with matched healthy controls.
• Acquired angioedema type 1 (AAE1): Diagnosis and treatment of underlying lymphoproliferative disease often eliminates the root cause. Antifibrinolytics, such as tranexamic acid and epsilon-aminocaproic acid, may be administered for possible prevention of episodes. Androgen may be helpful.
• AAE2: Antifibrinolytics, such as tranexamic acid and epsilon-aminocaproic acid, may be administered for possible prevention of episodes. Immunosuppressive therapy may be successful.
• Idiopathic angioedema: Antihistamines are primarily used. Dehydroepiandrosterone 1-thyroxine is used for thyroid dysfunction. Prednisone therapy may be considered.
• Nonhistaminergic angioedema (INAE): Consider antifibrinolytics such as tranexamic acid and epsilon-aminocaproic acid.
• Allergic angioedema: Avoid the substance that causes the allergic reaction. Antihistamines and adrenaline (epinephrine, possibly the self-injector EpiPen) are used in case of emergency.
• ACE inhibitor–induced angioedema: The medication is either suspended or changed. 
• Investigational new drugs for hereditary angioedema therapy 
• Three new compounds, the plasma kallikrein inhibitor Dx-88 (Dyax Corp./Genzyme), the bradykinin B2 receptor antagonist Icatibant (Jerini AG), and the recombinant human C1INH (Pharming Group NV) are under investigation at present as potential therapies for hereditary angioedema.
• Dx-88 is a recombinant peptide of 7054 kDa produced in Pichia pastoris for treatment of hereditary angioedema. Three clinical studies with Dx-88 have been completed.¹⁰ A fourth is currently underway. In these completed studies, all types of attacks were successfully treated by either intravenous or subcutaneous administration of Dx-88. The safety profiles appear good, except for one case of anaphylactoid reaction.
• Icatibant is a potent, specific, and selective peptidomimetic bradykinin B2-receptor antagonist. Two clinical trials showed a significant reduction in the time to onset of symptom relief.¹¹ Significant reduction of symptom severity was also achieved. Overall, the results are encouraging. Side effects have not been reported.
• Recombinant human C1 inhibitor (rhC1INH) has been developed by the Pharming Group NV. It was produced in the milk of transgenic rabbits. A favorable safety profile and biologic activity were proved in a phase 1 study.¹² The efficacy in treating angioedema was assessed in an open-label study. The symptom relief was more rapid compared with the control group. No patient experienced side effects or symptom relapse. A randomized, double-blind study is currently in progress.
• Any agent confirmed to be effective would significantly change the future treatment of hereditary angioedema.
• Other updates on the current status of emerging therapies of hereditary angioedema are as follows: 
• Berinert P, a purified, virus-inactivated, human plasma-derived C1 inhibitor concentrate was tested in two international, multicenter prospective trials.¹³ Experience with this agent in Europe and Canada indicates it is effective and safe.
• Cinryze is a nonfiltered C1INH replacement therapy demonstrated to be effective and safe in acute and prophylactic arms of phase 3, double-blind, placebo-controlled study and is now available for use in the United States.¹⁴
• Rhucin, a recombinant human C1INH replacement therapy from transgenic rabbits, has been shown to be effective and safe in phase 2 and phase 2/3 studies.¹⁴
• Follow-up on DX-88 (ecallantide) achieved all primary and secondary efficacy end points in a placebo-controlled, double-blind, phase 3 study, with a second phase 3 study ongoing.¹⁴
• Icatibant was studied in 2 phase 3 trials: For Angioedema Subcutaneous Treatment (FAST) 1 did not achieve statistical significance for the primary end point but did so for secondary end points.¹⁴  FAST 2 achieved statistical significance for primary and secondary end points.

Surgical Care

• Tracheostomy is used in severe cases of laryngeal edema to maintain the airway.

Consultations

• Consultation with an otolaryngologist for possible tracheostomy may be necessary in cases with severe laryngeal edema.
• Consultation with allergists for workup to differentiate between hereditary angioedema and other similar conditions and initiation of proper prophylaxis for patients is appropriate.
• Abdominal ultrasonography by a radiologist may be useful in acute attack.

Activity

• Patients should be told that an acute hereditary angioedema attack could lead to a potentially fatal outcome
• Direct patients as follows:
  • No contact sports are allowed.
  • If surgery or dental procedures are necessary, the patient should be evaluated for prophylactic management.
  • The patient should wear a MedicAlert bracelet or carry an identification card at all times.

Medication

Treatment of urticaria-related angioedema is the same as that for urticaria. Drug therapy for hereditary angioedema (HAE) may be for preventive measures or for the treatment of an acute attack. Few pediatric cases have been reported. Minor episodes of subepithelial swelling need no treatment, but patients with edema of the face and neck should be closely observed for spreading and for signs of airway involvement. Airway involvement can be a true medical emergency in this disorder

Currently, numerous products for the treatment of hereditary angioedema are in trial, including genetically engineered a recombinant C1 esterase inhibitor, a kallikrein inhibitor (Dx-88), and a bradykinin B2-receptor antagonist. They will be reported in detail when clinical data become available.

Androgens

Oral androgens have provided the most successful preventive therapy. Synthetic attenuated androgens (eg, danazol, stanozolol) taken prophylactically increase the serum concentration of C1INH, presumably by enhancing the function of the C1INH gene. When danazol is used prophylactically in adolescents or preadolescents, the concentration of C1INH and C4 are increased in the plasma.

Danazol (Danocrine)

Increases levels of C4 component of complement and reduces attacks associated with angioedema. In hereditary angioedema, danazol increases level of deficient C1 esterase inhibitor.

Stanozolol (Winstrol)

Synthetic androgen with immunosuppressive properties. Increases levels of C1 esterase inhibitor and C4 component of the complement. Its effects are believed to be identical to that of danazol but with fewer adverse effects. This drug is no longer available in the US.

Oxymetholone (Anadrol-50)

Anabolic and androgenic derivative of testosterone in PO formulation. Synthetic attenuated androgen with relatively few adverse effects.

Oxandrolone (Oxandrin)

Considered to be one of the safer anabolic steroids available. Has gained orphan drug status to treat Turner syndrome, constitutional delayed growth or puberty of boys, and alcoholic hepatitis. Has recently been used to treat AIDS-wasting syndrome. Hepatotoxicity more commonly observed in the group receiving 17 alpha alkylated androgen has not been observed. Successful prevention of HANE is reported with oxandrolone when other androgens were ineffective.

Antifibrinolytic agents

These agents have been successfully used as preventive therapy. The effect may depend on physiologic or pathologic enhancement of plasminogen activation in blood, which may promote activation of C1INH.

Aminocaproic acid (Amicar)

Antifibrinolytic agent used for immediate short-term treatment. Thought to prevent extensive edema formation after onset of an attack. Even if the patient has bouts of intestinal edema, symptoms are markedly ameliorated.

Tranexamic acid (Cyklokapron)

Used for immediate short-term treatment. Also prevents extensive edema formation and helps amelioration of intestinal symptoms.

Complement replacement agents

Fresh frozen plasma (FFP) is used for treatment of acute attacks. Replacement therapy is logical in the case of an ongoing attack. Numerous reports indicate that FFP may relieve an episode of edema. Symptoms may worsen because the plasma also contains sufficient substrate to the enzyme that is to be replaced. A change in response to this treatment probably results from differences between the onset of symptoms and the time of an attack. When patient arrives at the emergency department (ED), the attack has probably been underway for a number of hours or more than a day. Some believe that early administration of FFP may worsen edema.

Fresh frozen plasma (FFP)

Plasma is the fluid compartment of blood containing many components essential to the complement cascade (ie, C1 esterase inhibitor).

Serine Proteinase Inhibitors (serpins)

Recently FDA-approved and indicated for routine prophylaxis against angioedema attacks. Derived from human plasma. Investigational use for prevention prior to the scheduled or unscheduled surgery or for treating an acute attack.

C1 inhibitor, human (Cinryze)

C1 inhibitor is a normal constituent of human blood and is one of the serine proteinase inhibitors (serpins). Regulates activation of pathway for complement and intrinsic coagulation. Also regulates fibrinolytic system. Available as a sterile, lyophilized preparation derived from human plasma. Specific activity is 4-9 U/mg protein. One unit corresponds to the mean quantity of C1 inhibitor present in 1 mL of normal fresh plasma. Indicated for routine prophylaxis against angioedema attacks in adolescents and adults with hereditary angioedema.

C1 esterase inhibitor, human (Berinert)

Serine proteinase inhibitor found in human blood that regulates activation of the complement pathway, intrinsic coagulation system, and fibrinolytic system. Binds to and neutralizes substrates that activate these systems, thereby suppressing activity. Available as a pasteurized, lyophilized preparation derived from purified human plasma. One unit corresponds to the mean quantity of C1 inhibitor present in 1 mL of normal fresh plasma. Indicated for acute abdominal and facial angioedema attacks in adolescents and adults with hereditary angioedema.

Sympathomimetic agents

These agents directly or indirectly stimulate adrenergic receptors. They are used as supportive emergency treatment for airway edema.

Epinephrine (Adrenalin)

Oropharyngeal spray of 1:1000 racemic epinephrine helps reduce edema, especially in the upper airway (eg, laryngeal edema).

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