**2. Management of urticaria**

Urticaria is commonly defined as the sudden appearance of wheals that are typically pruritic and resolve within 24 h without any skin changes, although some lesions may last up to 48 h [1]. The updated classification of urticaria distinguishes acute and chronic urticaria. Acute urticaria is defined as the one persisting less than 6 weeks, whereas chronic urticaria (CU) persists for at least 6 weeks [1]. Chronic urticaria is spontaneous (CSU) or inducible (CIU) [2]. CSU is a common disorder with a prevalence of 1% that is characterized by recurrent wheals, angioedema, or both for more than 6 weeks (with or without free intervals). CSU is self‐limited but in many patients, symptoms recur for several years and can be refractory to standard therapies [3, 4].

The international urticaria guidelines advise standard dose, second‐generation H1‐antihistamines as first‐line therapy [5]. However, H1 antihistamine treatment leads to absence of symptoms in fewer than 50% of patients, and in about 10% of cases, they fail to control the disease even at higher than licensed doses [5, 3]. Up‐dosing of second‐generation H1 antihistamines (up to fourfold), as recommended by the urticaria guideline as second‐line therapy, can improve response, but many patients remain symptomatic. The urticaria guideline recommends add‐ on omalizumab, cyclosporin A (CsA) or montelukast third line in patients with an inadequate response to high‐dose H1 antihistamines [5]. In refractory patients, short courses of oral steroids may induce a remission in about 50% of cases [3]. Other approaches include intravenous immu‐ noglobulin, rituximab, dapsone, and anticoagulants are also limited by paucity of data on their efficacy and adverse effect profile [3, 6].

According to guidelines prepared in accordance with data obtained mostly in adult studies, the primarily preferred drug in acute and chronic urticaria exacerbations in children is second‐ generation H1 antihistamines. Guidelines recommend that the dose should be increased three or fourfold in cases where response to H1 antihistamines treatment is not obtained at normal doses. If success of therapy cannot be achieved with H1 antihistamines used at the usual dose, high‐dose H1 antihistamines is recommended. It has been reported that corticosteroids may be used short term (up to 10 days) in periods of urticaria exacerbations. However, guidelines also state that a definite recommendation cannot be made because there are insufficient ran‐ domized controlled studies in this area. The primary treatment option in long‐term treatment of chronic urticaria is again second‐generation nonsedative H1 antihistamines. However, the number of randomized controlled studies is substantially low for evidence‐based rec‐ ommendations in children. In patients who do not respond to high‐dose H1 antihistaminic treatment, corticosteroid, omalizumab, cyclosporin A, and montelukast constitute tertiary treatment options. However, these drugs are recommended only in eligible patients because of the adverse effects and costs of these drugs [7].

It is clear that the current evidence‐based treatment algorithm does not fit every urticaria patient. It is important that physicians do not just consult the algorithm but read the guideline line by line and employ an individualized approach for the care of each patient.

#### **2.1. H1 antihistamines**

addition of H2 antagonist, or leukotriene receptor antagonists. First‐generation antihista‐ mines like hydroxyzine or doxepin can be considered in patients whose symptoms remain uncontrolled in bed time. Systemic corticosteroids are frequently used for refractory patients with urticaria and might be considered in some patients for only short‐time use. Alternative therapies including omalizumab are approved by the Food and Drug Administration (FDA) for patients with chronic refractory urticaria and cyclosporine. Anti‐inflammatory agents including dapsone, sulfasalazine, hydroxychloroquine, and colchicine have been used in

Acute attacks of HAE are unresponsive to antihistamines or corticosteroids. C1‐INH replacement, plasma kallikrein inhibitor, bradykinin receptor antagonist, and fresh frozen plasma have been approved for the treatment of acute attacks. Angioedema caused by ACE inhibitors can be an acute emergency with laryngeal or tongue edema. There is no response to antihistamines or corticosteroids. Fresh frozen plasma, C1 inhibitor, and bradykinin recep‐ tor antagonist appear to be safe and effective therapeutic options for the management of

Urticaria is commonly defined as the sudden appearance of wheals that are typically pruritic and resolve within 24 h without any skin changes, although some lesions may last up to 48 h [1]. The updated classification of urticaria distinguishes acute and chronic urticaria. Acute urticaria is defined as the one persisting less than 6 weeks, whereas chronic urticaria (CU) persists for at least 6 weeks [1]. Chronic urticaria is spontaneous (CSU) or inducible (CIU) [2]. CSU is a common disorder with a prevalence of 1% that is characterized by recurrent wheals, angioedema, or both for more than 6 weeks (with or without free intervals). CSU is self‐limited but in many patients, symptoms recur for several years and can be refractory to

The international urticaria guidelines advise standard dose, second‐generation H1‐antihistamines as first‐line therapy [5]. However, H1 antihistamine treatment leads to absence of symptoms in fewer than 50% of patients, and in about 10% of cases, they fail to control the disease even at higher than licensed doses [5, 3]. Up‐dosing of second‐generation H1 antihistamines (up to fourfold), as recommended by the urticaria guideline as second‐line therapy, can improve response, but many patients remain symptomatic. The urticaria guideline recommends add‐ on omalizumab, cyclosporin A (CsA) or montelukast third line in patients with an inadequate response to high‐dose H1 antihistamines [5]. In refractory patients, short courses of oral steroids may induce a remission in about 50% of cases [3]. Other approaches include intravenous immu‐ noglobulin, rituximab, dapsone, and anticoagulants are also limited by paucity of data on their

According to guidelines prepared in accordance with data obtained mostly in adult studies, the primarily preferred drug in acute and chronic urticaria exacerbations in children is second‐ generation H1 antihistamines. Guidelines recommend that the dose should be increased three

some patients with limited evidence for efficacy in chronic urticaria.

ACEI‐induced angioedema.

standard therapies [3, 4].

efficacy and adverse effect profile [3, 6].

**2. Management of urticaria**

94 A Comprehensive Review of Urticaria and Angioedema

Current international guidelines recommend a licensed dose of second‐ or third‐generation (non‐sedating) antihistamines for the treatment of all forms of urticaria as the first‐line therapeutic option. Second‐generation H1 antihistamines include fexofenadine, loratadine, and cetirizine. Third‐generation antihistamines include desloratadine and levocetirizine. These medications should be taken continuously at the lowest necessary dose rather than on demand. This treatment with licensed doses of H1 antihistamines leads to an absence of symptoms in fewer than 50% of patients with CSU [5].

If CSU symptoms persist after 2 weeks of treatment with licensed doses of second‐generation H1 antihistamines, it is recommended to increase the dose up to four times the licensed dose instead of combining different H1 antihistamines to obtain control as a second‐line treatment. But there are only few controlled studies that have assessed the efficacy and safety of non‐ sedating antihistamines [5, 6]. This dose increase results in a higher degree of efficacy in some, but not all, patients, with up to one‐third of patients remaining symptomatic [5].

First‐generation H1 antihistamines (diphenhydramine and hydroxyzine) are lipophilic compounds which cross the blood‐brain barrier and therefore sedating and anticholinergic side effects. They impair cognitive function, learning, and performance. First‐generation H1 antihistamines have been advocated for use by the US guidelines as step two therapy at night and can be titrated up to higher doses as step three therapy if tolerated by the patient. Non‐sedating second‐ and third‐generation H1 antihistamines have lower pro‐ pensity to cross the blood‐brain barrier. Because of this, non‐sedating H1 antihistamines are favored [6].

In studies mentioned above, higher‐than‐standard doses of antihistamines were not associated with an increase in adverse effects in most cases. Antihistamines also have anti‐ inflammatory effects in the treatment of urticaria when used at higher doses than licensed doses. Anti‐inflammatory activity may result from the activation of genes responsible for the synthesis and/or synthesis of pro‐inflammatory mediators [6].

#### **2.2. H2 antihistamines**

H2 antihistamines such as cimetidine and ranitidine are more typically used as add‐on ther‐ apy in combination with H1 antihistamines and leukotriene receptor antagonists (LTRAs). A review of the Global Urticaria Forum's attendees' opinions suggested that although these agents are old and generally well tolerated by patients, they are unlikely to be used in clinical practice [8].

#### **2.3. Leukotriene receptor antagonists**

Cysteinyl leukotrienes are potent pro‐inflammatory mediators, the effects of which can be blocked by LTRAs such as montelukast, zafirlukast, and pranlukast. LTRAs are recommended as add‐on step two therapies by the US guidelines and in the third step in the Europe Union's (EU) guidelines. LTRAs have been found to significantly improve CU symptoms when used in conjunction with H1 antihistamines but are not as effective as H1 antihistamines when used as monotherapy. Combination therapy of antihistamines plus LTRAs may be more effective in patients with aspirin and nonsteroidal anti‐inflammatory drug‐exacerbated CSU. LTRAs appear to be well tolerated, with a good side‐effect profile. Montelukast is not cur‐ rently licensed for the treatment of CSU [1, 5, 9, 10].

#### **2.4. Third‐line treatments**

If a patient's CSU symptoms persist after 1–4 weeks of second‐line treatment, add‐on omalizumab, CsA, or montelukast are recommended as third‐line options. Both omalizumab and CsA are effective third‐line CSU treatments; montelukast appears to have lower efficacy in this setting.

#### **2.5. Omalizumab**

Omalizumab, a humanized recombinant immunoglobin (Ig) G1 kappa monoclonal anti‐IgE, is effective in antihistamine‐unresponsive patients although optimal treatment duration needs to be defined [3]. Omalizumab is currently the only agent licensed for the third‐line treatment of CSU [8]. The FDA approved the omalizumab for CU is 150 to 300 mg subcutaneously every 4 weeks. The clinical response starts after 1 week at the earliest, and the complete response can be prolonged up to 4–6 months. Studies found that complete control in approximately one‐ third of patients, partial control in another one‐third, and one‐third were unresponsive [1].

Omalizumab carries a label warning for anaphylaxis, although no cases of anaphylaxis were reported in the phase III trials of omalizumab in CSU. Other known risks associated with omalizumab include increased risks of cardiac and neurovascular events and a controversial increased risk of lymphoma. Omalizumab is generally well tolerated in patients with CSU and is rated as pregnancy category B [5, 1].

#### **2.6. Cyclosporin A**

doses. Anti‐inflammatory activity may result from the activation of genes responsible for the

H2 antihistamines such as cimetidine and ranitidine are more typically used as add‐on ther‐ apy in combination with H1 antihistamines and leukotriene receptor antagonists (LTRAs). A review of the Global Urticaria Forum's attendees' opinions suggested that although these agents are old and generally well tolerated by patients, they are unlikely to be used in clinical

Cysteinyl leukotrienes are potent pro‐inflammatory mediators, the effects of which can be blocked by LTRAs such as montelukast, zafirlukast, and pranlukast. LTRAs are recommended as add‐on step two therapies by the US guidelines and in the third step in the Europe Union's (EU) guidelines. LTRAs have been found to significantly improve CU symptoms when used in conjunction with H1 antihistamines but are not as effective as H1 antihistamines when used as monotherapy. Combination therapy of antihistamines plus LTRAs may be more effective in patients with aspirin and nonsteroidal anti‐inflammatory drug‐exacerbated CSU. LTRAs appear to be well tolerated, with a good side‐effect profile. Montelukast is not cur‐

If a patient's CSU symptoms persist after 1–4 weeks of second‐line treatment, add‐on omalizumab, CsA, or montelukast are recommended as third‐line options. Both omalizumab and CsA are effective third‐line CSU treatments; montelukast appears to have lower efficacy

Omalizumab, a humanized recombinant immunoglobin (Ig) G1 kappa monoclonal anti‐IgE, is effective in antihistamine‐unresponsive patients although optimal treatment duration needs to be defined [3]. Omalizumab is currently the only agent licensed for the third‐line treatment of CSU [8]. The FDA approved the omalizumab for CU is 150 to 300 mg subcutaneously every 4 weeks. The clinical response starts after 1 week at the earliest, and the complete response can be prolonged up to 4–6 months. Studies found that complete control in approximately one‐ third of patients, partial control in another one‐third, and one‐third were unresponsive [1].

Omalizumab carries a label warning for anaphylaxis, although no cases of anaphylaxis were reported in the phase III trials of omalizumab in CSU. Other known risks associated with omalizumab include increased risks of cardiac and neurovascular events and a controversial increased risk of lymphoma. Omalizumab is generally well tolerated in patients with CSU

synthesis and/or synthesis of pro‐inflammatory mediators [6].

**2.2. H2 antihistamines**

**2.3. Leukotriene receptor antagonists**

96 A Comprehensive Review of Urticaria and Angioedema

**2.4. Third‐line treatments**

in this setting.

**2.5. Omalizumab**

rently licensed for the treatment of CSU [1, 5, 9, 10].

and is rated as pregnancy category B [5, 1].

practice [8].

Cyclosporin A (CsA) could be a suitable drug for the treatment of CSU as it directly inhibits mast cell degranulation as well as targeting T‐cells. Similarly, CsA directly inhibits part of the basophil histamine release assay (BHRA) [5]. Response of autoreactive CSU to CsA has been associated with disappearance of autoantibodies and CsA may be disease‐modifying in these patients [5]. A low‐dose CsA treatment (3 mg/kg per day or less) has been shown to cause full remission of symptoms in a number of different randomized controlled trials and real‐world studies [11–14].

CsA is also effective in the majority of antihistamine‐resistant CSU patients, but its use is limited by potential side effects [3]. The most common adverse events associated with the use of CsA include hypertension, fatigue, gastrointestinal problems, and headache [15]. It is also thought that long‐term use of CsA may be responsible for the development of non‐melanoma skin cancer [16]. In patients receiving CsA therapy, monitoring of blood pressure and renal function is particularly important [13]. CsA is not currently licensed for the treatment of CSU and should be preferred only as a short‐term treatment option [5].

Cyclosporin has been reported to be effective in some studies of CSU, including three double‐blind [12–18], and one study reported that 40% of patients achieved complete remis‐ sion in 9 months [18].

#### **2.7. Other treatment options**

Other possible options for the treatment of CSU are anti‐inflammatory medications (hydroxychloroquine, dapsone, sulfasalazine, and colchicine) and immunosuppressants (mycophenolate, tacrolimus, azathioprine, and methotrexate) supported by low levels of evidence as defined by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system (**Table 1**).


(+) recommendation for medication, (−) recommendation against medication, and Ig: immunoglobulin

**Table 1.** Quality of evidence and strength of recommendation for use of intervention in CSU based on the GRADE system.

#### **2.8. Dapsone**

In the current international urticaria guideline, the use of dapsone and its effectivity is still unclear. However, in a double‐blind, placebo‐controlled study, dapsone has been reported as a promising agent in patients with CSU unresponsive to antihistamines [19]. Supportive evidence is needed to recommend the use of dapsone in urticaria patients [8].

#### **2.9. Azathioprine**

Additional new therapies such as azathioprine are under investigation for use in urticaria, although the evidence supporting their use is currently limited and not robust enough to warrant a change in current guidance [8].

#### **2.10. Corticosteroids**

Oral corticosteroids are commonly used in management of acute urticaria, and prednisone has been shown to significantly improve control of symptoms compared to antihistamines alone. Short courses (10 days–3 weeks) of corticosteroids may be used at any time if disease exacerbations are required in CU [5, 1].

### **3. Management of angioedema**

Although both urticaria and allergic angioedema are associated with mast cell activation, there are many differences between them. While urticaria affects the skin, angioedema usu‐ ally affects the mucosal tissue as well. In addition, middle and papillary dermis are involved in urticaria, whereas reticular dermis and submucosal tissues are involved in angioedema. Angioedema usually resolves in less than 24–48 h, disappear without aftereffects and are more painful than itchy [20, 2, 1].

Most cases of angioedema are attributable to the histamine and bradykinin. Histamine‐ mediated (allergic) angioedema occurs through a type I hypersensitivity reaction, whereas bradykinin‐mediated (non‐allergic) angioedema is iatrogenic or hereditary in origin. Bradykinin‐mediated angioedema is divided into three distinct types: hereditary angioedema (HAE), angiotensin‐converting enzyme inhibitor (ACEI)‐induced angioedema, and acquired angioedema (AAE) [20] (**Table 2**). Although their clinical presentations bear similarities, the treatment algorithm differs significantly from each other. Corticosteroids and epinephrine are effective only in the management of histamine‐ mediated angioedema [20].

Priority of the treatment of angioedema is to provide airway protection. Intramuscular epi‐ nephrine may be required in the presence of acute laryngeal edema or anaphylaxis. It is administered in adult patients at doses of 1:1000 mg 0.2–0.5 mg and in children at doses of 0.01 mg/kg (up to 0.03 mg). These doses may be repeated at intervals of 5–15 min and if necessary with monitoring [20].


ACE, angiotensin‐converting enzyme; ARB, angiotensin receptor blocker; NSAID, nonsteroidal anti‐inflammatory drug.

**Table 2.** Clinical and diagnostic features of various types of angioedema.

#### **3.1. Hereditary angioedema**

**2.8. Dapsone**

**2.9. Azathioprine**

**2.10. Corticosteroids**

warrant a change in current guidance [8].

98 A Comprehensive Review of Urticaria and Angioedema

exacerbations are required in CU [5, 1].

**3. Management of angioedema**

more painful than itchy [20, 2, 1].

mediated angioedema [20].

necessary with monitoring [20].

In the current international urticaria guideline, the use of dapsone and its effectivity is still unclear. However, in a double‐blind, placebo‐controlled study, dapsone has been reported as a promising agent in patients with CSU unresponsive to antihistamines [19]. Supportive

Additional new therapies such as azathioprine are under investigation for use in urticaria, although the evidence supporting their use is currently limited and not robust enough to

Oral corticosteroids are commonly used in management of acute urticaria, and prednisone has been shown to significantly improve control of symptoms compared to antihistamines alone. Short courses (10 days–3 weeks) of corticosteroids may be used at any time if disease

Although both urticaria and allergic angioedema are associated with mast cell activation, there are many differences between them. While urticaria affects the skin, angioedema usu‐ ally affects the mucosal tissue as well. In addition, middle and papillary dermis are involved in urticaria, whereas reticular dermis and submucosal tissues are involved in angioedema. Angioedema usually resolves in less than 24–48 h, disappear without aftereffects and are

Most cases of angioedema are attributable to the histamine and bradykinin. Histamine‐ mediated (allergic) angioedema occurs through a type I hypersensitivity reaction, whereas bradykinin‐mediated (non‐allergic) angioedema is iatrogenic or hereditary in origin. Bradykinin‐mediated angioedema is divided into three distinct types: hereditary angioedema (HAE), angiotensin‐converting enzyme inhibitor (ACEI)‐induced angioedema, and acquired angioedema (AAE) [20] (**Table 2**). Although their clinical presentations bear similarities, the treatment algorithm differs significantly from each other. Corticosteroids and epinephrine are effective only in the management of histamine‐

Priority of the treatment of angioedema is to provide airway protection. Intramuscular epi‐ nephrine may be required in the presence of acute laryngeal edema or anaphylaxis. It is administered in adult patients at doses of 1:1000 mg 0.2–0.5 mg and in children at doses of 0.01 mg/kg (up to 0.03 mg). These doses may be repeated at intervals of 5–15 min and if

evidence is needed to recommend the use of dapsone in urticaria patients [8].

Hereditary angioedema (HEA) is a rare, autosomal dominant disorder characterized by a quantitative (type I) or qualitative (type II) deficiency of C1 esterase inhibitor (C1‐INH) protein. HAE with normal C1‐INH (type III) occurs because of one of two known mutations in the gene for factor XII [20].

#### **3.2. C1‐INH replacement therapy**

C1‐INH replacement therapy maintains a central role for the treatment of angioedema attacks in patients with HAE. Berinert is a purified, pasteurized, and lyophilized form of C1‐INH concentrate which is derived from human plasma. It was approved by the US FDA in 2009 for the treatment of acute abdominal, facial, and, more recently, laryngeal attacks of HAE in adult and adolescent patients [20]. It is approved in the European Union and the USA for adults and adolescents (≥13 years of age) for the treatment of acute angioedema attacks in patients with HEA due to C1‐INH deficiency [21] (**Table 3**).

#### **3.3. Plasma kallikrein inhibitor**

Ecallantide (Kalbitor) received FDA approval in 2009 for use in the treatment of acute exacer‐ bations of HEA in people aged 16 years and more. However, the EU rendered a negative opin‐ ion regarding its approval. Ecallantide can be used against attacks of HAE at any anatomical location, including abdominal/gastrointestinal, laryngeal, and peripheral attacks [22] (**Table 3**).

#### **3.4. Bradykinin receptor antagonist**

Icatibant (Firazyr) is a highly selective competitive bradykinin β2 receptor antagonist, and it is available as 30 mg in 3‐ml solution as a ready‐to‐use syringe for immediate subcutaneous injection in an HAE attack [20] (**Table 3**).


**Table 3.** Treatment options of hereditary angioedema.

#### **3.5. ACE inhibitor‐induced angioedema**

concentrate which is derived from human plasma. It was approved by the US FDA in 2009 for the treatment of acute abdominal, facial, and, more recently, laryngeal attacks of HAE in adult and adolescent patients [20]. It is approved in the European Union and the USA for adults and adolescents (≥13 years of age) for the treatment of acute angioedema attacks in patients with

Ecallantide (Kalbitor) received FDA approval in 2009 for use in the treatment of acute exacer‐ bations of HEA in people aged 16 years and more. However, the EU rendered a negative opin‐ ion regarding its approval. Ecallantide can be used against attacks of HAE at any anatomical location, including abdominal/gastrointestinal, laryngeal, and peripheral attacks [22] (**Table 3**).

Icatibant (Firazyr) is a highly selective competitive bradykinin β2 receptor antagonist, and it is available as 30 mg in 3‐ml solution as a ready‐to‐use syringe for immediate subcutaneous

20U/kg body weight IV at a rate of

30 mg (3 ml) SC in three 10‐mg (1 ml)

If attack persists, additional dose of 30 mg (3 ml) may be administered

for use when C1‐INH concentrate is

If attack persists, additional injections of 30 mg (3 ml) may be administered

No more than 3 injections in 24 h

Monitor patients with known risk factors for thrombotic events

Epinephrine should be immediately available to treat any acute severe hypersensitivity reactions following discontinuation of administration

hypersensitivity symptoms and acute HAE symptoms, monitor patients closely for hypersensitivity reactions

Administer in a setting equipped to manage anaphylaxis and HEA

Baseline, liver function test, hepatitis

For patients who never received Firazyr previously, the first treatment should be given in a medical institution or under the guidance of

Given the similarity in

virology

a physician

**Therapy and indication Dosage Monitoring tests**

4 ml/min

injections

Fresh frozen plasma 2U at 1–12 h before the event (only

Bradykinin β2 receptor antagonist 30 mg (3 ml) injected SC in the

C1‐INH, C1 esterase inhibitor; IV, ıntravenously; SC, subcutaneously.

**Table 3.** Treatment options of hereditary angioedema.

within a 24‐h period

not available)

abdominal area.

at intervals of ≥ 6h

HEA due to C1‐INH deficiency [21] (**Table 3**).

100 A Comprehensive Review of Urticaria and Angioedema

**3.3. Plasma kallikrein inhibitor**

**3.4. Bradykinin receptor antagonist**

injection in an HAE attack [20] (**Table 3**).

C1 esterase inhibitor [human] (Berinert; CSL Behring)

Indicated for the treatment of acute abdominal or facial attacks of HEA in adult and adolescent patients

Plasma kallikrein inhibitor (kalbitor

Indicated for attacks at all anatomic

(Fizary [Icatıbant] Shire Orphan

Indicated for attacks at all anatomic

[ecallantide]; Dyax Corb)

sites

Therapies)

sites

ACEI‐induced angioedema is due to excessive accumulation of bradykinin. ACEI‐induced angioedema is most commonly present with swelling of face, lips, tongue, and larynx and rarely involves visceral organs. Urticaria and itching are notably absent. Life‐threatening edema of the upper airway is present in 25–39% of cases of ACEI‐induced angioedema. Although ACEI‐induced angioedema most commonly occurs shortly after treatment is initiated, it can develop long after treatment has started [20]. The nonallergic nature of the reaction renders traditional therapies (corticosteroids and antihistamines) as ineffective. Fresh frozen plasma, C1 inhibitor, and icatibant appear to be safe and effective therapeutic options for the management of ACEI‐induced angioedema [22].

#### **4. Management of anaphylaxis**

Anaphylactic findings may include diffuse urticarial plaques, angioedema, gastrointestinal symptoms, and hypotension. In severe forms of anaphylaxis, loss of consciousness due to vascular collapse may develop. Pulmonary symptoms such as hyperinflation, peribronchial obstruction, and submucosal edema are frequently observed during ana‐ phylaxis [20].

Elevation of lower extremities and placing in a supine position of the patient (semi‐reclining if dyspneic or vomiting) are recommended [23]. An important component of acute man‐ agement of anaphylaxis is volume expansion. The largest catheter possible should be placed on the largest peripheral vessel, and the rate should be titrated according to pulse and blood pressure. Adults are infused with 1–2 L iv of normal saline (5–10 mL/kg in the first 5 min) and 30 mL/kg iv in the first h in children. Antihistamines act slower than epi‐ nephrine and should not be administered alone in the treatment of anaphylaxis or acute allergic angioedema. The combined use of H1 and H2 blockers is more effective than the H1 antihistamines alone. Diphenhydramine should be administered to 25–50 mg iv in adults and 1 mg/kg iv (up to 50 mg) in children. Similar oral doses may be sufficient for mild episodes. Ranitidine should be infused 1 mg/kg iv in adults, 12.5–50 mg, iv for 10 min, in children. Inhaled β2 agonists are useful when bronchospasm is resistant to epinephrine injection alone. Systemic corticosteroids are not sufficient to prevent anaphy‐ laxis. Although the use of parenteral corticosteroids (iv methylprednisolone) provides a benefit in histamine‐mediated angioedema, the therapeutic effect is not immediate [20]. Epinephrine is the first choice as recommended in all guidelines. It is recommended to inject from an autoinjector IM in the mid‐outher of the thigh. The first‐aid dose of epi‐ nephrine is 0.01 mg/kg of a 1 mg/mL (1:1000) dilution to a maximum dose of 0.5 mg in an adult or 0.3 mg in a child. This dose can be repeated every 5–15 min as needed [24]. Intravenous epinephrine (0.1 mg in 100 mL saline, 1:100.000 solution, initially at a rate of 30–100 mL/h) may be administered in cases that do not respond to recurrent epinephrine injection and fluid therapy. Hemodynamic monitoring is recommended during intrave‐ nous epinephrine therapy [23].
