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Year : 2022  |  Volume : 2  |  Issue : 3  |  Page : 85-91

Evaluation of anaphylaxis: A simplified approach

Department of Pulmonary, Critical Care and Sleep Medicine, VMMC and Safdarjung Hospital, New Delhi, India

Date of Submission22-Jun-2022
Date of Acceptance07-Jul-2022
Date of Web Publication17-Aug-2022

Correspondence Address:
Dr. Pranav Ish
Department of Pulmonary, Critical Care and Sleep Medicine, VMMC and Safdarjung Hospital, New Delhi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jalh.jalh_21_22

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Anaphylaxis has been defined as a serious allergic reaction that can even amount to death. However, the approach to the patient remains grossly individualized. Treatment aims at rapid intervention to prevent mortality. This review gives a detailed yet simplified approach to anaphylaxis, its diagnosis, and management.

Keywords: Anaphylaxis, epinephrine, management, treatment

How to cite this article:
Rathi V, Ish P. Evaluation of anaphylaxis: A simplified approach. J Adv Lung Health 2022;2:85-91

How to cite this URL:
Rathi V, Ish P. Evaluation of anaphylaxis: A simplified approach. J Adv Lung Health [serial online] 2022 [cited 2022 Sep 25];2:85-91. Available from: http://www.jalh.com/text.asp?2022/2/3/85/353868

  Introduction Top

The word anaphylaxis is a combination of ancient Greek words “ana” which implies “against” and “phylaxis” that stands for “protection.” In 1901, Charles Richet and Paul Portier injected sea anemone venom, to immunize pet animals against it. This dog which had previously shown no reaction to the venom and now developed wheeze and died within 25 min. Thus, instead of protection against the venom, they ended up with the opposite result. The term anaphylaxis was thus coined.[1]

The United States National Institute of Allergy and Infectious Disease (NIAID) and the Food Allergy and Anaphylaxis Network (FAAN) have defined anaphylaxis as “a serious allergic reaction that is rapid in onset and may cause death.”[2]

  Pathophysiology Top

Anaphylaxis is due to a massive release of inflammatory mediators from mast cells and basophils after exposure to a particular allergen. These mediators are mainly histamine and the products of arachidonic acid metabolism (leukotrienes, prostaglandins, thromboxane, and platelet-activating factor). They lead to vasodilation and increased vascular permeability, cause smooth muscle spasms and also lead to eosinophil chemotaxis.[3]

Anaphylaxis can be triggered by one of several pathways:[3],[4]

  1. Immunologic

    • Immunoglobulin E (IgE) dependent: Foods such as nuts and milk products, drugs such as antibiotics and nonsteroidal anti-inflammatory drugs, insect sting, and radio-contrast media
    • IgE independent: Radio-contrast media, high-molecular-weight iron, some monoclonal antibodies.

  2. Nonimmunologic (previously called anaphylactoid reaction) is due to direct mast cell activation: Physical factors such as cold and exercise, alcohol, and drugs such as opioids
  3. Idiopathic: Previously unknown allergen trigger now showing a reaction, patients with underlying mastocytosis, and clonal mast cell disorder.

Thus, a single trigger can result in anaphylaxis using multiple pathways.

Food and medication are two of the most common triggers. The incidences of food-triggered anaphylaxis decrease, whereas medication-triggered ones increase with advancing age.[5] Egg and milk allergies seem to be common across continents, whereas peanut and tree nut allergies are the most common cause of anaphylaxis in Western countries but rarely encountered in Asian countries.[6]

  Risk Factors for Severe Anaphylaxis Top

Certain risk factors have been identified [Table 1] that increase the risk of severe or fatal anaphylaxis. These include age, underlying asthma, allergic rhinitis, cardiovascular diseases, atopic diseases, and concurrent medications such as beta-blockers and Angiotensin-converting enzyme (ACE) inhibitors.[2],[7],[8],[9]
Table 1: Risk factors for severe anaphylaxis

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  Biphasic Reactions Top

Sometimes in anaphylaxis, symptoms reoccur after initial resolution. The mechanism for this is poorly understood. The second reaction may be similar to, more severe, or less severe to the initial episode. There are some possible predisposing factors such as oral administration of antigen, anaphylaxis in a patient on beta-blockers, underlying cardiac disease, and presence of hypotension or laryngeal edema during the initial episode.[10],[11]

  History Top

History of exposure to a known or suspected trigger and time taken from exposure to the development of symptoms is the crucial factor in making a diagnosis [Table 2]. The previous history of a similar episode and any known allergens must also be elicited.[2],[7]
Table 2: Essential features in patient history for anaphylaxis

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  Clinical Features Top

Anaphylaxis usually presents with multisystem involvement [Figure 1]. A cutaneous rash is almost ubiquitous, and its absence argues against but does not rule out anaphylaxis.[3]
Figure 1: Signs and symptoms of anaphylaxis

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Diagnostic criteria

With often broad and atypical presentations of anaphylaxis and with no diagnostic tests available, the dilemma in diagnosis is typical in an emergency setting, leading to a delay in epinephrine administration. Thus, the FAAN and the NIAID formulated diagnostic criteria to provide the treating physician with a rapid and straightforward method [Figure 2] to make the diagnosis of anaphylaxis.[2]
Figure 2: Diagnostic criteria for anaphylaxis

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Differential diagnosis

The differential diagnoses of anaphylaxis are broad. Acute severe asthma, syncope, and panic attacks are some of the most common diagnostic dilemmas.[2],[4],[7],[12],[13] Diagnoses which can be confused with anaphylaxis are:

  1. Presyncope or syncope
  2. Hereditary angioedema accompanied by a rash
  3. Asthma, pulmonary embolism, and congestive heart failure
  4. Isolated skin reactions, for example, adverse drug reactions
  5. Vocal cord dysfunction
  6. Mast cell disorders
  7. Flushing syndromes: Carcinoid, medullary carcinoma of the thyroid, vasoactive intestinal polypeptide tumors, and mastocytosis
  8. Food poisoning: Monosodium glutamate and scombroid poisoning
  9. Psychiatric disorders: Panic attacks and Munchausen stridor
  10. Miscellaneous: Red man syndrome (adverse effect of vancomycin), capillary leak syndrome, and paradoxical pheochromocytoma.

  Laboratory Investigations Top

Acute anaphylaxis is primarily a clinical diagnosis. Some investigations such as serum tryptase and histamine levels taken during the acute phase may help confirm the diagnosis. However, both histamine and tryptase are nonspecific.[4],[13]

  1. Total tryptase: A higher level during the acute episode as compared to baseline serum level confirms the diagnosis of anaphylaxis. However, a normal value during the acute episode does not completely exclude the diagnosis. If the levels are more than 11.4 ng/mL in both acute and baseline samples, then suspicion should go toward mastocytosis or clonal mast cell disorder.[14]
  2. Histamine: Twenty-four-hour urine histamine and N-methylhistamine estimation can also be helpful in diagnosis
  3. Histamine metabolites: Levels of plasma histamine return to normal after a quarter to 1 h of an acute episode. Therefore, for patients investigated more than an hour of the onset of anaphylaxis, the estimation of 24-h urinary histamine metabolites is better.
  4. Additional laboratory tests: To rule out anaphylaxis mimickers such as:

    1. Carcinoid – serotonin level in serum and 5-hydroxyindoleacetic acid in urine
    2. Pheochromocytoma – levels of free metanephrine in plasma and urinary levels of vanillylmandelic acid
    3. Gastrointestinal tumor secreting vasoactive polypeptide – substancePand vasoactive intestinal polypeptide
    4. Hereditary angioedema – levels of c4 and c1 esterase inhibitor
    5. Diagnostic imaging – evaluation for hydatid cysts.

  Management Top

Anaphylaxis has a sudden onset, and its symptoms can rapidly turn life-threatening. Hence, prompt diagnosis and early initiation of treatment are essential. Management should begin in the prehospital setup. If precious early minutes are lost, further treatment becomes difficult.

Management in a prehospital setup

  1. Allergen removal: If possible, the inciting allergen should be removed (e.g., Stinger of an insect). Definitive treatment (i.e., epinephrine) should not be delayed if removal of the trigger is not feasible
  2. Triage: Management begins with an assessment for airway patency, respiratory distress, and shock. Cardiopulmonary resuscitation should be started if required
  3. Call for help: Arrangements to take the patient to the nearest hospital emergency should be made
  4. If the patient has an epinephrine autoinjector on his/her person, a stat dose should be administered in the mid-anterolateral aspect of the thigh
  5. The patient should be placed in a supine or left lateral decubitus position (in case of pregnant females). Patients in respiratory distress may be more comfortable in a sitting up position.

Even if the symptoms have subsided, the patient may require further monitoring and should, therefore, be shifted to a hospital emergency.

Management of anaphylaxis in a hospital setup

  1. Triage: Evaluation of the airway patency and maintenance of breathing and circulation. If signs of airway edema (hoarseness or stridor) are noted, the patient should be prepared for early elective intubation. If required, cardiopulmonary resuscitation should be started [Figure 3].
  2. Allergen removal: If possible, the inciting allergen should be removed (e.g., an intravenous [IV] infusion be stopped). However, after food-induced anaphylaxis, the patient should not be made to vomit. Administration of epinephrine should not be delayed for want of removal of the trigger
  3. Epinephrine: Epinephrine is the single most important step for acute management of anaphylaxis.[15] A patient presenting with acute symptoms of anaphylaxis, even if they are not life-threatening, should immediately receive epinephrine, because mild symptoms of anaphylaxis can rapidly turn life-threatening. To treat an anaphylactic reaction, the best route to deliver epinephrine in most individuals is intramuscular with the best site considered being anterolateral aspect of the thigh.[16] A dose of 0.01 mg/kg of 1:1000 epinephrine up to 0.5 mg should be administered in adults, whereas it should be kept to 0.3 mg in children.[2],[13],[17] The doses can be repeated every 5–15 min if no significant improvement is seen
  4. Positioning: In general, a supine position is preferred. Left lateral position is indicated in case of pregnant females, to prevent a decreased venous return to the heart due to the uterus compressing upon inferior vena cava. Although Trendelenburg position has been traditionally used and is also advised by some guidelines, there is insufficient evidence to support its use.[18],[19] In a patient with respiratory difficulty, a sitting up position may be considered
  5. Oxygen inhalation: In all patients of anaphylaxis, irrespective of their respiratory status, oxygen inhalation should be considered. In patients with respiratory or cardiovascular compromise, and those not responding to initial treatment with epinephrine, oxygen is a must.[13] Up to 100% oxygen should be administered through a facemask at a flow rate of 6–10 L/min. The idea is to maintain the patient's oxygen saturation of at least 94%–96%[4],[18]
  6. Hemodynamic monitoring: Continuous hemodynamic monitoring including blood pressure, pulse rate, pulse oximetry, and electrocardiographic monitoring should be started. An IV access should be obtained as early as possible
  7. Fluid resuscitation: There is significant plasma leak and vasodilation during anaphylaxis which can be counteracted with aggressive fluid resuscitation. In the early stages of anaphylaxis, successive IV fluid boluses (1000 mL in adults, 20 mL/kg in children) should be administered to maintain blood pressure. When the blood pressure starts to stabilize, fluid rates should be adjusted
  8. Inhaled beta-agonists: If bronchospasm is not relieved postepinephrine administration, an inhaled beta-agonist, such as salbutamol can be used. It can be administered through a metered-dose inhaler (2–6 inhalations) or nebulizer (2.5–5 mg in 3 mL of saline in adults and 2.5 mg in 3 mL in case of children; repeated as necessary)[2],[12],[13],[20]
  9. Anti-histamines and corticosteroids: These are considered adjuncts to epinephrine in the treatment of anaphylaxis. However, their role in the acute management of anaphylaxis is questionable.
Figure 3: Algorithm for management of anaphylaxis in a hospital setting

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While their use is justified based on their mechanism of action and effectiveness in other allergic reactions, the onset of action is not rapid enough to be useful in the acute management of anaphylaxis.[4],[13],[20]

Antihistamines used are

H1 antihistamine – Diphenhydramine is to be administered by slow intramuscular or by slow IV infusion. In adults, the dose is 25–50 mg and in children, 1 mg/kg to a maximum of 50 mg, administered over 10–15 min.[4],[13] First-or second-generation H1 antihistamines can also be used orally.

H2 antihistamines like cimetidine can also be used at 4 mg/kg IV.


Strong evidence supporting the use of corticosteroids in the acute management of anaphylaxis is lacking. In theory, corticosteroids, owing to their anti-inflammatory property could reduce biphasic reaction, but there is no definitive evidence to indicate this.[11] The dose of IV corticosteroids should be 1.0–2.0 mg/kg methylprednisolone or its equivalent.[2],[13],[21]

  Refractory Anaphylaxis Top

Some patients do not respond to the treatment of anaphylaxis. Such patients should typically be managed by a specialist team of emergency medicine, critical care, or anesthesia.

  • Advanced airway:
  • Ready preparedness for airway management including intubation is required. If there are signs of airway edema such as hoarseness or stridor which have not responded to the initial epinephrine dose, intubation should be considered. Laryngoscopy should be presumed to be difficult given the high potential for laryngeal edema.
  • Key points to be considered before intubation:

    • 3–4 min preoxygenation with 100% oxygen should be done
    • Backup airway equipment should be checked
    • Suction should be ready
    • Paralytics should be used with caution.
    • Parenteral vasopressors: Patients with hypotension refractory to 2–3 intramuscular doses of epinephrine and fluid resuscitation may require IV epinephrine infusion or additional vasopressors such as dopamine or vasopressin.

Intravenous epinephrine

  • Epinephrine infusion is given in a 1:1,000,000 dilution. It is started at 1 μg/min in adults and titrated according to hemodynamic response (up to a maximum of 10 μg/min in adults and adolescents). Starting dose in children – 0.1 μg/kg/min.[12],[22] There is an increased risk of cardiac arrhythmias and inappropriate dosing with bolus administration of IV epinephrine and therefore should be avoided whenever possible. In patients with cardiovascular collapse or impending collapse unresponsive to epinephrine infusion, a bolus of IV epinephrine might be necessary. It might also be required when epinephrine infusion is not immediately available. Slow IV bolus of 50 μg (0.5 mL of 1:10,000) can be given in such cases.

Other routes

  • If IV access cannot be obtained, the IV infusion dose can be used through intraosseous route. In case neither is established, but an endotracheal tube is in place, epinephrine can be given through that. Through this route, 1:1000 epinephrine diluted in 10 mL of sterile water is given in a dose of 2.5 mg in adults and 0.1 mg/kg in children (maximum 2.5 mg).

  • If the shock does not respond to epinephrine infusion, dopamine or vasopressin infusion can be started.

  • Glucagon:

    • In cases where, bronchospasm and hypotension are refractory to epinephrine, especially in patients who are on beta-blockers, a response may be seen to IV glucagon.[23] Glucagon directly activates adenylyl cyclase, bypassing adrenergic receptors, and might reverse the refractory hypotension. Hence, in patients who are on beta-blockers, glucagon infusion may be used before escalating to epinephrine infusion
    • IV dose of glucagon is 1–5 mg in adults and 20–30 μg/kg (maximum-1 mg) in children, to be administered over 5 min. This is followed by an infusion of 5–15 μg/min, titrated according to clinical response.[18]

  • Extracorporeal membrane oxygenation (ECMO): ECMO can be considered in patients who are unresponsive to traditional resuscitative efforts.

  Observation and Monitoring Top

After the apparent resolution of symptoms, patients should be monitored for some time in the health-care setup before being discharged. The duration for monitoring should be adjusted based on the length and severity of the anaphylactic reaction, response to treatment, previous history of biphasic reactions, medical comorbidities, and the patient's accessibility to medical care. Longer periods of monitoring should be considered for patients of food allergy, those requiring more than one dose of epinephrine, and patients with pharyngeal edema or hypotension. In general, patients of anaphylaxis should be monitored for at least 4 h and if required, even for 8–10 h.[4],[2],[11]

  Long-Term Management Top

Treatment of an acute episode should not be the end of management. Long-term management should be discussed with the patient. Patients need to be educated to spot their symptoms and be equipped with epinephrine autoinjector. Furthermore, efforts should be made to identify the trigger causing anaphylaxis, as avoidance of triggers is the key to long-term prevention.

  Conclusion Top

Anaphylaxis is an acute emergency which can rapidly worsen and turn fatal. Early recognition of symptoms and prompt initiation of treatment are the key to saving lives. The importance of epinephrine in the management of anaphylaxis cannot be overemphasized. A clear written protocol for its diagnosis and management can be helpful in preventing confusion in emergencies.

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Conflicts of interest

There are no conflicts of interest.

  References Top

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  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2]


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