Anaphylaxis

Anaphylaxis is an acute, potentially life-threatening, type 1 hypersensitivity reaction, involving the sudden IgE-mediated release of histamine mediators from mast cells and basophils in response to a trigger (e.g., food, insect stings, medication). Anaphylactoid reactions (a subtype of pseudoallergy) are IgE-independent reactions that result from direct mast-cell activation (e.g., in response to opioids); the clinical presentation and management are the same as for anaphylaxis. Typical signs and symptoms of both reactions include the acute onset of urticarial rash, angioedema, stridor, dyspnea, bronchospasm, circulatory failure (distributive shock), vomiting, and diarrhea. The diagnosis is clinical and is based on combinations of typical symptoms, plus the presence of a known or suspected trigger. Rapid recognition and treatment are key to prevent death from airway loss, respiratory failure, or cardiovascular collapse. Management consists of initial resuscitation measures that focus on administering IM epinephrine, removing triggers, securing the airway, and giving IV fluid boluses, which take precedence over adjunctive treatment like steroids and antihistamines.

• Anaphylaxis: a severe type 1 hypersensitivity reaction that can cause life-threatening and multisystem effects due to IgE-mediated mast cell activation
• Anaphylactoid reaction
  • A reaction that is clinically similar to anaphylaxis but is mediated by direct nonimmune-mediated activation of either mast cells or the complement cascade (see “Pseudoallergy”)
  • Examples include reactions to radiocontrast media and vancomycin
• Anaphylactic shock: a type of distributive shock that results from anaphylaxis

• Trigger is idiopathic in 20% of patients ^[1]
• Most common triggers leading to fatal anaphylaxis ^[1][2][3]
  • Younger patients: food allergies; (e.g., peanut, tree nuts), insect stings (e.g., bee stings)
  • Older patients: drug reactions, radiocontrast media
  • Hospitalized patients: food, medications (e.g., antibiotics, NSAIDs), latex

• Anaphylaxis (type I hypersensitivity reaction) or anaphylactoid reactions → degranulation of mast cells → massive histamine release → systemic vasodilation → increased capillary leakage → anaphylactic shock
• See also “Hypersensitivity classification.”

Onset of symptoms ^[2][4]

In general, the onset of symptoms is acute (within minutes to hours of exposure to a likely antigen).

Affected organ systems ^[2][4]

• Skin or mucous membranes
  • Flushing, erythema
  • Urticaria, pruritus
  • Swelling of the eyelids, angioedema
  • Nasal congestion, sneezing
• Respiratory
  • Cough, hoarseness
  • Chest tightness
  • Dyspnea (due to bronchospasm or laryngeal edema), tachypnea
  • Stridor, wheezing
  • Hypoxia, cyanosis
• Gastrointestinal
  • Nausea, vomiting (especially in food allergies)
  • Abdominal pain, diarrhea
• Cardiovascular
  • Hypotension
    • Adults: SBP < 90 mm Hg OR decrease ≥ 30% from baseline ^[5]
    • Children: definition depends on age
  • Tachycardia, weak peripheral pulses
  • Signs of end-organ dysfunction
    • Altered mental status, syncope
    • Decreased urine output, anuria
    • Skin changes (e.g., mottling)
    • Low temperature
    • Delayed capillary refill (e.g., > 2 seconds)
    • Ischemic chest pain

Beware of atypical manifestations without skin/mucosal symptoms (10% of patients) to avoid misdiagnosis and treatment delay. ^[1]

Diagnostic criteria for anaphylaxis ^[1][4][6]

If any of the following criteria are fulfilled, anaphylaxis is likely. The onset of symptoms must be acute (minutes to hours).

• 1) Known allergen exposure with hypotension (SBP < 90 mm Hg or ≥ 30% decrease from the baseline)
• 2) Acute illness with skin and/or mucosal symptoms (e.g., hives, swollen lips, tongue, and/or uvula) AND ≥ 1 of the following:
  • Cardiovascular: SBP < 90 mm Hg or ≥ 30% decrease from baseline and/or altered mental status, syncope, ischemic chest pain, incontinence, or anuria
  • Respiratory: dyspnea, hypoxia, stridor, hoarseness, wheezing, cough
• 3) Suspected allergen exposure AND ≥ 2 of the following:
  • Gastrointestinal: abdominal pain, nausea, vomiting, diarrhea
  • Cardiovascular: systolic BP < 90 mm Hg or ≥ 30% decrease from baseline, and/or altered mental status, syncope, ischemic chest pain, incontinence, anuria
  • Respiratory: dyspnea, hypoxia, stridor, hoarseness, wheezing, cough
  • Skin/mucosal: hives, angioedema, pruritus, flushing

If anaphylaxis diagnostic criteria are met, empiric treatment should be given without delay.

• Stabilize the patient (ABCDE approach).
  • Airway assessment and management (see “Airway management and ventilation in anaphylaxis”)
  • Rapid sequence intubation (RSI) for airway compromise
  • Oxygen: Provide FiO₂ of 100% (e.g., high-flow O₂ by nonrebreather mask).
  • Aggressive IV fluid resuscitation if hypotension present (large-bore IV access; administer 1–2 L 0.9% saline IV bolus)
  • Position the patient supine.
• If anaphylaxis is likely (see diagnostic criteria for anaphylaxis), start initial treatment immediately: ^[2][4][7]
  • Remove inciting allergen
  • Administer epinephrine IM 1:1,000 (1 mg/mL) into the anterolateral thigh
    • Repeat every 5–15 minutes as needed
    • IM epinephrine injections always require a more concentrated solution (1:1,000)
    • Epinephrine autoinjector may be used.
  • See “Anaphylactic transfusion reactions” for specific considerations in patients with reactions during or up to 3 hours after transfusion of blood products.
• Once stabilized, consider adjunctive therapy with antihistamines; , corticosteroids (e.g., methylprednisolone)
• Continuous reassessment and subsequent management

The most important measures in anaphylaxis are to remove the inciting allergen and administer epinephrine as soon as possible. Delay can lead to airway compromise, respiratory failure, refractory shock, and death.

Epinephrine injections for anaphylaxis should always be given intramuscularly in a concentration of 1:1,000 (as opposed to the 1:10,000 solution used in cardiac arrest). Injecting the 1:1,000 solution into a vein can lead to cardiac arrhythmia/arrest.

Anaphylaxis is a clinical diagnosis (see “Diagnostic criteria for anaphylaxis”).

Laboratory studies ^[2][8][9]

• Not routinely indicated but can be useful to confirm anaphylaxis or screen for bradykinin-mediated angioedema.
• Serum mast-cell tryptase (MCT): if elevated, supports the diagnosis of anaphylaxis
  • Normal result does not rule out anaphylaxis
  • Low sensitivity in food-triggered reaction
• Complement C4 levels: can be low in hereditary angioedema (see “Laboratory findings in bradykinin-mediated angioedema”)

Imaging ^[2][9]

• Not routinely indicated but can be useful to rule in/out mimics.
• Screening for upper airway foreign bodies and infections (e.g., peritonsillar abscess, deep neck space infection, epiglottitis): neck x-ray, CT neck
• Evaluating for other causes of respiratory distress (e.g., pneumonia, pulmonary embolism, ARDS): CXR, CTA Chest
• Assessing cardiac function and evaluating for other causes of shock (e.g., cardiomyopathy): echocardiogram

See also “Airway management” and “Mechanical ventilation” for more details.

• Lethargic patients without other overt signs of airway compromise
  • Initiate basic airway maneuvers (e.g., head-tilt/chin-lift maneuver, jaw-thrust maneuver, bag-mask ventilation)
  • Use basic airway adjuncts, if tolerated: nasopharyngeal airway (NPA) , oropharyngeal airway (OPA)
• Rapid declining patients or signs of airway compromise: Maximize epinephrine therapy and prepare for early endotracheal intubation.
  • Anticipate a difficult airway and difficult ventilation.
  • Early anesthesia or ENT consult for awake fiberoptic intubation or surgical airway management
• Respiratory failure or signs of complete airway obstruction: Perform rapid sequence intubation (RSI).
  • Intubation medications
    • Induction agent: Ketamine preferred
    • Paralytics: use with caution
    • Pretreatment with inhaled racemic epinephrine can be given while preparing for intubation to improve airway edema.
  • Additional considerations
    • Follow a difficult airway algorithm (e.g., using adjuncts like videolaryngoscopy and/or gum-elastic bougie)
    • Postintubation: sedate ideally with ketamine and follow ventilation strategy for obstructive lung disease
• Severe bronchospasm: Administer a bronchodilator.
  • SABA: e.g., albuterol nebulizer OR albuterol MDI
  • Consider a muscarinic antagonist additionally: e.g., ipratropium (off-label use)

Obtain early anesthesia or ENT consultation in patients with a rapid decline or anticipated airway compromise.

Refractory anaphylaxis ^[2][4][7]

• Anaphylactic shock refractory to repeated IM epinephrine and fluids
  • Continuous IV epinephrine infusion 1:1,000,000 (1 mcg/mL)
    • 1:1,000,000 epinephrine solutions may not commercially available and require mixing.
    • Administration via central venous access recommended
• Anaphylactic shock refractory to IV epinephrine infusion
  • Administer IV glucagon , especially if the patient is on a β-blocker
  • Consider other vasopressors
  • Ensure adequate fluid status
  • Consider consulting ECMO team if above measures fail.
• Cardiac arrest: Start ACLS protocol.

Adjunctive therapy ^[2][4][7]

• Antihistamines: Consider a combination of an H1-antagonist and H2-antagonist in severe cases.
  • H1-antagonists: e.g., diphenhydramine
  • H2-antagonists: e.g., cimetidine (off-label) ^[10][11][12]
• Corticosteroids
  • Methylprednisolone
  • OR prednisone

Antihistamines and steroids should be administered in anaphylaxis only after the initial resuscitation measures (IM epinephrine, fluids and/or vasopressors) have been given.

A lack of response to epinephrine, antihistamines, and steroids should raise suspicion of differential diagnoses such as bradykinin-mediated angioedema, which requires its own specific treatment (see “Treatment of angioedema”).

Monitoring and disposition ^[2][4][7]

• Monitor in acute-care setting at least 4–8 hours
  • Continuous pulse oximetry monitoring
  • Continuous cardiac monitoring
  • Clinical reassessment for biphasic anaphylactic reactions
• Extend monitoring if patient requires ≥ 2 doses of IM epinephrine OR IV epinephrine
• ICU admission for patients needing advanced airway, mechanical ventilation, and/or vasopressor support
• Prior to discharge:
  • Alert bracelet and allergy documentation (if trigger is identified)
  • Patient counseling on identification and avoidance of triggers
  • Prescription and training on epinephrine autoinjector use
  • Consider allergy/Immunology referral (e.g., anaphylaxis due to Hymenoptera stings)

• Administer IM epinephrine and repeat as needed
• Stop offending trigger
• Administer supplemental oxygen.
• Airway management
  • Start basic airway maneuvers (see airway management)
  • Consult anesthesia/ENT for assistance with intubation.
  • Secure airway using techniques for difficult airway
  • Administer bronchodilators
• Position supine if tolerated.
• IV fluid resuscitation
• Continuous epinephrine infusion for refractory shock
• Consider adjunctive treatment (steroids, antihistamines).
• Continuous telemetry and pulse oximetry
• Close clinical monitoring for biphasic reaction
• Transfer to ICU or medical service.

The differential diagnoses listed here are not exhaustive.

• Biphasic anaphylactic reactions ^[3][13][14]
  • Definition: recurrence of anaphylaxis symptoms despite initially successful treatment and without re-exposure to an antigen
  • Frequency: occurs in 5–20% of patients with anaphylaxis
  • Onset: typically 6–24 hours after treatment
  • Not prevented by corticosteroids
• Respiratory failure, cardiac arrest, death
  • Risk factors include: ^[1][2]
    • Delayed administration of epinephrine
    • Improper patient positioning
    • History of peanut/tree nut allergy, previous severe/near-fatal anaphylaxis, previous biphasic reaction
    • Comorbidities: asthma, cardiovascular disease, mast-cell activation disease (e.g., mastocytosis)
• Drug side effects
• Complications of intubation or ventilation strategies

We list the most important complications. The selection is not exhaustive.

Pretreatment for in-hospital triggers ^[15][16][17]

• Consider corticosteroid and/or antihistamine pretreatment if known triggers are crucial to clinical care and difficult to avoid: e.g., radiocontrast material (most common), chemotherapeutic agents, blood products, antivenom.
• Regimens vary by institution and indication. ^[17]