Anaphylaxis

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Diagnostic approach

• ABCDE approach
• Targeted clinical evaluation to identify trigger and assess severity
• Imaging to rule out differential diagnoses as indicated (e.g., neck imaging, chest imaging, cardiac imaging)

Diagnostic criteria

Anaphylaxis is likely if any of the following criteria are fulfilled:

• Known allergen exposure with hypotension
• Skin and/or mucosal involvement plus cardiovascular or respiratory involvement
• Suspected allergen exposure with ≥ 2 systems involved (GI, cardiovascular, respiratory, skin)

Management checklist

• Removal of allergen if possible
• Epinephrine
• Rapid sequence intubation for airway compromise
• Supplemental O₂ for hypoxia
• Bronchodilators (e.g., albuterol) as needed
• IV fluids for hypotension
• Consider antihistamines, e.g., diphenhydramine AND cimetidine (off-label)
• Consider corticosteroids, e.g., methylprednisolone OR prednisone
• Continuous cardiac telemetry
• Continuous pulse oximetry
• Close clinical monitoring for biphasic reaction
• Admit to ICU or medical service.

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 hives, 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. ^[2]
• Most common triggers leading to fatal anaphylaxis ^[2][3][4]
  • 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

Consider alternate etiology in infants with a reaction after their first exposure to a food, as this is unlikely to trigger anaphylaxis. ^[5]

Food allergens are more likely to trigger anaphylaxis through ingestion than through inhalation or contact. ^[5]

• 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 ^[3][6]

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

Affected organ systems ^[3][6]

• Skin or mucous membranes
  • Flushing, erythema
  • Hives, 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 ^[7]
    • 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. ^[2]

• Cardiac arrest: Initiate BLS or ACLS with additional considerations (see "Cardiac arrest in anaphylaxis").
• If anaphylaxis is likely (e.g., diagnostic criteria for anaphylaxis are met or clinical suspicion is high), start initial treatment immediately. ^[3][5][8][9]
  • Remove inciting allergen if possible.
  • 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. ^[5]
  • Intranasal epinephrine (neffy®) may be given as an alternative to IM epinephrine in patients weighing ≥ 30 kg. ^[10][11]
  • See “Anaphylactic transfusion reactions” for specific considerations in patients with reactions during or up to 3 hours after transfusion of blood products.
• Concurrently 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 0.9% saline IV bolus) ^[12]
  • Position the patient supine.
• Once stabilized, consider adjunctive therapy with antihistamines; , corticosteroids (e.g., methylprednisolone).
• Continuous reassessment and ongoing 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.

The intramuscular epinephrine concentration given in anaphylaxis (1:1000) is higher than the intravenous epinephrine concentration given in cardiac arrest (1:10,000). IV administration of 1:1000 epinephrine can lead to arrhythmia or cardiac arrest.

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 video laryngoscopy and/or gum-elastic bougie)
    • Prepare for an emergency surgical airway in case of a cannot intubate-cannot oxygenate (CICO) scenario.
    • 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)
  • Treatment generally follows guidelines to treat severe asthma exacerbations; for dosages see:
    • Inpatient and ED management of asthma exacerbation
    • Management of acute asthma exacerbations in children ≤ 5 years

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

General principles

• Anaphylactic shock is a type of distributive shock caused by a type 1 hypersensitivity reaction to an allergen.
• Clinical features: See cardiovascular manifestations in "Diagnostic criteria for anaphylaxis."

Initial management of anaphylactic shock ^[12]

• Immediate IM epinephrine repeated every 5–15 minutes as needed ^[13]
• IV fluid resuscitation
• If possible, prompt removal of the inciting allergen

Refractory anaphylactic shock ^[8][12][13]

• 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 require mixing if not commercially available.
    • Administration via central venous access is recommended.
• Shock refractory to IV epinephrine infusion
  • Administer IV glucagon , especially if the patient is taking a beta blocker. ^[12][14]
  • Consider other vasopressors.
  • Ensure adequate fluid status.
  • Consider ECLS if the above measures are unsuccessful.

Cardiac arrest in anaphylaxis ^[12]

The following applies to adults and children.

• Start ACLS or PALS.
• If there is no IV or IO access, consider IM epinephrine if this does not interfere with high-quality CPR. ^[12]
• In patients with IV or IO access:
  • Administer IV epinephrine (1:10,000) per the advanced life support protocol.
    • See "Resuscitation medications" for adult dosage.
    • See "Epinephrine for pediatric cardiac arrest" for pediatric dosage.
  • Continue IV fluid resuscitation.
• Cardiac arrest refractory to standard resuscitation medications
  • Consider glucagon in patients thought to be taking beta blockers.
  • Consider ECLS.

In cardiac arrest due to anaphylactic airway obstruction, consider an advanced airway; in a CICO scenario, consider an emergency surgical airway.

Diagnostic criteria for anaphylaxis ^{[2][6][13][15]}

If any of the following criteria are fulfilled, anaphylaxis is likely. The onset of symptoms must be acute (minutes to hours). ^[5]

• 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 clinical suspicion is high, consider administering epinephrine even if the diagnostic criteria are not met. ^[5]

Laboratory studies ^[3][16][17]

• 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
  • If possible, sample acute-phase serum MCT within 2 hours of symptom onset. ^[5]
  • Obtain a second baseline serum MCT for patients with any of the following: ^[5]
    • Recurrent anaphylaxis
    • Severe anaphylaxis (e.g., manifesting with hypotension)
    • Unclear trigger or etiology
• Complement C4 levels: can be low in hereditary angioedema (see “Laboratory findings in bradykinin-mediated angioedema”)

Imaging ^[3][17]

• 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

Adjunctive therapy ^[3][8][9]

Consider adding the following for symptomatic therapy of severe anaphylaxis. They are not effective to prevent biphasic anaphylactic reactions. ^[13]

• Antihistamines: Consider a combination of an H1-antagonist and H2-antagonist in severe cases.
  • H1-antagonists: e.g., diphenhydramine ^[9]
  • H2-antagonists: e.g., cimetidine (off-label) ^{[9][18][19][20]}
• Corticosteroids ^[9][21]
  • Methylprednisolone ^[9]
  • OR prednisone ^[9]

Consider antihistamines and steroids for symptom management in severe anaphylaxis only after initial resuscitation measures (IM epinephrine; fluids and/or vasopressors). Routine administration to prevent biphasic anaphylactic reactions is not indicated. ^[13]

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

Monitoring and disposition ^[3][8][9]

• Monitor in an acute care setting for at least 4–8 hours and until full symptom resolution. ^[13]
  • Continuous pulse oximetry monitoring
  • Continuous cardiac monitoring
  • Clinical reassessment for biphasic anaphylactic reactions
• Extend monitoring if the patient requires ≥ 2 doses of IM epinephrine OR IV epinephrine. ^[13]
• 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 ^[5]
  • Arrange allergy/immunology referral (e.g., for consideration of immunotherapy for anaphylaxis due to Hymenoptera stings). ^[13]

The differential diagnoses listed here are not exhaustive.

• Biphasic anaphylactic reactions ^[4][22][23]
  • 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
  • Risk factors ^[13]
    • Severe anaphylaxis
    • ≥ 2 doses of epinephrine required
    • Wide pulse pressure
    • Skin or mucous membranes affected
    • Unknown trigger
    • Medication trigger in children
  • Onset: typically 6–24 hours after treatment
  • Management ^[13]
    • Treat with epinephrine immediately.
    • Observe for an extended period (see "Ongoing management").
    • Consider adjunctive treatment with corticosteroids and antihistamines; however, neither is effective for prevention.
• Respiratory failure, cardiac arrest, death
  • Risk factors include: ^[2][3]
    • 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

• 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. ^[13]
• Regimens vary by institution and indication (see "Contrast allergy premedication" for a sample regimen).

Patient and caregiver education and counseling ^[2][3][13]

• Identification and avoidance of triggers
• Anaphylaxis recognition
  • Key symptoms (See “Clinical features.”)
  • Anaphylaxis diagnostic criteria
  • Biphasic anaphylactic reactions
• Criteria to call emergency services or return to hospital (e.g., recurrent anaphylaxis, biphasic reaction)
• Correct positioning while waiting for emergency services
  • Predominantly cardiovascular symptoms: supine
  • Predominantly respiratory symptoms: sitting
  • Unconsciousness: recovery position
• Use of medical ID bracelets
• Setting up of support networks (e.g., training of friends and/or family)

Safe and effective autoinjector use

• Number of autoinjectors: Provide ≥ 2 doses based on the patient's needs.
• Where to store (e.g., home, workplace, handbag, vehicle)
• Maintenance (e.g., restocking, checking expiration dates)
• How to administer (e.g., inject in anterolateral thigh, can use over clothing)
• When to administer: as soon as possible, before calling emergency services

Counsel patients to carry prescribed epinephrine autoinjectors with them at all times. ^[5]

Consider epinephrine nasal spray as a needle-free alternative to an epinephrine autoinjector. ^[10][11]