Anaphylaxis

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Epidemiology: Anaphylaxis
Risk Factors: Severe or Fatal Anaphylaxis
Pathophysiology: Anaphylaxis Types
Precautions
Causes: Common
Symptoms
Signs: Anaphylaxis typical presentation
Signs: Mild
Signs: Moderate
Signs: Severe (Anaphylaxis)
Labs: Confirms diagnosis (do not rely on labs to make or treat acute episode)
Differential Diagnosis
Diagnosis: Anaphylaxis
Management: Emergency Department
Management: Home
Prognosis
Prevention
References
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II. Epidemiology: Anaphylaxis

Anaphylaxis most commonly occurs in the home environment, the setting for 40-50% of cases
Incidence: 2.1 cases per 1,000 person-years
Lifetime Prevalence: 0.05 to 2%
Mortality: 1%
Peak ages
1. Children 2-12 years old
2. Adults 50-69 years old

III. Risk Factors: Severe or Fatal Anaphylaxis

Comorbid Asthma
1. Mild Asthma confers a 2 fold risk of Anaphylaxis of any severity (and Severe Asthma a 3 fold risk)
Known Food Allergy, Hymenoptera Sting allergy or medication allergy
Mast Cell Disorders
Underlying cardiovascular disease
Age >50 years old

IV. Pathophysiology: Anaphylaxis Types

IgE Mediated Anaphylaxis (most cases)
1. Antibodies bind Antigen and activate Mast Cells and Basophils
2. Mast Cells and Basophils release chemical mediators
Non-Immune Anaphylaxis (direct activation)
1. Direct Mast Cell or Basophil activation by receptor binding or complement

V. Precautions

Anaphylaxis is a life threatening condition that requires immediate ABC Management and Epinephrine injection IM
Biphasic reactions occur in up to 20% of cases
1. Second acute anaphylactic reaction despite no repeat exposure to the original allergen
2. Second reaction may be delayed up to 8 hours later (24-72 hour delay has been reported in atypical cases)
Lack of skin involvement (e.g. hives) results in misdiagnosis (esp. children)
1. Children may present without hives, but rather with gastrointestinal symptoms and respiratory symptoms
Cardiovascular compromise alone (e.g. Hypotension) without other system involvement may be due to Anaphylaxis
1. More common in drug-induced Anaphylaxis
2. See Criteria 3 under diagnosis below

VI. Causes: Common

Idiopathic (10-20% of Anaphylaxis)
1. See Urticaria
2. Consider Mastocytosis
Hymenoptera Allergy (15-25% of Anaphylaxis)
1. See Insect sting
2. Results in >50 fatal U.S. reactions per year
3. Occurs with Insect Bites of bees, wasps, fire ants
Food Allergy (32-37% of anaphylactic episodes, especially in children under age 4 years)
1. Cow's Milk (2-10%, esp. in infants)
2. Egg whites (1-4%)
3. Fish (10-15%)
4. Peanuts (2-13%)
5. Tree nuts (7-12%)
6. Sesame
7. Food additives
8. Shellfish
Medications (21-58% of cases, most common in age over 50-55 years)
1. Penicillin Allergy (14% of Anaphylaxis, 75% of anaphylactic deaths)
2. NSAIDs (7-12% of Anaphylaxis case)
3. Aspirin
4. Radiographic Intravenous Contrast Material
5. Allopurinol
6. ACE Inhibitors (esp. ACE inhibitor Induced Angioedema)
7. Opioids
8. Interferon
Occupational Allergans
1. Allergic Contact Dermatitis (e.g. Latex Allergy)
2. Chemical exposures (e.g. dyes, bleaches, Insecticides)
Miscellaneous
1. Anaphylactoid Reaction to Radiocontrast (1-5% of Anaphylaxis cases)
2. Animal dander
3. Infection with Echinococcus species (Hydatid Disease)
4. Physical reactions (e.g. cold, heat, Sun Exposure or Exercise, similar to physical Urticaria - rare Anaphylaxis)

VII. Symptoms

Anaphylaxis symptom onset within 1-2 hours of allergan exposure
1. Food Allergy reactions have onset within 30 minutes of exposure
2. Insect reactions often start within minutes of exposure
3. Parenteral medication reactions may start within minutes of exposure

VIII. Signs: Anaphylaxis typical presentation

Urticaria and Angioedema (90% of cases)
Respiratory distress, especially upper airway obstruction (70% of cases)
1. Lower airway obstruction may occur, especially in Asthma
Cardiovascular collapse with Hypotension (45% of cases)
Gastrointestinal symptoms such as Vomiting (45% of cases)
Neurologic symptoms such as Headache or Dizziness (15% of cases)

IX. Signs: Mild

General
1. Feeling impending doom
2. Pruritus (uncommon without rash)
3. Metallic Taste in mouth
Naso-ocular
1. Itchy nose or eyes
2. Sneezing
3. Clear, watery Eye Discharge or Nasal Discharge
Skin (occurs)
1. Urticaria: Hives
2. Angioedema: Facial swelling and Lip swelling

X. Signs: Moderate

Neurologic
1. Dizziness
2. Weakness
Gastrointestinal
1. Nausea, Vomiting
2. Bloody Diarrhea
3. Abdominal Pain
4. Fecal urgency or Incontinence
Genitourinary
1. Uterine cramps
2. Urinary urgency or Incontinence

XI. Signs: Severe (Anaphylaxis)

Airway Compromise
1. Hoarseness or Dysphonia
2. Stridor
3. Inability to manage own secretions
4. Airway posturing (sniffing position)
Breathing Compromise
1. Wheezing and bronchospasm
2. Dyspnea
3. Tachypnea
4. Hypoxia
5. Increased work of breathing
Circulatory compromise
1. Hypotension
2. Tachycardia
3. Hypoperfusion
4. Syncope

XII. Labs: Confirms diagnosis (do not rely on labs to make or treat acute episode)

Serum Tryptase
1. Marker of systemic Mast Cell degranulation
2. Levels rise 30 minutes after onset and peak at 1-2 hours of Anaphylaxis
3. Serum Tryptase is often normal in food-related reactions
4. Consider in cases in which Anaphylaxis diagnosis is unclear
  1. Obtain level on presentation, within 1-2 hours, and again in 24 hours after presentation
5. Levels consistent with systemic Mast Cell activation
  1. Serum Tryptase>11.4 ng/ml OR
  2. Serum Tryptase increase over baseline of 20% PLUS 2 ng/ml
Serum Histamine
1. Requires special handling for accuracy
2. Obtain first level within 1 hour of symptom onset
3. Compare to baseline level

XIII. Differential Diagnosis

Allergic Reaction without Anaphylaxis
1. More mild, self limited symptoms with only one organ system involved
2. Two or more involved systems or isolated cardiovascular compromise is consistent with Anaphylaxis
Flushing
1. See Flushing
2. Carcinoid Syndrome
3. Medullary Carcinoid of the Thyroid
4. Vasomotor Symptoms of Menopause
5. Red Man Syndrome (Vancomycin)
Respiratory compromise (e.g. Wheezing, Stridor)
1. See Wheezing
2. Foreign Body Aspiration
3. Acute Asthma Exacerbation
4. COPD Exacerbation
5. Vocal Cord Dysfunction
Following Eating
1. Foreign Body Aspiration
2. Scombroid Fish Poisoning
3. Sulfite Intake
4. Monosodium Glutamate
Other form of shock
Other causes

XIV. Diagnosis: Anaphylaxis

High likelihood if ONE of the following three criteria present
Criteria 1: Acute illness onset within minutes to hours AND
1. Skin or mucosal effects (e.g. Hives, Pruritus, Flushing, swollen lips/Tongue/uvula) AND
2. Respiratory distress (e.g. Dyspnea, bronchospasm) or cardiovascular collapse (e.g. Hypotension, Syncope)
Criteria 2: Acute illness onset within minutes to hours after likely allergen exposure AND a least TWO of the following
1. Skin or mucosal effects (e.g. Hives, Pruritus, Flushing, swollen lips/Tongue/uvula)
  1. Hives may be absent (esp. in children) who may have cardiopulmonary and gastrointestinal symptoms
  2. Skin or mucosal effects are required as 1 of the 2 criteria for WHO Anaphylaxis diagnosis
2. Respiratory distress (e.g. Dyspnea, bronchospasm, Stridor, Hypoxemia)
3. Cardiovascular collapse (e.g. Hypotension, Syncope)
4. Gastrointestinal symptoms persist (e.g. severe abdominal cramping, repeated Vomiting)
Criteria 3: Acute Hypotension, Bronchospasm or laryngeal involvement within minutes to hours after likely allergen exposure
1. Systolic Blood Pressure with 30% decrease from baseline (children) or <90 mmHg (adults)
2. See Hypotension
3. See Pediatric Vital Signs for age specific cut-offs for low Blood Pressure
4. More common in drug-induced Anaphylaxis (in which cardiovascular compromise is only system involved)
Summary
1. Anaphylaxis is present if allergen exposure and Hypotension or two compromised organ systems
References
1. Sampson (2006) Ann Emerg Med 47(4): 373-80 [PubMed]

XV. Management: Emergency Department

General Measures
1. ABC Management
2. Supplemental Oxygen
Anaphylaxis (All patients)
1. Epinephrine is the mainstay of Anaphylaxis management and must not be delayed
  1. Administer within 5 minutes of presentation
    1. Surviving severe Anaphylaxis cases share rapid Epinephrine delivery in common
    2. Sampson (1992) N Engl J Med 327(6): 380-84 [PubMed]
  2. Narrow window of opportunity with Epinephrine
    1. Prior to complete airway obstruction and cardiovascular collapse
  3. Epinephrine Vasoconstricts (raises Blood Pressure), bronchodilates and decreases airway edema
  4. Epinephrine also stabilizes Mast Cells and Basophils
  5. Epinephrine IM is safe even in older patients and should not be withheld when Anaphylaxis criteria are met
    1. Epinephrine has no absolute contraindications
    2. Kawano (2017) Resuscitation 112:53-8 +PMID:28069483 [PubMed]
2. Epinephrine (1:1000 concentration = 1 mg/ml)
  1. Intramuscular dosing preferred over subcutaneous (due to more reliable and faster rise in blood levels)
    1. Typically injected in the anterolateral thigh
  2. Repeat every 5 to 15 minutes prn up to 3 doses
  3. Cardiac monitoring required for repeat dosing
  4. Epinephrine via vial
    1. Adult: 0.5 mg (0.5 ml) of 1:1000 Epinephrine IM
    2. Child: 0.01 mg/kg (0.01 ml/kg) IM up to 0.3 mg (0.3 ml)
  5. Epinephrine Autoinjector (preferred if available, as reduces errors and speeds delivery)
    1. Adult and children over 30 kg or 66 pounds: 0.3 mg autoinjector
    2. Children under 30 kg or 66 pounds: 0.15 autoinjector
3. Dirty Epinephrine Drip
  1. See Dirty Epinephrine Drip
4. Unresponsive to Epinephrine
  1. Glucagon (esp. if patient uses Beta-Blockers)
    1. Dose: 3.5 to 5 mg IV in adults (20 to 30 mcg/kg up to 1 mg in children) over 5 minutes
    2. May repeat if no Blood Pressure response within 10 minutes
  2. Norepinephrine may also be considered
Hypotension (due to vasodilitation and third spacing)
1. Fluid Resuscitation with Isotonic Saline (NS, LR)
  1. Adult: 1-2 Liters Normal Saline
  2. Child: 10-20 ml/kg per bolus until Hypotension improves
  3. Large volumes may be required
2. Pressors (e.g. Norepinephrine, Dopamine) may be required
3. Consider Epinephrine by continuous IV infusion
Respiratory distress
1. Nebulized Beta Adrenergic Agonist (e.g. Albuterol)
  1. Consider for signs of lower airway obstruction
2. Consider Endotracheal Intubation
Urticaria, Pruritus or Flushing
1. General: H1 Antagonists
  1. Not a first-line agent in Anaphylaxis management
  2. Use only as an adjunct to Epinephrine and ABC Management
  3. Effects are delayed 1-2 hours from delivery
  4. Does not reverse upper airway obstruction or improve Hypotension
2. Diphenhydramine (Benadryl) every 6 hours prn
  1. Adult: 25-50 mg IM, IV, or PO
  2. Child: 1.25 mg/kg IM, IV or PO
Corticosteroids for severe or persistent symptoms not resolved in 30 min
1. Background
  1. Not a first-line agent in Anaphylaxis management
  2. Use only as an adjunct to Epinephrine and ABC Management
  3. Effects are delayed 6 hours from delivery
  4. Studies proving benefit are lacking
  5. Consider for prevention of biphasic reaction, protracted reaction or in comorbid Asthma with Wheezing
  6. Does not prevent Anaphylaxis relapse
    1. Grunau (2015) Ann Emerg Med 66(4): 381-9 +PMID:25820033 [PubMed]
2. Preparations
  1. Hydrocortisone 5 mg/kg IV
  2. Methylprednisolone (Solu-Medrol) every 6 hours
    1. Adult: 60-125 mg IV/IM
    2. Child: 0.5-1 mg/kg IV/IM
  3. Predisone 60 mg orally in adults (or Methyprednisolone 1-2 mg/kg orally in children)
  4. Dexamethasone (Decadron) 10 mg IV or Orally
Disposition
1. Observation of moderate to severe reactions for 4 to 6 hours (or 6 to 10 hours per some guidelines)
  1. Minimum observation time is 2-3 hours (or >1 hour without symptoms)
    1. Observe long enough to witness waning of first Epinephrine dose
  2. Prolonged reaction (esp >4 hours) or multiple Epinephrine doses may require 12-24 hour observation
2. Delayed, biphasic reactions are uncommon
  1. Biphasic anaphylactic reactions were originally thought to occur several hours later in up to 20% of cases
  2. More recent data suggests biphasic reactions in 0.4% of cases
  3. Returning to the Emergency Department (bounce-back) for non-Anaphylaxis is common
    1. Rash or other allergic, non-anaphylactic symptoms prompts return in up to 6% of patients in first week
  4. References
    1. Grunau (2014) Ann Emerg Med 63(6):736-44 +PMID:24239340 [PubMed]
3. Discharge medications
  1. See Below
Hospitalization Indications
1. Severe initial Anaphylaxis presentation
  1. Cyanosis
  2. Altered Mental Status
  3. Severe Hypotension
  4. Wide Pulse Pressure
  5. Drug-Induced Anaphylaxis in children
2. Multiple Epinephrine doses needed
3. Prior serious, protracted Anaphylaxis or bipashic reaction
4. Risk factors for severe or fatal Anaphylaxis (see above)
5. Continued Vasopressor (e.g. Epinephrine infusion) or airway compromise (Advanced Airway)
6. Refractory course (consider higher level of care)

XVI. Management: Home

See prevention recommendations below
Epinephrine Autoinjector (EpiPen, Twinject, Adrenaclick)
1. Administer at onset of anxaphylaxis symptoms and present immediately for medical care or call 911
2. Prescribe to all patients with Anaphylaxis history
  1. Less than 50% of children with Anaphylaxis receive Epinephrine before emergency department arrival
  2. Robinson (2017) Ann Allergy Asthma Immunol 19(2):164-9 +PMID:28711194 [PubMed]
Prednisone
1. Corticosteroids most effective if started early
  1. Administer within 1-2 hours if possible, but effect delayed for 6 hours after dose
2. Prednisone 1-2 mg/kg/day up to 40-60 mg/day for 3 days
Antihistamines (H1 Blockers)
1. Cetirizine (Zyrtec)
  1. Adults
    1. Start at 10 mg orally once to twice daily and may advance up to 20 mg orally twice daily
    2. May use Diphenhydramine for breakthrough Pruritus (esp at night)
  2. Children 6 months to 2 years: 2.5 mg orally daily
  3. Children 2-5 years old: 2.5 to 5 mg orally daily
  4. Children >5 years old: 5 to 10 mg orally daily
2. Diphenhydramine (Benadryl)
  1. Liquid has better absorption than tablets
  2. Adult: 25-50 mg orally every 6 hours for 3 days
  3. Child: 5 mg/kg/day orally divided every 6 hours (or 1.25 mg/kg per dose)
H2 Blocker
1. Background
  1. May improve Urticaria beyond H1 Blocker alone, but evidence is weak
  2. Fedorowicz (2012) Cochrane Database Syst Rev (3):CD008596 [PubMed]
2. Famotidine (Pepcid) for 3 days
3. Cimetidine (Tagamet) for 3 days
4. Ranitidine (Zantac)
  1. Dose: 1-2 mg/kg/dose up to 150 mg twice daily for 2-3 days

XVII. Prognosis

Hospitalization: 5% of Anaphylaxis presentations
Anaphylaxis-related deaths
1. U.S. overall: 186 to 225 per year
2. U.S. Hospital or Emergency Department presentations: 0.3% fatality rate

XVIII. Prevention

Medical Alert Bracelet should be worn
Strict avoidance of allergen
Anaphylaxis action plan
1. https://www.healthychildren.org/SiteCollectionDocuments/AAP_Allergy_and_Anaphylaxis_Emergency_Plan.pdf
2. Share with school and childcare
3. Includes patient identification including photo of patient, and emergency contact information
4. Includes list of allergans (including food allergans)
5. Includes symptoms and signs of Anaphylaxis
6. Includes key management including ephinephrine autoinjector
Epinephrine Autoinjector, home injectable devices (EpiPen, Twinject, Adrenaclick)
1. Keep one in place where most of time spent
2. Bring an injector when traveling or at work (have available at all times)
Consider allergist referral
Consider Skin Testing and Desensitization therapy
1. Indicated if re-exposure is likely or unavoidable
Clinic office administration of medications and injections
1. Should include a policy to observe patient after injection for 20-30 minutes

XIX. References

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