Anaphylaxis
According to the World Allergy Organization (WAO):
Anaphylaxis is a severe, life-threatening systemic hypersensitivity reaction characterized by rapidly developing airway, breathing and/or circulation problems, usually associated with skin and mucosal changes.
Types of Anaphylaxis
|
Feature |
IgE-Mediated Anaphylaxis (Classic) |
Non-IgE Mediated Anaphylaxis (Formerly “Anaphylactoid”) |
|
Frequency |
Most common type |
Less common |
|
Immune Mechanism |
IgE antibody-mediated hypersensitivity |
Direct mast cell/basophil activation without IgE |
|
Sensitization Required? |
Yes (requires prior exposure) |
No (may occur on first exposure) |
|
Pathogenesis |
Allergen → APC → Th2 response → IL-4/IL-13 release → IgE production → IgE binds mast cells → Re-exposure causes mast cell degranulation |
Direct activation of mast cells and basophils leading to mediator release |
|
Trigger Exposure |
Usually occurs after re-exposure to allergen |
Can occur during first exposure |
|
Mediator Release |
Histamine, tryptase, leukotrienes, prostaglandins |
Histamine, tryptase, leukotrienes, prostaglandins |
|
Clinical Presentation |
Urticaria, angioedema, bronchospasm, hypotension, shock |
Clinically indistinguishable from IgE-mediated anaphylaxis |
|
Laboratory Findings |
May demonstrate allergen-specific IgE |
Usually no allergen-specific IgE |
|
Examples |
Penicillin, Foods (peanut, shellfish, milk), Insect stings (bee, wasp), Latex |
Vancomycin, Opioids (morphine, codeine), Radiocontrast media, Neuromuscular blockers |
|
Diagnosis |
History ± skin testing ± serum-specific IgE |
Primarily clinical; allergy testing often negative |
|
Treatment |
IM epinephrine, oxygen, fluids, adjuncts |
Identical to IgE-mediated anaphylaxis |
Common Triggers
|
Category |
Common Triggers |
|
Drugs |
Penicillin, Cephalosporins, Sulfonamides Aspirin, Ibuprofen, Diclofenac Rocuronium, Succinylcholine, Atracurium Iodinated contrast media Monoclonal antibodies |
|
Foods (Adults) |
Peanuts, Tree nuts, Fish, Shellfish |
|
Foods (Children) |
Milk, Egg, Peanut |
|
Insect Venom |
Bee, Wasp, Hornet stings |
|
Latex |
Latex exposure (especially healthcare workers and patients with repeated surgical procedures) |
|
Exercise-Induced Anaphylaxis |
Food-dependent exercise-induced anaphylaxis (FDEIA) |
|
Occupational Exposure |
Healthcare workers exposed to latex and medical products |
|
Perioperative Anaphylaxis |
Neuromuscular blockers, antibiotics, latex, chlorhexidine, contrast agents |
Pathophysiology
Massive vasodilation—>Capillary leak—>Third spacing—>Reduced venous return—>Reduced cardiac output—>Shock(Up to:35–50% of intravascular volume may extravasate within minutes.)
Diagnostic Criteria-NIAID/FAAN Criteria
|
Criterion 1 |
Criterion 2 |
|
Acute illness + Skin/mucosal involvement |
After likely allergen exposure: |
|
AND at least one:
|
Two or more:
|
|
Examples:
|
|
Criterion 3
Known allergen exposure AND hypotension
Clinical Features
Symptoms usually occur within:
- Seconds to minutes
- Most within 30 minutes
|
System |
Findings |
|
Skin |
Urticaria, flushing, itching,Conjunctivitis, conjunctival swelling, and tearing.Nasal discharge & congestion, sneezing. |
|
Airway |
Stridor, hoarseness,Tongue edem,Uvular edema,Laryngeal edema |
|
Respiratory |
Wheeze, bronchospasm |
|
Cardiovascular |
Hypotension, shock |
|
GI |
Vomiting, diarrhea,Abdominal cramps |
|
Neurologic |
Dizziness, syncope |
Skin manifestations may be absent
Seen in:Up to 20% of fatal cases
Therefore:Absence of rash DOES NOT exclude anaphylaxis.
Biphasic Anaphylaxis
Recurrence after apparent recovery ,WITHOUT re-exposure.
Timing—Usually:1–12 hours,May occur up to 72 hours.
Risk Factors
- Severe initial reaction
- Delayed epinephrine
- Multiple epinephrine doses
- Hypotension
Persistent anaphylaxis
- This refers to ongoing anaphylaxis for >4 hours.
Refractory Anaphylaxis
Definition:Persistent symptoms despite:
- 2 IM epinephrine doses
- Adequate fluids
Differential Diagnosis
|
Differential Diagnosis |
Key Features |
|
Vasovagal Syncope |
Bradycardia—Pallor—No urticaria—No wheeze |
|
Panic Attack |
Hyperventilation—Anxiety—No hypotension |
|
Severe Asthma |
Wheezing—No urticaria—No shock |
|
Angioedema |
• Bradykinin-mediated (especially) • ACE inhibitor-induced angioedema • Hereditary angioedema • No urticaria • Poor response to epinephrine |
Management
ABCDE Approach
Look for:
- Stridor
- Hoarseness
- Tongue swelling
- Drooling
Early airway involvement predicts difficult intubation
Key Principle—Intubate early rather than late.,Late intubation may become impossible.
EPINEPHRINE IS THE FIRST-LINE TREATMENT
- α1—Vasoconstriction—Reduces edema—Increases BP
- β1—Increased cardiac output
- β2—Bronchodilation—Inhibits mast cell mediator release
- indicated for anyone with definite or probable anaphylaxis.
Adult Dose
IM Epinephrine
- 1 mg/mL solution (1:1000)
- Dose:0.5 mg IM
- Site:Mid-anterolateral thigh
- Repeat:Every 5 min if needed upto 3 doses then epinephrine infusion :5–15 mcg/min Titrate according to symptom.wean off after 30 min of symptom resolves.
Pediatric Dose
- 0.01 mg/kg IM
- Maximum:0.5 mg
Why IM Thigh?
Faster absorption than:Deltoid,Subcutaneous tissue
Peri-Arrest / Profound Shock
IV Bolus Epinephrine
Experienced clinicians only.
Typical:10–50 mcg aliquots.Titrated carefully.
Fluid Resuscitation
- Massive capillary leak occurs.
- Adults—1–2 L crystalloid rapidly,May require:3–5 L or more.
- Children—20 mL/kg boluses
Bronchospasm Treatment
Nebulized:Salbutamol 2.5–5 mg,Repeated as needed.
Upper Airway Edema
Nebulized epinephrine:5 mL of 1 mg/mL solution
Antihistamines
H1 Blocker
- Diphenhydramine 50 mg IV QID.
- Famotidine 20 mg IV B.D
- Benefits:Itching.Urticaria
- Limitations:Does NOT treat Shock
Corticosteroids SINGLE SHOT
- Hydrocortisone
- Methylprednisolone 60 mg IV
- dexamethasone 10 mg IV
Role:Historically used to prevent biphasic reactions.
Current evidence:Weak.
Methylene Blue—for refractory anaphylaxis
Additional Mast Cell Stabilizers & Mediator Inhibitors
Important: These agents are NOT first-line treatments for acute anaphylaxis and should never delay or replace epinephrine. They may be considered in selected patients with recurrent anaphylaxis, idiopathic anaphylaxis, mast cell activation syndrome (MCAS), or mastocytosis, although supporting evidence is limited.
|
Drug/Class |
Mechanism & Clinical Use |
|
Second-Generation H1 Antihistamines (Cetirizine, Fexofenadine) |
Used prophylactically to reduce recurrent episodes and chronic mediator-related symptoms (urticaria, flushing, pruritus). Doses up to 4× standard antihistamine doses may be used in refractory cases. |
|
Cetirizine |
Potent H1 blocker with rapid and reliable absorption. Typical dose: 20–40 mg/day in divided doses. May cause dose-related sedation. |
|
Fexofenadine |
Non-sedating H1 blocker. Typical dose: 180–360 mg/day in divided doses. Often preferred when daytime alertness is important. |
|
Montelukast |
Leukotriene receptor antagonist. May reduce bronchospasm and mediator-related symptoms. Common dose: 10 mg once daily. Frequently used as adjunctive therapy in MCAS and recurrent anaphylaxis. |
|
Zileuton |
5-Lipoxygenase inhibitor that blocks leukotriene synthesis. Occasionally used in refractory mast cell disorders when symptoms persist despite antihistamines. |
|
Cromolyn Sodium |
Mast cell stabilizer. Particularly useful for gastrointestinal manifestations (abdominal pain, diarrhea, food-triggered symptoms). Limited systemic absorption (≈1–2%), therefore little benefit for systemic symptoms. |
Patients on beta-blockers
Note that The usual therapies for anaphylaxis will generally work finest use conventional therapy if they fails then do this
- Higher doses of epinephrine than usual
- Methylene blue
- isoproterenol infusion
- Glucagon—Mechanism:Bypasses beta receptors.but its evidence is weak, Dose:Adult 1–5 mg IV over 5 minutes Then infusion if needed.
Evaluation of a Patient
Step 1: Confirm That the Event Was Truly Anaphylaxis
Step 2: Was a Likely Trigger Identified?
If YES
Proceed with allergy evaluation:
- Skin prick testing
- Specific IgE (sIgE) testing
- Drug allergy testing (when appropriate)
If Allergy Testing is Negative
Consider:
- Hidden allergens
- Cofactor-dependent anaphylaxis
- Exercise
- Alcohol
- NSAIDs
- Mast cell disorders
- Idiopathic anaphylaxis
Measure baseline serum tryptase.
Step 3: No Trigger Identified (Idiopathic Anaphylaxis)
Measure:
Baseline Serum Tryptase (BST)
Best obtained:
- At least 24–48 hours after complete recovery
- When patient is asymptomatic
A persistently elevated baseline tryptase suggests:
- Systemic mastocytosis
- Hereditary α-tryptasemia
- Other mast cell activation disorders
Step 4: Interpretation of Baseline Tryptase
Elevated Baseline Tryptase
Evaluate for:Systemic Mastocytosis
Consider especially when:
- Recurrent unexplained anaphylaxis
- Severe insect sting reactions
- Elevated REMA score
- Syncope without obvious trigger
Investigations:
- KIT D816V mutation analysis
- Bone marrow examination (selected patients)
- Flow cytometry for aberrant mast cells
Hereditary α-Tryptasemia (HaT)
Consider when:
- Baseline tryptase >8 ng/mL
- Family history of similar symptoms
- Recurrent flushing or anaphylaxis
Genetic testing may be indicated.
Normal Baseline Tryptase
Does not exclude anaphylaxis.
Proceed according to clinical suspicion.
Step 5: Measure Acute Tryptase During Future Episodes
If diagnosis remains uncertain:
Obtain:Acute Serum Tryptase
Ideally:Within 30 minutes–2 hours of symptom onset
And compare with baseline value.
Significant Mast Cell Activation
The accepted criterion is:
Acute tryptase > (1.2 × baseline tryptase + 2 ng/mL)
This is currently preferred over using an isolated elevated tryptase value.
Step 6: If Acute Tryptase Is Elevated
Consider:Mast Cell Activation Syndrome (MCAS)
Diagnostic requirements:
- Typical recurrent symptoms
- Objective mast cell mediator elevation
- Response to mast-cell-directed therapy
Also consider:
- Systemic mastocytosis
- Hereditary α-tryptasemia
Step 7: If Tryptase Is Not Elevated
Consider Alternative Diagnoses
Endocrine and Neuroendocrine Disorders
- Carcinoid syndrome—24-hour urine 5-HIAA
- VIPoma—Serum VIP
- Medullary thyroid carcinoma—Calcitonin
- Pheochromocytoma—Plasma or urine metanephrines
Cardiovascular Disorders
- Vasovagal syncope
- Postural orthostatic tachycardia syndrome (POTS)
- Dysautonomia
Psychiatric Disorders
- Panic attacks
- Functional neurological disorders
Discharge Planning
Observation Period
|
Observation Duration |
Who Qualifies? |
|
Fast-Track Discharge (≈2 hours after symptom resolution) |
• Rapid response (within 5–10 min) to a single IM epinephrine doseadministered within 30 min of symptom onset • Complete resolution of symptoms • Patient has and knows how to use an epinephrine auto-injector • Reliable supervision and access to emergency care after discharge |
|
Observe for at Least 6 Hours |
• Required 2 doses of IM epinephrine to control the reaction OR • Previous history of biphasic anaphylaxis |
|
Observe for At Least 12 Hours (or Admit) |
• Severe reaction requiring >2 doses of IM epinephrine • Severe asthma or marked respiratory compromise • Risk of ongoing allergen absorption (e.g., sustained-release medications, food allergens) • Late-night presentation when deterioration may be missed • Poor access to emergency medical care • Significant hypotension or refractory symptoms |
Every patient should receive:
1. Trigger avoidance advice
2. Allergy referral
3. 2c Epinephrine auto-injector
Examples:EpiPen—Jext
4. Written emergency action plan
References
- Irwin RS, Rippe JM. Irwin and Rippe’s Intensive Care Medicine. 9th ed. Philadelphia: Wolters Kluwer; 2024.
- Oh TE, Young P, editors. Oh’s Intensive Care Manual. 9th ed. Philadelphia: Elsevier; 2023.
- Vincent JL, Abraham E, Kochanek PM, Moore FA, Fink MP. Textbook of Critical Care. 8th ed. Philadelphia: Elsevier; 2025.