Pathophysiology and Treatment of Anaphylaxis
Pathophysiology
Anaphylaxis is an acute, life-threatening systemic reaction resulting from the sudden release of mediators from mast cells and basophils, triggered by either IgE-dependent (true anaphylaxis) or IgE-independent (anaphylactoid) mechanisms, though both present identically and require the same urgent treatment. 1
Mechanistic Pathways
IgE-mediated pathway: Allergen cross-links IgE bound to FcεRI receptors on mast cells and basophils, causing immediate release of preformed mediators (histamine, tryptase) and de novo synthesis of inflammatory mediators (leukotrienes, prostaglandins, platelet-activating factor). 1, 2
IgG-dependent pathway: Mouse models demonstrate that some patients with life-threatening anaphylaxis have low or undetectable allergen-specific IgE, suggesting IgG antibodies can trigger anaphylaxis through alternative mechanisms. 1
Complement activation: Anaphylatoxins C3a, C4a, and C5a can directly activate mast cells and basophils, with elevated serum C3a associated with severe anaphylaxis in insect sting challenges. 1
Direct mast cell activation: Certain agents (vancomycin, quinolones, radiocontrast media) can directly trigger mast cell degranulation without requiring antibody involvement. 1, 2
Mediator Effects on Target Organs
Cardiovascular system: Mediators cause profound vasodilation, increased vascular permeability leading to third-spacing of fluid, and potential cardiovascular collapse. 1, 2
Respiratory system: Bronchospasm from smooth muscle contraction, laryngeal edema from increased vascular permeability, and mucous gland hypersecretion. 1, 2
Cutaneous manifestations: Histamine acts on blood vessels and nerve endings causing flushing, pruritus, urticaria, and angioedema (present in 90% of cases). 3, 2
Gastrointestinal tract: Smooth muscle contraction and increased secretions cause nausea, vomiting, diarrhea, and abdominal cramping. 4, 2
Clinical Recognition
The more rapidly anaphylaxis develops, the more likely it is to be severe and potentially life-threatening, with most severe reactions occurring within 30 minutes of exposure. 1, 5
Key Clinical Features
Cutaneous symptoms (90% of cases): Flushing, pruritus, urticaria, angioedema—though their absence does not rule out anaphylaxis, particularly in severe cardiovascular collapse. 3, 1
Respiratory symptoms (40-60%): Bronchospasm, wheezing, chest tightness, shortness of breath, laryngeal edema, stridor. 3, 5
Cardiovascular symptoms (30-35%): Hypotension, tachycardia, syncope, cardiovascular collapse, shock. 3, 5
Gastrointestinal symptoms (25-30%): Nausea, vomiting, diarrhea, abdominal cramping. 3
Critical Diagnostic Pitfall
- Bradycardia can occur in anaphylaxis due to the Bezold-Jarisch reflex, distinguishing it from vasovagal syncope where bradycardia occurs with hypotension but without pruritus. 3, 5
Immediate Treatment Protocol
Epinephrine is the drug of choice and must be administered promptly at the onset of apparent anaphylaxis—if there is any doubt, it is better to administer epinephrine. 1
First-Line Treatment: Epinephrine
Intramuscular route (preferred): 0.3-0.5 mg (0.3-0.5 mL of 1:1000 solution) IM into the anterolateral thigh (vastus lateralis) for adults and children ≥30 kg. 5, 6
Pediatric dosing: 0.01 mg/kg (0.01 mL/kg of 1:1000 solution), maximum 0.3 mg IM for children <30 kg. 5, 6
Repeat dosing: Every 5-15 minutes if symptoms persist or worsen. 1, 5, 6
Intravenous epinephrine: Reserved for cardiopulmonary arrest or protracted anaphylaxis unresponsive to multiple IM doses. Use 1-3 mg (1:10,000 dilution) slowly IV over 3 minutes, then 3-5 mg IV over 3 minutes, followed by 4-10 mg/min infusion if needed. 1, 6
Pediatric resuscitation: 0.01 mg/kg (0.1 mL/kg of 1:10,000 solution, maximum 0.3 mg) repeated every 3-5 minutes for ongoing arrest. 1
Critical Management Principle
Never delay epinephrine administration to give antihistamines or corticosteroids first—this delay is directly associated with increased mortality and biphasic reactions. 6, 7
Secondary Interventions (Do Not Replace Epinephrine)
Positioning: Place patient supine with legs elevated (unless respiratory distress or vomiting, then semi-recumbent). 1, 8
Oxygen: High-flow oxygen via face mask or non-rebreather. 1, 8
Volume resuscitation: Rapid IV fluid bolus with 1-2 L normal saline at 5-10 mL/kg in first 5 minutes for adults; crystalloids or colloids in 20 mL/kg boluses for children. 1, 8
H1 antihistamines: Diphenhydramine 50 mg IV (valuable only in mild reactions, not for cardiovascular collapse or respiratory distress). 1, 6, 8
H2 antihistamines: Ranitidine 50 mg IV (adjunctive only). 1, 8
Corticosteroids: Methylprednisolone 1-2 mg/kg IV every 6 hours or prednisone 0.5 mg/kg PO (to prevent biphasic/protracted reactions, not for acute treatment). 1, 8
Refractory Hypotension Management
Vasopressors: Dopamine 400 mg in 500 mL at 2-20 μg/kg/min or vasopressin 0.01-0.04 U/min for hypotension despite epinephrine and volume replacement. 1, 6
Atropine: 600 μg IV for bradycardia. 1
Glucagon: 1-5 mg IV infusion over 5 minutes for patients on beta-blockers (epinephrine may be less effective). 1, 8
Respiratory-Specific Interventions
Inhaled beta-2 agonists: For persistent bronchospasm despite epinephrine. 8
Advanced airway management: Prepare for intubation or cricothyrotomy if laryngeal edema causes airway obstruction. 1, 8
Observation and Monitoring
Observation periods must be individualized, with extended observation of at least 6 hours warranted for severe anaphylaxis or patients requiring more than one dose of epinephrine, as these are risk factors for biphasic reactions. 1, 6
Biphasic Reactions
Incidence: 1-7% of patients experience biphasic anaphylaxis, with symptoms recurring hours after initial resolution. 1, 5
Risk factors: Severe initial presentation, requiring >1 dose of epinephrine, delayed epinephrine administration. 5, 6
Monitoring: Continue observation until all signs and symptoms completely resolve, with transfer to emergency department or ICU for continued monitoring. 6
Post-Acute Management
After resolution of the acute episode, all patients must be provided with an epinephrine autoinjector and receive proper instruction for self-administration in case of subsequent episodes. 1
Essential Follow-Up Actions
Epinephrine autoinjector prescription: Patients must carry this at all times and be trained in proper use. 5, 7, 9
Written emergency action plan: Provide personalized allergy and anaphylaxis emergency plan with specific instructions. 9
Allergist-immunologist referral: All individuals experiencing anaphylaxis require consultation for detailed history, diagnostic testing, identification of triggers, and evaluation for immunotherapy (e.g., venom immunotherapy) or desensitization options. 1
Medical identification: Instruct patient to wear Medic Alert jewelry or carry identification denoting their condition. 1
Common Triggers and Risk Factors
Most Common Triggers
Foods: Peanuts, tree nuts, fish, shellfish, milk, eggs in children; shellfish, peanuts, fish in adults. 1
Insect venoms: Hymenoptera stings cause 23% of anaphylaxis cases, with 40 deaths per year in the US (likely underestimated). 1
Medications: Penicillin and beta-lactam antibiotics most common; also NSAIDs, radiocontrast media. 1, 2
High-Risk Patient Populations
Severe uncontrolled asthma: Increases risk of fatal anaphylaxis. 8
Beta-blocker therapy: Anaphylaxis may be more severe and refractory to epinephrine, requiring glucagon. 1, 8
ACE inhibitor use: Consider discontinuation in patients with history of anaphylaxis. 1
Cardiovascular disease and older age: Risk factors for perioperative anaphylaxis fatality. 1