Anaphylaxis

Anaphylaxis – High-Yield Study Guide for Medical Students

Definition

Anaphylaxis is an acute, life-threatening, systemic hypersensitivity reaction characterized by rapid onset and involvement of multiple organ systems, usually driven by mast-cell and basophil mediator release. It typically presents with compromised airway, breathing, and/or circulation, often accompanied by skin and mucosal changes following exposure to a likely trigger (e.g., food, drug, insect sting).

Epidemiology

Anaphylaxis can occur at any age, with increasing incidence reported worldwide. Common settings include community exposures (foods, insect stings) and healthcare environments (perioperative drugs, contrast media). Foods (e.g., peanuts, tree nuts, shellfish, milk, egg) predominate in children and young adults, whereas medications (e.g., beta-lactams, neuromuscular blockers, NSAIDs) and insect stings are more common triggers in older adults. Fatal anaphylaxis is relatively rare but often associated with delayed epinephrine, comorbid asthma, cardiovascular disease, or beta-blocker use.

Pathophysiology

Anaphylaxis is most often mediated by IgE-dependent type I hypersensitivity. On first exposure, allergen is processed by antigen-presenting cells, leading to Th2 activation and class-switching of B cells to produce allergen-specific IgE. These IgE antibodies bind FcεRI receptors on mast cells and basophils, sensitizing them. Re-exposure leads to cross-linking of IgE and rapid cellular degranulation.

Mast-cell and basophil activation releases preformed mediators (e.g., histamine, tryptase) and newly synthesized mediators (e.g., leukotrienes, prostaglandins, platelet-activating factor, cytokines). These mediators cause:

• Vasodilation and increased vascular permeability → intravascular volume loss, edema, distributive shock
• Bronchoconstriction and mucus secretion → wheeze, dyspnea, respiratory failure
• Smooth muscle contraction → abdominal cramps, vomiting, diarrhea
• Cutaneous vasodilation and edema → flushing, urticaria, angioedema

Non–IgE-mediated ("anaphylactoid" or "non-immunologic anaphylaxis") reactions produce a very similar clinical picture but result from direct mast-cell activation (e.g., radiocontrast, opioids, vancomycin, exercise, cold exposure) or complement activation. Regardless of mechanism, the final common pathway is massive mediator release leading to rapid cardiovascular and respiratory compromise.

Common Triggers

Key triggers to remember for exams and clinical practice include:

• Foods: peanuts, tree nuts, shellfish, fish, milk, egg, wheat, soy, sesame
• Medications: beta-lactam antibiotics, other antibiotics (e.g., sulfonamides), NSAIDs, aspirin, biologics, chemotherapeutics
• Insect stings: bees, wasps, hornets, yellow jackets, fire ants
• Perioperative agents: neuromuscular blockers, latex, chlorhexidine, dyes, colloids
• Other: latex, immunotherapy injections, contrast media, exercise-induced anaphylaxis, idiopathic anaphylaxis

Clinical Presentation

Anaphylaxis usually develops within minutes to 1 hour of exposure, but onset may be delayed (especially with food). The presentation is heterogeneous; not all patients have skin manifestations. Think of involvement of at least two organ systems following exposure to a likely allergen, or isolated hypotension/respiratory compromise after a known trigger.

Typical Symptoms and Signs by System

• Cutaneous and mucosal
  • Urticaria (hives), flushing, pruritus
  • Angioedema (lips, tongue, eyelids, face, extremities)
  • Conjunctival injection, periorbital edema
• Respiratory
  • Sensation of throat tightness, lump in throat
  • Hoarseness, stridor, dysphonia due to laryngeal edema
  • Wheezing, dyspnea, chest tightness, cough, tachypnea
  • Use of accessory muscles, cyanosis, hypoxemia
• Cardiovascular
  • Hypotension, dizziness, presyncope, syncope
  • Tachycardia, weak or thready pulse
  • Shock, arrhythmias, cardiac arrest in severe cases
• Gastrointestinal
  • Crampy abdominal pain
  • Nausea, vomiting
  • Diarrhea
• Neurologic
  • Sense of impending doom, anxiety
  • Confusion, agitation
  • Loss of consciousness in severe hypotension or hypoxia

Clinical Variants

• Biphasic anaphylaxis: recurrence of symptoms after initial resolution, typically within 8–12 hours but up to 72 hours. No re-exposure to allergen is required.
• Protracted anaphylaxis: symptoms persist for hours to days despite treatment.
• Idiopathic anaphylaxis: no identifiable trigger despite thorough evaluation.

Diagnostic Criteria

Anaphylaxis is a clinical diagnosis. Laboratory tests (e.g., serum tryptase) can support but must not delay management. Widely used criteria consider anaphylaxis "highly likely" when one of the following situations occurs after exposure to a likely allergen:

• Criterion 1: Acute onset (minutes to hours) with involvement of skin/mucosa (e.g., generalized hives, pruritus, flushing, swollen lips/tongue/uvula) and at least one of:
  • Respiratory compromise (dyspnea, wheeze/bronchospasm, stridor, reduced PEF, hypoxemia)
  • Reduced blood pressure or signs of end-organ hypoperfusion (syncope, hypotonia, collapse, incontinence)
• Criterion 2: Two or more of the following occurring rapidly after exposure to a likely allergen:
  • Involvement of skin–mucosal tissue
  • Respiratory compromise
  • Reduced blood pressure or associated symptoms
  • Persistent gastrointestinal symptoms (crampy abdominal pain, vomiting)
• Criterion 3: Reduced blood pressure after exposure to a known allergen for that patient:
  • Adults: systolic BP <90 mmHg or >30% decrease from baseline
  • Children: low age-specific systolic BP or >30% decrease from baseline

Assessment and Initial Evaluation

In suspected anaphylaxis, immediate simultaneous assessment and treatment are critical. Apply the ABC approach (Airway, Breathing, Circulation):

• Airway: look for stridor, hoarseness, tongue or oropharyngeal swelling, difficulty speaking, altered mental status.
• Breathing: assess respiratory rate, oxygen saturation, work of breathing, wheeze or silent chest, cyanosis.
• Circulation: check heart rate, blood pressure, capillary refill, peripheral perfusion, presence of shock.

Take a focused history of timing, suspected triggers, prior reactions, comorbidities (e.g., asthma, cardiovascular disease, mastocytosis), and medications (e.g., beta-blockers, ACE inhibitors). Examination should emphasize skin, airway, lungs, cardiovascular system, and mental status.

Laboratory and Ancillary Tests

Anaphylaxis is primarily a clinical diagnosis, and treatment should never be delayed for testing. However, certain tests can be useful:

• Serum tryptase: may be elevated when measured 1–3 hours after onset; helps support diagnosis, particularly in perioperative events or when the diagnosis is uncertain. Normal tryptase does not exclude anaphylaxis.
• Complete blood count, electrolytes, blood gas, lactate: useful in severe shock or respiratory failure.
• ECG, troponin: in older patients, or when cardiovascular compromise or myocardial ischemia is suspected.
• Allergy workup (outpatient): skin prick testing, specific IgE, and graded challenge for trigger identification and long-term prevention; should be done after recovery, ideally by an allergist.

Immediate Management (Emergency Treatment)

Anaphylaxis management priorities are early epinephrine, airway protection, rapid volume resuscitation, and removal of the offending trigger when possible. Do not wait for all criteria to be met—treat based on clinical suspicion.

Positioning and Initial Actions

• Stop exposure to suspected trigger (e.g., discontinue infusion, remove insect stinger).
• Call for help and initiate emergency response protocols.
• Position patient supine with legs elevated (Trendelenburg modification) to improve venous return. Avoid sitting or standing suddenly, which may precipitate cardiovascular collapse.
• In pregnancy, place in left lateral position to avoid aortocaval compression.
• Administer high-flow oxygen (e.g., via non-rebreather mask).

Epinephrine: First-Line, Life-Saving Therapy

Epinephrine is the drug of choice and must be given intramuscularly (IM) in the mid-anterolateral thigh as soon as anaphylaxis is suspected. Delay in epinephrine is associated with worse outcomes and fatality.

• IM dosing (1 mg/mL solution, 1:1000):
  • Adults: 0.3–0.5 mg IM in the mid-anterolateral thigh.
  • Children: 0.01 mg/kg IM (maximum 0.3–0.5 mg per dose).
  • Repeat every 5–15 minutes as needed based on clinical response.
• Epinephrine auto-injectors typically deliver fixed doses (e.g., 0.15 mg pediatric, 0.3 mg adult); use what is immediately available in an emergency.
• No absolute contraindications to epinephrine in anaphylaxis; use with caution in patients with cardiovascular disease but do not withhold if anaphylaxis is present.

Airway and Breathing Management

• Administer high-flow oxygen; target SpO2 ≥94%.
• Monitor closely for signs of airway compromise (stridor, hoarseness, tongue swelling, progressive respiratory distress).
• Early involvement of anesthesia or critical care for airway management if airway edema is progressing.
• Consider early endotracheal intubation in patients with significant laryngeal edema, altered mental status, or impending respiratory failure; airway may rapidly become impossible.
• In refractory upper airway obstruction, be prepared for surgical airway (cricothyrotomy) if intubation fails.

Circulation and Fluid Resuscitation

• Establish IV access with one or two large-bore cannulas.
• Administer rapid IV isotonic crystalloid boluses (e.g., 0.9% saline or balanced crystalloids).
  • Adults: initial bolus 1–2 L; repeat as needed.
  • Children: 20 mL/kg bolus; repeat as needed.
• Monitor blood pressure, heart rate, urine output, mental status, and signs of perfusion.
• Persistent hypotension despite repeated IM epinephrine and aggressive fluids may require IV epinephrine infusion in a monitored setting, titrated to blood pressure and perfusion.

Adjunctive Medications (Not First-Line)

These therapies are adjuncts to, not substitutes for, epinephrine. They may help control symptoms but do not reverse life-threatening airway or circulatory compromise.

• H1 antihistamines (e.g., diphenhydramine, cetirizine, chlorpheniramine)
  • Help alleviate urticaria and itching.
  • Onset of action is slower than epinephrine; no role as monotherapy in anaphylaxis.
• H2 antihistamines (e.g., ranitidine, famotidine)
  • May provide additional benefit for cutaneous symptoms when combined with H1 blockers.
• Systemic glucocorticoids (e.g., methylprednisolone IV, prednisone PO)
  • Role in preventing biphasic reactions is debated; onset is delayed (hours).
  • May be considered in moderate-to-severe reactions, especially with asthma or protracted symptoms.
• Inhaled β2-agonists (e.g., salbutamol/albuterol)
• For bronchospasm not fully relieved by epinephrine, particularly in patients with asthma.
• Glucagon
  • Consider in patients on beta-blockers with refractory hypotension or bronchospasm, as glucagon activates adenylate cyclase independently of β-adrenergic receptors.
• Vasopressors (e.g., norepinephrine, vasopressin)
• In ICU settings for persistent shock despite optimal epinephrine and fluids.

Monitoring and Observation

• Continuous monitoring of vital signs (HR, BP, RR, SpO2) in the acute phase.
• Observe for potential biphasic reactions; observation duration is usually at least 4–6 hours after symptom resolution for mild reactions and longer (e.g., 12–24 hours) for severe, refractory, or high-risk cases (e.g., severe asthma, late presentation, need for multiple epinephrine doses).
• Document the event in detail: suspected trigger, timing, clinical manifestations, treatments, and response.

Post-Acute and Long-Term Management

• Trigger identification: arrange referral to an allergist for detailed evaluation, including skin testing, serum specific IgE, and possible challenge tests.
• Epinephrine auto-injector prescription: all patients at risk of recurrent anaphylaxis should have at least one, preferably two, auto-injectors available at all times.
• Education:
  • Recognition of early symptoms of anaphylaxis.
  • Correct use of auto-injector (site, technique, timing).
  • Importance of early epinephrine and seeking urgent medical evaluation even after apparent resolution.
  • Reading food and medication labels, avoiding known triggers.
• Action plan: provide a written emergency action plan outlining steps to take in future episodes.
• Specific immunotherapy: consider venom immunotherapy for Hymenoptera venom anaphylaxis; this can significantly reduce future risk.
• Comorbidity optimization: aggressive management of asthma, cardiovascular disease, and mast-cell disorders to reduce morbidity.

Key Clinical Pearls and Exam Tips

• Epinephrine IM in the thigh is the cornerstone of treatment and should not be delayed for any reason. Antihistamines and steroids are adjuncts only.
• Skin signs may be absent in up to 10–20% of anaphylactic reactions; do not exclude anaphylaxis if hypotension or respiratory compromise follows exposure to a likely allergen.
• In exam vignettes, look for rapidly developing hypotension, wheezing, or throat swelling after exposure to foods, medications, or stings as classic clues.
• Patients on beta-blockers may have blunted responses to epinephrine; think of glucagon in refractory cases.
• Biphasic reactions can occur without re-exposure; reason behind recommended observation period after apparent recovery.
• For perioperative anaphylaxis, consider neuromuscular blockers, antibiotics, latex, and chlorhexidine as common culprits.
• Elevated serum tryptase can support the diagnosis and is especially useful in unclear or perioperative episodes, but normal levels do not rule it out.
• Always inquire about previous reactions, mastocytosis, and family history of mast-cell disorders when evaluating recurrent or severe anaphylaxis.
• On OSCEs, emphasize ABCs, immediate epinephrine, oxygen, IV access, fluids, and continuous monitoring.

Summary for Rapid Review

• Definition: acute, potentially fatal, systemic hypersensitivity reaction with multi-system involvement.
• Mechanism: mast-cell and basophil mediator release (often IgE-mediated) leading to vasodilation, increased permeability, and bronchospasm.
• Clinical: acute onset of skin/mucosal symptoms plus respiratory compromise and/or hypotension after exposure to a likely allergen.
• Diagnosis: clinical; do not delay treatment for tests.
• Treatment: immediate IM epinephrine, airway and oxygen, IV fluids, adjunctive antihistamines and corticosteroids, monitor for biphasic reactions.
• Prevention: avoidance of triggers, epinephrine auto-injector, patient education, and allergist referral.