Anaphylactic Shock

Quick Answer

Anaphylactic shock is a life-threatening systemic hypersensitivity reaction causing distributive shock through massive mast cell and basophil degranulation. Immediate IM adrenaline 0.5 mg (1:1,000) is first-line treatment, with repeat doses every 5 minutes if no improvement. Aggressive IV fluid resuscitation (20-30 mL/kg) and airway management are critical. Serum tryptase measurement 1-2 hours post-onset confirms diagnosis. Observe for biphasic reactions (5-20% incidence) for minimum 6-8 hours. Refractory cases may require IV adrenaline infusion, glucagon (if on beta-blockers), or vasopressin for catecholamine-resistant shock.

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CICM Exam Focus

Primary Exam Relevance:

• Histamine and tryptase as mediators (pharmacology)
• IgE-mediated Type I hypersensitivity mechanism
• Cardiovascular physiology: distributive shock, SVR changes

Second Part Exam Relevance:

• Recognition and immediate management of anaphylaxis in ICU
• Differentiating IgE-mediated vs anaphylactoid reactions
• Invasive monitoring and vasoactive infusion management
• Refractory anaphylaxis: IV adrenaline, glucagon, vasopressin, methylene blue
• Serum tryptase interpretation and timing
• Biphasic reaction prediction and observation requirements

Common Exam Scenarios:

• Post-operative anaphylaxis to neuromuscular blocker (rocuronium, suxamethonium)
• Contrast-induced anaphylactoid reaction during CT scan
• Drug-induced anaphylaxis in beta-blocked patient (refractory hypotension)
• Biphasic reaction after initial ED treatment

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Key Points

1. Adrenaline is the ONLY first-line medication - IM 0.5 mg (1:1,000) into anterolateral thigh
2. Distributive shock physiology: Up to 35% of intravascular volume shifts to extravascular space within 10 minutes
3. Serum tryptase timing: Peak 1-2 hours, remains elevated 6-8 hours (confirms mast cell activation)
4. Biphasic reactions: Occur in 5-20% of cases, typically 4-12 hours after initial event
5. Refractory anaphylaxis: Consider IV adrenaline infusion (0.05-0.1 mcg/kg/min), glucagon (beta-blocker patients), vasopressin
6. Airway priority: Early intubation if stridor, tongue swelling, or threatened airway
7. Fluid resuscitation: 20-30 mL/kg crystalloid rapidly (may need 4-6 litres in adults)
8. H1/H2 blockers are ADJUNCTS ONLY - do not delay adrenaline

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Epidemiology

Incidence

Anaphylaxis incidence has been increasing globally over the past two decades:

• General population: 50-200 per 100,000 person-years (0.05-0.2% annual incidence)
• Lifetime prevalence: 0.5-2% in Western countries
• ICU admission: 10-15% of anaphylaxis cases require intensive care
• Hospital admission rate: 3-5 per 100,000 population annually in Australia/NZ

High-Risk Populations:

• Previous anaphylaxis: 40-60% recurrence risk with re-exposure
• Asthma: 2-3x increased risk of severe/fatal anaphylaxis
• Cardiovascular disease: Increased mortality risk (OR 2.7)
• Beta-blocker therapy: 2-3x risk of refractory anaphylaxis

Mortality

• Overall mortality: 0.05-0.3% of anaphylaxis cases (1-3 per 1,000 cases)
• Fatal anaphylaxis rate: 0.3-1 per million population per year
• ICU mortality: 1-2% of ICU-admitted anaphylaxis patients
• Iatrogenic anaphylaxis: Higher mortality (contrast media, perioperative drugs)

Common Fatal Triggers:

1. Foods (especially peanuts, tree nuts) - 30-50%
2. Insect stings (Hymenoptera) - 20-30%
3. Medications (antibiotics, NSAIDs) - 15-25%
4. Unknown/idiopathic - 10-20%

Time to Cardiac Arrest:

• Food-induced: 30-35 minutes (median)
• Insect venom: 15-20 minutes (median)
• IV medications: 5 minutes (median)
• IV contrast: below 5 minutes (often immediate)

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Pathophysiology

Mechanism Classification

1. IgE-Mediated (Type I Hypersensitivity)

Sensitization Phase:

• Initial allergen exposure → antigen processing by dendritic cells
• Activation of Th2 lymphocytes → IL-4, IL-13 secretion
• B-cell differentiation to IgE-producing plasma cells
• IgE binds to FcεRI receptors on mast cells and basophils (no symptoms)

Re-Exposure (Effector Phase):

• Allergen cross-links membrane-bound IgE antibodies
• FcεRI aggregation triggers intracellular signaling cascade
• Calcium influx → degranulation within 5-30 minutes
• Release of preformed mediators (histamine, tryptase) + newly synthesized mediators

Key Triggers:

• Foods: Peanuts, tree nuts, shellfish, eggs, milk
• Insect venom: Bees, wasps, ants (Hymenoptera)
• Medications: Penicillins, cephalosporins, monoclonal antibodies
• Latex

2. Anaphylactoid (Non-IgE-Mediated)

Direct Mast Cell Activation:

• No prior sensitization required
• Direct membrane disruption or receptor-mediated degranulation
• Clinically INDISTINGUISHABLE from IgE-mediated anaphylaxis

Common Triggers:

• Radiocontrast media (especially ionic, hyperosmolar)
• Opioids (morphine, codeine) - direct histamine release
• Vancomycin ("Red Man Syndrome")
• Neuromuscular blockers (rocuronium, suxamethonium)
• NSAIDs (COX-1 inhibition → leukotriene overproduction)

3. Complement-Mediated

• Activation of complement cascade (C3a, C5a production)
• Anaphylatoxins bind to mast cell/basophil receptors → degranulation
• Triggers: Blood products, immunoglobulins, dextrans

Mediators and Effects

Preformed Mediators (Immediate Release)

Histamine:

• Source: Mast cell and basophil granules (100-fold increase in plasma)
• Receptors: H1 (vasodilation, bronchospasm, pruritus), H2 (vasodilation, gastric acid)
• Peak: 5-10 minutes
• Half-life: 1 minute (rapidly metabolized by histamine-N-methyltransferase, diamine oxidase)
• Effects:
  • Increased vascular permeability (endothelial gap junctions)
  • Arteriolar and venous vasodilation (↓ SVR, ↓ preload)
  • Coronary vasoconstriction (H1) + vasodilation (H2) - net variable effect
  • Bronchoconstriction (H1 on airway smooth muscle)
  • Negative inotropy and chronotropy (direct H2 cardiac effect)

Tryptase:

• Source: Mast cell-specific neutral protease (α-tryptase: constitutive, β-tryptase: activation-specific)
• Peak: 60-90 minutes (1-2 hours post-symptom onset)
• Elevated duration: 6-8 hours
• Half-life: ~2 hours
• Clinical utility: Gold standard biomarker for anaphylaxis diagnosis
  • Total tryptase greater than 11.4 μg/L suggests mast cell activation
  • Acute tryptase >(1.2 × baseline) + 2 μg/L diagnostic formula
• Effects:
  • Activates complement (C3, C5) and coagulation cascades
  • Increases vascular permeability
  • Cleaves fibrinogen, kininogen

Newly Synthesized Mediators (Delayed Release)

Leukotrienes (LTC₄, LTD₄, LTE₄):

• Synthesized via 5-lipoxygenase pathway from arachidonic acid
• Peak: 15-30 minutes
• Effects:
  • Potent bronchoconstriction (1,000x more potent than histamine)
  • Increased vascular permeability
  • Mucus hypersecretion

Prostaglandins (PGD₂):

• Synthesized via cyclooxygenase pathway
• Peak: 15-30 minutes
• Effects:
  • Vasodilation and hypotension
  • Bronchoconstriction
  • Coronary vasoconstriction

Platelet-Activating Factor (PAF):

• Synthesized from membrane phospholipids
• Peak: 30-60 minutes
• Effects:
  • Severe hypotension (most potent vasodilator)
  • Bronchoconstriction
  • Platelet aggregation and thrombosis
  • Myocardial depression (negative inotropy)
  • Associated with biphasic reactions

Cytokines (TNF-α, IL-4, IL-6, IL-13):

• Delayed release (hours)
• Perpetuate inflammatory response
• Contribute to late-phase reactions and biphasic anaphylaxis

Cardiovascular Pathophysiology

Distributive Shock Mechanism

1. Massive Vasodilation:

   • Arteriolar dilation → ↓ SVR (can drop by 50-70%)
   • Venodilation → ↓ venous return → ↓ preload
   • Relative hypovolemia despite normal blood volume

2. Capillary Leak:

   • Endothelial gap junction widening (histamine, leukotrienes)
   • Up to 35% of intravascular volume shifts to interstitium within 10 minutes
   • Absolute hypovolemia (hemoconcentration, ↑ hematocrit)

3. Myocardial Depression:

   • Direct negative inotropy (histamine H2, PAF)
   • Coronary vasospasm → myocardial ischemia (esp. with pre-existing CAD)
   • Takotsubo-like cardiomyopathy reported in severe cases

4. Paradoxical Bradycardia:

   • Occurs in 10-15% of cases (especially IV drug-induced)
   • Bezold-Jarisch reflex: Vigorous ventricular contraction on empty ventricle
   • Vagal stimulation from GI/respiratory symptoms

Haemodynamic Patterns

Early (Compensated):

• ↓ SVR (50-70% reduction)
• ↑ CO (initially, due to tachycardia)
• ↓ BP (SBP below 90 mmHg or greater than 30% drop)
• Wide pulse pressure (low diastolic)

Decompensated:

• ↓↓ SVR (profound vasodilation)
• ↓↓ CO (due to severe hypovolemia, myocardial depression)
• ↓↓ BP (SBP below 70 mmHg, MAP below 50 mmHg)
• Lactic acidosis (tissue hypoperfusion)

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Clinical Presentation

Diagnostic Criteria

ASCIA/ANZAAG Clinical Criteria (2022):

Anaphylaxis is highly likely when any ONE of the following criteria is met:

Criterion 1: Acute onset involving skin/mucosa AND one of:

• Respiratory compromise (dyspnoea, wheeze, stridor, hypoxaemia)
• Reduced BP or end-organ dysfunction (hypotonia, syncope, incontinence)

Criterion 2: Two or more of the following after allergen exposure:

• Skin/mucosal involvement (urticaria, angioedema, flushing)
• Respiratory compromise
• Reduced BP or end-organ dysfunction
• Persistent GI symptoms (cramping, vomiting)

Criterion 3: Reduced BP after known allergen exposure:

• Adults: SBP below 90 mmHg or greater than 30% decrease from baseline
• Children: Age-specific low SBP or greater than 30% decrease from baseline

Organ System Involvement

Skin/Mucosal (80-90% of Cases)

Earliest and most common manifestation:

• Urticaria (hives): Pruritic, erythematous, raised wheals; blanching with pressure
• Angioedema: Non-pitting subcutaneous/submucosal swelling (lips, tongue, eyelids, genitalia)
• Flushing: Diffuse erythema (face, neck, chest) - "red as a beet"
• Pruritus: Palms, soles, scalp, perineum

Note: 10-20% of anaphylaxis cases have NO skin involvement (especially hypotensive reactions)

Respiratory (70% of Cases)

Upper Airway:

• Angioedema: Tongue, uvula, larynx → airway obstruction
• Stridor: Inspiratory noise indicating laryngeal edema (CRITICAL SIGN)
• Hoarseness/dysphonia: Vocal cord edema
• Sensation of throat closing

Lower Airway:

• Bronchospasm: Expiratory wheeze, prolonged expiration
• Dyspnoea: Increased work of breathing, accessory muscle use
• Chest tightness: "Feeling like can't get air in"
• Hypoxaemia: SpO₂ below 92% (severe bronchospasm or airway obstruction)

Respiratory Failure:

• Type II (hypercapnic): Exhaustion, ↓GCS, PaCO₂ greater than 50 mmHg
• Complete airway obstruction → cannot ventilate → cardiac arrest

Cardiovascular (45% of Cases, 100% in Anaphylactic Shock)

Hypotension:

• SBP below 90 mmHg or greater than 30% decrease from baseline
• Dizziness, lightheadedness, presyncope
• Syncope (sudden loss of consciousness)

Shock:

• Tachycardia (HR greater than 100 bpm) - most common
• Paradoxical bradycardia (10-15% of cases)
• Cold, clammy skin (vs. warm in typical distributive shock)
• Prolonged capillary refill time (greater than 2 seconds)
• Altered mental status (confusion, agitation, coma)

Cardiac Arrest:

• Pulseless electrical activity (PEA) - most common rhythm (60%)
• Asystole (25%)
• Ventricular fibrillation/tachycardia (15%)

Takotsubo Cardiomyopathy:

• Stress-induced cardiomyopathy (transient apical ballooning)
• Troponin elevation, ECG changes (ST elevation, T-wave inversion)
• Reversible with supportive care

Gastrointestinal (45% of Cases)

• Nausea and vomiting (30%)
• Crampy abdominal pain (25-30%)
• Diarrhoea (10-15%)
• Incontinence (bowel/bladder) in severe cases

Neurological (15% of Cases)

• Altered mental status: Confusion, agitation, lethargy
• Sense of impending doom: Anxiety, panic
• Headache
• Seizures: Rare, due to cerebral hypoperfusion
• Loss of consciousness: Syncope (vasovagal vs. hypotensive)

Severity Grading

Ring and Messmer Grading (Modified):

CICM candidates must recognize Grade III-IV as requiring ICU admission.

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Triggers and Risk Factors

Common Triggers (ICU/Perioperative Setting)

Neuromuscular Blockers (50-70% of Perioperative Anaphylaxis)

Highest Risk:

• Rocuronium: Most common trigger (up to 50% of NMB anaphylaxis)
• Suxamethonium: Second most common (20-30%)
• Atracurium, vecuronium: Lower risk but still significant

Mechanism:

• IgE-mediated against quaternary ammonium ion (common epitope)
• Cross-reactivity between NMBs common (50-70%)

Clinical Pearl: Sugammadex (rocuronium reversal) has been successfully used to chelate and inactivate rocuronium in rocuronium-induced anaphylaxis (case reports, off-label use).

Antibiotics (15-20% of Perioperative Anaphylaxis)

Beta-Lactams (Penicillins, Cephalosporins):

• Cross-reactivity: Penicillins ↔ Cephalosporins (1-10% depending on side-chain)
• Cefazolin (surgical prophylaxis) is a common culprit

Vancomycin:

• Red Man Syndrome: Anaphylactoid (non-IgE) histamine release
• Infusion rate-dependent (slow infusion to greater than 60 min reduces risk)
• True IgE-mediated anaphylaxis rare

Fluoroquinolones, Tetracyclines:

• Less common, but IgE-mediated reactions documented

Radiocontrast Media (10-15% of ICU Anaphylaxis)

High-Osmolar Ionic Contrast (HOICM):

• Anaphylactoid (non-IgE) in greater than 90% of cases
• Incidence: 1-3% (mostly mild), severe 0.1-0.2%

Low-Osmolar Non-Ionic Contrast (LOCM):

• Lower incidence: 0.2-0.7% (mostly mild), severe 0.02-0.04%
• Still anaphylactoid, not IgE-mediated

Iso-Osmolar Contrast:

• Lowest risk, but reactions still occur

Risk Factors:

• Previous reaction to contrast (20-60% recurrence risk)
• Asthma, atopy
• Beta-blocker use
• Mastocytosis

Premedication (Limited Efficacy):

• Prednisone 50 mg PO 13h, 7h, 1h before procedure
• Diphenhydramine 50 mg PO/IV 1h before
• Reduces mild reactions by 50-60%, does NOT prevent severe anaphylaxis

Blood Products

Plasma, Platelets, Immunoglobulins:

• IgA deficiency: Anti-IgA antibodies → anaphylaxis with IgA-containing products
• Screen IgA levels in patients with recurrent transfusion reactions
• Use washed/IgA-deficient products if IgA deficiency confirmed

Red Blood Cells:

• Less common, but ABO incompatibility can cause anaphylactoid reactions

Colloids

Gelatin:

• IgE-mediated, incidence ~0.1-0.3%
• Cross-reactivity with gelatin-containing foods/vaccines

Dextran:

• Anaphylactoid via complement activation
• Rare in modern practice

Hydroxyethyl Starch (HES):

• Anaphylactoid, incidence 0.06-0.2%
• Use declining due to renal toxicity concerns

Other ICU Drugs

Protamine:

• Used to reverse heparin (cardiac surgery, dialysis)
• Risk factors: Previous NPH insulin exposure, fish allergy, vasectomy
• Incidence: 0.5-1% (mild), 0.1% (severe)

Propofol:

• Rare IgE-mediated anaphylaxis (below 0.1%)
• No cross-reactivity with soy/egg allergy (phenolic core is allergen, not lipid emulsion)

Chlorhexidine:

• Increasing recognition as perioperative trigger
• Skin preparation, urinary catheters, central line dressings

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Investigations

Immediate (During Acute Event)

1. Clinical Diagnosis (Bedside)

Anaphylaxis is a CLINICAL diagnosis - do NOT delay treatment for investigations.

Measure:

• Blood pressure: Every 1-2 minutes during resuscitation
• Heart rate: Tachycardia vs. paradoxical bradycardia
• Oxygen saturation: Target SpO₂ greater than 94%
• Respiratory rate: Increased work of breathing, stridor

2. Arterial Blood Gas (ABG)

Indications:

• Respiratory distress, hypoxaemia (SpO₂ below 92%)
• Shock, altered mental status
• Cardiac arrest

Findings:

• Respiratory alkalosis (early): Hyperventilation due to dyspnoea, anxiety
• Metabolic acidosis (late): Lactic acidosis from tissue hypoperfusion
• Respiratory acidosis: Severe bronchospasm, exhaustion, impending respiratory arrest
• Hypoxaemia: PaO₂ below 60 mmHg (8 kPa)

3. ECG

Indications:

• All patients with cardiovascular symptoms (hypotension, chest pain, arrhythmia)
• Age greater than 50 years or cardiovascular risk factors

Findings:

• Tachycardia: Sinus tachycardia (most common)
• Ischaemia: ST-segment changes (depression/elevation), T-wave inversion
  • "Kounis syndrome: Allergic myocardial infarction (coronary vasospasm + plaque rupture)"
• Arrhythmias: Atrial fibrillation, ventricular ectopy, bradycardia
• Takotsubo pattern: ST elevation (especially V1-V4), prolonged QTc

4. Chest X-Ray

Indications:

• Persistent respiratory symptoms after initial treatment
• Rule out complications: Pneumothorax, aspiration pneumonitis, pulmonary oedema

Findings:

• Hyperinflation (bronchospasm)
• Patchy infiltrates (aspiration)
• Cardiomegaly, pulmonary oedema (cardiac dysfunction)

Confirmatory (Post-Event)

1. Serum Tryptase (GOLD STANDARD)

Optimal Timing:

• First sample: 1-2 hours after symptom onset (peak level)
• Second sample: 24 hours later (baseline level)
• DO NOT wait for tryptase results before giving adrenaline

Interpretation:

• Total tryptase greater than 11.4 μg/L suggests mast cell activation
• Diagnostic formula: Acute tryptase >(1.2 × baseline tryptase) + 2 μg/L
• Persistently elevated baseline (greater than 20 μg/L): Consider systemic mastocytosis

Limitations:

• False negatives in 25-40% of anaphylaxis cases
  • Food-induced anaphylaxis (lower mast cell burden in GI tract)
  • Rapid, severe reactions (death before peak tryptase)
  • Predominantly basophil-mediated reactions (tryptase is mast cell-specific)
• Tryptase can be elevated in:
  • Cardiac arrest (non-specific elevation)
  • Systemic mastocytosis
  • Acute myeloid leukaemia
  • Renal failure (↓ clearance)

Clinical Pearl: A normal tryptase does NOT exclude anaphylaxis - diagnosis is clinical.

2. Histamine (Plasma/Urine)

Plasma Histamine:

• Peak: 5-10 minutes
• Returns to baseline: 30-60 minutes
• Difficult to capture due to rapid metabolism
• Requires rapid processing (cold centrifugation, immediate freezing)

Urine Histamine Metabolites (N-methylhistamine):

• Peak: 1-2 hours
• Elevated up to 12-24 hours
• Less commonly measured (specialized labs)

Utility: Limited due to timing constraints and availability.

3. Specific IgE Testing (Allergen Identification)

Skin Prick Testing (SPT):

• Timing: Minimum 4-6 weeks after event (to avoid refractory period)
• Indications: Suspected food, venom, or drug allergy
• Positive: Wheal ≥3 mm larger than negative control
• Sensitivity: 70-90% (varies by allergen)

Intradermal Testing (IDT):

• More sensitive than SPT but higher false-positive rate
• Used for drug allergy testing (especially penicillins, NMBs)
• Risk: Can trigger severe reactions (must have resuscitation available)

Serum Specific IgE (RAST/ImmunoCAP):

• Measures allergen-specific IgE antibodies in serum
• Safer than skin testing (no reaction risk)
• Sensitivity: 60-90% (varies by allergen)
• Example allergens: Penicillin, cephalosporin, peanut, shellfish, latex

Basophil Activation Test (BAT):

• Flow cytometry-based assay
• Measures CD63/CD203c upregulation on basophils after allergen exposure
• Utility: Drug allergy (especially NMBs, antibiotics)
• Specialized test, limited availability

4. Cardiac Biomarkers

Troponin I/T:

• Elevated in 10-30% of severe anaphylaxis cases
• Indicates myocardial injury (Kounis syndrome, stress cardiomyopathy)
• Peak: 6-12 hours, remains elevated 7-14 days

Echocardiography:

• Indications: Troponin elevation, ECG changes, haemodynamic instability
• Findings: Regional wall motion abnormalities (Takotsubo), global hypokinesia, reduced LVEF

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Management

Immediate Management (First 5 Minutes)

1. STOP Allergen Exposure

• Discontinue suspected drug/infusion immediately
• Remove venom source (bee sting, remove stinger with scraping motion, not squeezing)

2. Call for Help

• Activate emergency response (MET call, code blue)
• Prepare for airway management and cardiac arrest

3. Adrenaline IM (FIRST-LINE TREATMENT)

Dose:

• Adults: 0.5 mg (0.5 mL of 1:1,000 = 1 mg/mL)
• Children: 0.01 mg/kg (max 0.5 mg)
  • below 7.5 kg: 0.1 mg
  • 7.5-20 kg: 0.15 mg
  • 20-50 kg: 0.3 mg
  • greater than 50 kg: 0.5 mg

Route:

• Intramuscular (IM) into anterolateral thigh (vastus lateralis)
• NOT subcutaneous (slower absorption)
• NOT IV bolus (risk of arrhythmia, hypertensive crisis unless cardiac arrest)

Repeat Dosing:

• Every 5 minutes if no improvement in symptoms
• Prepare for IV adrenaline infusion if ≥3 IM doses required

Mechanism:

• α₁: Vasoconstriction (↑ SVR, ↑ BP)
• β₁: Inotropy and chronotropy (↑ CO)
• β₂: Bronchodilation, inhibits mast cell degranulation

Absorption:

• IM (thigh): Peak plasma level 8-10 minutes
• SC: Peak 15-20 minutes (unreliable)
• IV infusion: Immediate (use for refractory shock)

4. Position Patient

• Supine position with legs elevated (↑ venous return)
• Do NOT sit up or stand - can precipitate fatal cardiovascular collapse ("empty heart syndrome")
• Exception: Severe respiratory distress - allow semi-recumbent (45°) if absolutely necessary

5. Airway Assessment and Oxygen

Airway:

• Assess for stridor, hoarseness, tongue/lip swelling
• Early intubation if:
  • Stridor (laryngeal oedema)
  • Tongue/uvula swelling progressing rapidly
  • Impending airway obstruction

Intubation Challenges:

• Laryngeal oedema → difficult visualization
• Consider smaller ETT (e.g., 6.0-6.5 mm instead of 7.5-8.0 mm)
• Surgical airway (cricothyroidotomy) may be needed if cannot intubate/ventilate

Oxygen:

• High-flow oxygen via non-rebreather mask (15 L/min)
• Target SpO₂ greater than 94% (greater than 92% if COPD)

6. IV Access and Fluid Resuscitation

IV Access:

• Two large-bore IV cannulae (14-16G)
• Prepare for rapid fluid resuscitation

Fluid Resuscitation:

• Crystalloid (0.9% NaCl or Hartmann's): 20 mL/kg IV bolus (1-2 L in adults)
• Repeat 20 mL/kg boluses as needed
• Total fluid requirement: Often 4-6 litres in first hour (up to 35% of blood volume lost to interstitium)

Haemodynamic Goals:

• SBP greater than 90 mmHg (or return to baseline)
• MAP greater than 65 mmHg
• Urine output greater than 0.5 mL/kg/h
• Lactate clearance, improved mental status

Colloids:

• Avoid in anaphylaxis (gelatin, HES, dextran can themselves trigger anaphylaxis)
• Use crystalloid exclusively

Secondary Management (Next 15 Minutes)

7. Adjunctive Medications

H1 Antihistamines:

• Promethazine 25 mg IV OR Chlorpheniramine 10 mg IV OR Diphenhydramine 25-50 mg IV
• NOT first-line - only give AFTER adrenaline
• Mechanism: Blocks histamine H1 receptors (reduces urticaria, pruritus, angioedema)
• Sedation side effect (promethazine > diphenhydramine)

H2 Antihistamines:

• Ranitidine 50 mg IV OR Famotidine 20 mg IV
• Blocks histamine H2 receptors (theoretical benefit for hypotension, tachycardia)
• Limited evidence for efficacy in anaphylaxis

Corticosteroids:

• Hydrocortisone 200 mg IV OR Methylprednisolone 125 mg IV
• NOT effective for immediate symptoms (onset 4-6 hours)
• Theoretical benefit: Prevent biphasic reactions (conflicting evidence)
• No harm in giving - universally recommended in guidelines

Bronchodilators (If Bronchospasm Persists):

• Salbutamol (Albuterol) 5 mg nebulized with oxygen
• Ipratropium 500 mcg nebulized (can add to salbutamol)
• Does NOT replace adrenaline - only adjunct
• Does NOT treat upper airway obstruction (stridor, laryngeal oedema)

8. Monitoring

Non-Invasive:

• ECG continuous monitoring: HR, rhythm
• Automated BP: Every 1-2 minutes (then every 5 min after stabilization)
• Pulse oximetry: SpO₂ target greater than 94%
• Capnography (if intubated): EtCO₂ target 35-45 mmHg

Invasive (If Refractory Shock):

• Arterial line: Beat-to-beat BP monitoring, ABG sampling
• Central venous catheter: CVP monitoring, secure IV access for vasopressors
• Urinary catheter: Urine output monitoring (target greater than 0.5 mL/kg/h)

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Refractory Anaphylaxis

Definition: Anaphylaxis requiring ≥3 doses of IM adrenaline OR persistent hypotension despite 2-3 L IV fluids.

Incidence: 5-10% of anaphylaxis cases.

Risk Factors:

• Beta-blocker therapy (antagonizes adrenaline)
• ACE inhibitor/ARB therapy (potentiates bradykinin)
• Severe underlying cardiovascular disease
• Delayed adrenaline administration (greater than 30 min from symptom onset)

IV Adrenaline Infusion

Indications:

• ≥3 IM adrenaline doses with inadequate response
• Ongoing cardiovascular collapse
• Cardiac arrest

Preparation:

• Dilution: 1 mg adrenaline in 100 mL 0.9% NaCl = 10 mcg/mL
• Administer via infusion pump with dedicated IV line
• Requires ICU/HDU monitoring (arterial line recommended)

Dosing:

• Starting rate: 0.05 mcg/kg/min (3.5 mcg/min for 70 kg patient = 21 mL/h of 10 mcg/mL solution)
• Titrate by 0.05 mcg/kg/min increments every 2-5 minutes
• Typical range: 0.05-0.5 mcg/kg/min
• Maximum: 1 mcg/kg/min (equivalent to 70 mcg/min for 70 kg = septic shock dosing)

Monitoring:

• Continuous ECG: Risk of arrhythmia (VT, VF, SVT)
• Arterial BP: Beat-to-beat monitoring
• Signs of overdose:
  • Hypertension (SBP greater than 180 mmHg)
  • Tachycardia (HR greater than 140 bpm)
  • Tremor, anxiety, chest pain
  • Ventricular arrhythmias

Weaning:

• Once haemodynamically stable (SBP greater than 100, HR below 100) for 30-60 minutes
• Wean by 0.01-0.02 mcg/kg/min decrements every 10-15 minutes
• Monitor for rebound hypotension

Glucagon (For Beta-Blocked Patients)

Rationale:

• Beta-blockers antagonize adrenaline's β₁ and β₂ effects
• Glucagon activates adenylate cyclase independently of β-receptors
• Increases cAMP → positive inotropy/chronotropy, bronchodilation

Indications:

• Refractory hypotension/bradycardia in patient on beta-blocker
• Poor response to IM/IV adrenaline

Dosing:

• Bolus: 1-5 mg IV over 1-2 minutes (if ≤1 mg ineffective, give 5 mg)
• Infusion: 5-15 mcg/min (0.3-0.9 mg/h) - titrate to effect
• Onset: 1-3 minutes
• Duration: 10-15 minutes (hence need for infusion)

Side Effects:

• Nausea and vomiting (50-80% of patients) - protect airway
• Hyperglycaemia (↑ glycogenolysis)
• Hypokalaemia

Contraindications:

• Phaeochromocytoma (can precipitate hypertensive crisis)

Limitations:

• Requires hepatic glycogen stores (ineffective in starvation, chronic alcohol use)
• Variable efficacy (case reports/series only, no RCTs)

Vasopressin

Rationale:

• V₁ receptor agonist → vasoconstriction independent of adrenergic system
• Effective in catecholamine-resistant shock (acidosis, hypoxia)
• Synergistic with adrenaline

Indications:

• Refractory anaphylactic shock despite IV adrenaline infusion
• Cardiac arrest (part of ACLS algorithm)

Dosing:

• Bolus: 2-10 units IV (in cardiac arrest, give 40 units × 1)
• Infusion: 0.01-0.04 units/min (0.6-2.4 units/h) - titrate to MAP greater than 65 mmHg
• Onset: 2-5 minutes

Monitoring:

• Risk of digital/limb ischaemia (potent vasoconstrictor)
• Hyponatraemia (SIADH effect at high doses)
• Coronary/mesenteric vasoconstriction (rare at low doses)

Evidence:

• Case reports/series show efficacy in refractory anaphylaxis
• Used in septic shock (VASST trial) - mortality benefit in less severe shock
• No RCTs in anaphylaxis

Other Rescue Therapies (Limited Evidence)

Methylene Blue

Mechanism:

• Inhibits guanylate cyclase → reduces cGMP → vasoconstriction
• Blocks nitric oxide pathway

Dosing:

• 1-2 mg/kg IV over 20-60 minutes
• Onset: 15-30 minutes

Indications:

• Refractory distributive shock unresponsive to adrenaline/vasopressin

Evidence:

• Case reports in anaphylactic shock (limited)
• Used in septic shock, cardiac surgery vasoplegic syndrome

Side Effects:

• Blue discoloration (skin, urine)
• Haemolysis in G6PD deficiency (contraindicated)
• Serotonin syndrome (if on SSRIs)

Extracorporeal Membrane Oxygenation (ECMO)

Indications:

• Refractory cardiac arrest despite optimal management
• Severe refractory shock with end-organ hypoperfusion

Evidence:

• Case reports of successful use in anaphylactic cardiac arrest
• Requires ECMO-capable centre

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Biphasic Reactions

Definition: Recurrence of anaphylaxis symptoms after initial resolution, without further allergen exposure.

Epidemiology

• Incidence: 5-20% of anaphylaxis cases (varies by study)
• Timing: Typically 4-12 hours after initial event (range 1-72 hours, median 8-10 hours)
• Severity: Usually milder than initial reaction, but can be severe/fatal

Pathophysiology

• Mechanism unclear - proposed theories:
  1. Slow allergen release (e.g., from GI absorption of food allergen)
  2. Secondary mediator release (leukotrienes, PAF, cytokines)
  3. Inadequate initial treatment (insufficient adrenaline)

Risk Factors

Predictors of Biphasic Reaction:

• Severe initial reaction (Grade III-IV, requiring ≥2 doses adrenaline)
• Delayed initial adrenaline (greater than 60 minutes from symptom onset)
• Food allergen (especially peanut, tree nut)
• Unknown allergen/idiopathic anaphylaxis
• Inadequate initial treatment (no adrenaline, or only antihistamines)

NOT predictive (despite common belief):

• Corticosteroid administration (does NOT prevent biphasic reactions)

Observation Period

ASCIA/ANZAAG Recommendations:

Minimum observation:

• Grade I-II (mild-moderate): 4 hours post-treatment
• Grade III-IV (severe): 6-8 hours post-treatment
• Refractory/multiple adrenaline doses: 12-24 hours (ICU admission)

Extended observation (12-24 hours):

• Severe initial reaction (required intubation, cardiac arrest)
• Unknown allergen (cannot ensure avoidance)
• Remote location (limited access to emergency care)
• Ongoing symptoms at 4-6 hours

Discharge Criteria:

• Complete resolution of symptoms for minimum 4 hours
• Patient/family educated on biphasic reaction risk
• Prescribed adrenaline auto-injector (e.g., EpiPen) + demonstration of use
• Follow-up with allergist arranged
• Written anaphylaxis action plan provided

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Post-Acute Management

ICU Admission Criteria

Absolute Indications:

• Grade III-IV anaphylaxis (severe hypotension, cardiac arrest)
• Required ≥3 doses IM adrenaline or IV adrenaline infusion
• Intubation/mechanical ventilation
• Persistent haemodynamic instability requiring vasopressor support
• Cardiac complications (Kounis syndrome, Takotsubo cardiomyopathy)
• Refractory bronchospasm requiring continuous nebulizers/IV salbutamol

Relative Indications:

• Beta-blocker therapy (higher risk of refractory/biphasic reaction)
• Significant comorbidities (CAD, COPD, asthma)
• Delayed presentation (greater than 4 hours from symptom onset)
• Unknown allergen (ongoing exposure risk)

Allergen Identification

Referral to Allergist/Immunologist:

• All patients with anaphylaxis should be referred for allergen testing
• Timing: 4-6 weeks post-event (avoid refractory period)

Testing Modalities:

• Skin prick testing (SPT): Foods, venoms, latex
• Intradermal testing (IDT): Drugs (penicillin, NMBs)
• Serum specific IgE: All suspected allergens
• Drug provocation testing: Graded challenge under supervision (high-risk procedure)

Perioperative Anaphylaxis:

• Refer to anaesthesia/allergy clinic for comprehensive drug testing
• Test all perioperative drugs (NMBs, antibiotics, latex, chlorhexidine, etc.)
• Provides safe alternatives for future anaesthesia

Adrenaline Auto-Injector Prescription

Indications (All Anaphylaxis Patients):

• Any Grade I-IV anaphylaxis
• History of food/insect allergy with previous systemic reaction

Devices in Australia/NZ:

• EpiPen: 150 mcg (paediatric), 300 mcg (adult), 500 mcg (adult greater than 50 kg)
• Anapen: 150 mcg, 300 mcg, 500 mcg
• Jext: 150 mcg, 300 mcg

Patient Education:

• When to use: Recurrent symptoms (urticaria + respiratory/CV symptoms)
• How to use:
  1. Remove from case
  2. Form fist around device, remove blue safety cap
  3. Place orange tip against outer mid-thigh (can be through clothing)
  4. Push down firmly until click heard
  5. Hold for 3 seconds
  6. Remove and massage injection site
• After use: Call ambulance (000 in Australia/NZ), bring used device to hospital
• Two devices: Prescribe 2 auto-injectors (in case second dose needed before ambulance arrival)

Expiry:

• Check expiry date every 6 months
• Replace if expired or if solution discoloured/contains particles

Anaphylaxis Action Plan

Written plan should include:

• Patient name, photo, allergen(s)
• Symptoms to recognize (urticaria, angioedema, wheeze, vomiting, hypotension)
• Action steps:
  1. Inject adrenaline auto-injector immediately
  2. Call ambulance (000)
  3. Lie patient flat (or sit if breathing difficulty)
  4. Give second dose after 5 minutes if no improvement
  5. Transfer to hospital
• Medications: Adrenaline dose, location of auto-injector
• Emergency contacts: Parent/guardian, doctor

Provide to:

• Patient/family
• School/workplace (if relevant)
• Primary care physician

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Special Populations

Beta-Blocker Therapy

Increased Risk:

• Severity: 2-3x more likely to have severe/refractory anaphylaxis
• Mortality: Higher mortality risk (case-control studies, OR 2.5-3.0)

Mechanisms:

• β-blocker antagonizes adrenaline β₁ (inotropy/chronotropy) and β₂ (bronchodilation)
• Unopposed α-adrenergic stimulation → paradoxical hypertension, reflex bradycardia
• Increased histamine release (some β-blockers promote mast cell degranulation)

Management Differences:

• Higher adrenaline doses required (less effective)
• Glucagon (see above) - first-line for refractory hypotension/bradycardia
• Atropine 0.6 mg IV for bradycardia (if glucagon unavailable)
• Consider IV fluid boluses earlier (may be more effective than adrenaline)

Long-Term:

• Do NOT discontinue beta-blocker without cardiology consultation (rebound risk in CAD)
• Ensure adrenaline auto-injector + family/patient education on glucagon

ACE Inhibitor/ARB Therapy

Mechanism:

• ACE inhibitors block degradation of bradykinin (vasodilator)
• ARBs potentiate bradykinin pathway
• Can worsen angioedema and hypotension in anaphylaxis

Evidence:

• Observational studies show increased severity in ACE-I/ARB users
• Consider temporary discontinuation (48-72 hours) before high-risk procedures (contrast, surgery)

Mastocytosis

Definition:

• Clonal proliferation of mast cells in skin/organs
• Elevated baseline tryptase (greater than 20 μg/L)

Anaphylaxis Risk:

• 22-49% of mastocytosis patients experience anaphylaxis
• Often triggered by Hymenoptera venom (bees, wasps)
• Higher risk of severe/fatal anaphylaxis

Diagnosis:

• Persistently elevated baseline tryptase (greater than 20 μg/L)
• Bone marrow biopsy (mast cell aggregates, KIT D816V mutation)

Management:

• Always carry adrenaline auto-injector (×2)
• Venom immunotherapy if venom-triggered (highly effective, 95% protection)
• Avoid mast cell degranulators: NSAIDs, opioids, alcohol, contrast media
• H1 + H2 antihistamines prophylaxis (daily)

Pregnancy

Considerations:

• Anaphylaxis in pregnancy can cause fetal hypoxia (maternal hypotension, hypoxaemia)
• Uterine contractions may occur (histamine stimulates uterine smooth muscle)

Management:

• Same as non-pregnant patients: Adrenaline IM 0.5 mg is safe and essential
• Left lateral tilt (if greater than 20 weeks gestation) - relieves aortocaval compression
• Continuous fetal monitoring (if viable fetus, greater than 24 weeks)
• IV fluid resuscitation: Aggressive (normal pregnancy has ↑ blood volume)

Safety of Adrenaline in Pregnancy:

• FDA Category C (theoretical risk of uterine vasoconstriction)
• Benefits outweigh risks - maternal death = fetal death
• No evidence of teratogenicity or fetal harm at therapeutic doses

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CICM Viva Scenarios

Viva 1: Perioperative Anaphylaxis to Rocuronium

Stem: A 45-year-old woman is undergoing elective laparoscopic cholecystectomy. She has been induced with propofol 200 mg, fentanyl 100 mcg, and rocuronium 50 mg. Two minutes after intubation, the surgeon notes facial swelling and urticaria on the chest. BP drops from 120/70 to 70/40 mmHg, HR increases from 75 to 130 bpm. SpO₂ decreases to 88% on FiO₂ 1.0 with bilateral wheeze.

Question 1: What is your immediate diagnosis and management?

Model Answer: This is Grade III perioperative anaphylaxis, most likely to rocuronium (most common NMB trigger).

Immediate management (ABCDE approach):

1. Stop surgery and announce anaphylaxis to team
2. Discontinue all IV drugs (likely trigger is rocuronium)
3. Call for help (senior anaesthetist, extra staff)

Airway:

• Airway already secured (intubated)
• Assess ETT position, ensure bilateral air entry
• Increase FiO₂ to 1.0

Breathing:

• Wheeze suggests bronchospasm - increase PEEP to 5-8 cmH₂O
• Increase tidal volume slightly (6-8 mL/kg) to overcome bronchospasm
• Salbutamol 5 mg nebulized via ETT circuit

Circulation:

• Adrenaline 0.5 mg IM (anterolateral thigh) immediately
• IV fluid bolus 20 mL/kg (1-2 L) 0.9% NaCl rapid infusion
• Prepare IV adrenaline infusion (if hypotension persists)

Drugs:

• Repeat adrenaline 0.5 mg IM every 5 minutes if BP below 90 mmHg
• Hydrocortisone 200 mg IV
• Promethazine 25 mg IV (after adrenaline)
• Ranitidine 50 mg IV

Exposure:

• Examine for extent of urticaria/angioedema

Question 2: BP remains 70/40 mmHg despite 2 doses of IM adrenaline and 2 L IV fluids. What now?

Model Answer: This is refractory anaphylaxis. Requires IV adrenaline infusion.

IV adrenaline infusion:

• Prepare: 1 mg adrenaline in 100 mL 0.9% NaCl (10 mcg/mL)
• Starting rate: 3.5 mcg/min (70 kg patient = 0.05 mcg/kg/min = 21 mL/h)
• Titrate by 0.05 mcg/kg/min increments every 2-5 minutes
• Monitor: Continuous ECG, arterial line (insert now), SpO₂

Additional measures:

• Further fluid boluses (may need 4-6 L total)
• Vasopressin 2-10 units IV bolus if still refractory (then infusion 0.01-0.04 units/min)
• Noradrenaline infusion as second-line vasopressor

Monitoring:

• Arterial line (beat-to-beat BP)
• ECG (risk of arrhythmia with IV adrenaline)
• ABG (assess lactate, acidosis)

Question 3: What investigations will you send?

Model Answer: Immediate:

• Arterial blood gas: Assess oxygenation, lactate, acidosis
• Serum tryptase: NOW (within 15 min of reaction), then 1-2 hours post-onset, then 24 hours (baseline)
• ECG: Check for ischaemia (Kounis syndrome), arrhythmia
• Troponin: If ECG changes or high-risk patient

Post-Event (24h-6 weeks later):

• Allergy referral: Skin prick/intradermal testing for rocuronium and other NMBs
• Specific IgE: Rocuronium, suxamethonium, other NMBs, latex, chlorhexidine
• Basophil activation test (if available): Confirms rocuronium allergy

Question 4: How will you manage this patient post-operatively?

Model Answer: ICU Admission:

• Grade III anaphylaxis requiring multiple adrenaline doses and IV infusion
• Requires close haemodynamic monitoring, observation for biphasic reaction

Monitoring:

• Continuous ECG, arterial BP
• Hourly observations (HR, BP, RR, SpO₂, urine output)
• Observation period: Minimum 12-24 hours (severe reaction, refractory)

Wean adrenaline infusion:

• Once stable (SBP greater than 100, HR below 100) for 30-60 minutes
• Decrease by 0.01-0.02 mcg/kg/min every 10-15 minutes
• Monitor for rebound hypotension

Continue:

• Hydrocortisone 100 mg IV Q6H × 24 hours (taper over 48-72h)
• Ranitidine 50 mg IV Q12H × 24-48 hours
• Promethazine 25 mg IV Q12H PRN (if urticaria persists)

Discharge Planning:

• Allergy referral: Must identify safe alternative NMB for future anaesthesia
• Medical alert bracelet: "Rocuronium anaphylaxis"
• Letter to GP and patient: Document reaction, avoid rocuronium, refer to allergy clinic

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Viva 2: Refractory Anaphylaxis in Beta-Blocked Patient

Stem: A 68-year-old man presents to ED with anaphylaxis following a bee sting 30 minutes ago. He has urticaria, angioedema of the face, wheeze, and hypotension (BP 75/50 mmHg). He is on metoprolol 50 mg BD for hypertension. He has received 2 doses of IM adrenaline 0.5 mg (at 5-minute intervals) and 2 L IV 0.9% NaCl, but BP remains 70/45 mmHg with HR 60 bpm.

Question 1: Why is this patient refractory to adrenaline?

Model Answer: Beta-blocker antagonism of adrenaline:

• Metoprolol is a β₁-selective blocker (also blocks β₂ at higher doses)
• Blocks adrenaline's β₁ effects: ↓ inotropy, ↓ chronotropy (hence bradycardia HR 60 despite shock)
• Blocks adrenaline's β₂ effects: ↓ bronchodilation (worsens wheeze), ↓ inhibition of mast cell degranulation
• Unopposed α-adrenergic stimulation: Can cause paradoxical hypertension, reflex bradycardia

Beta-blocker patients:

• 2-3x more likely to have severe/refractory anaphylaxis
• Higher mortality risk (OR 2.5-3.0)

Question 2: What is your specific management for this beta-blocked patient?

Model Answer: 1. Glucagon (First-Line for Beta-Blocked Refractory Anaphylaxis):

• Mechanism: Activates adenylate cyclase independently of β-receptors → ↑ cAMP → inotropy, chronotropy, bronchodilation
• Dose: 5 mg IV bolus over 1-2 minutes (if 1 mg ineffective, escalate to 5 mg)
• Infusion: 5-15 mcg/min (0.3-0.9 mg/h) titrated to effect (duration of bolus 10-15 min)
• Side effects: Nausea/vomiting (50-80%) - protect airway, turn patient to lateral position

2. IV Adrenaline Infusion:

• Prepare: 1 mg in 100 mL 0.9% NaCl (10 mcg/mL)
• Starting rate: 3.5 mcg/min (0.05 mcg/kg/min for 70 kg = 21 mL/h)
• Titrate to MAP greater than 65 mmHg
• May require higher doses in beta-blocked patients (up to 0.5-1 mcg/kg/min)

3. Atropine (For Bradycardia):

• Atropine 0.6 mg IV (repeat up to 3 mg total)
• Blocks vagal tone, increases HR
• Use if glucagon unavailable or ineffective for bradycardia

4. Aggressive Fluid Resuscitation:

• May be MORE effective than adrenaline in beta-blocked patients
• Continue 20 mL/kg boluses (may need 4-6 L total)

5. Vasopressin (If Still Refractory):

• 2-10 units IV bolus, then infusion 0.01-0.04 units/min
• V₁ receptor agonist, independent of adrenergic system

Question 3: Should you discontinue metoprolol long-term?

Model Answer: Do NOT discontinue beta-blocker acutely without cardiology consultation:

• Rebound risk: Myocardial ischaemia, infarction, arrhythmia (especially if CAD)
• Beta-blocker indication: Likely post-MI, heart failure, or arrhythmia (not just hypertension)

Long-term plan:

• Cardiology review: Assess if beta-blocker can be switched to alternative (CCB, ACE-I)
• If beta-blocker essential:
  • Ensure adrenaline auto-injector (×2 EpiPens)
  • Prescribe glucagon for home use (family trained)
  • Venom immunotherapy (if Hymenoptera allergy confirmed) - 95% effective
  • Medical alert bracelet: "Bee sting allergy, on beta-blocker"

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SAQ Practice Questions

SAQ 1: Pathophysiology

Question: A 35-year-old woman develops anaphylaxis 5 minutes after eating peanuts at a restaurant.

(a) Describe the IgE-mediated mechanism of anaphylaxis (30%) (b) Explain the cardiovascular pathophysiology of anaphylactic shock (40%) (c) Why is serum tryptase measured 1-2 hours after symptom onset rather than immediately? (30%)

Model Answer:

(a) IgE-Mediated Mechanism (3 marks):

1. Sensitization phase (previous exposure):

   • Allergen (peanut protein) processed by dendritic cells
   • Activation of Th2 lymphocytes → IL-4, IL-13 secretion
   • B-cell differentiation to IgE-producing plasma cells
   • IgE binds to FcεRI receptors on mast cells/basophils (no symptoms)

2. Re-exposure (effector phase):

   • Allergen cross-links membrane-bound IgE antibodies
   • FcεRI aggregation → signal cascade → calcium influx
   • Degranulation within 5-30 minutes

3. Mediator release:

   • Preformed: Histamine, tryptase (immediate)
   • Newly synthesized: Leukotrienes, prostaglandins, PAF (15-60 min)

(b) Cardiovascular Pathophysiology (4 marks):

1. Massive Vasodilation:

   • Histamine (H1/H2), leukotrienes, PAF → arteriolar + venodilation
   • ↓ SVR (50-70% reduction) → hypotension
   • ↓ Venous return (venodilation) → ↓ preload

2. Capillary Leak:

   • Histamine, leukotrienes → endothelial gap junction widening
   • Up to 35% of intravascular volume shifts to interstitium within 10 minutes
   • Absolute hypovolemia (hemoconcentration, ↑ hematocrit)

3. Myocardial Depression:

   • Histamine H2, PAF → direct negative inotropy
   • Coronary vasospasm (H1, leukotrienes) → myocardial ischaemia

4. Distributive Shock:

   • Low SVR + low preload + reduced contractility
   • ↓ BP (SBP below 90 mmHg), ↑ HR (compensatory tachycardia)
   • Tissue hypoperfusion → lactic acidosis

(c) Tryptase Timing (3 marks):

1. Tryptase kinetics:

   • Tryptase is released from mast cell granules during degranulation
   • Peak level: 60-90 minutes (1-2 hours) after symptom onset
   • Elevated duration: Remains elevated for 6-8 hours
   • Half-life: ~2 hours

2. Immediate measurement:

   • Too early - tryptase has not yet reached peak level
   • May be falsely normal if measured within first 30-60 minutes

3. Optimal timing:

   • 1-2 hours post-onset: Captures peak level
   • 24 hours: Baseline level (to compare acute vs. baseline)
   • Diagnostic formula: Acute tryptase >(1.2 × baseline) + 2 μg/L

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SAQ 2: Management

Question: A 52-year-old man develops anaphylaxis in the ICU 10 minutes after starting IV piperacillin-tazobactam. He has facial swelling, urticaria on chest, wheeze, and BP 70/40 mmHg (baseline 130/80 mmHg). He is on carvedilol for heart failure.

(a) Outline your immediate management (first 5 minutes) (40%) (b) After 2 doses of IM adrenaline and 2 L IV fluids, BP remains 70/40 mmHg with HR 65 bpm. What is your next management? (40%) (c) What observation period is required and why? (20%)

Model Answer:

(a) Immediate Management (4 marks):

ABCDE Approach:

A - Airway:

• Assess for stridor, tongue/lip swelling (signs of airway compromise)
• Give high-flow oxygen 15 L/min via non-rebreather mask (target SpO₂ greater than 94%)
• Prepare for intubation if stridor or progressive angioedema

B - Breathing:

• Assess wheeze, respiratory rate, SpO₂
• Salbutamol 5 mg nebulized (for bronchospasm)

C - Circulation:

• STOP piperacillin-tazobactam infusion immediately (likely trigger)
• Adrenaline 0.5 mg IM (anterolateral thigh) - FIRST-LINE treatment
• IV access ×2 large-bore (14-16G)
• IV fluid bolus 20 mL/kg (1-2 L) 0.9% NaCl rapid infusion

D - Drugs:

• Repeat adrenaline 0.5 mg IM every 5 minutes if BP below 90 mmHg
• Hydrocortisone 200 mg IV
• Promethazine 25 mg IV (after adrenaline)
• Ranitidine 50 mg IV

E - Exposure:

• Examine for extent of urticaria/angioedema

(b) Refractory Anaphylaxis in Beta-Blocked Patient (4 marks):

Problem: Carvedilol (non-selective β-blocker) antagonizes adrenaline → refractory hypotension + bradycardia.

Management:

1. Glucagon (first-line for beta-blocked patients):

   • 5 mg IV bolus over 1-2 minutes
   • Infusion: 5-15 mcg/min (0.3-0.9 mg/h) titrated to BP/HR response
   • Mechanism: Bypasses β-receptors, ↑ cAMP → inotropy, chronotropy
   • Side effect: Nausea/vomiting (protect airway)

2. IV Adrenaline Infusion:

   • Prepare: 1 mg in 100 mL 0.9% NaCl (10 mcg/mL)
   • Starting rate: 3.5 mcg/min (0.05 mcg/kg/min) = 21 mL/h for 70 kg
   • Titrate every 2-5 min to MAP greater than 65 mmHg
   • Requires arterial line + continuous ECG monitoring

3. Atropine (for bradycardia):

   • 0.6 mg IV (repeat Q3-5min up to 3 mg total)
   • Blocks vagal tone

4. Further fluid resuscitation:

   • Continue 20 mL/kg boluses (may need 4-6 L total)
   • May be more effective than adrenaline in beta-blocked patients

5. Vasopressin (if still refractory):

   • 2-10 units IV bolus, then infusion 0.01-0.04 units/min
   • Independent of adrenergic system (V₁ receptor agonist)

(c) Observation Period (2 marks):

Minimum 12-24 hours in ICU:

Reasons:

1. Biphasic reaction risk (5-20% incidence):

   • Symptom recurrence 4-12 hours after initial event
   • This patient had severe reaction (Grade III, refractory, required IV adrenaline)
   • Severe reactions have higher biphasic risk

2. Beta-blocker:

   • Higher risk of prolonged/recurrent symptoms
   • Requires extended monitoring

3. Ongoing treatment:

   • Weaning IV adrenaline infusion
   • Monitoring haemodynamic stability
   • Continue corticosteroids, antihistamines for 24-48 hours

Discharge criteria (after 12-24h):

• Complete resolution of symptoms for ≥4 hours
• Off IV adrenaline for ≥6 hours without rebound hypotension
• Allergy referral arranged
• Prescribed adrenaline auto-injector + glucagon (for beta-blocker)

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References

1. Simons FER, et al. World Allergy Organization Guidelines for the Assessment and Management of Anaphylaxis. J Allergy Clin Immunol. 2011;127(3):587-593. [PMID: 21377030]

2. Simons FER, et al. World Allergy Organization anaphylaxis guidelines: 2013 update of the evidence base. Int Arch Allergy Immunol. 2013;162(3):193-204. [PMID: 24008815]

3. Australasian Society of Clinical Immunology and Allergy (ASCIA). Guidelines for the management of anaphylaxis. 2022. [www.allergy.org.au]

4. Muraro A, et al. EAACI Food Allergy and Anaphylaxis Guidelines: diagnosis and management of food allergy. Allergy. 2014;69(8):1008-1025. [PMID: 24909706]

5. Brown SGA. Clinical features and severity grading of anaphylaxis. J Allergy Clin Immunol. 2004;114(2):371-376. [PMID: 15316518]

6. Mertes PM, et al. Perioperative anaphylaxis. Immunol Allergy Clin North Am. 2009;29(3):429-451. [PMID: 19563990]

7. Hepner DL, Castells MC. Anaphylaxis during the perioperative period. Anesth Analg. 2003;97(5):1381-1395. [PMID: 14570656]

8. Harper NJN, et al. Suspected anaphylactic reactions associated with anaesthesia. Anaesthesia. 2009;64(2):199-211. [PMID: 19143700]

9. Ring J, Messmer K. Incidence and severity of anaphylactoid reactions to colloid volume substitutes. Lancet. 1977;1(8009):466-469. [PMID: 65572]

10. Lieberman P, et al. The diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol. 2010;126(3):477-480. [PMID: 20692689]

11. Kemp SF, et al. Epinephrine: the drug of choice for anaphylaxis. A statement of the World Allergy Organization. Allergy. 2008;63(8):1061-1070. [PMID: 18691309]

12. Campbell RL, et al. Epinephrine in anaphylaxis: higher risk without a prescription. Mayo Clin Proc. 2014;89(4):532-544. [PMID: 24636537]

13. Kounis NG. Kounis syndrome: an update on epidemiology, pathogenesis, diagnosis and therapeutic management. Clin Chem Lab Med. 2016;54(10):1545-1559. [PMID: 27071153]

14. Triggiani M, et al. Anaphylaxis and cardiovascular diseases: current concepts on mechanisms and management. Curr Opin Allergy Clin Immunol. 2008;8(3):274-280. [PMID: 18560304]

15. Lee S, Hess EP, et al. Biphasic anaphylactic reactions in pediatrics. Pediatrics. 2000;106(4):762-766. [PMID: 11015520]

16. Grunau BE, et al. Incidence of clinically important biphasic reactions in emergency department patients with allergic reactions or anaphylaxis. Ann Emerg Med. 2014;63(6):736-744. [PMID: 24325204]

17. Sampson HA, et al. Second symposium on the definition and management of anaphylaxis: summary report. J Allergy Clin Immunol. 2006;117(2):391-397. [PMID: 16461139]

18. Schwartz LB. Diagnostic value of tryptase in anaphylaxis and mastocytosis. Immunol Allergy Clin North Am. 2006;26(3):451-463. [PMID: 16931288]

19. Brown SGA, et al. Serum tryptase in anaphylaxis: validity and interpretation. J Allergy Clin Immunol Pract. 2013;1(6):623-631. [PMID: 24565709]

20. Vadas P, et al. Platelet-activating factor, histamine, and tryptase levels in human anaphylaxis. J Allergy Clin Immunol. 2013;131(1):144-149. [PMID: 23040367]

21. Triggiani M, et al. Pathophysiology of anaphylaxis. Int J Immunopathol Pharmacol. 2011;24(4 Suppl):S21-S26. [PMID: 22032782]

22. Fisher MM, Baldo BA. Anaphylaxis during anaesthesia: current aspects of diagnosis and prevention. Eur J Anaesthesiol. 1994;11(4):263-284. [PMID: 7925333]

23. Tacquard C, et al. Anaesthetic management of patients with anaphylaxis to neuromuscular blocking agents: practical recommendations. Eur J Anaesthesiol. 2018;35(3):169-175. [PMID: 29189419]

24. Tsur A, Kalansky A. Sugammadex in rocuronium anaphylaxis: dose matters. Anesthesiology. 2014;120(6):1551. [PMID: 24809933]

25. Dewachter P, et al. Perioperative anaphylaxis: what should be known. Curr Allergy Asthma Rep. 2015;15(5):21. [PMID: 26141576]

26. Levy JH, et al. Perioperative anaphylaxis to sugammadex—really? Anesthesiology. 2011;115(1):217-218. [PMID: 21606828]

27. Kranke P, et al. Refractory anaphylactic shock: polyvalent management in the operating room. Anesth Analg. 2007;105(5):1308-1315. [PMID: 17959958]

28. Manivannan V, et al. Vasopressin in the treatment of refractory anaphylactic shock: a case series. J Intensive Care Soc. 2019;20(1):75-79. [PMID: 30792807]

29. Kill C, et al. Effective treatment of norepinephrine-refractory anaphylactic shock with vasopressin. Acta Anaesthesiol Scand. 2004;48(10):1296-1298. [PMID: 15504190]

30. Schummer W, et al. Anaphylactic shock: is vasopressin the drug of choice? Anesthesiology. 2004;101(4):1025-1027. [PMID: 15448542]

31. Evora PRB, et al. Methylene blue for vasoplegic syndrome treatment in heart surgery: fifteen years of questions, answers, doubts and certainties. Rev Bras Cir Cardiovasc. 2009;24(3):279-288. [PMID: 20011869]

32. Levin AI, et al. The use of methylene blue in the treatment of refractory hypotension during anaphylactic shock. Ann Allergy Asthma Immunol. 2013;110(3):217-218. [PMID: 23548538]

33. Jerschow E, et al. Fatal anaphylaxis in the United States, 1999-2010: temporal patterns and demographic associations. J Allergy Clin Immunol. 2014;134(6):1318-1328. [PMID: 25280385]

34. Turner PJ, et al. Fatal anaphylaxis: mortality rate and risk factors. J Allergy Clin Immunol Pract. 2017;5(5):1169-1178. [PMID: 28888247]

35. Greenberger PA, et al. Risk factors for cardiovascular effects during anaphylaxis. Curr Allergy Asthma Rep. 2017;17(7):45. [PMID: 28580559]

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Document Information:

• Last Reviewed: January 24, 2026
• Next Review: January 24, 2027
• Author: MedVellum CICM Content Team
• Evidence Level: High (Guideline-based, systematic reviews, RCTs)
• Target Audience: CICM Second Part candidates, ACEM Fellowship candidates, ICU trainees

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Disclaimer: This content is for educational purposes only and should not replace clinical judgment or local protocols. Always follow your institution's guidelines and seek senior advice when managing critically unwell patients.