Perioperative Anaphylaxis: Recognition and Management

Quick Answer

Perioperative anaphylaxis is a severe, life-threatening systemic hypersensitivity reaction occurring during or immediately after anaesthesia, with an estimated incidence of 1 in 10,000 to 1 in 20,000 anaesthetics. NMBA (neuromuscular blocking agents) are the most common trigger (50-60%), followed by antibiotics (15-20%) and chlorhexidine (10-15%). Immediate recognition requires a high index of suspicion as patients cannot communicate symptoms while anaesthetised. Key signs include hypotension unresponsive to vasopressors, bronchospasm, tachycardia, and cutaneous flushing/urticaria (though skin signs may be absent or missed). Intramuscular (IM) adrenaline 0.5-1 mg (1:1000) into the anterolateral thigh is first-line for all suspected cases, with IV adrenaline reserved for experienced practitioners or cardiac arrest scenarios. Refractory cases require adrenaline infusion, second-line vasopressors (vasopressin, noradrenaline), and consideration of methylene blue or ECMO as rescue therapies.

Clinical Pearl: Skin signs may be absent in 20% of perioperative anaphylaxis cases, and hypotension may be the sole manifestation. A sudden drop in end-tidal CO₂ with cardiovascular collapse suggests anaphylaxis over other causes.[1]

Epidemiology and Triggers

Incidence and Mortality

Common Triggers

Perioperative Allergen Hierarchy (based on large registries):

IgE-mediated mechanisms account for 60-70% of reactions; non-IgE (anaphylactoid) account for 30-40% (direct mast cell activation, complement activation).[7,8,9]

Specific Risk Factors

[10,11,12]

Pathophysiology

IgE-Mediated (Type I Hypersensitivity)

Mechanism:

1. Sensitisation: First exposure → allergen-specific IgE production → binds to FcεRI receptors on mast cells/basophils
2. Re-exposure: Allergen cross-links IgE on mast cells
3. Activation: Mast cell degranulation within minutes
4. Mediator release:

• Histamine: Vasodilation, increased vascular permeability, bronchoconstriction
• Tryptase: Marker of mast cell activation
• Prostaglandins (PGD₂): Bronchoconstriction, vasodilation
• Leukotrienes (LTC₄, D₄, E₄): Potent bronchoconstrictors, increased permeability
• Platelet-activating factor (PAF): Shock, vascular leakage
• Cytokines (TNF-α, IL-6): Prolonged inflammation

Clinical Features: Rapid onset (minutes), potentially biphasic (relapse 4-8 hours)

[13,14,15]

Non-IgE Mediated (Anaphylactoid)

Mechanisms:

• Direct mast cell activation: Vancomycin ("red man syndrome"), opioids, dextran
• Complement activation: Blood products, protamine (formation of C3a, C5a anaphylatoxins)
• Bradykinin pathway activation: ACE inhibitor-associated angioedema (different from anaphylaxis but important differential)

Clinical Features: Similar to IgE-mediated but may be dose-dependent; tryptase may be less elevated

[16,17]

Physiological Effects

[18,19]

Recognition in the Anaesthetised Patient

Diagnostic Challenges

Unique Perioperative Factors:

• Patient cannot report symptoms (pruritus, "sense of doom")
• Surgical drapes obscure skin signs
• Anaesthetic agents may mask early signs
• Hypotension attributed to other causes (hypovolaemia, depth of anaesthesia, drug effects)
• Bronchospasm may be attributed to asthma, COPD, or mechanical causes

Key Recognisable Signs (in order of typical appearance):

1. Hypotension resistant to fluid/vasopressor therapy

• Sudden drop in arterial pressure
• Unresponsive to usual interventions
• May be profound (systolic <60 mmHg)

2. Tachycardia (usually)

• May be absent in severe shock (bradycardia is ominous sign)
• Reflex to hypotension

3. Bronchospasm

• Increased peak airway pressures
• Decreased tidal volumes
• Difficult ventilation
• Expiratory wheeze (may be absent if severe)

4. Cutaneous signs (if visible)

• Flushing of face/upper chest
• Urticaria
• Angioedema (tongue, lips)
• May be ABSENT in 20%

5. Cardiovascular collapse

• Pulseless electrical activity (PEA) arrest
• Ventricular fibrillation (rare)

6. Rise in EtCO₂ followed by fall in EtCO₂ (if cardiac output falls)

[20,21,22]

Differential Diagnosis

Mimics of Perioperative Anaphylaxis:

Key Distinguisher: Anaphylaxis typically has sudden onset, resistance to standard therapy, and multi-system involvement (cardiovascular + respiratory + skin).

[23,24,25]

Immediate Management

Initial Response ("CALL FOR HELP" Principle)

1. Call for help: Alert all available staff (anaesthetic, surgical, nursing)
2. Remove suspected trigger: Stop administration of all potential allergens
3. Maintain anaesthesia: Deepen with volatile or propofol (prevents awareness, reduces mediator release)
4. 100% oxygen: High-flow oxygen, ensure airway patency
5. Secure airway: May need intubation if laryngeal oedema; existing ETT may need downsizing if tongue swelling

Adrenaline (Epinephrine) Administration

Drug of Choice for All Anaphylaxis—No Substitute

Mechanism:

• α₁-agonism: Vasoconstriction (reverses vasodilation, reduces oedema)
• β₁-agonism: Inotropic/chronotropic support
• β₂-agonism: Bronchodilation

Routes and Dosing:

IM Administration Details:

• Site: Anterolateral thigh (vastus lateralis)
• NOT deltoid (slower absorption)
• Repeat every 5-15 minutes if no response
• Peak concentration: 8-20 minutes

IV Adrenaline Caution:

• Only for experienced practitioners
• High risk of arrhythmias, hypertension, myocardial ischaemia if overdosed
• Always dilute (1:10,000 or more dilute)
• Give slowly, titrate to response
• IV route preferred in cardiac arrest

[26,27,28,29]

Fluid Resuscitation

Large Volume Required due to massive capillary leak:

• Crystalloid: 10-20 mL/kg rapidly (500-1000 mL in adult)
• Continue as needed: May require 2-4 L or more
• Colloids: Controversial (theoretical risk with gelatin-based if gelatin allergy)
• Blood products: If coagulopathy or blood loss present

Monitoring: CVP, urine output, arterial pressure

[30,31]

Adjunctive Therapies

Important: Antihistamines and steroids are adjunctive only—do NOT delay adrenaline for these.

[32,33,34]

Airway Management

Indications for Intubation:

• Laryngeal oedema compromising airway
• Severe bronchospasm not responding to medical therapy
• Impending airway obstruction
• Need for deep sedation/paralysis to control ventilation

Cautions:

• Risk of failed intubation in severe laryngeal oedema
• Have surgical airway equipment ready
• Consider awake fibreoptic intubation if time permits (rarely possible)
• Use largest ETT possible (swelling may occlude small tube)
• NB: Intubation itself does NOT treat anaphylaxis—adrenaline is primary therapy

[35]

Refractory Anaphylaxis

Definition

Failure to respond to:

• 2-3 doses of IM adrenaline
• Adequate fluid resuscitation (20-30 mL/kg)
• Optimised airway and ventilation

Second-Line Vasopressors

Vasopressin: Particularly useful when shock refractory to high-dose adrenaline; provides catecholamine-independent vasoconstriction.

[36,37,38]

Methylene Blue

Rescue Therapy for Refractory Vasodilatory Shock:

• Mechanism: Inhibits nitric oxide synthase and guanylate cyclase → reduces cGMP → vasoconstriction
• Dose: 1-2 mg/kg IV over 15-20 minutes (can repeat)
• Indication: Vasopressor-refractory shock with adequate cardiac output
• Cautions:
• Methaemoglobinaemia risk
• Contraindicated in G6PD deficiency
• May cause serotonin syndrome if on SSRIs
• Blue discolouration of urine/skin

Evidence: Case series suggest benefit in refractory anaphylactic shock; no RCTs.

[39,40]

Glucagon

• Dose: 1-5 mg IV bolus; 5-15 mcg/min infusion
• Indication: Patients on beta-blockers (adrenaline less effective)
• Mechanism: Bypasses β-receptor via cAMP pathway
• Side effects: Hyperglycaemia, gastrointestinal symptoms

[41,42]

ECMO/CPR

Extracorporeal Membrane Oxygenation:

• Consider in refractory cardiac arrest with potentially reversible cause
• Provides oxygenation and circulation while treating underlying cause
• Requires specialist centre
• Case reports of successful use in anaphylactic cardiac arrest

High-Quality CPR:

• Standard ACLS protocols if cardiac arrest
• Prolonged CPR may be required (anaphylaxis is reversible with adrenaline)

[43,44]

Post-Event Management

Monitoring and Observation

Minimum 4-6 hours in monitored setting due to risk of:

• Biphasic reaction (4-8 hours after initial event)
• Protracted anaphylaxis
• Delayed hypotension

ICU Admission Indications:

• Refractory course requiring infusions
• Intubation/mechanical ventilation
• Cardiac arrest
• Significant comorbidities
• Ongoing haemodynamic instability

[45,46]

Investigation of Reaction

Tryptase Levels (Critical for Diagnosis):

Interpretation:

• Acute tryptase >20 mcg/L + (acute - baseline) >2 mcg/L = Mast cell activation
• Tryptase highly specific but NOT sensitive (negative doesn't exclude anaphylaxis)

Other Tests:

• Plasma histamine (if available, very short half-life)
• 24-hour urine N-methylhistamine
• Complement levels (if complement activation suspected)

[47,48,49]

Allergist Referral and Follow-Up

All Patients with Suspected Perioperative Anaphylaxis Require:

• Referral to clinical immunology/allergy specialist
• Skin prick testing or serum specific IgE (4-6 weeks post-event)
• Detailed anaesthetic record review with allergist
• ANZCA Perioperative Anaphylaxis Investigation Clinic referral if available

Testing Strategy:

• All agents administered within 60 minutes of reaction
• Commonly cross-reacting agents (NMBA, antibiotics)
• Chlorhexidine (often overlooked)
• Latex

Alert Systems:

• Medical alert bracelet
• ANZCA alert system notification
• Hospital allergy register
• GP notification

[50,51,52]

Indigenous Health Considerations

Aboriginal and Torres Strait Islander Peoples

Access and Equity Considerations:

Remote and rural Indigenous communities face significant barriers to optimal anaphylaxis management:

Pre-hospital Challenges:

• Adrenaline auto-injectors (EpiPens): Availability and cost barriers in remote areas
• Recognition: Training for remote health workers and community members
• Transport: Delays in reaching definitive care (hours to days in remote areas)

Perioperative Considerations:

1. Documentation: Clear documentation of any known allergies in accessible systems (shared electronic records when available)
2. Alert Systems: Ensure allergy alerts are prominent and visible to all anaesthetic providers
3. Follow-up Access:

• Allergist referral may require travel to regional centres
• Telemedicine consultations increasingly used
• Coordinate with visiting specialist services

4. Cultural Context:

• Historical medical mistrust may affect reporting of allergies
• Use Aboriginal Health Workers to support history-taking
• Ensure family members are aware of diagnosed allergies

Pharmacogenetic Considerations:

• Limited data on specific Indigenous pharmacogenetic variations affecting anaphylaxis treatment
• Standard protocols apply, but individual responses may vary

[53,54,55]

Māori Health Considerations

Whānau Involvement:

For Māori patients experiencing perioperative anaphylaxis:

• Early communication with whānau about the event and causative agent
• Ensure understanding of importance of allergy alert systems
• Discuss implications for future anaesthetics (avoidance vs. allergy testing)

Equity in Follow-Up:

• Ensure equivalent access to allergist services regardless of geographic location
• Coordinate with Māori Health Services for ongoing allergy management
• Address barriers to follow-up appointments (transport, cost, time)

Health Literacy:

• Clear explanation of anaphylaxis trigger and future avoidance
• Visual aids and written materials
• Te reo Māori resources if needed

[56,57,58]

ANZCA Final Exam Focus

Key Viva Questions

Q: "A patient under general anaesthesia suddenly develops severe hypotension (60/40 mmHg) and bronchospasm. Outline your differential diagnosis and management."

Model Answer: "My immediate differential includes anaphylaxis, which is life-threatening and must be addressed urgently, alongside other possibilities such as anaesthetic overdose, tension pneumothorax, pulmonary embolism, hypovolaemia, or cardiac failure. Anaphylaxis is suggested by the acute cardiovascular and respiratory compromise, particularly if resistant to standard interventions.

My immediate management would follow a systematic approach: First, I'd call for help and ensure 100% oxygen delivery while deepening anaesthesia to prevent awareness. I'd stop all potential allergen infusions immediately. The critical intervention is intramuscular adrenaline 0.5 to 1 milligrams into the anterolateral thigh—this is life-saving and must not be delayed. I'd administer rapid fluid resuscitation, 10 to 20 millilitres per kilogram of crystalloid, and prepare for repeated adrenaline doses every 5 to 15 minutes if the response is inadequate.

For the bronchospasm, I'd administer salbutamol and ipratropium nebulisers, consider magnesium 2 grams intravenously, and adjust ventilation to prolong expiratory time. I'd give intravenous hydrocortisone 200 milligrams and chlorphenamine for adjunctive therapy, recognising these have slower onset. If the patient remains refractory, I'd escalate to intravenous adrenaline infusion, add noradrenaline or vasopressin for persistent hypotension, and consider methylene blue in vasopressor-refractory cases."

Q: "Why is intramuscular adrenaline preferred over intravenous in the initial management of anaphylaxis?"

Model Answer: "Intramuscular adrenaline into the anterolateral thigh is preferred for several important reasons. First, the vastus lateralis muscle has excellent vascularity, resulting in rapid and reliable absorption with peak plasma concentrations achieved in 8 to 20 minutes. Second, the safety profile is significantly better than intravenous administration. IV adrenaline, even in small doses, carries substantial risks of severe hypertension, ventricular arrhythmias, and myocardial ischaemia, particularly if administered rapidly or in excessive dosage.

Intramuscular administration provides a depot effect with more gradual absorption, reducing these cardiovascular risks while still delivering therapeutic levels. Additionally, IM adrenaline can be administered immediately by any healthcare provider without needing intravenous access. However, in perioperative settings where intravenous access is already established and practitioners are experienced, carefully titrated IV adrenaline is acceptable, particularly in cardiac arrest scenarios where rapid achievement of therapeutic levels is critical."

Q: "What is the role of tryptase measurement in perioperative anaphylaxis, and how do you interpret the results?"

Model Answer: "Tryptase is the most important laboratory investigation in suspected anaphylaxis because it is highly specific for mast cell activation, which is the central pathophysiological mechanism. Tryptase is stored in mast cell granules and released during degranulation, making it an objective marker of the event. The protocol involves measuring serum tryptase as soon as possible during or immediately after the reaction, again at 1 to 2 hours, and finally at over 24 hours to establish a baseline.

Interpretation criteria require the acute tryptase to exceed 20 micrograms per litre, and there must be a difference of at least 2 micrograms per litre between the acute sample and the baseline. An elevated acute tryptase with a significantly higher level than baseline confirms mast cell activation and supports the diagnosis of anaphylaxis. However, a negative tryptase does not exclude anaphylaxis, as it has limited sensitivity—approximately 60 to 70 percent of cases show elevation. Factors affecting levels include the severity of the reaction, timing of sampling, and individual variation in mast cell tryptase content."

SAQ Practice Question

Question (20 marks): A 45-year-old woman undergoes elective laparoscopic cholecystectomy. After induction with propofol and fentanyl, and administration of rocuronium, she develops severe hypotension (55/30 mmHg), tachycardia (145 bpm), and difficulty ventilating (peak pressures 45 cmH₂O). The surgeons report no significant bleeding.

a) What is your most likely diagnosis and differential diagnoses? (4 marks) b) Describe your immediate management priorities (10 marks) c) What investigations are required, and how would you manage this patient post-operatively? (6 marks)

Model Answer:

a) Diagnosis and differential (4 marks):

Most likely diagnosis: Perioperative anaphylaxis (likely due to rocuronium or less commonly propofol/fentanyl)

Differential diagnoses:

1. Anaesthetic overdose: Consider if excessive doses given; pupils dilated, minimal response
2. Tension pneumothorax: From laparoscopy/ventilation; unilateral ↓ air entry, tracheal deviation
3. Pulmonary embolism: Acute hypotension, ↑ CVP, risk factors present
4. Severe bronchospasm: Asthma exacerbation, anaphylactoid reaction
5. Malignant hyperthermia: If succinylcholine/volatile used; hyperthermia, rigidity
6. Hypovolaemia: Underestimated blood loss, insensible losses
7. Myocardial infarction/ischaemia: Cardiac failure, arrhythmia
8. Local anaesthetic toxicity: If local infiltration used

b) Immediate management priorities (10 marks):

Call for help and remove triggers:

1. Call for assistance (surgeon, other anaesthetists, nurses)
2. Stop administration of ALL potential triggers (cease rocuronium, propofol, fentanyl infusions)
3. Deepen anaesthesia with volatile agent or propofol TIVA to prevent awareness

Airway and oxygenation: 4. Administer 100% oxygen, ensure airway patency 5. Assess need for intubation if not already intubated (this patient is likely intubated post-induction) 6. Adjust ventilator settings: reduce respiratory rate, prolong expiratory time for bronchospasm

Adrenaline administration (CRITICAL): 7. Intramuscular adrenaline 1 mg (1:1000) into anterolateral thigh IMMEDIATELY 8. Prepare for repeat dosing every 5 minutes if inadequate response 9. Alternatively, if IV access secure and experienced: IV adrenaline 50-100 mcg carefully titrated

Fluid resuscitation: 10. Rapid crystalloid infusion: 500-1000 mL (10-20 mL/kg) stat 11. Prepare for large volume requirements (2-4 L may be needed)

Adjunctive therapies: 12. Salbutamol 5 mg nebulised or via breathing circuit for bronchospasm 13. Ipratropium 0.5 mg nebulised 14. Hydrocortisone 200 mg IV (slow onset, prevents biphasic reaction) 15. Chlorphenamine 10-20 mg IV 16. Magnesium sulphate 2 g IV over 10 minutes (refractory bronchospasm)

Monitoring and access: 17. Ensure large-bore IV access (2-3 wide-bore cannulae) 18. Arterial line for continuous BP monitoring and blood sampling 19. Consider CVP for fluid assessment and drug administration 20. Continuous SpO₂, ECG, EtCO₂ monitoring

Refractory management (if above inadequate): 21. Adrenaline infusion 0.05-0.1 mcg/kg/min 22. Noradrenaline infusion for refractory hypotension 23. Vasopressin 1-4 units IV if catecholamine-resistant 24. Methylene blue 1-2 mg/kg if vasopressor-refractory shock 25. Consider intraoperative allergy testing or postpone surgery

c) Investigations and post-operative management (6 marks):

Investigations:

1. Serum tryptase levels (CRITICAL):

• Sample 1: Immediately/as soon as possible (during event)
• Sample 2: 1-2 hours post-event
• Sample 3: >24 hours (baseline)

2. Full blood count (eosinophils may be elevated later)
3. Coagulation screen (DIC risk in severe reactions)
4. Serum biochemistry (electrolytes, renal function)
5. Plasma histamine (if available, but very short half-life)
6. 12-lead ECG (myocardial ischaemia, arrhythmias)
7. Chest X-ray (pulmonary oedema, aspiration)

Post-operative management:

1. Monitoring: Minimum 4-6 hours in high-dependency setting (risk of biphasic reaction)
2. Documentation: Detailed anaesthetic record of timing, agents, response to treatment
3. Referral:

• Urgent referral to clinical immunology/allergy specialist
• ANZCA Perioperative Anaphylaxis Investigation Clinic

4. Follow-up testing: Skin prick testing or specific IgE at 4-6 weeks
5. Alert systems:

• Medical alert bracelet (causative agent identified)
• ANZCA alert notification
• Hospital allergy register
• GP notification

6. Patient/family education:

• Explanation of event and identified/suspected trigger
• Importance of future allergy alerts
• Provision of EpiPen if identified allergy

7. Surgical planning:

• Complete surgery if safe to proceed (if trigger identified and discontinued)
• Or postpone pending investigation

Summary and Key Takeaways

References

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