Anaphylaxis

This covers both perioperative and non-perioperative anaphylaxis. Treatment recommendations for perioperative anaphylaxis are detailed separately, due to the nature of the disease (typically of more rapid onset and aggressive progression), and the immediate availability of resuscitation equipment and personnel.

Anaphylaxis is a serious and life-threatening generalised Type 1 hypersensitivity reaction characterised by a triad of:

Epidemiology and Risk Factors

Triggers of non-perioperative anaphylaxis:

  • Food
    • 60% of anaphylaxis in children
    • 16% of anaphylaxis in adults
  • Insect venoms
    • 16% of anaphylaxis in children
    • 55% of anaphylaxis in adults
  • Drugs
    • 8% of anaphylaxis in children
    • 21% of anaphylaxis in adults

Perioperative Anaphylaxis

Epidemiology:

  • 56% female
  • Overall less common in paediatrics
    • May be due to less use of antibiotics and muscle relaxants
    • More likely to present with bronchospasm

Pathophysiology

Anaphylaxis may be:

  • Immune mediated
    • IgE mediated:
      • Allergen-specific IgE binding to high-affinity receptors on mast cells and basophils
      • Contact with allergen with multiple specific IgE receptors on the cell surface
        Interaction with multiple receptors is termed cross-linking, and key to initiating intracellular signaling.
      • Degranulation cells occurs, leading to release of a vast number of mediators:
        • Histamine
          Principle mediator of initial cardiovascular effects.
        • Prostaglandins
        • Leukotrienes
        • Tryptase
        • Platelet-activating factor
        • Cytokines
        • Chemokines
    • Immune complex mediated
  • Non-immune mediated
    • Describes a clinical appearance of anaphylaxis where immunological sensitisation has not been detected
    • Probably relates to G-protein induced release of vasoactive mediators

Aetiology

Perioperative anaphylaxis:

  • ~46% are antibiotic associated
    Teicoplanin and amoxacillin-clavulanate have the highest risk.
  • ~33% are related to neuromuscular blocking drugs
    • Suxamethonium: ~11/100,000
    • Rocuronium: 6/100,000
    • Atracurium: 4/100,000
  • ~10% chlorhexidine
    Typically presents more slowly, unless IV (i.e. chlorhexidine-impregnated CVC) source.
    • ↑ incidence due to ↑ use
    • An untested patient with a history of perioperative anaphylaxis should be managed as having chlorhexidine hypersensitivity
  • Patent Blue die
    Highest risk single therapy at ~15/100,000.
    • May present with blue urticaria

All causes:

  • Food
    • 90% from 8 groups
      • Persistent into adulthood
        • Peanuts
        • Tree nuts
        • Fish
        • Crustacea
      • Paediatric
        Tend to resolve in teens.
        • Milk
        • Egg
        • Wheat
        • Soy
    • Red meat
  • Latex
    Associated with cross-reactivity to many fruits:
    • Avocado
    • Banana
    • Chestnut
    • Kiwifruit
    • Papaya
  • Drugs
    • Antibiotics
      • Cephalosporins
    • Neuromuscular blocking drugs
    • NSAIDs
      Similar mechanism by which they induce bronchospasm in asthmatics.
    • Contrast media
    • Protamine
      May cause:
      • True anaphylaxis
      • Direct histamine release from mast cells
        Dose and rate related.
      • Thromboxane release
        Heparin-protamine combination may lead to profound ↑ in PVR and cardiovascular collapse, which may be mistaken for anaphylaxis.
  • Gelatin-based colloids
  • Chlorhexidine
  • Blood products
    1:20:000 to 1:50,000 administrations, by:
    • IgA-deficient recipients with anti-IgA antibodies
    • Transfused allergy into donor blood to a sensitised recipient
    • Recipient with antibodies to plasma proteins
    • Transfusion of IgE antibody from the donor that reacts with a recipient allergen

Clinical Manifestations

  • Unanticipated hypotension or tachycardia should raise suspicion
  • Absence of skin signs does not rule out the diagnosis

Symptoms and signs of anaphylaxis:

  • Typically occur acutely and progress rapidly
    • 83% present within 10 minutes
    • 2% present after 60 minutes
  • Relate to involvement of different organ systems
  • Relate to the region of the body affected
    Typically tissues with high concentrations of mast cells.
    • Skin
      • Urticaria
      • Erythema
      • Angioedema
      • Airway swelling
    • Respiratory
      • Bronchospasm
        Leading symptom in life-threatening reactions.
        • Present in 50%
        • First symptom in ~20%
      • Capnograph changes will be evident in ~30%
    • GIT
      • Nausea
      • Vomiting
      • Diarrhoea
    • CVS
      • Hypotension
        May be isolated.
      • Haemoconcentration
        Due to interstitial oedema.
        • 35-70% of circulating volume may extravasate in 10-15 minutes
      • Cardiac arrest
        PEA most common.

Skin signs are uncommon in severe anaphylaxis due to lack of perfusion.

Isolated severe hypotension was typically managed poorly in NAP6.

Prodromal symptoms:

  • Itching
  • Metallic taste
  • Fearfulness
  • Headache
  • Disorientation

Presentation of Perioperative Anaphylaxis

  • Timing
    • ~80% occurs within 10 minutes of drug administration
      Antibiotic-associated anaphylaxis typically occurs more rapidly and aggressively.
    • ~2% occurs after 60 minutes
  • Features
    • Bronchospasm
      • Occurs in 50%
      • First feature in ~20%
      • Capnograph changes in ~30%
    • Skin signs
      Uncommon in severe reactions.

Classification

Anaphylaxis is classified into four grades, based on severity:

  • Grade 1 (Mild)
    • Mucocutaneous signs only
    • Does not require treatment with adrenaline
    • Does require monitoring
  • Grade 2 (Moderate)
    • Multi-organ manifestations
      Typically:
      • Bronchospasm
      • Hypotension
        Perioperatively, consider hypotension out of proportion to what would be expected by the drugs given or the operative stage.
      • Mucocutaneous signs
        Typically allows differentiation from isolated bronchospasm or other causes of hypotension.
  • Grade 3 (Life-threatening)
    • Life threatening
      • Hypotension
      • Elevated airway pressures
    • Requires immediate treatment to avoid progression
    • Cutaneous signs frequently absent due to poor cardiac output state
      May only appear following resuscitation.
  • Grade 4 (Cardiac arrest)
    • Absence of palpable central pulse or grossly inadequate blood pressure
    • Management follows a ALS protocol
      Consider more frequent use of adrenaline (Q1-2 minutely) and early initiation of vasopressors when initial therapy is inadequate.

Diagnostic Approach and DDx

Differential diagnoses include:

  • Respiratory
    • Status asthmaticus
    • Airway foreign body
    • Laryngotracheitis
    • Tension pneumothorax
    • Acid aspiration
    • Dislodged, kinked, or obstructed airway device
  • CVS
    • Cardiogenic shock
    • Embolism
    • MI
  • Endocrinological
    • Carcinoid syndrome
    • Pheochromocytoma
    • Thyrotoxic crisis
    • Hypoglycaemia
  • Skin diseases
    • Urticaria
    • Hereditary/acquired angioedema
  • Toxins
    • Ethanol
    • Histaminosis

Investigations

Laboratory:

  • Bloods
    • Tryptase
      To confirm diagnosis. Send at:
      • 0-1 hours
      • 4 hours
      • 24 hours
    • RAST testing
      Measurement of level of allergen-specific IgE antibody.

Other:

  • Skin testing
    Test of degree of histamine release on exposure to certain agents.

Tryptase Testing

  • Tryptase is a protease enzyme stored in granules in mast cells and basophils
    Two subtypes:
    • α-tryptase is secreted constitutively and found in health
    • β-tryptase is released by mast cells in anaphylaxis, and may be raised in cutaneous mastocytosis
  • Will not be elevated in a basophil or complement-mediated anaphylaxis
  • Acute elevation supports anaphylaxis diagnosis
    • Level >20μg/L is considered positive, assuming a normal baseline
      Magnitude of elevation is relevant, and is more likely to have an agent identified.
    • Peak level usually within 15-120 minutes
    • Declines over 3-6 hours
  • Should be measured at the 1 (as close as possible to onset), 4, and 24 hour mark
    • 24 hour value gives a baseline level, which can then be used to identify whether there was substantial mast cell degranulation
    • Samples require refrigeration if ⩾1 hour to laboratory

RAST Testing

  • In vitro testing evaluating IgE response to specific agents
    • Limited to IgE mediated reactions
  • Only available for a small number of agents:
    • Suxamethonium
      Limited sensitivity.
    • Penicillin
    • Ampicillin
    • Amoxicillin
    • Cefaclor
    • Latex
    • Chlorhexidine

Skin Testing

  • Gold standard
  • Most useful for:
    • Neuromuscular blocking drugs
      Only method to determine cross-reactivity in NMBD-induced anaphylaxis.
    • Latex
    • β-lactam antibiotics
  • Requirements:
    • Must be performed 6 weeks after the event
      Ensure mast cell recovery has occurred.
    • Several day cessation of:
      • Antihistamines
      • Psychotropic drugs
  • May involve either:
    • Skin prick testing
      Agent is applied to the forearm, and then a needle prick made through the agent.
    • Intradermal testing
      Injection of dilute agents into the dermis.

Management

  • Call for help and assign roles
  • Give adrenaline
  • Commence volume resuscitation
  • Consider early securing of the airway

Resuscitation:

  • Human factors
    Call for help and allocate key roles:
    • Team leader
      Usually most senior person present.
    • Card reader
      Call out required actions of immediate management cards, and to communicate with the team leader.
    • Giver of adrenaline
  • A
    • Intubation
      • Intubate if angioedema present
        Early administration of adrenaline may avoid the need for intubation, but airway difficulty will ↑ as angioedema worsens.
      • Consider early intubation
  • B
    • Bronchodilators
  • C
    • Secure IV access
    • Volume resuscitation
      Reverses haemoconcentration due to interstitial oedema.
      • Can consider colloid, provided colloid was not given prior to onset of anaphylaxis
    • Adrenaline
      • Key therapy
        • Prevents further mast cell degranulation
        • Bronchodilator
        • Vasoconstrictor
      • Doses may vary depend on patient factors
        • ↑ Risk of CVS compromise with overdose
          • Extremes of age
          • Hypertension
          • Ischaemic heart disease
          • Hyperthyroidism
        • Catecholamine resistance
          • β-blockade
          • ACE-I use
        • Catecholamine sensitivity
          • Amphetamines
          • Cocaine
      • Intramuscular
        When no IV access, or no haemodynamic monitoring.
        • Appropriate when IV access is unavailable
        • Reduces chance of severe CVS side effects
        • Provides ‘depot’ for continued release
          Up to 40 minutes. Useful as a ‘pseudo-infusion’, whilst establishing a real infusion.
      • Intravenous
        • Appropriate in severe anaphylaxis
        • May be repeated every 1-2 minutes, as required
        • If >3 doses are required, then commence an infusion
    • Arterial line insertion
      Monitoring, titration, and blood sampling for tryptase.
    • Consider central line insertion
      If ongoing vasopressor requirement.
    • VA ECMO
      • Indicated for systolic failure in resuscitated shock
      • Difficult to achieve circuit flows in a hypovolaemic state
  • Disability
    • Maintain anaesthesia
      Consider processed EEG monitoring.
  • E
    • Position supine
    • Consider leg elevation
  • I
    • Cease administration of triggers
      • Drug infusions
      • Colloids
      • Chlorhexidine
        Remove chlorhexidine-impregnated CVC, IDC, and lubricants.
      • Latex

Management reflects the nature of operative anaphylaxis, namely:

  • High frequency of sudden onset, severe symptoms
  • Presence of an anaesthetist
Intraoperative Adrenaline Dosing
Situation Adults Paediatrics
IM bolus (Q5M) 500μg 150μg in ⩽6 300μg in 6-12
IV bolus in Moderate/Grade II 20μg 2μg/kg
IV bolus in life threatening/Grade III 100-200μg 4-10μg/kg
IV bolus in cardiac Arrest/Grade IV 1mg 10μg/kg
Starting infusion rate 3μg/min 0.1μg/kg/min
Maximum infusion rate 40μg/min 2μg/kg/min

Specific Therapy:

  • Pharmacological
    • Glucagon
      Recommended in patients on β-blockers due to role in β-blocker overdose.
      • 1-2mg IV Q5M

Disposition:

  • Grade 1 and 2 anaphylaxis which has settled quickly should be have at least 6 hours of close monitoring
  • Grade 3 and Grade 4 anaphylaxis requires admission to ICU/ for monitoring and ongoing therapy as required
    • 30% extubated within 6 hours
    • 70% extubated within 24 hours
  • All patients require a letter containing descriptions of the reaction and agents administered
  • Allergy clinic
    Formal follow-up is important
    • As anaesthetists are mostly wrong about the likely causative agent
    • For patients with any of the following:
      • Unexplained cardiac arrest
      • Unexplained and unexpected hypotension
      • Unexplained bronchospasm, particularly when:
        • Severe
        • Associated with desaturation
        • Treatment resistant
      • Angioedema
    • To provide education for future anaesthetics
      • Notably, no cause is found in ~50% of cases

Refractory Management

Anaphylaxis refractory to maximal management occurs in patients:

  • On β-blockers
  • On ACE-Is
  • With spinal blockade

For hypotension, consider:

  • TOE or TTE to guide resuscitation
  • ECMO/CPB to establish adequate perfusion
  • Alternative vasopressors
    • Vasopressin
      • Adults: 1-2 unit bolus, then 2 units/hr
      • Paediatrics: 0.04 units/kg bolus, then 0.02-0.06 units/kg/hr
    • Noradrenaline
      • Adults: 3-40μg/min
      • Paediatrics: 0.1-0.2μg/kg/min
    • Metaraminol
    • Phenylephrine

For bronchospasm, consider:

  • Excluding:
    • Pneumothorax
    • Airway device malfunction
  • Bronchodilators
    • Salbutamol
      • 1200μg (12 puffs) via MDI
      • 100-200μg IV, +/- infusion at 5-25μg/min
    • Magnesium
      2g over 20 minutes.
    • Inhalational anaesthetics
    • Ketamine

Post-Crisis Management

Consider:

  • Steroids
    No evidence that use of corticosteroids affects outcome.
    • May be reasonable as part of secondary management in a stable patient
    • May have a role in reducing rebound
    • Dexamethasone 0.1-0.4mg/kg, up to 12mg
    • Hydrocortisone 2-4mg/kg, up to 200mg
  • Antihistamines
    • No role in acute phase
    • May be used for symptomatic management of urticaria, angioedema, and pruritus
      Appropriate in mild anaphylaxis.
    • No effect on hypotension and bronchospasm
    • Oral agents have a preferred side-effect profile compared to IV

Marginal and Ineffective Therapies

  • Sugammadex
    Has no role in the management of rocuronium anaphylaxis.

Complications

  • Death
  • C
    • Takotsubo cardiomyopathy
    • Coronary spasm
      Kounis syndrome.

Prognosis

Mortality is associated with:

  • ↑ Age
  • Comorbidities
    • CAD
    • HTN
      • β-blocker
      • ACE inhibitor

References

  1. Cook T, Harper N. Anaesthesia, Surgery, and Life-Threatening Allergic Reactions: Report and findings of the Royal College of Anaesthetists’ 6th National Audit Project: Perioperative Anaphylaxis. Royal College of Anaesthetists’. 2018.
  2. Ring J, Beyer K, Biedermann T, et al. Guideline for acute therapy and management of anaphylaxis: S2 Guideline of the German Society for Allergology and Clinical Immunology (DGAKI), the Association of German Allergologists (AeDA), the Society of Pediatric Allergy and Environmental Medicine (GPA), the German Academy of Allergology and Environmental Medicine (DAAU), the German Professional Association of Pediatricians (BVKJ), the Austrian Society for Allergology and Immunology (ÖGAI), the Swiss Society for Allergy and Immunology (SGAI), the German Society of Anaesthesiology and Intensive Care Medicine (DGAI), the German Society of Pharmacology (DGP), the German Society for Psychosomatic Medicine (DGPM), the German Working Group of Anaphylaxis Training and Education (AGATE) and the patient organization German Allergy and Asthma Association (DAAB). Allergo Journal International. 2014;23(3):96-112. doi:10.1007/s40629-014-0009-1.
  3. Kolawole H, Crilly H, Kerridge R, Marshall S, Roessler P. Australian and New Zealand College of Anaesthetists (ANZCA) and Australian and New Zealand Anaesthetic Allergy Group (ANZAAG) Perioperative Anaphylaxis Management Guidelines: Background Paper. ANZCA/ANZAAG. 2016.
  4. ANZCA. PS60: Guidelines on the Perioperative Management of Patients with Suspected or Proven Hypersensitivity to Chlorhexidine.
  5. Bersten, A. D., & Handy, J. M. (2018). Oh’s Intensive Care Manual. Elsevier Gezondheidszorg.