Anaphylaxis

Last updated 14th Jan 2018 - Tom Heaton
Anaphylaxis is defined as a severe, life threatening, generalised or systemic hypersensitivity reaction.
It is characterised by rapid onset of life threatening compromise of:
  • airway and/or
  • breathing and/or
  • Circulation
  • often alongside skin and mucosal changes​

Epidemiology

It is estimated that around 1 in 300 people will experience anaphylaxis in their lifetime.
The reported incidence of anaphylaxis is around 1-3 events per 10,000 population per year.
Some details about the epidemiology are hard to unpick, and this is a major focus of the most recent RCOA audit, NAP-6.
Anaphylaxis may be fatal in 3-6% of cases, with another 2% having a poor neurological outcomes. 

Pathophysiology

Anaphylaxis is a type 1 hypersensitivity reaction.
Exposure to a foreign protein (antigen) results in production of IgE, which binds to mast cells (and basophils) throughout the body.
Repeat exposure to this antigen, via binding to this IgE, results in massive release of the vasoactive components of the mast cells.
These include histamine, prostaglandins, tryptase, substance A, leukotrienes.
Despite the pathophysiology involving previous sensitisation, direct previous exposure to the specific drug is not necessary, for example with muscle relaxants.
Daily life provides a source of these antigens in sources such as food and cosmetics which can provide the sensitisation.

Anaphylactoid reactions are clinically indistinguishable from anaphylactic ones.
The pathophysiology is slightly different, as the vasoactive substance release is not mediated via IgE, but via another mechanism.
Contrast media is the most common cause of this.
Less severe reactions are much more commonly seen with drugs causing direct histamine release e.g. morphine, atracurium, mivacurium. 

This is an excellent video from the Osmosis team describing Type 1 hypersensitivity reactions in a bit more details: https://www.youtube.com/watch?v=2tmw9x2Ot_Q

Causes

The most common causes in perioperative anaphylaxis are:
  1. Muscle relaxants (70%)
    • The aminosteroid agents are a more common cause of anaphylaxis, whilst the benzylisoquinoliniums often have an anaphylactoid basis.
    • Suxamethonium is the most common cause
  2. Latex (10%)
  3. Colloids (5%)
  4. Induction agents (4%)
    • Thiopentone is the agent with apparently to greatest association
  5. Antibiotics (3%)
    • Penicillins are the most commonly indicated
  6. Benzodiazepines
  7. Opioids

Other, less common causes include bone cement, atropine, protamine, and contrast media.

There are a number of other triggers that may occur in the non-theatre environment.
  1. Food
    1. Nuts
    2. Fish/shellfish
    3. Eggs
    4. Dairy
  2. Venom
    1. Stings
  3. Drugs (including those above)
    1. Antibiotics
    2. NSAIDs
    3. Opioids

The route of administration may impact on the speed of onset of symptoms:
  • IV - onset in 5 mins
  • Stings - 10-15mins
  • Oral - 30-35 mins​

Presentation

Anaphylaxis is likely if the following 3 criteria are met:
  1. Sudden onset with rapid progression
  2. Life threatening airway and/or breathing and/or circulatory compromise
  3. Skin and/or mucosal changes

In more detail, these may be:

Airway problems
  • Airway oedema
  • Stridor
  • Hoarseness

Breathing problems
  • Bronchospasm, with wheeze
  • Shortness of breath
  • Hypoxia

Circulation problems
  • Tachycardia
  • Hypotension
  • Pale/clammy
  • Obtunded neurology
  • Cardiac arrest

Skin/mucosal changes
  • Urticaria
  • Erythema
  • Flushing
  • Angioedema

Skin or mucosal changes can be absent or very difficult to spot in around 20% of cases.
Conversely, they can very commonly be present without anaphylaxis e.g. histamine release from direct drug interaction.

The NAP-6 defined 5 different grades of severity of anaphylaxis:
  1. Rash, erythema +/- swelling
  2. Unexpected hypotension +/- bronchospasm +/- grade 1 features (not requiring treatment)
  3. Unexpected severe hypotension +/- severe bronchospasm +/- airway swelling +/- grade 1 features
  4. Requiring CPR
  5. Fatal​

Management

Guidance on management has been provided by the Resuscitation Council (UK) and by the AAGBI.
As with urgent acute medical conditions, an ABC approach is appropriate.

Initial Management
  • Stop any possible precipitating agent
  • Inform the team of the suspected anaphylaxis
  • Call for help

Airway/Breathing
  • Ensure airway is secure. Intubation may be needed if not already the case
  • Increase FiO2 to 100%
  • Focused respiratory assessment

Circulation
  • Elevate legs if hypotensive
  • Treat with adrenaline IV
    • 50 mcg - adult dose (0.5ml of 1:10,000 solution)
    • 1 mcg/kg - paediatric dose
    • 0.5mg in the IM dose
  • Doses may need to be repeated
  • An infusion may be needed if significant ongoing compromise
  • Give a crystalloid fluid bolus (500-1000ml)

Disability
  • Ensure adequate anaesthesia if surgery is in progress
  • Assess conscious level if not anaesthetised

Exposure
  • Look for evidence of rash or mucosal changes
  • Consider whether there is less obvious ongoing allergen exposure e.g. CVC, latex, colloid

Secondary Management
  • Chlorphenamine IV
    • Adult - 10mg
    • 6-12 years - 5mg
    • 6m-6 years - 2.5mg
    • <6m - 250mcg/kg
  • Hydrocortisone IV
    • Adults - 200mg
    • 6-12 years - 100mg
    • 6m-6 years - 50mg
    • <6m - 25mg
  • Treat ongoing bronchospasm if present:
    • IV salbutamol
    • Magnesium
  • Take investigations - see below
  • Finish surgery as soon as possible
  • Inform critical care and prepare for transfer

In the event of cardiac arrest, then normal ALS algorithms should be followed.
This will likely involve the non-shockable algorithm and involve early administration of adrenaline.

Investigation

Investigation of the cause of the episode is important to optimise the patient’s future care.
This includes:
  1. Confirming anaphylaxis
  2. Identifying the responsible agent

Mast Cell Tryptase
Mast cell tryptase is the initial investigation of choice to confirm diagnosis.
Tryptase is a protease almost exclusively found in mast cells which has a more useful plasma profile than some of the other agents e.g. histamine.
Its plasma half life is around 3 hours, with a peak level at 1 hour.
Multiple measurements of serum tryptase levels are taken to try and provide a profile that confirms anaphylaxis:
  • Immediately
  • At 1 hour
  • At 24 hours (assumed to represent baseline levels)
In anaphylaxis, the levels will peak at the 1 hour measurement, before returning back to baseline levels at the 24 hour test.
Normal levels are 0.8-1.5 ng/ml, with peaks of over 20 ng/ml in anaphylaxis, and slightly lower (but still notably raised) in anaphylactoid reactions.
Samples are taken in a clotted serum tube and require refrigeration.

Allergen Identification
Identification of the specific causative agent can be undertaken at a later time.
This will involve referral to the regional allergy centre.
Here there will be specialist review of the notes (e.g. timeframe of events compared to drug administration) and allergen testing.
The options for allergen testing include:
  • Skin prick testing
  • Intradermal injection
  • Challenge testing
Skin prick testing is perhaps the most common, but is relatively insensitive for some drug classes e.g. opioids, benzodiazepines.
Intradermal testing is more sensitive but less specific than skin prick testing.
Challenge testing has the clear disadvantage of the risk of precipitating a further anaphylaxis episode.

As part of their follow up, patients will be given a self administration adrenaline device e.g. Epipen.
This contains 300 mcg of adrenaline (for adults).

Differential Diagnosis

There are a number of life threatening and non life threatening conditions that may imitate anaphylaxis, especially in the early stages.
  • Severe asthma/bronchospasm
  • Severe sepsis
  • Vasovagal syncope
  • Panic attack
  • Angioedema​

Future

The 6th national audit project (NAP-6) from the Royal College of Anaesthetists was into perioperative anaphylaxis.
This aimed to provide more detailed information on this condition.
The results from this should be available soon. 

Links & References

  1. Ryder, S-A. Waldmann, C. Anaphylaxis. CEACCP. 2004. 4(4): 111-113. https://academic.oup.com/bjaed/article/4/4/111/308027
  2. NAP 6 Perioperative Anaphylaxis. RCOA. http://www.nationalauditprojects.org.uk/NAP6home
  3. AAGBI. Management of a patient with suspected anaphylaxis during anaesthesia: safety drill. 2009. https://www.aagbi.org/sites/default/files/ana_web_laminate_final.pdf
  4. Resuscitation Council (UK). Advanced life support (7th ed). 2016
  5. Henderson, R. Anaphylaxis and its treatment. Patient.info. 2015. https://patient.info/doctor/anaphylaxis-and-its-treatment
  6. Osmosis. Type 1 hypersensitivity (IgE mediated hypersensitivity): causes, symptoms, pathology. 2016. https://www.youtube.com/watch?v=2tmw9x2Ot_Q
  7. Mills, A. et al. Anaesthesia-related anaphylaxis: investigation and follow up. CEACCP. 2014. 14(2): 57-62. https://academic.oup.com/bjaed/article/14/2/57/271412​