Resuscitation
A 40 year old man is brought into the Emergency Department after collapsing following a bee sting. His pulse is 140 bpm and BP 86/35 mmHg. You note a widespread erythema. His husband informs you he has a known peanut allergy with a history of anaphylaxis. What type of hypersensitivity reaction is anaphylaxis?
Answer:
Anaphylaxis is an immediate systemic reaction caused by rapid, IgE-mediated immune release of potent mediators from tissue mast cells and peripheral blood basophils (type I hypersensitivity reaction).Anaphylaxis
Allergy / Resuscitation
Last Updated: 28th February 2023
The World Allergy Organization defines “anaphylaxis” as an acute, potentially lethal, multisystem syndrome resulting from the sudden release of mast cell and basophil-derived mediators into the circulation.
Anaphylaxis vs Anaphylactoid Reactions
Classical definitions:
- Anaphylaxis is an immediate systemic reaction caused by rapid, IgE-mediated immune release of potent mediators from tissue mast cells and peripheral blood basophils (type I hypersensitivity reaction).
- Anaphylactoid reactions are immediate systemic reactions that mimic anaphylaxis but that are not caused by IgE-mediated responses.
The World Allergy Organization has redefined anaphylaxis as resulting from either an immunological or non-immunological mechanism. Regardless of the mechanism involved, the signs and symptoms of anaphylaxis are the same.
- “Immunologic anaphylaxis” is used to denote IgE-mediated, and immune complex and/or complement-mediated reactions.
- “Nonimmunologic anaphylaxis” (replacing the older terminology "anaphylactoid reaction") is caused by agents or events that induce sudden, massive mast cell or basophil degranulation in the absence of immunoglobulins. These reactions may be due to activation of complement without immune complex formation, direct mast cell and basophil activation resulting in histamine release, or other mechanisms. “Nonimmunologic anaphylaxis” is felt to involve reactions to NSAIDS, local anaesthetics, monoclonal antibodies, and chemotherapeutic agents amongst others.
For clinicians and patients, the important takeaway message is that anaphylaxis, regardless of the underlying mechanism, is a serious and potentially life-threatening event that must be treated immediately with adrenaline.
Epidemiology
Anaphylaxis is common and affects about 1 in 300 of the European population at some stage in their lives.
Anaphylaxis can be triggered by any of a very broad range of triggers, but those most commonly identified are food, drugs, stinging insects and latex. Food is the commonest trigger in children and drugs the commonest in adults. Virtually any food or drug can be implicated but certain foods (nuts) and drugs (muscle relaxants, antibiotics, NSAIDs, aspirin) cause most reactions. A significant number of cases of anaphylaxis are idiopathic.
The overall prognosis of anaphylaxis is good, with a case fatality ratio of less than 1%. Patients with pre-existing asthma, especially poorly controlled asthma, are at particular risk of life-threatening reactions.
Clinical Features
Anaphylaxis is likely if a patient who is exposed to a trigger develops a sudden illness with rapidly progressing skin changes (flushing, urticaria, angioedema) and life-threatening airway and/or breathing and/or circulation problems. The reaction is usually unexpected.
Note that:
- skin or mucosal changes alone are not a sign of anaphylaxis
- skin and mucosal changes can be subtle or absent in up to 20% of reactions
- gastrointestinal symptoms may also be present (e.g. vomiting, abdominal pain, incontinence)
Most reactions occur over several minutes; rarely, reactions may be slower in onset. The speed of onset of the reaction depends on the trigger e.g. intravenous medications (5 mins) will cause a more rapid onset than insect stings (10-15 mins) which in turn will cause a more rapid onset than ingestion of food (30 mins).
| Assessment | Clinical Features |
|---|---|
| Airway |
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| Breathing |
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| Circulation |
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| Disability |
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| Exposure |
|
Differential Diagnosis
- Life-threatening asthma
- Sepsis
- Inducible laryngeal obstruction
- ACE inhibitor-induced angioedema
- Faint (vasovagal)
- Panic attack
- Breath-holding attack in child
- Idiopathic (non-allergic) urticaria or angioedema
Management
- General measures
- Death can occur in minutes if a patient stands, walks or sits up suddenly. Patients must not walk or stand during acute reactions.
- Patients with airway or breathing problems may prefer to sit as this makes breathing easier.
- Lying flat with or without leg elevation is helpful for patients with low blood pressure.
- Patients who are breathing normally and unconscious should be placed in the recovery position.
- Pregnant patients should lie on their left side to prevent aortocaval compression.
- Removal of the trigger should be attempted if possible, but do not delay definitive treatment.
- Monitor all patients with suspected anaphylaxis as soon as possible - minimum monitoring includes pulse oximetry, non-invasive blood pressure and 3-lead ECG.
- High flow oxygen
- Initially the highest concentration of oxygen possible should be given using a non-rebreather mask with an oxygen reservoir.
- Once pulse oximetry is feasible target an SpO2 of 94 - 98%.
- Adrenaline (see doses below)
- This is the most important drug for treatment of anaphylaxis and works best when given as early as possible after the onset of the reaction:
- As an alpha-receptor agonist, it reverses peripheral vasodilation and reduces oedema. As a beta-receptor agonist it dilates bronchial airways, increases the force of myocardial contraction, and suppresses histamine and leukotriene release.
- The intramuscular route is best for most individuals; the best site for IM injection is the anterolateral aspect of the middle third of the thigh.
- For adults, the initial dose is 0.5 mg = 500 micrograms = 0.5 mL of 1:1000 adrenaline. After the initial dose of adrenaline, further doses can be given at about 5 min intervals according to the patient's response.
- If features of anaphylaxis persist despite 2 doses of IM adrenaline, the refractory anaphylaxis algorithm should be followed, and an adrenaline infusion started with expert support.
- Nebulised adrenaline may be effective as an adjunct to treat upper airway obstruction caused by laryngeal oedema, but only after treatment with IM (or IV) adrenaline and not as an alternative. Recommended doses are 5 mL of 1 mg ML (1:1000) adrenaline.
- Adrenaline remains the first line vasopressor for treatment of anaphylaxis. Consider other vasopressors and inotropes (e.g. noradrenaline, vasopressin, metaraminol and glucagon) when initial resuscitation with adrenaline and fluids has not been successful. Only use these drugs in specialist settings where there is experience in their use.
- Intravenous fluid
- A rapid IV fluid challenge (crystalloid 10 mL/kg in a child or 500 - 1000 mL in an adult) should be administered and the response monitored; further doses can be given if necessary.
- There is no evidence to support the use of colloid over crystalloid fluid in resuscitation, therefore crystalloid fluid (Hartmann's solution or 0.9% saline) should be given as colloids have a higher risk of hypersensitivity reactions.
- Airway management
- Airway obstruction may occur rapidly in severe anaphylaxis; warning signs are swelling of the tongue and lips, hoarseness and stridor. Consider early tracheal intubation; delay may make intubation extremely difficult. Early involvement of a senior anaesthetist is mandatory. A surgical airway may be required if tracheal intubation is not possible.
- Updates in ALS 12th edition (2021):
- Antihistamines
- Antihistamines are not recommended for the treatment of anaphylaxis. They are of no benefit in treating life-threatening symptoms of anaphylaxis and their use may delay more appropriate treatment. Antihistamines may be helpful in alleviating cutaneous symptoms but should only be given after the patient has been stabilised. In this context, use a non-sedating oral antihistamine, such as cetirizine.
- Corticosteroids
- The routine administration of corticosteroids is not advised. Consider giving steroids after initial resuscitation for refractory reactions or ongoing asthma/resistant shock. Steroids should not be given preferentially to adrenaline. The evidence that corticosteroids help shorten protracted symptoms or prevent biphasic reactions is very weak. Oral corticosteroids may be indicated where an acute asthma exacerbation may have contributed to the severity of the anaphylaxis. Steroids should be given via the oral route where possible.
- Antihistamines
- Cardiac arrest associated with anaphylaxis
- Start CPR immediately and follow current guidelines
- Prolonged CPR may be necessary
- Cardiac arrest with suspected anaphylaxis should be treated with the standard 1 mg dose of IV or IO adrenaline for cardiac arrest; if this is not feasible, consider 0.5 mg IM adrenaline if cardiac arrest is imminent or has just occurred
- Aggressive fluid resuscitation
| Age Group | IM Adrenaline (1:1000) |
|---|---|
| Adult | 500 mcg (0.5 mL) |
| Child > 12 years | 500 mcg (0.5 mL) |
| Child 6 - 12 years | 300 mcg (0.3 mL) |
| Child 6 months - 6 years | 150 mcg (0.15 mL) |
| Child < 6 months | 100-150 mcg (0.1 - 0.15 mL) |
Investigations
Emergency treatment should not be delayed and should be based on a clinical diagnosis of anaphylaxis. In addition to the usual investigations appropriate for a medical emergency, the specific test to help confirm the diagnosis of anaphylaxis is measurement of mast cell tryptase. Tryptase is a major component of mast cell granules, therefore in anaphylaxis mast cell degranulation leads to markedly increased blood tryptase concentration.
Tryptase concentration in the blood may not increase significantly until 30 minutes or more after the onset of symptoms and peaks 1 - 2 hours after onset. The minimum requirement is one sample taken within 2h (and no later than 4h) from onset of symptoms, but ideally three timed samples are taken - the initial sample as soon as feasible after resuscitation has started, the second sample 1 - 2 hours (but no later than 4 h) after the start of the symptoms and the third sample either at 24 h or in convalescence (for baseline levels).
Biphasic Reactions
There are four recognised temporal patterns of anaphylaxis: uniphasic, protracted, refractory, and biphasic.
- Uniphasic anaphylaxis — Uniphasic anaphylactic reactions are the most common type, accounting for an estimated 80 to 94 percent of all episodes. A uniphasic response typically peaks within hours after symptom onset and then either resolves spontaneously or after treatment, usually within several hours.
- Protracted anaphylaxis — A protracted or persistent anaphylactic reaction lasts hours to days without clearly resolving completely. The exact frequency of protracted episodes of anaphylaxis is unknown, although they appear to be uncommon. The literature consists only of case reports and small series.
- Refractory anaphylaxis — Refractory anaphylaxis can be defined as continued symptoms of anaphylaxis despite appropriate epinephrine dosing and symptom-directed treatment (e.g. intravenous fluids for hypotension).
- Biphasic anaphylaxis — Biphasic reactions are characterised by an initial reaction that meets criteria for anaphylaxis, followed by an asymptomatic period of one hour or more, and then a subsequent return of symptoms meeting the criteria for anaphylaxis without further exposure to antigen. Biphasic reactions have been reported with an array of allergens, including ingested, injected, and intravenously administered substances, as well as in idiopathic anaphylaxis. The time period between the resolution of the first reaction and the start of the second can range from 1 hour to up to 48 hours. The severity of recurrent symptoms in biphasic reactions is unpredictable. In most patients, recurrent symptoms are less severe than the initial symptoms. However, in a minority of patients, recurrent symptoms are more severe or even fatal.
Discharge and Follow-Up
All patients should be reviewed by a senior clinician and a decision made about the need for further treatment and duration of observation. There is no reliable way of predicting who will have a biphasic reaction so decisions about discharge must be made for each patient by an experienced clinician. Prior to discharge, a healthcare with the appropriate skills should offer people the following:
- Information about anaphylaxis, including the signs and symptoms, and the risk of a biphasic reaction (with clear instructions about returning to hospital if symptoms return)
- Information about what to do if anaphylaxis occurs
- Consideration of administering an adrenaline auto-injector or a replacement, including a demonstration of correct use and advice about when to use it
- Advice about how to avoid the suspected trigger
- Information about the need for referral to a specialist allergy service
- Information about patient support groups
Refractory Anaphylaxis
If there is no improvement in respiratory or cardiovascular symptoms despite 2 appropriate doses of intramuscular adrenaline, the refractory anaphylaxis algorithm should be followed.
- Seek expert help early and establish dedicated peripheral IV or IO access
- Give rapid IV fluid bolus and start adrenaline infusion
- 1 mg (1 mL of 1 mg/mL [1:1000]) adrenaline in 100 mL of 0.9% sodium chloride
- prime and connect with an infusion pump via a dedicated line
- start at 0.5 - 1.0 mL/kg/hr (adults and children) and titrate according to clinical response
- continuous monitoring and observation is mandatory (++ BP is likely to indicate adrenaline overdose)
- Give IM adrenaline every 5 minutes until IV adrenaline infusion has been started
- Give high flow oxygen - titrate to SpO2 94-98%
- Monitor HR, BP, SpO2, ECG
- Take blood sample for mast cell tryptase
- Continue adrenaline infusion and treat ABC symptoms
- Airway
- Partial upper airway obstruction/stridor - nebulised adrenaline (5 mL or 1 mg/mL)
- Total upper airway obstruction - expert help, difficult airway algorithm
- Breathing
- If apnoeic - bag mask ventilation and consider tracheal intubation
- Severe/persistent bronchospasm - nebulised salbutamol and ipratropium with oxygen; consider IV bolus and/or infusion of salbutamol or aminophylline; inhalational anaesthesia
- Circulation
- Give further fluid boluses and titrate to response - 10 mL/kg per bolus for children and 500-1000 mL per bolus for adults, using glucose-free crystalloid
- Place arterial cannula for continuous BP monitoring
- Establish central venous access
- If refractory to adrenaline infusion - consider adding a second vasopressor IN ADDITION to adrenaline e.g. noradrenaline, vasopressin, metaraminol, consider glucagon in patients on beta-blockers; consider extracorporeal life support
- Airway
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- Biochemistry
- Blood Gases
- Haematology
| Biochemistry | Normal Value |
|---|---|
| Sodium | 135 – 145 mmol/l |
| Potassium | 3.0 – 4.5 mmol/l |
| Urea | 2.5 – 7.5 mmol/l |
| Glucose | 3.5 – 5.0 mmol/l |
| Creatinine | 35 – 135 μmol/l |
| Alanine Aminotransferase (ALT) | 5 – 35 U/l |
| Gamma-glutamyl Transferase (GGT) | < 65 U/l |
| Alkaline Phosphatase (ALP) | 30 – 135 U/l |
| Aspartate Aminotransferase (AST) | < 40 U/l |
| Total Protein | 60 – 80 g/l |
| Albumin | 35 – 50 g/l |
| Globulin | 2.4 – 3.5 g/dl |
| Amylase | < 70 U/l |
| Total Bilirubin | 3 – 17 μmol/l |
| Calcium | 2.1 – 2.5 mmol/l |
| Chloride | 95 – 105 mmol/l |
| Phosphate | 0.8 – 1.4 mmol/l |
| Haematology | Normal Value |
|---|---|
| Haemoglobin | 11.5 – 16.6 g/dl |
| White Blood Cells | 4.0 – 11.0 x 109/l |
| Platelets | 150 – 450 x 109/l |
| MCV | 80 – 96 fl |
| MCHC | 32 – 36 g/dl |
| Neutrophils | 2.0 – 7.5 x 109/l |
| Lymphocytes | 1.5 – 4.0 x 109/l |
| Monocytes | 0.3 – 1.0 x 109/l |
| Eosinophils | 0.1 – 0.5 x 109/l |
| Basophils | < 0.2 x 109/l |
| Reticulocytes | < 2% |
| Haematocrit | 0.35 – 0.49 |
| Red Cell Distribution Width | 11 – 15% |
| Blood Gases | Normal Value |
|---|---|
| pH | 7.35 – 7.45 |
| pO2 | 11 – 14 kPa |
| pCO2 | 4.5 – 6.0 kPa |
| Base Excess | -2 – +2 mmol/l |
| Bicarbonate | 24 – 30 mmol/l |
| Lactate | < 2 mmol/l |
