Anaphylaxis

Anaphylaxis is a serious, rapidly progressing, systemic hypersensitivity reaction with airway, breathing or circulatory compromise, usually with skin and mucosal change. Adrenaline given early by the intramuscular route is the treatment that saves lives, and delay is the most important cause of death.

Diagnosis. Probable when one of the following occurs.

• Acute onset (minutes to hours) of skin or mucosal involvement (urticaria, flushing, swelling) plus respiratory compromise or reduced blood pressure or end organ dysfunction.
• Two or more of skin or mucosal involvement, respiratory compromise, reduced blood pressure, and persistent gastrointestinal symptoms after exposure to a likely allergen.
• Reduced blood pressure after exposure to a known allergen (systolic pressure under 90 mmHg or a fall of over 30% from baseline in adults; age specific limits in children).

Skin signs are absent in about 10 to 20%, especially in severe reactions.

Mechanisms. IgE mediated mast cell and basophil activation (foods, venom, drugs, latex), and non-IgE mechanisms (opioids, contrast media, neuromuscular blocking agents, NSAIDs). Complement and bradykinin mechanisms are involved in some reactions.

Triggers. Food (peanut, tree nut, milk, egg, fish, shellfish, wheat, sesame), drugs (penicillins and other beta-lactams, NSAIDs, neuromuscular blockers, chlorhexidine, contrast media), insect venom (wasp, bee), latex, vaccines, exercise with cofactors, and idiopathic reactions.

Severity. Mild is skin only. Moderate involves respiratory, cardiovascular or gastrointestinal signs. Severe is hypoxia, hypotension or collapse. Reactions can be biphasic, with recurrence 1 to 72 hours later in about 5%.

Key distinctions. Cofactors lower the threshold (exercise, alcohol, NSAIDs, infection, menstruation, beta blockers, ACE inhibitors). A reaction with no skin signs but isolated angioedema, normal blood pressure and no urticaria points to bradykinin mediated angioedema, which does not respond to adrenaline.

History (obtain after treatment starts). Exposure in the preceding minutes to hours (food, drug, sting, latex, exercise), onset and sequence of symptoms, previous reactions, atopy, asthma, mastocytosis, drugs (beta blockers, ACE inhibitors), alcohol, pregnancy, and what treatment was given.

Examination.

• Airway: voice change, stridor, swollen lips, tongue or uvula, drooling, hoarseness.
• Breathing: wheeze, respiratory rate, saturation, accessory muscle use.
• Circulation: pulse, blood pressure, capillary refill, mottling.
• Disability: drowsiness, confusion, collapse. Exposure: urticaria, erythema, angioedema, a sting site.
• Gastrointestinal: vomiting, cramping, diarrhoea.

Red flags.

• Stridor, hoarseness, tongue swelling, wheeze, saturation under 92%.
• Systolic pressure under 90 mmHg, collapse, confusion, bradycardia in a child.
• Asthma or beta blocker use, previous severe reaction, delayed adrenaline.
• Persistent symptoms after two intramuscular doses.

Special groups.

• Pregnancy: left lateral position, adrenaline is not withheld, and urgent obstetric review (foetal compromise).
• Children: weight or age based adrenaline doses and early help; refer all for allergy assessment.
• Older adults: cardiovascular disease raises risk with adrenaline, but it is still given.
• Beta blocker use: reduced response to adrenaline, so give glucagon early.
• Perioperative: hypotension, bronchospasm or rash soon after induction.

Cardiovascular and respiratory. Vasovagal syncope, asthma exacerbation, cardiogenic shock, pulmonary embolism, septic shock, foreign body airway obstruction, vocal cord dysfunction.

Angioedema without anaphylaxis. ACE inhibitor associated angioedema, hereditary angioedema, acquired C1 esterase inhibitor deficiency, idiopathic angioedema.

Flushing and mediator disorders. Systemic mastocytosis (with episodes of mast cell activation), carcinoid syndrome, phaeochromocytoma, scombroid poisoning (histamine from spoiled fish), alcohol flush reaction, monosodium glutamate reaction.

Drug and infusion reactions. Vancomycin infusion reaction (red man syndrome), contrast related non-allergic reaction, serum sickness, transfusion reaction.

Metabolic and psychiatric. Hypoglycaemia, panic attack, hyperventilation.

Diagnosis is clinical. Treatment is never delayed for tests.

Tryptase. Take serum mast cell tryptase as soon as possible after the start of treatment, ideally 1 to 2 hours after onset (usable up to 6 hours), and a baseline at 24 hours or more after recovery (or from a stored sample). An acute level over (1.2 x baseline + 2) micrograms/L supports mast cell activation. A normal level does not exclude anaphylaxis, particularly in food triggered reactions. A persistently raised baseline (over 11.4 micrograms/L) prompts evaluation for mastocytosis.

Other tests. Blood gas and lactate in severe reactions, ECG in older adults and those with cardiac disease, troponin if chest pain (adrenaline can cause myocardial injury, and Kounis syndrome can occur), and chest radiograph if respiratory signs persist.

Allergy work up (after recovery, not in the emergency). Specific IgE tests, skin prick tests, component resolved diagnostics, drug provocation and perioperative allergy testing, with tests at 4 to 6 weeks after a reaction to cut false negatives. Test results should always be interpreted with the history.

Limitations. Specific IgE and skin tests have false positives. Tryptase timing is critical. Normal baseline tryptase does not exclude mastocytosis.

Immediate steps, within minutes. Remove the trigger when possible (stop the infusion, remove the sting without delay). Call for help. Lie the patient flat with legs raised (sit up with breathing difficulty, left lateral if pregnant, recovery position if unconscious but breathing). Do not stand or walk the patient, as sudden upright posture has caused fatal cardiac arrest.

Adrenaline intramuscular (first line, given at once).

• Adrenaline 0.5 mg IM (0.5 mL of 1 mg/mL), into the anterolateral mid thigh, in adults and children over 12 years. Repeat every 5 minutes if there is no improvement.
• Children: 300 micrograms (0.3 mL) at 6 to 12 years, 150 micrograms (0.15 mL) under 6 years, or 0.01 mg/kg; maximum single dose 0.5 mg in adults and 0.3 mg in children; repeat every 5 minutes; monitor ECG, pulse, blood pressure and saturation.
• Common effects are tremor, palpitations, anxiety and pallor. Adrenaline is not withheld for cardiac disease or older age in anaphylaxis, though ECG monitoring is used.
• Perioperative anaphylaxis: adrenaline 50 micrograms IV boluses (0.5 mL of 100 micrograms/mL) every 1 to 2 minutes titrated to blood pressure, with arterial monitoring, since IV boluses carry a risk of arrhythmia and are used only with continuous monitoring.

Airway, oxygen and fluid.

• High flow oxygen 15 L/min by reservoir mask (titrate to saturation 94 to 98% once stable). Intubate early by an experienced operator for progressive stridor, tongue or laryngeal oedema, with front of neck access prepared.
• Rapid isotonic crystalloid 500 to 1000 mL IV in adults (20 mL/kg in children), repeated while hypotensive; large volumes may be needed because of vasodilatation and capillary leak.

Refractory anaphylaxis (no response after two IM doses).

• Adrenaline infusion 0.05 to 0.5 micrograms/kg/min IV, titrated to blood pressure (for example 1 mg in 100 mL isotonic saline, 10 micrograms/mL), through a secure large vein or intraosseous access in a monitored setting; monitor arterial pressure, ECG and peripheral perfusion; extravasation causes tissue injury.
• Vasopressin or noradrenaline as second line vasopressors in critical care.
• Beta blocker use: glucagon 1 to 5 mg IV over 5 minutes, then 5 to 15 micrograms/min infusion; watch for vomiting, hyperglycaemia and aspiration.
• Bronchospasm: salbutamol 5 mg nebulised, repeated every 15 to 20 minutes; ipratropium 500 micrograms nebulised; magnesium sulphate 2 g IV over 20 minutes for severe asthma like symptoms.
• Upper airway oedema: nebulised adrenaline 5 mg (5 mL of 1 mg/mL) repeated every 15 to 20 minutes while preparing for airway control.

Second line drugs (never in place of adrenaline).

• Antihistamine: chlorphenamine 10 mg IV or IM (slow IV over 1 minute) every 6 hours for up to 4 doses (children 2.5 to 5 mg depending on age); maximum 40 mg daily; sedation and hypotension with fast IV injection.
• Alternatively, oral cetirizine 10 mg once daily for skin symptoms (non-sedating). Antihistamines relieve itch and urticaria but do not treat airway or circulatory compromise.
• Corticosteroids: not advised routinely. Evidence for preventing biphasic reactions is limited. Hydrocortisone 200 mg IV may be given for a severe asthma like component, with monitoring of glucose.

Mimics.

• Hereditary or acquired C1 esterase inhibitor angioedema (and ACE inhibitor angioedema where specialist treatment is chosen): icatibant 30 mg subcutaneously as a single dose, repeated after 6 hours if needed, maximum 3 doses in 24 hours, or C1 esterase inhibitor concentrate 20 units/kg IV.
• Adrenaline, antihistamines and steroids do not work in these, though adrenaline is given if anaphylaxis cannot be excluded. Stop the ACE inhibitor and secure the airway early.
• Scombroid poisoning: antihistamine and supportive care.

Monitoring. Continuous ECG, saturation, blood pressure every 5 minutes at first, respiratory rate, urine output and level of consciousness.

Referral and escalation. Critical care for persistent hypotension, airway compromise or need for infusion. Anaesthesia or ENT for airway control. Allergy and immunology for all after the event. Obstetrics for pregnancy.

Admission criteria. Observe for at least 6 to 12 hours after the last symptom for patients with good response to one dose and no severe features.

Observe for at least 12 to 24 hours, or admit, with:

• a severe reaction, more than one adrenaline dose, asthma, previous biphasic reaction or delayed treatment;
• a trigger that is likely to continue absorbing (large oral ingestion);
• patients who live far from emergency care or alone.

Discharge and safety netting. Before discharge, provide:

• two adrenaline auto-injectors with a dose chosen from the product label for body weight (about 150 micrograms for 7.5 to 25 kg and 300 micrograms for over 25 kg, with a 500 micrograms product for adults over 50 kg in some countries);
• training and practice;
• a written emergency action plan;
• trigger avoidance advice;
• a medical alert;
• referral to allergy services.

Patients are told to inject at once for any reaction with breathing difficulty or collapse, to call emergency services, and to lie down. Review the need to stop or change ACE inhibitors and beta blockers with the prescribing team.