Anaphylaxis

Anaphylaxis is a serious, systemic hypersensitivity reaction that is usually rapid in onset and may cause death.^[1] It is a clinical diagnosis made at the bedside — treatment must never wait for laboratory confirmation. Intramuscular epinephrine is the only first-line treatment and the sole intervention proven to reduce mortality; no other drug reverses anaphylaxis, and antihistamines and corticosteroids are adjuncts only, never substitutes.^[2]

Up to 10-20% of anaphylactic reactions occur with no skin or mucosal involvement at all, which is a leading cause of missed or delayed diagnosis and a contributor to fatal cases.^[1] Pharmacists are frequently the first point of contact for a patient developing a reaction after starting a new medication, being stung, or eating a food allergen — prompt recognition and immediate epinephrine, not "wait and see," is what prevents death. Food is the leading trigger in children, while medications and insect venom are more common triggers in adults.^[3]

Urticaria (hives) — raised, slightly elevated wheals on the chest wall, a common early skin sign of an allergic reaction. (James Heilman, MD, CC BY-SA 3.0, Wikimedia Commons)

Allergic angioedema — severe facial and periorbital swelling; this child is unable to open his eyes due to the swelling. (James Heilman, MD, CC BY-SA 3.0, Wikimedia Commons)

Do not require skin or mucosal findings to diagnose anaphylaxis. A patient with only sudden hypotension, bronchospasm, or laryngeal symptoms after a known or highly probable allergen exposure still meets diagnostic criteria and needs immediate epinephrine.^[1]

• Previous anaphylaxis of any severity or cause — the single strongest predictor of a future episode.
• Known food, drug (especially antibiotics and NSAIDs), or insect-venom (hymenoptera) allergy.
• Poorly controlled asthma or any underlying reactive airway disease — a major risk factor for a severe or fatal reaction.^[1]
• Mastocytosis, another clonal mast cell disorder, or an elevated baseline serum tryptase — anaphylaxis can be the first presentation of an underlying mast cell disorder.^[1]
• Cardiovascular disease.
• Concurrent beta-blocker or ACE-inhibitor use, which can blunt the response to epinephrine and worsen reaction severity.^[1]
• Cofactors that lower the reaction threshold or amplify severity for a given exposure: physical exercise (including food-dependent, exercise-induced anaphylaxis), acute infection, alcohol intake, sleep deprivation, psychological stress, NSAID use, and the perimenstrual period.^[1]
• Age extremes — infants and young children may be unable to report symptoms; older adults have less cardiovascular reserve to compensate for distributive shock.
• A prior biphasic reaction, or a reaction that required more than 1 dose of epinephrine — both predict a more severe course on re-exposure.

Anaphylaxis is a clinical diagnosis made at the bedside — treatment must never wait for laboratory confirmation. Anaphylaxis is highly likely when any 1 of the following 3 classic criteria is fulfilled:^[3]

The World Allergy Organization's 2020 update simplifies this to 2 criteria for teaching purposes — combining criteria 1 and 2 above, and explicitly stating that acute hypotension, bronchospasm, or laryngeal involvement after a known or highly probable allergen exposure counts as anaphylaxis even with no skin involvement at all, since skin signs are absent in 10-20% of reactions and their absence has contributed to missed, fatal anaphylaxis.^[1] Both frameworks describe the same clinical reality — do not wait for multi-system involvement or skin findings before treating a presentation that is otherwise consistent with anaphylaxis.

Differential diagnosis

Consider vasovagal syncope (pale and bradycardic, not flushed and tachycardic, and normo/hypertensive once supine), an acute asthma exacerbation without other features, a panic/anxiety attack, vocal cord dysfunction, hereditary or ACE-inhibitor-associated angioedema (no urticaria, no hypotension), scombroid poisoning (histamine toxicity from spoiled fish — usually affects multiple diners from the same meal at once), carcinoid syndrome, and other forms of shock (cardiogenic, hypovolemic, septic).^[1] When the presentation is genuinely ambiguous, treating empirically with epinephrine is the safer error.

Confirmatory testing

Serum tryptase can support the diagnosis retrospectively: draw as soon as feasible after reaction onset (tryptase rises within 15 minutes to 3 hours and peaks at 1-2 hours), and again for a true baseline at least 24 hours after full resolution. A normal tryptase drawn during the reaction does not rule out anaphylaxis — this is common with food-triggered reactions — but a peak substantially above baseline supports the diagnosis and should prompt investigation for an underlying mast cell disorder.^[1] Tryptase results should never delay treatment and rarely change acute management.

• Reverse the reaction and prevent death — the only intervention that reliably does this is prompt intramuscular epinephrine.
• Maintain a patent airway, adequate breathing, and adequate circulation until the reaction resolves.
• Prevent progression to, and promptly detect, a biphasic reaction.
• Before discharge, put in place everything needed to reduce the risk and severity of the next episode — an epinephrine autoinjector prescription with hands-on training, a written action plan, and an allergist referral.

• Call emergency services (911) immediately, simultaneously with — not after — giving epinephrine.
• Remove or stop ongoing exposure to the trigger where feasible (e.g., stop an infusion; remove an insect stinger by scraping rather than pinching it).
• Position appropriately: supine for most patients; sitting if in respiratory distress; on the left side (semi-recumbent) if pregnant; recovery position if unconscious or vomiting. Never have the patient sit up suddenly or stand while hypotensive.^[1]
• Give high-flow oxygen (ideally by non-rebreather mask) to any patient with respiratory distress or receiving repeat epinephrine doses.^[1]
• Start an IV crystalloid bolus for hypotension once IV access is available.
• Begin CPR immediately if the patient loses pulses or stops breathing, continuing per ACLS/PALS protocol alongside epinephrine dosing.
• Monitor blood pressure, heart rate, oxygen saturation, respiratory status, and mental status at frequent, regular intervals throughout treatment and the observation period that follows.^[1]

Pregnancy

Manage with the same urgency and the same first-line drug — epinephrine is not contraindicated in pregnancy, and untreated maternal anaphylaxis is a far greater risk to the fetus than treated anaphylaxis. Position the patient on the left side (semi-recumbent) rather than supine, to avoid aortocaval compression and preserve placental perfusion, and involve obstetric care alongside standard resuscitation.^[1]

Infants and young children

Anaphylaxis is harder to recognize in infants, who cannot report symptoms — irritability, sudden behaviour change, drooling, or feeding refusal may be the only clue alongside more typical signs. Food (especially cow's milk, egg, and peanut) is the leading trigger in this age group. Weight-based autoinjector selection is inherently imprecise below 25 kg with currently available fixed doses (see Drug Tables), but the consequences of withholding epinephrine — progression, biphasic reaction, death — far outweigh the mild, transient adverse effects of a modestly higher-than-calculated dose, so err toward treating.^[2]

Beta-blocker or ACE-inhibitor use

Both drug classes can blunt the response to epinephrine and are associated with more severe reactions; neither is a reason to withhold or under-dose epinephrine.^[1] If hypotension is refractory to repeated epinephrine dosing in a patient on a beta-blocker, give IV glucagon, which acts independently of the beta-adrenergic receptor.

Cardiovascular disease

Pre-existing cardiovascular disease does not forbid epinephrine use in anaphylaxis — no other drug has its life-saving effect, and the risk of withholding it exceeds the cardiac risk of standard IM dosing. Reserve extra caution for the IV route, which carries materially higher cardiovascular risk than IM and should only be used in a monitored setting.^[3]

Mastocytosis and other mast cell disorders

Patients with mastocytosis or another clonal mast cell disorder are at higher risk of severe — including venom-triggered — anaphylaxis, and anaphylaxis can be the first sign of the underlying disorder. An elevated baseline (not just peak) serum tryptase should prompt investigation for an underlying mast cell disorder and allergist referral.^[1]

Idiopathic anaphylaxis

No trigger is identified in roughly 1 in 10 to 1 in 5 carefully worked-up cases, after a detailed history, examination for cutaneous mastocytosis, skin testing, and allergen-specific IgE testing have all failed to reveal a cause. Idiopathic anaphylaxis is treated identically to IgE-mediated anaphylaxis and still requires an epinephrine autoinjector prescription and allergist follow-up.^[1]

Food, drug, venom, and exercise-induced triggers

Food is the leading trigger in children; medications and insect venom are more common triggers in adults.^[3] Exercise is a recognized cofactor that can trigger anaphylaxis on its own (exercise-induced anaphylaxis) or lower the threshold for a food or drug trigger the patient otherwise tolerates (food-dependent, exercise-induced anaphylaxis) — advise avoiding exercise for several hours after eating a known co-trigger food, and always carrying an epinephrine autoinjector during exercise when this history is present.^[1]

Observation period after treatment

Around half of biphasic reactions occur within 6-12 hours of the initial reaction resolving, though the reported range is wide.^[1] Risk-stratify the observation period rather than applying one fixed duration to everyone:

• Extend observation to at least 6 hours, and consider 12-24 hours or inpatient admission, for a severe initial reaction, a reaction requiring more than 1 epinephrine dose, delayed epinephrine administration, an unknown trigger, a history of a prior biphasic reaction, or significant comorbid asthma or cardiovascular disease.^[5]
• For a milder reaction with a rapid, complete response to a single epinephrine dose and none of the risk factors above, a shorter observation period (as little as 1-2 hours) can be reasonable — provided the patient has reliable access to a second epinephrine dose and to emergency care after discharge.^[6]
• Where individualized risk stratification is not being done, a minimum observation period of 4 hours after full symptom resolution is a reasonable default.^[5]

What to monitor

Blood pressure, heart rate, oxygen saturation, respiratory effort, and mental status at frequent, regular intervals throughout treatment and observation.^[1] Draw a baseline serum tryptase at least 24 hours after full symptom resolution if the diagnosis is uncertain or a mast cell disorder is suspected.

Before discharge

• Prescribe an epinephrine autoinjector — 2 doses, not 1 — and physically demonstrate its use, having the patient or caregiver "teach back" the technique; do not rely on a handout alone.^[1]
• Provide a written, personalized anaphylaxis emergency action plan covering how to recognize a reaction and exactly when and how to use the autoinjector.
• Refer to an allergist/immunologist for trigger confirmation, prevention counselling, and consideration of immunotherapy where relevant (e.g., venom).^[1]
• Recommend medical-alert identification (bracelet or wallet card) documenting the known or suspected trigger.

1. No improvement, or worsening, 5-15 minutes after the first IM epinephrine dose: give a second IM dose at the same weight-based dose.^[1]
2. Still refractory after 2 IM doses: escalate to a monitored emergency setting for an IV epinephrine infusion under continuous cardiac monitoring — do not attempt IV bolus dosing outside this setting given its arrhythmia risk.^[1]
3. Hypotension refractory to epinephrine in a patient taking a beta-blocker: give IV glucagon, and give a 20 mL/kg crystalloid bolus for ongoing hypotension.
4. Persistent bronchospasm despite epinephrine: add inhaled salbutamol as an adjunct — this treats bronchospasm specifically and is not a substitute for repeat epinephrine.
5. Upper airway obstruction (stridor, hoarseness, a sensation of throat closing) not resolving with epinephrine: consider nebulized epinephrine as an adjunct, and prepare early for advanced airway management — this can deteriorate quickly.
6. Cardiac or respiratory arrest at any point: begin CPR/ACLS or PALS immediately, continuing epinephrine dosing per protocol.
7. Once stabilized, do not discharge without completing the full checklist in Monitoring & Follow-Up — undertreated discharge planning, not the acute reaction itself, is what allows a preventable second episode to become fatal.

• Giving an antihistamine or corticosteroid first, or instead of, epinephrine — neither reverses airway obstruction or hypotension, and delaying epinephrine to give them is a leading cause of preventable death.^[4]
• Waiting to "see if it progresses" before giving epinephrine — clinicians cannot reliably predict which reactions will progress, and early treatment of even a single-system reaction after a known/probable allergen exposure is the safer default.^[1]
• Injecting subcutaneously instead of intramuscularly, or into a site other than the anterolateral thigh.
• Sitting or standing a hypotensive patient up, or having them walk — this can precipitate fatal empty-ventricle collapse.^[1]
• Withholding a repeat epinephrine dose out of concern for its transient, expected side effects (tremor, pallor, palpitations) when symptoms are not resolving.
• Withholding or under-dosing epinephrine because the patient takes a beta-blocker or has cardiovascular disease — the risk of withholding treatment exceeds the risk of the drug in this emergency.^[1]
• Discharging a patient without a prescribed and demonstrated epinephrine autoinjector, a written action plan, and an allergist referral.^[1]
• Cutting the observation period short in a patient with biphasic-reaction risk factors — severe initial reaction, multiple epinephrine doses required, unknown trigger, or a prior biphasic reaction.^[5]
• Assuming a normal tryptase drawn during the reaction rules out anaphylaxis — it does not, particularly for food triggers.^[1]
• Attempting IV bolus epinephrine outside a monitored resuscitation setting.

How to use this table: Doses are typical adult and pediatric doses and require patient-specific confirmation. Select any drug name to open its complete Pharmasist Drug Database page.

Epinephrine autoinjectors — weight-based selection (Canadian CSACI recommendations)

Product monographs advise wider weight bands (0.15 mg for 15-30 kg, 0.3 mg for ≥30 kg, and calling 911 instead of using a device below 15 kg); CSACI's own recommendations, reproduced below, use narrower bands to reduce the underdosing that occurs as a child's weight climbs through the older, wider bands^[3].

Epinephrine by ampule/syringe — IM dosing by age (hospital or clinic setting)

All doses are 1 mg/mL (1:1000) solution, given IM, repeated every 5-15 minutes as needed; maximum single dose 0.5 mg^[1].

Do not prescribe drawn-up ampule-and-syringe epinephrine as a routine community first-aid alternative to an autoinjector — studies of parents drawing up doses under time pressure found a 40-fold range in the amount actually drawn, with delays and dosing errors even among trained caregivers^[2].

Second-line antihistamines

Adjuncts for cutaneous symptoms only — neither drug reverses airway obstruction or hypotension, and neither should delay an epinephrine dose.

Second-line corticosteroids

Given with the goal of shortening protracted symptoms or reducing biphasic-reaction risk, but current evidence does not reliably support either benefit — do not delay epinephrine to obtain or give one of these.

Bronchospasm adjunct

Refractory hypotension

Reserved for anaphylaxis not responding to repeated IM epinephrine, particularly in a patient on a beta-blocker.