anaphylaxis

Acute, life-threatening systemic allergic reaction — lifetime prevalence ~1.6–5.1% (estimates vary). Fatal anaphylaxis is rare but severity is unpredictable, and delay in epinephrine contributes to fatal cases. The most common management error is not giving epinephrine early enough — or at all.

quick recognition

4 systems to consider: cutaneous, respiratory, cardiovascular, gastrointestinal
urticaria/angioedema are not required — absence does not rule out anaphylaxis
throat tightness alone does not meet criteria unless exposed to a known/highly probable allergen
onset typically minutes to a few hours after allergen exposure
anaphylaxis is a clinical diagnosis — do not wait for labs to treat

diagnosis

WAO 2020 criteria

Acutely (minutes to hours) after allergen exposure, highly likely when:

Criterion 1 — skin/mucosal involvement plus any of:

respiratory compromise (dyspnoea, wheeze, stridor, hypoxaemia)
reduced BP or associated symptoms (syncope, incontinence, hypotonia)
severe GI symptoms (especially after non-food allergens)

Criterion 2 — after exposure to a known or highly probable allergen:

hypotension
bronchospasm (excluding symptoms triggered by common inhalant allergens without ingestion)
laryngeal involvement (stridor, vocal changes, odynophagia)

NIAID/FAAN 2006 criteria

Cutaneous symptoms plus respiratory compromise or reduced BP
Two or more systems involved after exposure to a likely allergen (cutaneous, respiratory, cardiovascular, GI)
Reduced BP after exposure to a known allergen (SBP <90 or >30% drop)

2024 GA²LEN consensus (Dribin et al., JACI 2025)

Proposed to replace both NIAID 2006 and WAO 2020 criteria. Key shift: moves from binary “met/not met” criteria to a likelihood framework — “how likely is this anaphylaxis?” rather than yes/no. Integrates IM epinephrine indications directly into the diagnostic tool. Resolves discrepancies between prior criteria (e.g. multi-system involvement without skin findings, isolated laryngeal angioedema, GI symptoms with food allergens). Endorsed by 46 international experts and 31 medical organisations.

clinical course

Pattern	Frequency	Description
uniphasic	80–95%	symptoms peak and resolve within hours
biphasic	~5%	symptoms recur 1–72 h after complete resolution, without re-exposure
protracted	rare	symptoms persist >4 h
refractory	rare	persistent despite ≥3 doses epinephrine + supportive management

tryptase

specific serum marker for mast cell activation — supports but does not diagnose anaphylaxis
draw as early as possible, ideally within 30 min–2 h of onset (samples up to 4–6 h may still be informative)
can be normal in food-induced anaphylaxis or if normotensive
results may take weeks to return

mechanisms

Pathway	Trigger examples
IgE-mediated (most common)	foods, venoms, latex, drugs
IgG / immune complex	infusions, blood products
complement-mediated (C3a/C5a)	dialysis membranes, protamine
non-immunologic — direct mast cell	opioids, vancomycin, radiocontrast
physical	exercise, cold, heat
idiopathic	no identifiable trigger
cofactor-dependent	exercise + food/NSAIDs/alcohol
mastocytosis / mast cell activation disorder	multiple mechanisms

management

step 1: immediate actions

ABCs, IV access, O₂, monitors
remove trigger if ongoing (stop IV drug infusion)
lie patient supine (left lateral decubitus if pregnant → reduce aortocaval compression)
do not sit patients up unless in respiratory extremis

step 2: epinephrine

no contraindications to epinephrine

There are no absolute contraindications. Give epinephrine sooner rather than later if anaphylaxis is suspected, even if the diagnosis is uncertain. Full diagnostic criteria are not required before administration.

IM (first-line):

0.5 mg IM (0.01 mg/kg up to 0.5 mg) of 1 mg/mL (1:1,000) solution
inject into anterolateral thigh
repeat every 5–15 minutes as needed

IV (second-line — perioperative/ICU or refractory):

use 0.1 mg/mL (1:10,000) solution
push: 0.05–0.1 mg IV over 1–10 min (impending arrest, drip not yet available)
infusion: 5–15 mcg/min, titrate to effect (or weight-based: start 0.1 mcg/kg/min)

IV epinephrine risks

Higher risk of dosing errors, ventricular arrhythmia, hypertensive crisis, and pulmonary oedema. Not recommended as first-line outside perioperative/ICU settings.

Intranasal epinephrine: neffy (2 mg intranasal) — FDA-approved 2024, alternative for patients unable or unwilling to use IM injection

Epinephrine MOA: α₁ (vasoconstriction, decreased airway oedema) + β₁ (inotropy, chronotropy) + β₂ (bronchodilation, mast cell stabilisation)

PAF timing: platelet activating factor levels correlate with anaphylaxis severity and rise after initial mast cell degranulation → epinephrine is less effective once PAF-mediated cascades are established → early administration is critical

step 3: adjunctive therapy

IV crystalloid bolus — especially if persistently hypotensive after epinephrine
inhaled SABA — reasonable if ongoing expiratory wheezing, but consider whether anaphylaxis is being undertreated (may need more epinephrine instead)
glucagon — consider if on beta-blockers and not responding to epinephrine
- 1–5 mg slow IV bolus over 5 min, then 5–15 mcg/min infusion if needed
- rapid infusion → vomiting (caution with unprotected airway)

antihistamines and corticosteroids are not first-line

2020 practice parameter update suggests against glucocorticoids or antihistamines to prevent biphasic reactions. May be considered as secondary treatment only. Do not prioritise these over epinephrine.

step 4: escalation

stridor, muffled voice, airway compromise → call for anaesthesia/ICU/airway service
vitally unstable after 1–2 doses of epinephrine + IV fluids → activate code/ICU

monitoring and disposition

biphasic reaction risk factors

unknown trigger
severe initial reaction
required >1 dose of epinephrine
cutaneous manifestations
wide pulse pressure
delay in initial epinephrine administration (the most clearly modifiable factor, though evidence is mixed)

observation duration

Risk level	Minimum observation
lower risk, symptoms fully resolved	≥1 hour asymptomatic
severe reaction, >1 dose epi, unknown trigger, poor baseline cardiorespiratory reserve	≥6 hours (consider admission)

some guidelines recommend 12–24 h observation for patients with hypotension
all patients observed until complete resolution of signs and symptoms

what NOT to do

not recognising anaphylaxis — urticaria/angioedema are not required
not giving epinephrine at all — the most common fatal error
delaying epinephrine — waiting for full diagnostic criteria or trying antihistamines first
IV epinephrine when IM would suffice — higher risk, more complications
prioritising antihistamines or steroids over epinephrine — no evidence these prevent biphasic reactions or improve outcomes
confusing vasovagal syncope with anaphylaxis — vasovagal = bradycardia; anaphylaxis = tachycardia

differential diagnosis

Category	Mimics
common	vasovagal syncope (bradycardia, rapid recovery), acute spontaneous urticaria/angioedema, acute asthma
cardiovascular	MI, PE, other shock (hypovolaemic, cardiogenic, septic, obstructive)
flushing disorders	carcinoid, phaeochromocytoma, VIPoma
postprandial	scombroid poisoning, pollen-food allergy syndrome, food poisoning
angioedema (non-anaphylactic)	hereditary angioedema, ACE inhibitor–induced, DPP-IV inhibitor–induced
drug reactions	vancomycin infusion reaction (red man syndrome)
non-organic	vocal cord dysfunction, hyperventilation, panic attack (can trigger stress-induced urticaria), factitious disorder
mast cell disease	mastocytosis (can also cause anaphylaxis)

disposition and follow-up

refer to allergist as outpatient
epinephrine autoinjector prescription:
- yes → food allergy, venom allergy, idiopathic anaphylaxis
- probably not needed → drug allergy (avoidance is primary strategy)